Ординатура / Офтальмология / Английские материалы / Tumors of the Eye and Ocular Adnexa_Char_2001

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radiation vasculopathy associated with cobalt plaques can develop 20 years after treatment.79

The roles of radiation versus tumor effects in the production of visually destructive ocular morbidity is uncertain. Eyes with untreated uveal melanomas can develop disc neovascularization (Figure 8–17), neovascular glaucoma (Figure 8–18), and cystoid macular edema (Figure 8–19). In proliferative diabetic retinopathy, a number of vasoactive cytokines have been identified in the vitreous; several of these factors are also secreted by tumors.93,94 After charged particle irradiation, decreased vision from retinal damage, when neither the optic nerve nor the fovea has received significant radiation, has been noted.95,96 It is probable that both a uveal melanoma and the host’s response to it (cytokines and lymphocytic infiltration) produce significant ocular morbidity, independent of damage from either irradiation or other therapeutic modalities. This is discussed further below. If this hypothesis is correct, then it limits the potential of adjunct treatments to decrease eye damage after radiation. Ocular complications noted after radiation therapy are multifactorial in etiology. Patient age, tumor size (especially increased tumor thickness > 7 mm) and proximity to disc and fovea all independently affect visual outcome. Overall, approximately 85 percent of irradiated eyes are retained after treatment in many large centers, with patient survival affected by the same factors associated with primary uveal melanoma enucleation.88,90,95,97

Brachytherapy

Choice of Isotope

A number of different isotopes including cobalt-60 (60Co), iodine-125 (125I), iridium-192 (192Ir), ruthe- nium-106 (106Ru), gold-198 (198Au), palladium-103 (103Pd), strontium-90 (90Sr), and radom-222 (222Ra) have been used in radioactive plaques (brachytherapy) for uveal melanoma treatment.79–93,95,98–101 All forms of ocular brachytherapy share several features. First, the maximum radiation dose is delivered to the area contiguous to the plaque; the radiation exposure decreases exponentially over distance. Therefore, thicker tumors require exponentially more irradiation of the tumor base in order to deliver a tumoricidal dose to the apex of a melanoma. Sec-

ond, unless shielding is possible (see below), treatment of thicker tumors results in increased lateral radiation spread, placing more of the contiguous retina and optic nerve at risk for radiation vasculopathy. Third, with any form of radioactive plaque therapy, the dose for each melanoma must be calculated by a radiation physicist, and the plaque must be correctly positioned so that the entire tumor receives a therapeutic radiation dose. Several publications cite technical details of the medical physics involved in brachytherapy planning.102–105

There are a number of uncertainties in ocular brachytherapy. We do not know the ideal therapeutic dose that destroys a melanoma and minimizes radiation vascular complications. Most uveal melanomas have been treated with a total apical dose of between 70 and 100 gray (Gy) (7,000 and 10,000 rad) although doses between 50 and 120 Gy have been reported. The inaccuracy dose rate for 106Ru is probably about 30 percent and varies with other isotopes.106 A numerical figure, termed the relative biologic effect (RBE), is used to multiply the physical gray of different types of radiation to provide biologic equivalence. Unfortunately, for some of the istopes used in ocular brachytherapy, the RBE has been widely estimated between 1 and 4.

As reviewed elsewhere, radiation morbidity is mainly a function of total dose, volume treated, radiation characteristics, and dose fractionation. As discussed below, there are definite advantages (in terms of both tumor destruction and ocular morbidity) to some isotopes and charged particle irradiation. As examples, in a randomized prospective dynamically balanced study, we noted significantly better local tumor control with helium ions as compared with 125I brachytherapy. There is similarly a higher failure rate with 106Ru, compared with protons; the efficacy with 125I is strongly affected by dose rate.106 In contrast, while there are certain theoretic advantages to 125I over 60Co, as discussed below, the scleral dose to tumors approximately 5 mm thick is similar.107

The molecular mechanisms of both radiation cytotoxity and apoptosis in both uveal melanoma and retinoblastoma is unclear; direct tumor damage and indirect compromise of the vascular supply both play a role in radiation therapy’s effect.108 Most likely, the former is of greater importance, since we

Figure 8–17. Disc neovascularization in a melanoma-containing eye prior to therapy.

have observed a number of tumors with almost complete regression prior to development of radiation vascular changes.

The effect of brachytherapy versus enucleation on uveal melanoma–related mortality is uncertain. The majority of patients who have been treated with brachytherapy have had smaller tumors than those treated with enucleation.109 Retrospective studies have demonstrated no survival advantage with either radiation or enucleation.109–114

Historically, in most cases of uveal melanoma, brachytherapy was performed with either 60Co or 106Ru plaques.79–83,86 106Ru does not produce sufficiently penetrant radiation to be useful for very thick tumors. Perhaps because some larger lesions have been treated with this isotope, there has been a rela-

tively high failure rate.106,114,115 In one series of 100 cases, with a mean follow-up of 3.3 years, there was a 5-year local control rate of 59 percent.116 Eighteen metastases were reported in that series, and 7 occurred in the 19 patients who had local relapses. In another 106Ru series, 9 of 49 patients had local failures.117 In smaller tumors, up to 85 percent of eyes are retained at 5 years.118 Probably because of the problems with 106Ru in the case of thick tumors, adjuctive treatment with other modalities has often been used.114,119 Seregard recently reported in metaanalysis over 1,000 patients treated with Unfortunately, the problems with meta-analysis, in general, have shown up to a 35 percent inaccuracy in some studies, compared with randomized control data.121 In reports with 106Ru brachytherapy, there appears to be a slightly lower incidence of optic neuropathy than in some series, although selection criteria are probably different. In one report, the incidence of optic neuropathy was 10 percent.122,123 Over 2,500 cases of 106Ru radiation have been reported.114,120 Usually, the pattern of regression is the same as described for 125I; however, in 3 cases, calcification of the lesion did occur.87

As has been reported with helium ion, protons, and cobalt, faster shrinkage after plaque therapy is associated with the worse survival.95,97,114 This observation may appear to be counterintuitive; however, it is logical. More malignant, rapidly cycling tumors grow faster and respond to the DNA-induced radiation damage with rapid shrinkage; these cases have high tumor-related mortality.

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Several studies have been reported with longterm follow-up 60Co plaques.79–117,124–127 The local control rate with 60Co plaques has been approximately 70 to 80 percent. There is a significantly higher metastatic rate in those which have a local relapse.124,127 There is a higher incidence of failure in larger-diameter, thinner tumors, especially those located near the optic nerve.124,128 Local recurrences develop contiguous to the original tumor, although rarely, they can occur in another part of the eye. Figure 8–20 shows a marginal recurrence next to an area of presumed complete tumor destruction with chorioretinal atrophy. Figure 8–21 shows a recurrence inferior to a melanoma that had been treated elsewhere with 60Co radioactive plaque. In the latter instance and in the literature, 3 of 4 such cases developed metastatic disease.129 We reported metastatic risk as a correlate of postradiation recurrence patterns after 125I brachytherapy. Diffusely enlarging tumors were at significantly increased risk, but even those that had a small, relatively flat marginal recurrence also had a higher death rate.130 Of a reported 116 uveal melanomas treated with brachytherapy between 1968 and 1987, 20 had local recurrences; significant cataracts occurred with 32. The percentage of patients who retained 20/200 or better vision declined by 10 percent per year.127 Brady estimated that 58 percent of patients treated with cobalt plaques retained useful vision 5 years after treatment.126

Several different techniques have been used to monitor brachytherapy in addition to standard modalities, such as ultrasonography, clinical examination, and photography. These modalities may include different types of ultrasonography, magnetic resonance imaging (MRI), gadolinium-DTPA, and histologic measures of cell cycling.131–134 Doppler ultrasonography has been used to monitor radiation response; loss of tumor vascularity has been associated with effective radiation in a small number of 106Ru-treated cases.93–95

In a retrospective analysis of lens opacities after 60Co plaque brachytherapy, Kleineidam and colleagues noted that 22 percent developed cataract within 5 years; factors important in cataract production are tumor thickness, location of the anterior margin relative to the ora, and the diameter of the plaque.135

We have only used two types of uveal melanoma brachytherapy: 125I and 60Co plaques. We have treated approximately 400 uveal melanomas with 125I plaques; these tumors ranged in size from 6 × 6 × 2.3 mm to 18 × 15 × 11 mm. We used only 125I in radioactive plaque construction after consultations with radiation physicists at both the University of California, San Francisco, and the Lawrence Berkeley Laboratory. Potential advantages of other isotopes appear to us to be outweighed by possible confusion that could occur when several isotopes are used. It is conceivable that higher risk of treatment planning errors could ensue. There are a number of potential advantages and disadvantages with compared with other isotope radioactive plaques. We do not use beta-emitting isotopes, since they have much less penetration and cannot be optimally used with tumors 3 to 5 mm thick.86

Although we prefer to use 125I plaques, there are four potential advantages of 60Co plaque therapy over 125I brachytherapy: (1) a 60Co plaque has a long (5.26 year) half -life and can be reused for at least 5 years without recharging which decreases patient cost; (2) the radiophysics calculations associated with a long half -life, highly penetrant, high-energy isotope like 60Co are easier than those associated with 125I plaque construction. With 60Co, essentially the same treatment plan can be used on a number of patients over a several-month period because the slow radioactive decay results in little change in the isodose lines. At an institution with limited radiophysics expertise, errors are probably less likely with 60Co plaques. There are also higher failure and complication rates in less experienced centers;136 (3) cobalt plaques deliver a wider field of radiation for a given apical dose than does 125I plaque therapy; if localizing a tumor correctly is difficult, there may be a lower incidence of marginal misses with cobalt plaques; and (4) cobalt plaques may have a smaller radiation gradient between the tumor base and the apex in progressively thicker tumors. Fortunately, in our experience, this fourth potential limitation of 125I brachytherapy has not been borne out. We have treated tumors as thick as 11 mm without significant scleral necrosis. Scleral necrosis is probably not due to direct radiation, but is usually due to the release of inflammatory cytokines when the conjunctiva is not closed well over a lesion, and a

localized area of inflammation or infection ensues. Figure 8–22 shows scleral melt that occurred in a patient who had conjunctival retraction after removal of a plaque and suturing of the conjunctiva.

There are a number of potential advantages of 125I over 60Co plaques. 125I can be easily shielded with as little as 0.3 mm of gold; this thickness produces less than one part per million transmission.98,100,137 In contrast, 60Co plaques cannot be adequately shielded to protect noninvolved ophthalmic structures or the surgical team. More than one foot thickness of lead is needed to give equivalent 60Co shielding versus 0.3 mm thickness of gold for 125I. The ability to shield 125I plaques has a number of clinical ramifications. First, there is significantly less radiation exposure for the operative team, especially if a large number of cases are treated. Second, there may be fewer radiation induced vascular complications in both the eye and in contiguous orbital structures; however, no conclusive data support this hypothesis. With a very thick anteriorly located tumor, 125I can produce cataract, eyelash loss, and, if the tumor is in a superior temporal location, significant dryness. 60Co plaque therapy of a superior temporal melanoma usually results in a dry eye due to lacrimal gland radiation damage; this can usually be avoided with a conventionally shielded 125I plaque, unless a very thick, broad-based tumor in this location is being treated. Similarly, in an anterior nasal tumor, sufficient 60Co plaque radiation is delivered to the lacrimal excretory system to produce closure of the puncta and resultant epiphora; this complica-

tion can usually be avoided with 125I use. The lower penetration and softer gamma emission of 125I, compared with 60Co, results in lesser radiation spread. Various shapes and sizes of 125I plaque carriers have been constructed as shown in Figure 8–23. Cut-outs are used for tumors next to the optic nerve or sometimes when the isodose array is appropriately arranged so that the plaque carrier can be placed with the cut-out around the insertion of an extraocular muscle that is contiguous to the tumor and thus avoid the necessity of temporarily removing that muscle. The ability to attenuate 125I with a thin layer of gold has also allowed the production of rimmed

Figure 8–21. Recurrent tumor inferior to a melanoma treated in another center with 60Co radioactive plaque.

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plaques. Many investigators initially thought that rimmed plaques might further reduce the lateral spread of radiation with this form of brachytherapy in thin melanomas. Unfortunately, in tumors that are > 4.8 mm thick, the use of a gold rim or lip to attenuate lateral spread of radiation is not effective to decrease ocular morbidity (Figure 8–24).138 Treatment of thicker tumors necessitates higher energy seeds and the lip does not prevent side scatter from the seeds that are well away from it. In retrospective analysis of our 125I brachytherapy data, we did not observe a significant difference in visual outcome 3 years after treatment between those who did and those who did not receive rimmed or unrimmed 125I plaques (unpublished data).

There are no randomized prospective data comparing various isotopes used in uveal melanoma brachytherapy. As thicker tumors are treated, the complications associated with therapy increase, regardless of the isotope utilized. In our experience with over 400 125I brachytherapy cases, we have a long-term ocular retention rate of approximately 85 percent.139,140 As reported with 60Co plaques, we noted a higher local failure rate when tumors were relatively thin and near the optic nerve.

The initial use of 125I brachytherapy was for small tumors.98,99 Two groups reported a 12 to 14 percent local failure rate in 140 patients with a mean follow-up of under 4 years141,142 Garretson and colleagues noted a lower local failure rate in 26 patients, with a similar duration of follow-up.143 In a small series with a 6-year follow-up, Hill and collaborators noted a 29 percent failure rate.144 Lean has observed a higher brachytherapy failure rate

with larger tumors.145 In our experience with larger tumors, local control was 91 percent at 3 years and 83 percent at 5 years.146 It is difficult to compare the nonrandomized series. The group from London recently reported their results in patients treated with radioactive plaques, compared with proton beam irradiation. Unfortunately, there were significant differences in tumor size as well as percentage of tumors in the posterior pole in the different treatment arms, thus making it difficult to demonstrate meaningful differences. In that series, 106Ru had a higher failure rate than either 125I or proton radiation; however, these results must be interpreted cautiously.147 Similarly, it will be difficult to compare the COMS plaque data with many older series. We and others have noted higher plaque failure rates in tumors that are thin and come to the edge of the optic nerve. Such cases were excluded in the COMS, hence it should increase their local control rate.

In a randomized prospective study comparing 125I brachytherapy with helium ion–charged particle irradiation, we did not note, for the entire group of cases, a significant difference in visual outcome.139 As discussed above, in a retrospective analysis, we did not find the use of a rimmed plaque carrier more effective in improving visual outcome; however, surprisingly, we also did not find that this type of carrier increased our rate of marginal recurrences.

There are approximately 136 centers in the United States that have used 125I brachytherapy for various malignancies.148 The COMS is currently enrolling patients in a prospective, randomized trial to compare the tumor-related mortality of patients with tumors > 2 mm from the optic nerve that are < 16 mm in largest diameter and 2.5 to 10 mm in thickness. The two experimental groups receive either brachytherapy or enucleation. The author’s scepticism that this trial will show any difference is based on three objections: (1) there have never been any data to suggest better survival with enucleation than with radiation. In a study with a 5-year follow-up rate of 100 percent after helium ion radiation, we noted only a 10 percent tumor-related mortality in patients with tumors of the size the COMS originally chose to randomize in this trial.95 If those less-experienced centers attain a similar tumor control rate, it is very doubtful that radiation will do worse than enucleation; (2) given the control rates demonstrated with particles and plaques, it seems that for most patients, there are strong advantages to retain an eye rather than undergoing enucleation. The latter point is especially germane in a subset of patients of whom almost 70 percent have long-term visual acuities of ≥ 20/40; these patients have melanomas < 5 mm thick that are > 4 mm from the optic nerve and fovea;149 and (3) the pragmatic objection is to the design of the brachytherapy portion of that trial. For smaller tumors, “one size fits all” radiation dosimetry to a constant depth is being used. While undoubtedly it may allow a lower failure rate in thin tumors, this excess radiation will increase the morbidity.

There are a number of potential disadvantages with 125I brachytherapy. Figure 8–25 shows the limitations of a rimmed plaque for tumors contiguous with the optic nerve. The exterior diameter of the optic nerve is approximately 1 mm wider than it is inside the eye. A rimmed plaque cannot be used for a tumor in close proximity to the optic nerve, or a marginal miss (insufficient radiation to the posterior edge of the tumor) will occur. This issue undoubtably led the COMS participants not to treat tumors within 2 mm of the disc as part of the trial; and this should result in a better tumor control rate than we reported when tumors contiguous with the disc were treated. In tumors that are treated next to the disc, some other

Figure 8–24. In tumors > 5 mm in height (tumor + sclera ≥ 6 mm) the required 125I seed strength to treat the apex is such that a rim does sufficiently attenuate lateral radiation spread to decrease ocular morbidity.

approaches to suturing plaques may be advantageous.150 There is a higher incidence of secondary strabismus and vitreous hemorrhage after brachytherapy.139,151 In a few centers, patients with longstanding exudative detachments after brachytherapy have been treated with good results.152

125I plaques are more expensive to construct and have a shorter half-life than 60Co sources. Treatment planning is more complex, and since the 125I plaques are created with multiple radioactive seeds, irregular radiation isodose curves do occur.102,103,137,153

Some investigators have used a different isotope, 103Pd, that is a softer gamma emitter than 125I.100,154 We have chosen not to use this isotope for three reasons: (1) the basic radiobiology regarding its relative biologic effect is still uncertain;133,155,156 (2) as has been queried for thicker tumors when 125I is compared with 60Co, it is doubtful that the softer energy distribution of 103Pd will decrease ocular morbidity in the majority of the melanomas treated; and (3) as discussed above, we believe that unless there are substantial advantages in the use of an additional isotope, the risk of errors in calculations when more than one type of radiation source is used negates potential advantages. As discussed previously with 106Ru, it is difficult to compare patient groups, but a review of a recent paper on 103Pd demonstrates that many of these lesions were extrordinarily small, and probably in a significant minority, we would have opted for observation over treatment.155 The excellent survival and low failure rates are partially predicated on patient selection.

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Surgical Procedure for Brachytherapy

Preoperative consent for radioactive plaque therapy routinely includes consent for enucleation if unsuspected significant extraocular scleral tumor extension is found at surgery. Usually ultrasonography, MRI and/or computed tomography (CT) can detect extraocular tumor extension before surgery; however, these techniques are not always accurate. If there is a small, flat, focal area of extraocular extension, the patient is treated with a plaque; however, if a larger or diffuse extension is present, enucleation is usually, but not always, performed instead (Figures 8–26A and B).157

Radioactive plaque therapy requires accurate tumor localization. We routinely perform a 360° limbal peritomy and sling all four rectus muscles using 2-0 silk sutures. The tumor is localized with two separate techniques. An O’Malley light pipe with a corneal transilluminator is placed on the cornea (Figure 8–27A); the tumor casts a scleral shadow which is demarcated with diathermy marks to outline the borders of the lesion. In very elevated tumors, corneal transillumination alone produces an inaccurately large posterior shadow. This problem can be overcome in two ways: (1) we place a transilluminator 180° away from the tumor; and (2) we routinely localize posterior uveal tumors, using indirect ophthalmoscopy and a fiberoptic light pipe incorporated into a diathermy unit (Figures 8–27 and 8–28).

Figure 8–25. Rimmed plaques cannot be used next to the optic disc since the larger exterior diameter of the nerve, vis-a-vis the rim, delivers insufficient radiation for a tumor that is contiguous to the optic nerve.

Sutures of 5-0 dacron are used to attach an identical carrier (“dummy” plaque) without the radioactive isotope to the scleral area overlying the tumor. The carrier location is reconfirmed with point-source transillumination and indirect ophthalmoscopy; this allows sutures to be placed which will hold the actual plaque in situ, while minimizing radiation exposure to the surgical team (Figure 8–28).

The location of the radioactive plaque itself may not be an accurate guideline to the radiation delivery. The calculated radiation isodose lines necessary to encompass a given field with the appropriate radiation and their location, vis-a-vis both the plaque margins and tumor, are necessary to correctly situate the plaque. In many centers 125I plaques are individually fabricated; the tumor must be in the exact center of some plaques, and other plaques are constructed so that tumoricidal radiation is delivered up to 5 mm lateral to the plaque edge. Similarly, some plaques are constructed such that the radiation isodose lines are quite asymmetric; the plaque cannot be haphazardly placed over a tumor. We routinely have a radiation physicist with the isodose curves in the operating room at the time of surgery. We have found the above-mentioned plaque localization method acceptable. In a series of eyes enucleated for late complications after helium ion radiation, the location of the tantalum marker rings were within 0.5 mm of where they had been supposedly placed in all cases.158 We have, therefore, not routinely used ultrasonographic localization of radioactive plaques, since they are easier to localize than placing tantalum marker rings for particle radiation. We always suture a plaque with sutures that are at least 180° apart to avoid possible displacement of a plaque or tilting of its surface, overlying the sclera surface. Other investigators have used this technique, as shown in Figure 8–29. One can visualize the plaque correctly positioned under a uveal melanoma.

After placing a plaque, the eye is irrigated with antibiotic solution and the conjunctiva closed with a 6-0 gut suture. We are currently using a 70-GyE apical dose radiation to treat uveal melanomas; plaques usually remain in situ for 3 to 4 days to deliver this dose. We chose this dose arbitrarily to compare in a randomized prospective trial (see below) with 70 GyE of helium ion irradiation. Quivey and colleagues noted

that the lower dose rate delivered with 125I plaques was a significant correlate of tumor failure, as was a location of the tumor close to the optic disc.159 The clinically observed radiation response with both plaques and charged particles is similar, and it is discussed under the section on charged particle radiation.

There are some problems specific to radioactive plaques. First, occasionally, a tumor’s location requires temporary disinsertion of an extraocular muscle to deliver adequate irradiation. Even when a muscle does not have to be detached, the placement of the plaque under a muscle causes stretching. This results in a greater incidence of transient diplopia than is seen

after charged particle irradiation; however, we have rarely had to surgically correct strabismus. Second, there is a small increased risk that an untoward event could occur during the second operation necessary to remove a plaque; obviously a second procedure is not necessary with charged particle irradiation.

Figures 8–30 and 8–31 demonstrate successful brachytherapy of a small growing and a large (16 mm diameter and 8 mm thick) choroidal melanoma. In both these cases, long-term control was achieved with an excellent visual outcome. As discussed below, since both radiation shrinkage and complications are usually delayed, often by more than 1 year,

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Figure 8–28. Indirect ophthalmoscopy and point-source transillumination to delineate the margins of the tumor and the relationship to the edges of a rimmed radioactive plaque carrier.

long-term follow-up is necessary to ascertain the relative merits of newer radiation treatment modalities. Figure 8–32 illustrates a late marginal recurrence, after 125I brachytherapy. The tumor appeared to shrink after radiation, with exudate along the posterior aspect of the melanoma (Figures 8–32B). The tumor then developed some marginal “creep” toward the macula (Figure 8–32C), and this was successfully treated with laser (Figure 8–32D). While it would be expected that a tumor this close to the optic disc would have a poor visual outcome, acuity remains 20/50 approximately 10 years after laser.

A number of immediate and late complications can occur after radiation. Surgical complications include damage to the extraocular muscles, vitreous hemorrhage (especially with thick tumors that have

broken through Bruch’s membrane), and retinal detachment due to either an exudative response to radiation or an inadvertent suture. We caused this latter surgical complication in 2 out of about 1,000 patients. The case shown in Figure 8–33 is instructive. The easier, anterior, suture was 2 mm away from the tumor margin but did produce a retinal break. We treated this with cryotherapy at the time of plaque placement, but while the retina remained attached when the plaque was removed 4 days later, it detached in the next few weeks and had to be re-repaired. Probably, the radiation delivered to the tumor base and its surroundings prevented adequate adhesion, and in retrospect, perhaps a retinal detachment procedure at the time of plaque explant was indicated.

Several issues remain unresolved regarding the use of brachytherapy. Dose rate has been empiric, yet some preliminary data suggest that a relatively high dose delivery over 4 days results in better control than when plaques have been left in situ for as long as 10 to 14 days.159 The utility of adjuvant treatment with brachytherapy remains uncertain. Hyperthermia is discussed both under photocoagulation and after charged particles. Photocoagulation and, more recently, laser-induced hyperthermia (see section on laser) after plaque therapy have been used by several investigators.160,161 Augsburger and colleagues have noted that there is faster tumor regres-

Figure 8–29. B-scan ultrasound demonstrates radioactive plaque correctly positioned on the sclera surface of a melanoma.

sion but worse short-term visual outcome when sequential brachytherapy and laser are used.161 Finally, as mentioned previously, the results of the prospective trial of 125I brachytherapy and enucleation are awaited. Approximately 80 percent of patients treated with alternative brachytherapy and teletherapy irradiation have had their tumors successfully controlled without the need of

enucleation.79–88,98–100,117,122–132,139–141,142,162–164

Charged Particle Irradiation

Two different charged particles (proton and helium ion) have been used to treat uveal melanomas. Centers in Boston, San Francisco, Switzerland, France, England, Japan, Southern California, and Russia, have used proton-charged particle irradiation. Our center in San Francisco initially used helium ion radiation; more recently, because of cost constraints,

A

B

Figure 8–30. A, Small growing choroidal melanoma near the fovea. B, Five years later, vision remains good and the tumor has shrunk.

A

B

Figure 8–31. A, Larger (16 mm largest diameter and 8 mm thickness) choroidal melanoma. B, Tumor shown in Figure 8–31A with marked regression. Eye retained excellent vision.

we have switched to protons. Approximately 7,000 patients have been treated with these techniques. Charged particle irradiation has four potential advantages over brachytherapy for uveal melanoma therapy:167 (1) charged particle irradiation can be more precisely focused than any form of radioactive plaque. The lateral spread of helium ion irradiation decreases from 100 to 10 percent in 2.3 mm. Figure 8–34 compares lateral radiation spread with helium ions versus 125I radioactive plaques; (2) a uniform radiation dose is delivered to the entire tumor with charged particles; there is no gradient between the base and the apex of the lesion; (3) in some experimental tumors, the high linear energy transfer (LET) associated with some heavier particles makes them more tumoricidal than