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

conventional forms of radiation; and (4) particles can effectively treat larger tumors than can brachytherapy. Definitive trial data supporting the first three potential advantages have not been published.

There are a number of potential disadvantages to charged particle beam therapy. First, these techniques are only available in a few centers. The facilities are costly to build and maintain and they require a technically sophisticated support staff. Second, the external complications, as a result of the radiation beam passing through normal tissue on its path towards the tumor, are greater than similar adnexal complications associated with plaques; some of these complications, such as lash loss or transient epitheliitis (Figure 8–35), are usually minor. Cataract and neovascular glaucoma are more frequent with particles, although, as discussed below, the latter problem has been markedly diminished using multiple treatment beams.168 Treatment

of superior temporal or anterior nasal melanomas with particles can produce lacrimal gland damage in the first instance or lacrimal drainage system damage in the latter as the external radiation beam passes through and damages adnexal structures contiguous with the ocular tumor.169

Over 85 percent of eyes treated with either protons or helium ions have been retained.139,166,168,170,171 The 5-year tumor-related mortality appears to be approximately 20 percent; almost all metastatic events have occurred in patients with large or very large tumors.139,171 Seddon and colleagues analyzed tumor mortality after enucleation versus proton irradiation in a group of patients treated by two different groups of physicians at Harvard University.112 These retrospective data demonstrated that survival after proton beam irradiation was not worse than after enucleation, even though the proton-treated melanomas appeared to be slightly larger than those treated with

enucleation; other known risk factors were similar in the two groups.

The indications and contraindications for charged particle irradiation of uveal melanomas are still in flux. We have been able to control over 97 percent of treated tumors (with control defined as either stability or shrinkage of the intraocular tumor); however, some melanomas have a very high incidence of treatment complications that result in the eventual loss of the eye.139,171

The treatment of uveal melanomas with charged particle irradiation entails tumor localization with 2.5 mm tantalum marker rings for treatment planning, and radiation. The tumor and a 2-mm normal surround of uvea and retina are included in the high dose radiation field. The tumor is localized with both diffuse corneal transillumination and point-source transillumination with indirect ophthalmoscopy. The marker rings are usually placed on the sclera approximately 2 mm away from the tumor borders. A computer program—utilizing the clinical drawing, wideangle fundus photograph, and plain orthogonal radiographs of the tantalum marker rings—is used to develop the treatment field.172,173 As shown in Figure 8–36, the relationship of the visual structures, especially the optic nerve, fovea, and lens, to the radiation field is determined. Both the angle of gaze and the radiation beam are aligned to irradiate the tumor and minimize the dose to visually vital structures. In Figure 8–36A the melanoma and the optic nerve and

fovea would be in the treatment field; Figure 8–36B demonstrates that alteration in beam and gaze angle decreases dose to the optic nerve and fovea, while the tumor receives the full radiation scheduled.

Most serious treatment complications have occurred in eyes with large and very large tumors. One approach to decrease complications has been to lower the radiation dose. This foveal melanoma shown in Figure 8–37 was successfully controlled with 50 GyE; however, visually destructive radiation vasculopathy developed. In a phase I/II study, we found no difference in control, enucleation, or survival rate in cases that were treated with 50, 60, 70, or 80 GyE irradiation.174 In a prospective study

Figure 8–35. Lid complications. Severe lash loss and epitheliitis after helium ion irradiation. Usually, if the eyelid can be moved out of the entrance beam, the changes are less severe.

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using between 50 and 70 cGy, Gragoudas and colleagues found similar results.175

In both the Boston and San Francisco experiences, an independent risk factor for visual outcome was tumor size. Initially, it was thought that tumors that were at least 3 mm from the nerve or the fovea could be treated without radiation damage to these structures and therefore with retention of good vision. We have observed, with longer follow-up, that increasingly large tumors, especially those

>8 mm thick, have significantly poorer visual outcome, regardless of location.139 As discussed elsewhere, the marked increase in eye damage observed after irradiation of tumors > 8 mm thick has led us to attempt to resect especially tumors that are not

>12 mm in diameter and use adjunct radiation.

We have not been able to save functional eyes when

the melanoma involves more than 40 percent of the ocular volume. Anterior tumors that involve more than 180° of the ocular circumference also have a grim prognosis for retention of an useful eye. Many of these tumors have been sterilized, but most of these eyes were eventually lost due to radiation complications, such as neovascular glaucoma, scleral or corneal melt, or intractable pain.139,176 The advantage of retaining an eye with minimal vision is uncertain. Ross has pointed out that patients with some light perception probably have less sleep disturbances and less depression.177

We reported the results of a randomized, prospective, dynamically balanced trial comparing brachytherapy and helium ion irradiation in primary uveal melanomas < 15 mm in diameter and < 10 mm thick.139 Several pertinent findings from that study influence our management of patients. As mentioned previously, there was a significantly greater local failure rate with plaques, compared with particles (p < .001). Comparison with most other non-random- ized series have shown that this discrepancy in local failure rates with particles compared with plaques is real. The causation is multifactorial. One, the tumor shape and position affected this parameter; thinner, posterior tumors near the optic nerve had a much higher failure rate in our and other series.125,128,139 In addition, either the higher dose delivery rate with particles (in most centers four or five 1-minute fractions over 1 week) or the relative biologic effect of charged particles, compared with plaques, probably contributes to the better local tumor control.

In both treatment arms, if tumors were > 3 mm from the disc and fovea and < 6 mm thick, most had vision ≥ 20/50 at 3 years.139 The incidence of metastases was slightly higher in the brachytherapy group, although this has not yet reached statistical significance.

There were more external complications after treatment with particles, including lash loss,

cataract, and neovascular glaucoma. Most of these anterior segment complications were the result of including a large percentage of these structures in the entrance beam.176 Most neovascular glaucoma developed in the first 2 years after treatment, while cataract continued to develop at 7 percent per year with an overall incidence of 44 percent (Figure 8–38). Currently, we are using two field techniques in difficult larger tumors (Figure 8–39A, B, and C) to minimize anterior segment radiation. This newer approach with avoidance of the anterior segment in the entrance beam has diminished the incidence of neovascular glaucoma in our experience to less than 7 percent. Our current rate of neovascular glaucoma development is similar between particles and plaques.141,168

We attempted to further lower the radiation dose for uveal melanoma, using protons. Unfortunately, when we dropped below 40 Gy we had two failures. Given that there is an increased incidence of metastatic disease associated with local failure, we considered further dose diminution unwarranted.130,178

Several issues remain unresolved regarding the role of particle beams in uveal melanoma treatment. There is little question that particle beams provide better local control, and that there is less discrepancy in control rates if small, thin posterior tumors are excluded from brachytherapy. There is also no question that there is greater anterior segment complications with these proton beams, although the most serious anterior complication, neovascular glaucoma, has been reduced with multiple treatment fields. Cur-

rently, we use particles extensively in three situations: (1) small, thin tumors near the disc; in these cases there is better local control; (2) in tumors

<6 mm thick, and 3 to 6 mm from the optic nerve and fovea; in this group, we believe the visual results are slightly better than with brachytherapy; and (3) in very large tumors. In contrast, we prefer to use plaques in three other settings: (1) in relatively thick tumors near or involving the fovea, where with either technique, there will be radiation induced severe visual loss, but with a plaque there will not be as great anterior segment complications; (2) in tumors

<6 mm thick located anterior to the superior temporal equator where 125I brachytherapy is less likely to produce lacrimal gland damage; and (3) in patients who have lesions that could be treated by either approach, but find the logistics of particle treatment more onerous. There is little data on new approaches to decrease tumor-related mortality after particle irradiation. Glynn and colleagues noted that several different factors influence early as compared with late metastatic disease.179 Local failure, as would be expected, is associated with a worse prognosis, although in our experience, there is not as strong an association if the eye can be salvaged.180,181

Gragoudas and colleagues have noted that about 50 percent of patients who had cataract extraction after particles had > 20/100 vision.182 The reason many of these patients do not have better vision is that cataract is associated with larger tumors, and larger tumors also have more complications. In our experience, unfortunately, many of the patients who developed

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cataracts had very large tumors and also developed neovascular glaucoma with poor visual outcome.

The Boston group has shown that enucleation for late radiation complications does not negatively impact a patient’s survival.166 We have also analysed our data and have noted the same results (unpublished data).

Other Radiation Options

Other radiation approaches are being investigated. The gamma knife, which has been evolving since the 1970s, became a more useful delivery device when it was linked to a computer so that dose delivery with the multiple cobalt sources could be more precisely controlled (Figure 8–40). While a gamma knife does not produce as sharp a dose gradient as can be obtained with a proton beam, it is significantly better than most forms of brachytherapy for small volume (< 10 mm3) tumors. There is only phase I/II data available with this modality.183–185 The optimum dose in a single fraction to control the uveal melanoma and not produce excess morbidity is unknown.183–185 In approximately 200 reported patients, short-term local control has been good, but complications have been noted in single-fraction doses between 45 and 60 Gy.186–188 The issue of single-fraction doses is paramount for both tumor control (where single fraction gives more tumor destruction) and for ocular complications, where single fractions would have a higher chance of damage. As an example, in the treatment of age-related maculopathy, a single 7-Gy

Figure 8–38. Neovascularization of the iris anterior lens capsule and cataract after helium ion radiation.

fraction is equivalent to approximately 16 Gy given in four fractions over a week.189

Another approach is to use fractionated teletherapy either with a gamma knife or other approaches, such as intensity-modulated conformal therapy.190 There is a paucity of data available with this latter approach, although in other sites (see chapter on orbital sinus tumors) it has produced a good tumor destruction with markedly reduced complications.

In some centers, another means to deliver radiation, boron neutron capture, is also being investigated.191,192 There is insufficient human uveal melanoma data with this technique to allow meaningful analyses.

Effects of Radiation Therapy and

Follow-Up Guidelines

The major effect of ocular irradiation is to destroy the reproductive integrity of the tumor; tumors rarely regress completely. In large series from many centers, following successful treatment, tumors regress to approximately 40 percent of their pretreatment volume; only 10 percent of tumors entirely disappear on long-term follow-up. Direct radiation tumor damage primarily and indirect damage as a result of radiation vasculopathy that decreases tumor perfusion destroy the neoplastic proliferation capacity. While there are some immediate radiation effects on a tumor, most evidence of radiation tumor damage is delayed. DNA errors are induced in the cell at the time of treatment. These errors are manifested as tumor destruction when the cells enter mitosis; since the intermitotic phase of melanomas is variable and often prolonged, evidence of tumor shrinkage is usually delayed 3 to 18 months.139,193 In addition, as discussed previously, apoptotic pathways are activated by radiation and radiation alters the cytokine expression in tumor cells. Also, tumors that have rapid growth are more likely to regress more rapidly but have a poorer prognosis.139

After any form of alternative uveal melanoma irradiation, five features indicate tumor response. The most frequent early finding is resorption of subretinal fluid. Figures 8–41A and B demonstrate a uveal melanoma with an inferior exudative hemidetachment of the retina prior to helium ion therapy and the same tumor approximately 3 months later.

Usually, subretinal fluid is resorbed in 6 to 9 months. Loss of subretinal fluid usually occurs after treatment; however, in 10 percent of cases, there has been a transient increase in subretinal fluid, not associated with continued tumor activity. We hypothesize that some regressing tumors produce vasoactive and inflammatory humoral factors that result in transient, increased fluid. In those treated melanomas that have a transient increase in subretinal fluid and later show a decrease in tumor size, the fluid is resorbed in the first 12 to 15 months after treatment. Unfortunately, while transient mac-

ular detachments associated with exudative detachment in uveitis have a good prognosis for visual recovery, longstanding exudative macular detachments associated with tumors result in permanent central visual loss. We have treated some irradiated melanomas that had increased subretinal fluid after radiation with large spot size (3,000 micra) 810 mm long-duration confluent laser treatments and we noted marked diminution of the retinal detachment (unpublished observation).

The second clinical sign of radiation response is diminution of tumor thickness. There is a tendency

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Figure 8–40. Gamma Knife is a computer-controlled multiport cobalt device.

for continued tumor shrinkage to be most marked in the first 2 to 4 years after treatment, but it continues as long as 10 years. Figures 8–42A and B demonstrate a tumor prior to and after helium ion irradiation, showing regression from approximately 10 mm to 2.5 mm in thickness in 6 years. Figures 8–43A and B represent another case with marked regression, with the tumor regressing to approximately 20 percent of its pretreatment volume. Sometimes, the collar-button portion of the lesion will shrink less rapidly, although this is variable.194

Some tumors appear to either not shrink or shrink very slowly over a 5- to 10-year period. We have enucleated several eyes, with good tumor control (defined as the absence of growth or actual tumor shrinkage), but there were late complications that produced blindness and painful eyes. In none of those eyes were tumor cells cycling.195 In one case, we noted that while the tumor did not change after irradiation, it was entirely necrotic on histologic examination (Figure 8–44).196 As mentioned previously, enucleation of such eyes does not adversely affect survival.

As discussed under brachytherapy, several newer approaches including magnetic resonance spectroscopy (MRS), MRI, Doppler ultrasonography, and three-dimensional ultrasonography have been used to monitor melanomas after radiation. Quantitative A- scan is the most accurate method to demonstrate changes in tumor height; as previously discussed, however, there are limitations in the accuracy of this

technique. Changes in the echographic pattern occur, most notably loss of vascularity and increased internal reflectivity. While changes in ultrasound patterns occur frequently after treatment, they are not universal, do not precede clinical findings, and we are uncertain as to their meaning. Similarly, there are insufficient data with acoustic tissue typing to determine its accuracy in monitoring treated tumors.197 In some melanomas, a loss of tumor vascularity on fluorescein angiography occurs 12 to 24 months after treatment.

We have studied melanoma cell cycling in untreated and irradiated uveal melanomas. Approximately 1 to 5 percent of untreated melanoma cells in

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Figure 8–41. A, A large uveal melanoma with a secondary exudative detachment of the inferior fundus. B, The same melanoma 3 months after helium ion irradiation; the white areas are diathermy marks outlining the tantalum marker rings. Note the absence of subretinal fluid.

untreated tumors incorporate bromodeoxyuridine and are in the DNA synthesis phase of the cell cycle. In contrast, no cells are actively cycling after successful irradiation. We have incorporated DNA cell cycling studies into fine-needle aspiration biopsy (FNAB) techniques in a few patients. One patient with a uveal melanoma in his only eye that had been treated with a 60Co plaque was referred because of presumed tumor growth. FNAB and cell cycling studies were negative, and the patient has been followed up for 7 years since that time, and there has been no evidence of enlargement. In another oneeyed patient who had been treated at another institution with 60 Gy of photon radiation for his melanoma, FNAB and cell cycling studies demonstrated that the tumor was still active, and the eye was removed. Histologically, this tumor demonstrated numerous mitoses. The use of FNAB and DNA studies in the serial evaluation of irradiated patients with uveal melanomas remains experimental with very limited indications.

Finally, the clinical appearance of a successfully radiated melanoma is characteristic. These lesions develop a surface charcoal-like appearance (Figure 8–45). Usually, there is loss of normal retinal and choroidal vasculature in the area along with change in the retinal pigment epithelium (RPE), and decreased tumor thickness.198

It is not uncommon to have minimal or even no evidence of tumor shrinkage after radiation. Unless definite enlargement (at least 1 to 2 mm) is present on sequential ultrasound examinations or serial fundus photographs, we do not consider the treatment a failure. The dilemma is predicated on the observation that occasionally, immediately after surgery or radiation, there is some hemorrhage or edema. Further, in some cases, intratumor radiation vasculopathy can produce hemorrhagic enlargement of the mass. The destruction and removal of tumor cells and debris after irradiation is inefficient. We have examined a number of eyes, either at autopsy or after enucleation (because of radiation complications and pain), in which the tumor was entirely necrotic, yet a significant mass remained.196,197

The follow-up visit after any form of alternative radiation therapy is empiric; we chose these intervals because they seem reasonable. A post-treatment

baseline is established 3 months after treatment, since hemorrhage and edema can occur after surgery and irradiation. Patients are then examined every 4 months for the first year, using clinical and ultrasound evaluation, and then at progressively longer intervals. After the first year, we obtain fluorescein angiograms every 6 months to determine if radiation vasculopathy is present.

Most recurrences develop within 3 years of treatment. We have, however, seen rare recurrences as long as 10 years after plaque and 5 years after particle therapy (Figure 8–46).139,181 Three patterns of recurrence can typically develop: (1) a marginal recurrence, more common with a plaque, in which there is a small flat area of lateral extension from a side of the irradiated tumor. In a small minority of

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Figure 8–42. A, A large uveal melanoma prior to treatment. B, The

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Figure 8–43. A, A large melanoma prior to treatment. B, One year after helium ion irradiation, the tumor is markedly reduced in size.

cases, retrospective replanning of radiation shows an inadequate dose was delivered to that area of the neoplasm; (2) a generalized marked enlargement of the tumor, usually associated with increased thickness and diameter and recurrent subretinal fluid; and (3) a distant or ring (diffuse, 360°) recurrence.

The delineation of tumor enlargement resulting from radiation vasculopathy, as distinguished from neoplastic cell proliferation, can be more difficult. Usually, the time course and appearance are helpful in distinguishing these two etiologies of melanoma enlargement. If a tumor has no hemorrhagic changes around it or any intratumor hemorrhage and is enlarging rapidly within the first 2 years after treatement, it is most likely due to continued neoplastic proliferation. In contrast, if the tumor was treated

more than 5 years ago and had regressed considerably but now is enlarged with other significant signs of radiation vasculopathy, possible hemorrhagic enlargement is more likely the diagnosis. Other signs of radiation vasculopathy should be present, and significant hemorrhage should be visible in and around the tumor. The time course is often helpful to differentiate the etiology of a post-treatment tumor enlargement, since radiation vasculopathy as an etiology of tumor enlargement usually occurs later than does recurrent tumor cell proliferation. As discussed previously, tumor recurrence after radiation is associated with increased melanoma-associ- ated mortality.

Figure 8–45. A clinical “charcoal” appearance associated with a necrotic melanoma following irradiation treatment.

Post-treatment Complications

A number of radiation complications destructive to vision are associated with 50 GyE or more of brachytherapy or charged particle irradiation. We have treated smaller melanomas with as little as 42 GyE of helium ion irradiation and still encountered radiation retinopathy.

Intraocular radiation vasculopathy after any form of irradiation occurs within approximately 6 to 36 months.199 Retinopathy is usually characterized by areas of capillary nonperfusion, cottonwool spots, hemorrhages, microaneurysms, and exudates (Figures 8–47 to 8–49). Optic neuropathy has a typical appearance as shown in Figures 8–50 and 8–51; early changes are the presence of flame hemorrhages and edema of the nerve head; later atrophy with loss of normal disc microvasculature occurs.

Radiation retinopathy occurs slightly earlier with charged particle irradiation than it does with radioactive plaques; however, the incidence of posterior pole complications with plaques appears to be higher than with charged particles in our randomized intra-institu- tional study.139 The tumor plus 2 mm of normal surround are routinely treated with high-dose charged particle radiation to avoid the possibility of either a marginal miss secondary to clinically inapparent tumor or movement of the patient during treatment. Thus, if the tumor is within 3 mm of the fovea or nerve, (2 mm of normal surround plus lateral radiation beam fall-off), it is likely that these visually vital structures will receive sufficient irradiation to develop clinically significant irradiation vasculopathy.

The pattern and time course of radiation vascular complications vary. Lash loss and both conjunctival and lid erythema become evident within the first 6 weeks after charged particle irradiation (Figure 8–52). To avoid epiphora secondary to radiation stenosis of the lacrimal drainage system, silicone tubes are placed prior to irradiation of uveal melanomas in the nasal portion of the eye.169 In approximately 10 percent of patients with large anterior uveal melanomas, keratopathy develops because a significant portion of the cornea is in the high-dose radiation field. Radiation cataracts develop within 6 to 12 months, if the majority of the lens is included in the high-dose region of the treatment beam or in

the high-dose region for brachytherapy. In a series of 558 patients treated in Boston for posterior tumors that were within 6 mm of the optic disc, it was noted that the 5-year rates were 64 percent for maculopathy, 35 percent for radiation optic neuropathy, and 68 percent for vision loss.200 As we had previously described, diabetes was also noted to be an increased risk factor for vision loss in this latter series. The authors noted that the safe radiation dose to the optic nerve was about 30 Gy.201 Similar studies of eyes treated with brachytherapy have been done.202

We have previously studied the accuracy of charged particle radiation delivery; if the treated tumor is > 4 mm from the fovea or the nerve, these structures seldom receive significant radiation.200 We initially hypothesized that the focusability of charged particle beams would decrease the incidence of post-treatment visual loss; however, we had been overly optimistic. Retrospective evalua-

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Figure 8–46. A and B, Melanoma has been nicely flattened by 125I radioactive plaque. The new area of vertical growth occurred about 10 years after radiation.