Lasers in intraocular tumors

Introduction

The first attempts to treat intraocular tumors by means of photocoagulation were carried out in the late 1950s by Professor Meyer-Schwickerath, the former head of our department, with the xenon arc photocoagulator.1 This was the start of a new era in the treatment of intraocular tumors. Nowadays, lasers are an irreplaceable tool in the management of malignant and benign intraocular lesions. This short chapter will focus on current applications.

Malignant intraocular tumors

Choroidal melanoma

Lasers can be used as the primary therapy for small malignant melanomas. Over the years, argon laser coagulation has replaced xenon photocoagulation, although results of the latter technique appeared to be better in terms of tumor control.2 Various techniques of photocoagulation have been advocated. Small melanomas were first surrounded by laser spots, after which the tumor was treated by either argon or krypton red lasers or, in some cases, even in combination with cryotherapy.3,4 The results of primary tumor control using this approach have been disappointing, with a reported primary failure rate of up to 64% with argon photocoagulation.5 Other groups have also reported a high rate of failure when using the argon laser, and a considerable proportion of eyes have had to be removed.6,7

As early as 1992, a Dutch group reported on the potential effectiveness of thermotherapy applied via an infrared diode laser (810 nm), for destroying - choroidal melanomas of a depth of up to 3.9 mm.8

This method used subcoagulation temperatures and had the theoretical potential of being able to destroy tumor cells in even deeper scleral layers, since the 810-nm wavelength has better tissue penetration than the argon green laser (514 nm), thus possibly being more effective than argon laser coagulation. Within a few years, this method, also known as transpupillary thermotherapy (TTT), became one of the most popular treatments for small melanomas. Very promising tumor control rates (94%) were reported in the early days of TTT.9,10 However, with most ocular oncology centers having treated sufficient numbers of patients primarily with TTT, the limitations of this treatment modality have now become clear. In a recent study, Shields et al.11 found that 9% of tumors (n = 256) recurred. They also found that patients with tumors abutting or overhanging the optic disc, or those requiring more than three sessions for tumor control, were more likely ultimately to develop tumor recurrence. Other groups have also noted recurrences, predominantly occurring in juxtapapillary lesions.12,13

In order to increase absorption within the tumor, especially in non-pigmented lesions, many groups combined TTT with the intravenous application of indocyanine green (ICG) dye. This procedure has not been studied as exactly as TTT. Many parameters could influence the results of ICG-enhanced TTT, such as: 1. the grade of the pigmentation; 2. the concentration of ICG applied; 3. the time point of starting TTT after injection of the dye; 4. the ocular flow compression during TTT by the contact lens; and 5. the possible photochemical interaction between the diode laser and ICG. This final parameter was postulated by Costa et al.,14 who treated two patients with choroidal neovascularization. Recent research also revealed that the best time to apply TTT is

approximately five minutes after injection of the dye.15 Recently, De Potter and co-workers16 published the results of a prospective, randomized, controlled study with 60 patients primary treated with TTT with or without ICG. They found no beneficial effect of ICG administration prior to TTT on tumor regression.

We have used TTT as the primary treatment for small melanomas since 1997. We treat tumors located very close to the macula or optic disc where the risk of radiation-induced visual loss would be high if that modality were used exclusively. The definition of a small melanoma eligible for primary TTT is a basal diameter of less than 10 mm and a tumor height of less than 2.5 mm. These tumors are treated by Oosterhuis’ standard technique:9 810-nm diode laser, 2- or 3-mm spot size, power adjustable to the visible effect after one minute, at least one minute per spot, and as endpoint, a grayish-white appearance of the tumor surface, with retreatment after a period of at least two to three months until the tumor has completely regressed (Figs. 1a and b). We also share the conviction of other ocular oncology centers that the majority of small melanomas (such as those defined above) can be treated by TTT, and that recurrent disease appears relatively frequently. Tumor recurrence may occur many years after the initial treatment in cases which have been pronounced ‘completely regressed’. Recurrent tumors are not always pigmented, and painstaking investigation of the scar in the pretreated area is needed in order to detect any recurrence at an early stage.

Lasers can also be used as an adjunctive tool in combination with other treatment modalities in therapy regimes for medium or even large melanomas. While in the early days of photocoagulation, xenon arc was the photocoagulator of choice, nowadays the argon or diode laser, in terms of TTT, appears to

be the most useful tool. It is also possible to treat the flat margins of irradiated tumors which were insufficiently treated by radiation (in a geographic sense), or even circumscribed flat tumor recurrence, seen after irradiation or surgical therapy.17,18 With regard to argon laser coagulation, it is recommended using confluent spots with a long exposure time (>1 sec) and high power (>800 mW). For TTT, it is advisable to use the standard method described above.9 In these cases, careful re-evaluation of the laser-treated scar is necessary since tumor regrowth occurs more frequently in that area than in the irradiated space (Fig. 2).

Another interesting aspect of using lasers in the treatment of medium or large melanomas is the possibility of decreasing the radiation dose, and thus reducing the radiation-induced side-effects. The principle of the so-called ‘sandwich therapy’ was introduced by the Oosterhuis group9 and has found broad acceptance among ocular oncologists worldwide. The principle is simple: due to the TTT treatment on the top of the tumor, it is possible to decrease the height of the tumor to be treated by radiation. This makes it possible, for example, to treat melanomas with a height of even up to 8 mm with ruthenium plaques (e.g., 6 mm with ruthenium and 2 mm with TTT), or to reduce the total dose of radiation (Fig. 3). The treatment at the top of the tumor should be carried out in the same manner as primary TTT. However, it is still not clear when this should be done. From a biological point of view, it would appear to be beneficial to perform TTT just before or during brachytherapy, since hyperthermia can increase the effectiveness of radiation. However, care must be taken not to induce thermotolerance. Some groups prefer to perform TTT after brachytherapy. According to our experience, the latter may lead to insufficient treatment since, in some cases, a significant

exudative reaction, or even bleeding, following brachytherapy may prevent TTT from being performed as scheduled. Moreover, TTT before brachytherapy may also result in bleeding, especially in cases of tumors with retinal invasion, which might prevent the brachytherapy procedure. Therefore, we prefer to perform TTT during the first days of brachytherapy. It is also recommended that caution be applied when performing TTT in tumors with extensive collateral retinal detachment, since some cases of proliferative vitreoretinal disease after TTT cause severe retinal damage. Although no studies comparing primary TTT with ‘sandwich therapy’ in small melanomas exist, many ocular oncologists feel more comfortable performing ‘sandwich therapy’ (Fig. 4). Recently Shields and co-workers19 reported on their experience with combined plaque radiotherapy and

TTT in 270 patients with uveal melanoma. They found an excellent tumor control rate (97%) over 5 years of follow-up.

Various attempts have been made to treat uveal melanomas with photodynamic therapy, since these tumors can be visualized easily and are thus appropriate candidates for such therapy. The first attempts using the photosensitizer hematoporphyrin failed to achieve the expected level of tumor control.20 Recently, some preliminary results were presented using the photosensitizer verteporfin.21,22 However, photodynamic therapy still remains an experimental procedure for the treatment of uveal melanomas.

Retinoblastoma

The treatment of retinoblastomas has changed dramatically in the past decades. While most unilateral retinoblastomas are still treated by enucleation, the treatment of bilateral cases is far more complicated.23 Lasers have played a central role in the treatment of retinoblastomas since the very start of the laser era. Small tumors, or even circumscribed recurrences, were first treated first by xenon lasers,2,24,25 and later by argon lasers,26 while currently the diode laser is the method of choice.23,27 Over the years, the results were comparable between the various types of laser, and a tumor control rate of approximately 80% was achieved. The currently popular diode laser, used with an adjustable, indirect opthalmoscope, is far

easier to use than the xenon arc photocoagulator, and moreover has a more favorable absorption range within the eye than the argon laser. When treating retinoblastomas with an indirect ophthalmoscope, children should be anesthetized and the surgeon should first treat the area surrounding the tumor and then the tumor itself, until the effect of coagulation is visible (Fig. 5). Over-treatment, for example, a power that is too high or a long exposure time, may cause the spread of tumor cells within the vitreous cavity. This is a severe, eye threatening complication. Tumors treated by laser coagulation should be monitored closely since recurrent disease may develop even years after the initial therapy.23

In addition to laser coagulation, hyperthermia induced by the diode laser represents a novel and

powerful tool in the management of retinoblastomas. This is also performed with the indirect ophthalmoscope, or alternatively with an adapter in a surgical microscope, with the laser spot (preferably wide spots) over the tumor mass, by using low power but a long exposure time until an edema is visible across

the entire tumor. Due to the hyperthermia, it is possible to increase the uptake of chemotherapy within the tumor mass and thus improve the response. This procedure is called thermochemotherapy (TCT; Fig. 6) and can even be applied in medium and large retinoblastomas.23,28-31 In terms of thermotherapy,

the diode laser is also applicable as an adjunctive treatment after chemoreduction of the tumor mass. Similarly to laser coagulation, close and careful monitoring of children is recommended since recurrent disease may occur.

Benign intraocular tumors

Choroidal hemangiomas

Choroidal hemangiomas are a rare type of benign tumor of the eye. Although benign, choroidal hemangiomas are threatening the eye when exudative activity is present. The main goal of treatment is to improve or maintain visual acuity and, in severe cases, to preserve the eye. For many years, argon laser scatter coagulation was or still is the treatment of choice in many oncology centers. The disadvantages of this method are that multiple sessions are often required, and the visual outcome in the case of subfoveolar lesions is relatively poor.32,33 Radiotherapy is an alternative treatment option, but also carries some disadvantages. Proton beam irradiation or plaque radiotherapy is a much more invasive procedure than laser coagulation. Low-dose external beam irradiation is not invasive, but it carries the risk of secondary tumor induction.

The diode laser could be an alternative. An early report on the application of scatter coagulation with the diode laser found no response from the international community, since no real difference was expected between this type of treatment and argon laser coagulation.34 Other groups used the diode laser in the same way as for choroidal melanoma. The first results with TTT have now been published and they appear to be promising.35-37 However, TTT seems

to be unfavorable in tumors located in the fovea, which imposes considerable limitations on that method.37 Because of the limited number of cases studied in the above-mentioned reports (n = 19) and the short follow-up time, the results should be considered preliminary.

Another alternative therapy using laser light delivery is currently under investigation. Photodynamic therapy with verteporfin was performed in some cases (n = 5) of choroidal hemangioma with very promising results.38,39 This type of therapy has at least the theoretical advantage of no or minimal sideeffects in the treated and surrounding area (as well as outside the eye), which makes it favorable even for tumors located subfoveolarly (Fig. 7). Our group reported on 19 circumscribed, symptomatic hemangiomas treated with PDT.40 We performed a mean of 2.15 (range: 1-5) sessions of PDT using 6 mg/m2 body surface area verteporfin and a light dose of 100 J/cm2 at 692 nm. We found that in all but one tumors the subretinal fluid was completely resolved, the visual acuity improved by at least one line in 73.3% and by at least two lines in 42.1% of the patients. We noticed no recurrences, no local or systemic side effects during the follow-up time (mean: 10.6 months). PDT was also safely performed in hemangiomas located beneath the fovea which is a clear advantage over other kind of laser treatments (e.g., TTT or argon laser). An other group reported similar excellent results on 15 patients with choroidal hemangiomas treated with PDT.41

Retinal capillary hemangioma

This vascular tumor of the retina very often appears as an ocular manifestation in von Hippel-Lindau’s disease.42 Treatment of large capillary hemangiomas

still remains a challenge. Fortunately, small retinal capillary hemangiomas can be treated safely and effectively by laser coagulation.43,44 As with other intraocular tumors, these lesions were formerly treated by xenon arc photocoagulation and later by argon green lasers,43,44 or in some centers, by the dye yellow laser.45,46 The dye yellow laser has the theoretical advantage of better absorption of hemoglobin in blood-filled capillary tumors than the green or blue argon lasers. Treatment can take place directly over the tumor with confluent spots (Figs. 8a and b), according to the principle: ‘Do not tickle the tiger, kill him’. Close follow-up is recommended since an exudative reaction, or in some cases even complete retinal detachment, can occur shortly after laser treatment. Treatment of the feeder vessels it is not recommended. Recently, some cases treated by TTT with varying success were also reported.47,48

In advanced cases in which vitrectomy is needed, the endolaser can be used intraoperatively to treat small lesions (Figs. 8c and d).

Miscellaneous

Other intraocular tumors such as nevus, combined hamartoma of the retina, and retinal pigment epithelium or choroidal osteoma, often do not require any treatment. In some cases, secondary choroidal neovascularization with subsequent visual symptoms may develop. In these rare cases, the secondary neovascularization can be treated in the same way as in other conditions, such as age-related macular degeneration.

Conclusions

The introduction of laser treatment has changed the clinical praxis in ocular oncology. The application of laser as a coagulator, hyperthermia and thermotherapy has enabled new treatment modalities for both malignant and benign intraocular lesions. The main advantages of laser treatment compared to other modalities like irradiation are the broad availability, the relatively easy performance and thus reproducibility, the high precision during the treatment, and the safety for the adjacent tissues. On the other hand lasers as a sole treatment for malignant lesions failed to reach the tumor control rates known from irradiation therapy. A cautious selection of the tumors treated by laser is mandatory. Nowadays the infrared diode laser is the most popular laser in ocular oncology combining all the advantages and a satisfactory tumor control rate. New developments like photodynamic therapy in vascular lesions are very promising and deserve further clinical investigation.

References

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