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Indocyanine Green (ICG) Enhanced Transpupillary Thermotherapy (TTT) for Hypopigmented Choroidal Melanoma
Med. Laser Appl. 16: 299–305 (2001) © Urban & Fischer Verlag http://www.urbanfischer.de/journals/lasermed
Indocyanine Green (ICG) Enhanced Transpupillary Thermotherapy (TTT) for Hypopigmented Choroidal Melanoma BERNHARD M. STOFFELNS Department of Ophthalmology, University Mainz, Germany Submitted: June 2001 · Accepted: August 2001
Summary Objective: Transpupillary thermotherapy (TTT) using an infrared diode laser at 810 nm is a new treatment modality for small choroidal melanoma, but less effective in hypopigmented tumors. We evaluate the effectiveness of intravenous ICG as an adjuvant to increase heat uptake in the tumor tissue and it´s influence on tumor regression. Methods: In a prospective nonrandomized analysis 12 eyes suffering from primary choroidal melanoma (hypopigmented and posterior to the equator with thickness ≤4.5 mm) were treated with ICG augmented TTT (diode laser at 810 nm, beam diameter 2–3 mm, power setting 0.5–1.0 Watt, exposure time 6–26 minutes). The energy of the laser beam starting with 0.3 Watt at the tumor center was increased by 50 mW-steps for one minute till development of gray edema on the tumor surface indicates completion of the treatment spot, which were delivered in overlapping confluency, including 0.5 mm of clinically normal tissue around the tumor margin. 2 minutes after start of TTT 100 mg indocyanine green in 10 cc aqueous solvent were injected intravenously over 20 seconds. 8 tumors previously showed insufficient regression after TTT without dye or ruthenium-106 plaque radiotherapy. 4 amelanotic melanoma had no previous treatment. Patients were followed up for at least 9 month. Results: 6 eyes revealed tumor regression to a completely flattened scar within 2-4 month after one treatment session. 3 eyes flattened after two sessions within 6-8 month. 3 eyes were judged as failures (two required ruthenium-106 radiotherapy because of insufficient regression after two sessions TTT and one eye was enucleated because of regrowth after radiotherapy and TTT). Visual acuity was unchanged or improved in 7 eyes. Ocular side effects were epiretinal gliosis (2), macula edema (1) and temporary retrobulbar pain (3). No metastases were seen during follow-up. Conclusions: Indocyanine green is an effective dye to increase heat uptake and efficiacy of transpupillary thermotherapy for primary hypopigmented choroidal melanoma as well as residual tumor prominences with secondary loss of pigmentation after brachytherapy or TTT. Longer follow-up is necessary for data regarding ultimate local tumor control and metastatic disease.
Key words Uveal melanoma, transpupillary thermotherapy, indocyanine green
Introduction Enucleation was the standard treatment for choroidal melanoma until radiotherapy (5, 11) and photocoagulation (13) emerged as an “eye- and vision sparing” alternative. Although stabilization or reduction of tumor
size has been achieved in over 90% of cases, more than 40% of treated eyes developed significant radiation-associated complications (5, 11). In most cases ophthalmic plaque radiation is applied to the posterior segment of the eye, and may thus lead to an increased incidence of radiation retinopathy and optic neuropathy. 1615-1615/01/16/04-299 $ 15.00/0
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Indocyanine Green (ICG) Enhanced Transpupillary Thermotherapy
1995 Journee-de Korver et al. (7, 8) reported good results of hyperthermia using near infrared radiation at 810-nm as the primary treatment for choroidal melanoma in animals. Optimum tumor necrosis was achieved on heating the tumor to a temperature from 45° to 60 °C (9). Oosterhuis et al. 1998 (14, 15), from the same working group, confirmed the efficacy of infrared hyperthermia for human choroidal melanoma. Near infrared radiation was delivered by using a diode laser through the dilated pupil, and the new method was described as “transpupillary thermotherapy (TTT)” by the authors. Preliminary clinical results (6, 15, 17, 18, 21, 22) with this new treatment modality confirmed, that TTT is less effective in hypopigmented melanoma due to a decreased uptake of infrared laserlight converted into heat in the tumor tissue. Indocyanine green (ICG), a 790-nm chromophore, which is used for the imaging of retinal and choroidal vasculatures (4) for more than 30 years, had proved ability to enhance absorption of the 810-nm laserbeam as results obtained in a rabbit model (2) demonstrated. Here we present our first clinical experiences with intravenous ICG as an adjuvant to increase heat uptake in hypopigmented choroidal melanoma during transpupillary thermotherapy (TTT).
Material and Methods In a prospective nonrandomized analysis 12 eyes suffering from primary hypopigmented choroidal melanoma were treated with ICG augmented TTT. The eligibility criteria for treatment were based on reports on histolog-
301
ical and clinical results after transpupillary thermotherapy in the literature (9, 14). Included in this series were selected patients with primary choroidal melanoma located posterior to the equator of the eye measuring 12 mm or less in base and 4.5 mm or less in thickness. All patients had either documented growth or ophthalmoscopic risk factors (19) for growth and/or metastasis. Excluded were those patients with retinal, optic nerve, vitreous or extrascleral tumor extension, subretinal hemorrhage or media opacity prohibiting adequate visualization of the tumor. 8 hypopigmented melanoma previously showed insufficient regression after TTT without dye or ruthenium-106 plaque radiotherapy. 4 amelanotic melanoma had no previous treatment. Patient data included age, race, gender and visual acuity as well as results of evaluation for metastatic disease. The diagnosis of choroidal melanoma was based on results of the ophthalmoscopic examination, ultrasonography and fluorescein angiography. The basal dimensions of the tumor were determined by B-scan ultrasonography; tumor height was measured by A- and B-scan ultrasonography. Tumor data included tumor location (subfoveal, para- or extrafoveal, juxtapapillary), presence of subretinal fluid (present, absent), orange pigment (present, absent) and drusen (present, absent). Visual acuity and ultrasonographic tumor thickness were measured at each followup period. Fundus photography and fluorescein angiography were performed before treatment and on regression of the tumor into a flat chorioretinal scar. Additional fundus photographies were taken selectively for documentation of the regression course of selected tumors. Associated findings in the anterior and posterior eye segment were recorded.
Fig. 1. A 56-year old patient complained of blurred vision since 2 months. Visual acuity was dropped to 0.3. A: Fundus photograph showed an amelanotic choroidal melanoma located temporal to the fovea. Tumor thickness was 2.4 mm measured by ultrasonography. B: Early frame of fluorescein angiography showed hard exudation in the macula zone indicating for macular edema due to serous exudation of the melanoma, which is a highly significant sign for growth. Macular edema was the reason for blurred vision. Late frame of fluorescein angiography revealed the characteristic late staining in the melanoma parenchym. Fig. 2. Fundus photograph 2 months after ICG enhanced TTT. Tumor thickness had regressed to 1.1 mm. Chorioretinal scar developed at the tumor margins, but the tumor center was still exudative. Notice the hard exudates indicating for still persisting macular edema. Fig. 3. Fundus photograph 4 months after treatment revealed a completely flattened scar. Vision improved to 0.8 due to resorption of macular edema and parafoveal hard exudates, which is a most significant sign of tumor regression. Light hemorrhage at the tumor surface was caused by occlusion of retinal vessels in the treatment zone. Fig. 4. Fundus photograph 12 months after treatment revealed further loss of pigment clumbs in the treatment area allowing for visibility of underlying sclera and large choroidal vessels remaining perfused. Vision remained unchanged and no sign of tumor regrowth was noted.
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TTT was performed using a specially modified infrared diode laser at 810 nm with an adjustable beam width of 2.0 or 3.0 mm (Iris Medical Instruments, Mountain View, CA). The infrared diode laser system was adapted to a Haag-Streit slit-lamp biomicroscope (Koniz, Switzerland). The laser light was delivered through two infrared coated panfunduscope contact lenses (Mainster wide field and Mainster ultra wide field OMRA-PRP, Ocular Instruments, Bellevue, WA). The width of the laser beam used in the majority of patients was 3.0 mm; a diameter of 2.0 mm was used under special circumstances to avoid the optic disc or retinal vessels. Treatment was initiated at the center of the tumor with one spot/1 minute, using a low power setting of 300 mW. Continuous observation through the slit-lamp biomicroscope directed towards the tumor surface was ensured during the entire treatment period. The energy of the laser beam was increased in 50 mW-steps over 1 minute to achieve a treatment endpoint of gray-white appearance on completion of the treatment spot. The energy of the laser beam was lowered if the color change appeared early in the exposure period or in the presence of coagulation of retinal vessels. In our series power settings ranged from 500 to 1000 mW, and exposure times from 6 to 26 minutes. Spots were delivered in overlapping confluency, including 0.5–1.0 mm of clinically healthy tissue from the tumor margin. The number of laser spots ranged from 3 to 8, depending on the diameter of the tumor base. 2 minutes after start of TTT 100 mg indocyanine green in 10 cc aqueous solvent were injected intravenously over 20 seconds. After injection of the dye TTT was continued. The pupil was dilated with 5% phenylephrine hydrochloride and 0.25% tropicamid eyedrops prior to treatment. Retrobulbar anesthesia was achieved with an injection of 2 ml xylocaine 2% and 2 ml carbostesine for immobilization and pain prevention. Postoperatively, 0.1% dexamethasone eyedrops were administered three times a day for five days. Follow-up examinations were performed at 4-week intervals until the tumor had regressed to a flat chorioretinal scar. When complete tumor regression was assumed, the follow-up interval was extended to 3 months. In cases of partial regression, additional treatment was performed after a period of 3 months. The minimum follow-up was 9 months.
Results The mean patient age at treatment was 60.5 years (range, 46 to 75 years). All patients were white; there were 8 women and 4 men. Evaluation for metastatic disease in all patients revealed no sign of metastasis at the time of treatment as well as during follow-up. The mean tumor thickness before treatment was 2.0 mm (range, 1.0 to 3.1 mm), the mean maximum basal diameter measured was 8.2 mm (range, 6.0 to 10.1 mm). Tumor location was below the fovea in 3 eyes, and one tumor touched the optic disc. The posterior margin of eight tumors touched the posterior pole, but did not involve the foveal area. Exudative retinal detachment was observed preoperatively in 4 eyes, In four eyes with amelanotic melanoma ICG-augmented TTT was used as first treatment modality. In five eyes insufficient regression during 9–13 months after ruthenium-106 brachytherapy was noted. Three eyes with hypopigmented melanoma recieved 2 sessions of TTT without ICG-enhancement and showed no significant tumor regression. In all cases further treatment was recommended because of presentation of known risk factors (19) for tumor regrowth and metastasis. Postoperatively 6 eyes revealed tumor regression to a completely flattened scar within 2–4 months after one treatment session. 3 eyes flattened after two sessions within 6–8 months. Mean treatment parameters at the first session included power at 500 mW (range, 450 to 600 mW) for 17 minutes (range, 6 to 26 minutes), and power at 600 mW in all cases for 21 minutes (range, 18 to 22 minutes) at the second session. The endpoint of treatment in all hypopigmented melanoma was a faint gray color for both sessions. Three eyes were judged as failures (two required ruthenium-106 radiotherapy because of insufficient regression after two sessions TTT and one eye was enucleated because of significant regrowth after previous radiotherapy and TTT). Visual acuity was unchanged or improved in 5 eyes. The reason for improvement of vision was the postoperative resolution of subretinal fluid. Visual acuity was decreased in 7 eyes, which is primarily due to the tumor location, requiring three eyes to be treated through the foveola for subfoveal tumors. In four eyes the development of severe maculopathy due to epiretinal gliosis in three and macular edema in one case were noted and accounted for a poorer visual outcome.
Indocyanine Green (ICG) Enhanced Transpupillary Thermotherapy
Epiretinal gliosis, macular edema as well as temporary retrobulbar pain in two cases were the only ocular side effects documented during follow-up. No signs of direct heat-related alterations were recorded in cornea, lens and vitreous. Fluorescein angiography postoperatively was performed in that nine eyes with complete tumor flattening during 3–8 months. In all cases the angiographic frames revealed a sharp demarcation of the treated area by a zone of pigment epithelium atrophy. A comparison with the surrounding normal tissue allowed to distinguish the heat treated area as nonfluorescent in seven, and as hypofluorescent in two cases. Choriocapillary vessels in 4 eyes remained perfused residually in several areas of the thermotherapy field. Only that four eyes, which recieved ruthenium-plaque therapy first, developed complete atrophy of the choriocapillary layer in the treatment zone.
Discussion Transpupillary thermotherapy is a recently developed technique for treating minimally raised choroidal melanoma (up to 4.5 mm). A diode laser of wavelength 810 nm is used, which is minimally absorbed by ocular media and produces tissue necrosis within the tumor by causing a rise in temperature to levels of approximately 65 °C. Several studies presented in the literature (6, 20, 22) showed a satisfactory local tumor control and minmal ocular side effects. The infrared wavelength (1, 7) is absorbed in melanin in the retinal pigment epithelium and choroid. Absence of pigmentation in amelanotic melanomas allows for increased penetration of infrared light into tissue and for a decreased volume uptake of light converted into heat. The mean energy required for the treatment of amelanotic melanomas was 15% higher than for pigmented tumors; the reduction of tumor height 3 months after TTT was 33% more in pigmented than in amelanotic tumors (15). Some amelanotic tumors showed quite no response even after repeated TTT (22). Indocyanine green (4) is a water-soluble tricarbocyanine dye that is mostly protein bound, with globulins (95%) being the principal carrier. The dye absorbs light maximally at 790 nm and fluorescence at 835 nm. The dye is taken up exclusively by hepatic parenchymal cells and is se-
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creted entirely into the bile. It has been approved by the Food and Drug Administration (FDA) for such indications as ophthalmic angiography and measurement of cardiac output and hepatic function. Indocyanine green enhances absorption of the infrared laser beam, a mechanism unrelated to photodynamic therapy. Indocyanine green-enhanced laser treatment has been used experimentally in other surgical specialties for tissue welding (3) and for superficial vein ablation (10, 12). In ophthalmology, ICG-enhanced laser treatment has been used to close subretinal neovascularization (1, 16) in animals and in humans. Based on a prior report (2) that demonstrated effectiveness of ICG to enhance the photocoagulative effects of the infrared diode laser for treatment of experimental ocular melanoma in Greene hamster eyes, we used ICG for enhancement of TTT. In every eye we started TTT for two minutes and then injected the indocyanine green dye. Our speculation was, that the initial heat would disturb the cellular integrity in the tumot tissue allowing for increased leakage and staining of the tumor with dye, thus providing improved uptake of infrared light converted into heat. Our results are preliminary because further investigations have to proof the influence of tumor vascularity on the treatment outcome and the mechanism of dye enhanced TTT. Possibly the ICG-effect can be developed by intravenous infusion of ICG or repetitive ICG-enhanced laser sessions. We also realize that our report contends a small group of patients with a rare tumor and a relative short follow-up.. Our results demonstrate, that combination of intravenous ICG and TTT could be very effective in treatment of primary hypopigmented choroidal melanoma as well as residual tumor prominences with secondary loss of pigmentation after brachytherapy or TTT. Longer follow-up is necessary for data regarding ultimate local tumor control and metastatic disease. Indozyaningrün (ICG) verstärkte transpupillare Thermotherapie (TTT) pigmentarmer Aderhautmelanome Hintergrund: Die transpupillare Thermotherapie unter Verwendung eines infraroten Diodenlasers bei 810 nm ist eine neue Behandlungsoption für kleine Aderhautmelanome, die wenig effektiv ist bei schwacher Tumorpigmentierung. Wir untersuchten die Wirksamkeit von intravenöser Gabe von Indozyaningrün (ICG)
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zur Absorptionssteigerung des Laserlichtes und dessen Auswirkung auf die Tumorregression. Material und Methoden: In einer prospektiven, nicht randomisierten Untersuchung wurden 12 Augen mit primären Aderhautmelanomen (pigmentarm, zentral des Äquators, Prominenz ≤ 4,5 mm) behandelt mit ICG verstärkter TTT (Diodenlaser bei 810 nm, Spotdurchmesser 2–3 mm, Leistung 0,5–1,0 Watt, Exposition 6–26 Minuten). Die Laserleistung wurde beginnend im Tumorzentrum bei 0,3 W in 50-Milliwattschritten für jeweils eine Minute langsam erhöht, bis eine Grauweißfärbung der Tumoroberfläche das Behandlungsende dieses Spots anzeigte. Die Spots wurden in konfluierender Überlappung gesetzt unter Einschluss eines 0,5 mm breiten Randsaumes im klinisch gesunden Gewebe. 2 Minuten nach Behandlungsbeginn wurden 100 mg ICG in 10cc wässriger Lösung intravenös über 20 Sekunden injiziert. 8 Tumoren hatten zuvor eine ungenügende Rückbildung nach TTT ohne Adjuvans oder Rutheniumbrachytherapie gezeigt. 4 amelanotische Tumoren wurden primär mit ICG verstärkter TTT behandelt. Die Nachbeobachtungszeit betrug minimal 9 Monate. Ergebnisse: 6 Augen zeigten eine komplette Rückbildung zu einer flachen Narbe im Verlauf von 2–4 Monaten nach einmaliger TTT. 3 Augen entwickelten eine flache Narbe nach 2 Behandlungen innerhalb von 6–8 Monaten. 3 Augen wurden als Therapieversager beurteilt (2 erhielten eine Rutheniumbrachytherapie wegen ungenügender Regression nach 2 Sitzungen TTT und ein Auge wurde enukleiert wegen rezidivierendem Tumorwachstum nach Brachytherapie und TTT). Die postoperative Sehschärfe war unverändert oder besser in 7 Augen. Oculäre Nebenwirkungen waren epiretinale Gliose (2), Maculaödem (1) und vorübergehender Retrobulbärschmerz (3). Metastasen traten während des Kontrollintervalls nicht auf. Diskussion: Indozyaningrün ist ein wirksames Adjuvans, um die in Hitze konvertierte Lichtaufnahme und damit die Effektivität der transpupillaren Thermotherapie zu verstärken für pigmentarme Aderhautmelanome oder tumoröse Restprominenzen mit sekundärem Pigmentverlust nach Brachytherapie oder TTT. Längere Nachkontrollen sind nötig zur Evaluierung der letztendlichen Tumorkontrolle und Metastasierungsrate.
Schlüsselwörter Aderhautmelanom, Transpupillare Thermotherapie, Indozyaningrün
References 1. BALLES MW, PULIAFITO CA, KLIMAN GH, et al.: Indocyanine green dye enhanced diode laser photocoagulation of subretinal neovasular membranes. Invest Ophthalmol Vis Sci 31 (suppl): 282, abstract (1990) 2. CHONG LP, ÖZLER SA, DE QUEIROZ JM, LIGGETT PE: Indocyanine green-enhanced diode laser treatment of melanoma in a rabbit model. Retina 13: 251–259 (1993) 3. CHUCK RS, OZ MC, DELOHERY TM, et al.: Dye-enhanced laser tissue welding. Laser Surg Med 9, 471–477 (1989) 4. DESMETTRE T, DEVOISELLE JM, MORDON S: Fluorescence properties and metabolic features of indocyanine green (ICG) as related to angiography. Survey of Ophthalmology 45 (1): (2000)
5. FINGER PT: Radiation therapy for choroidal melanoma. Surv of Ophthalmol 42 (3): 215–232 (1997) 6. GODFREY DG, WALDRON RG, CAPONE A jr: Transpupillary thermotherapy for small choroidal melanoma. Am J Ophthalmol 128 (1): 88–93 (1999) 7. JOURNÉE-DE KORVER JG, OOSTERHUIS JA, KAKEBEEKEKEMME HM, DE WOLFF-ROUENDAAL D: Transpupillary thermotherapy (TTT) by infrared irradiation of choroidal melanoma. Doc Ophthalmol 82: 185–191 (1992) 8. JOURNÉE-DE KORVER JG, OSTERHUIS JA, VRENSEN GFJM: Light and electron microscopic findings on experimental melanomas after hyperthermia at 50 °C. Melanoma Res 5: 393–402 (1995) 9. JOURNÉE-DE KORVER JG, OOSTERHUIS JA, DE WOLFF-ROUENDAAL D, KEMME H: Histopathological findings in human choroidal melanomas after transpupillary thermotherapy. Br J Ophthalmol 81: 234–239 (1997) 10. LIBUTTI SK, OZ MC, CHUCK RS, et al.: A preliminary study of dye-enhanced laser photosclerosis. Surgery 109: 163–168 (1991) 11. LOMMATZSCH PK, KIRSCH JH: Ru 106/Rh 106 plaque-radiotherapy for malignant melanomas of the choroid. Doc Ophthalmol 68: 225–238 (1988) 12. MOAZAMI N, OZ MC, BASS LS, TREAT MR: Reinforcement of colonic anastomoses with a laser and dye enhanced fibrinogen. Arch Surg 125: 1452–1454 (1990) 13. MEYER-SCHWICKERATH G, BORNFELD N: Photocoagulation of choroidal melanomas – thirty years´ experience. In: LOMMATZSCH PK, BLODI FC (eds): Intraocular tumours. Springer, New York 1983, 269–276 14. OOSTERHUIS JA, JOURNÉE-DE KORVER HG, KAKEBEEKEKEMME HM, BLEEKER JC: Transpupillary thermotherapy in choroidal melanomas. Arch Ophthamol 113: 315–321 (1995) 15. OOSTERHUIS JA, JOURNEE-DE KORVER HG, KEUNEN JEE: Transpupillary thermotherapy. Results in 50 patients with choroidal melanoma. Arch Ophthalmol 116: 157–162 (1998) 16. PULIAFITO CA, GUYER DR, MONES JM, WEAVER Y: Indocyanine green digital angiography and dye-enhanced diode laser photocoagulation of choroidal neovascularization. Invest Ophthalmol Vis Sci 32(suppl): 712, abstract (1991) 17. ROBERTSON DM, BUETTNER H, BENNETT SR: Transpupillary thermotherapy as primary treatment for small choroidal melanomas. Arch Ophthalmol 117: 1512–1519 (1999) 18. SCHNEIDER H, FISCHER K, FIETKAU R, GUTHOFF RF: Transpupillare Thermotherapie des malignen Aderhautmelanoms. Klin Monatsbl Augenheilkd 214 (2): 90–95 (1999) 19. SHIELDS CL, SHIELDS JA, KIRATLI H, et al.: Risk factors for growth and metastasis of small choroidal melanocytic lesions. Ophthalmology 102: 1351–1361 (1995) 20. SHIELDS CL, SHIELDS JA, CATER J, LOIS N, EDELSTEIN C, GÜNDÜZ K, MERCADO G: Transpupillary thermotherapy for choroidal melanoma. Ophthalmology 105 (4): 581–590 (1998) 21. STOFFELNS BM: Der infrarote Diodenlaser (810 nm) zur transpupillaren Thermotherapie des malignen Aderhautmelanoms. Lasermedizin 14: 99–105 (1999)
Indocyanine Green (ICG) Enhanced Transpupillary Thermotherapy 22. STOFFELNS BM, AUGUSTIN AJ, PFEIFFER N: Transpupillare Thermotherapie zur nichtadiuvanten Primärbehandlung des malignen Aderhautmelanoms. Der Ophthalmologe 96 (Suppl. 1): 152, abstract (1999)
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Correspondence address: Bernhard M. Stoffelns, M.D., Department of Ophthalmology, Johannes Gutenberg University Mainz, Langenbeckstrasse 1, D - 55131 Mainz, Germany Tel.: ++49-6131-177133; Fax: ++49-6131-176620; e-mail: [email protected]
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Indocyanine Green (ICG) Enhanced Transpupillary Thermotherapy (TTT) for Hypopigmented Choroidal Melanoma BERNHARD M. STOFFELNS Department of Ophthalmology, University Mainz, Germany Submitted: June 2001 · Accepted: August 2001
Summary Objective: Transpupillary thermotherapy (TTT) using an infrared diode laser at 810 nm is a new treatment modality for small choroidal melanoma, but less effective in hypopigmented tumors. We evaluate the effectiveness of intravenous ICG as an adjuvant to increase heat uptake in the tumor tissue and it´s influence on tumor regression. Methods: In a prospective nonrandomized analysis 12 eyes suffering from primary choroidal melanoma (hypopigmented and posterior to the equator with thickness ≤4.5 mm) were treated with ICG augmented TTT (diode laser at 810 nm, beam diameter 2–3 mm, power setting 0.5–1.0 Watt, exposure time 6–26 minutes). The energy of the laser beam starting with 0.3 Watt at the tumor center was increased by 50 mW-steps for one minute till development of gray edema on the tumor surface indicates completion of the treatment spot, which were delivered in overlapping confluency, including 0.5 mm of clinically normal tissue around the tumor margin. 2 minutes after start of TTT 100 mg indocyanine green in 10 cc aqueous solvent were injected intravenously over 20 seconds. 8 tumors previously showed insufficient regression after TTT without dye or ruthenium-106 plaque radiotherapy. 4 amelanotic melanoma had no previous treatment. Patients were followed up for at least 9 month. Results: 6 eyes revealed tumor regression to a completely flattened scar within 2-4 month after one treatment session. 3 eyes flattened after two sessions within 6-8 month. 3 eyes were judged as failures (two required ruthenium-106 radiotherapy because of insufficient regression after two sessions TTT and one eye was enucleated because of regrowth after radiotherapy and TTT). Visual acuity was unchanged or improved in 7 eyes. Ocular side effects were epiretinal gliosis (2), macula edema (1) and temporary retrobulbar pain (3). No metastases were seen during follow-up. Conclusions: Indocyanine green is an effective dye to increase heat uptake and efficiacy of transpupillary thermotherapy for primary hypopigmented choroidal melanoma as well as residual tumor prominences with secondary loss of pigmentation after brachytherapy or TTT. Longer follow-up is necessary for data regarding ultimate local tumor control and metastatic disease.
Key words Uveal melanoma, transpupillary thermotherapy, indocyanine green
Introduction Enucleation was the standard treatment for choroidal melanoma until radiotherapy (5, 11) and photocoagulation (13) emerged as an “eye- and vision sparing” alternative. Although stabilization or reduction of tumor
size has been achieved in over 90% of cases, more than 40% of treated eyes developed significant radiation-associated complications (5, 11). In most cases ophthalmic plaque radiation is applied to the posterior segment of the eye, and may thus lead to an increased incidence of radiation retinopathy and optic neuropathy. 1615-1615/01/16/04-299 $ 15.00/0
300
1A
1B
B. M. STOFFELNS
2
3
4
Indocyanine Green (ICG) Enhanced Transpupillary Thermotherapy
1995 Journee-de Korver et al. (7, 8) reported good results of hyperthermia using near infrared radiation at 810-nm as the primary treatment for choroidal melanoma in animals. Optimum tumor necrosis was achieved on heating the tumor to a temperature from 45° to 60 °C (9). Oosterhuis et al. 1998 (14, 15), from the same working group, confirmed the efficacy of infrared hyperthermia for human choroidal melanoma. Near infrared radiation was delivered by using a diode laser through the dilated pupil, and the new method was described as “transpupillary thermotherapy (TTT)” by the authors. Preliminary clinical results (6, 15, 17, 18, 21, 22) with this new treatment modality confirmed, that TTT is less effective in hypopigmented melanoma due to a decreased uptake of infrared laserlight converted into heat in the tumor tissue. Indocyanine green (ICG), a 790-nm chromophore, which is used for the imaging of retinal and choroidal vasculatures (4) for more than 30 years, had proved ability to enhance absorption of the 810-nm laserbeam as results obtained in a rabbit model (2) demonstrated. Here we present our first clinical experiences with intravenous ICG as an adjuvant to increase heat uptake in hypopigmented choroidal melanoma during transpupillary thermotherapy (TTT).
Material and Methods In a prospective nonrandomized analysis 12 eyes suffering from primary hypopigmented choroidal melanoma were treated with ICG augmented TTT. The eligibility criteria for treatment were based on reports on histolog-
301
ical and clinical results after transpupillary thermotherapy in the literature (9, 14). Included in this series were selected patients with primary choroidal melanoma located posterior to the equator of the eye measuring 12 mm or less in base and 4.5 mm or less in thickness. All patients had either documented growth or ophthalmoscopic risk factors (19) for growth and/or metastasis. Excluded were those patients with retinal, optic nerve, vitreous or extrascleral tumor extension, subretinal hemorrhage or media opacity prohibiting adequate visualization of the tumor. 8 hypopigmented melanoma previously showed insufficient regression after TTT without dye or ruthenium-106 plaque radiotherapy. 4 amelanotic melanoma had no previous treatment. Patient data included age, race, gender and visual acuity as well as results of evaluation for metastatic disease. The diagnosis of choroidal melanoma was based on results of the ophthalmoscopic examination, ultrasonography and fluorescein angiography. The basal dimensions of the tumor were determined by B-scan ultrasonography; tumor height was measured by A- and B-scan ultrasonography. Tumor data included tumor location (subfoveal, para- or extrafoveal, juxtapapillary), presence of subretinal fluid (present, absent), orange pigment (present, absent) and drusen (present, absent). Visual acuity and ultrasonographic tumor thickness were measured at each followup period. Fundus photography and fluorescein angiography were performed before treatment and on regression of the tumor into a flat chorioretinal scar. Additional fundus photographies were taken selectively for documentation of the regression course of selected tumors. Associated findings in the anterior and posterior eye segment were recorded.
Fig. 1. A 56-year old patient complained of blurred vision since 2 months. Visual acuity was dropped to 0.3. A: Fundus photograph showed an amelanotic choroidal melanoma located temporal to the fovea. Tumor thickness was 2.4 mm measured by ultrasonography. B: Early frame of fluorescein angiography showed hard exudation in the macula zone indicating for macular edema due to serous exudation of the melanoma, which is a highly significant sign for growth. Macular edema was the reason for blurred vision. Late frame of fluorescein angiography revealed the characteristic late staining in the melanoma parenchym. Fig. 2. Fundus photograph 2 months after ICG enhanced TTT. Tumor thickness had regressed to 1.1 mm. Chorioretinal scar developed at the tumor margins, but the tumor center was still exudative. Notice the hard exudates indicating for still persisting macular edema. Fig. 3. Fundus photograph 4 months after treatment revealed a completely flattened scar. Vision improved to 0.8 due to resorption of macular edema and parafoveal hard exudates, which is a most significant sign of tumor regression. Light hemorrhage at the tumor surface was caused by occlusion of retinal vessels in the treatment zone. Fig. 4. Fundus photograph 12 months after treatment revealed further loss of pigment clumbs in the treatment area allowing for visibility of underlying sclera and large choroidal vessels remaining perfused. Vision remained unchanged and no sign of tumor regrowth was noted.
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TTT was performed using a specially modified infrared diode laser at 810 nm with an adjustable beam width of 2.0 or 3.0 mm (Iris Medical Instruments, Mountain View, CA). The infrared diode laser system was adapted to a Haag-Streit slit-lamp biomicroscope (Koniz, Switzerland). The laser light was delivered through two infrared coated panfunduscope contact lenses (Mainster wide field and Mainster ultra wide field OMRA-PRP, Ocular Instruments, Bellevue, WA). The width of the laser beam used in the majority of patients was 3.0 mm; a diameter of 2.0 mm was used under special circumstances to avoid the optic disc or retinal vessels. Treatment was initiated at the center of the tumor with one spot/1 minute, using a low power setting of 300 mW. Continuous observation through the slit-lamp biomicroscope directed towards the tumor surface was ensured during the entire treatment period. The energy of the laser beam was increased in 50 mW-steps over 1 minute to achieve a treatment endpoint of gray-white appearance on completion of the treatment spot. The energy of the laser beam was lowered if the color change appeared early in the exposure period or in the presence of coagulation of retinal vessels. In our series power settings ranged from 500 to 1000 mW, and exposure times from 6 to 26 minutes. Spots were delivered in overlapping confluency, including 0.5–1.0 mm of clinically healthy tissue from the tumor margin. The number of laser spots ranged from 3 to 8, depending on the diameter of the tumor base. 2 minutes after start of TTT 100 mg indocyanine green in 10 cc aqueous solvent were injected intravenously over 20 seconds. After injection of the dye TTT was continued. The pupil was dilated with 5% phenylephrine hydrochloride and 0.25% tropicamid eyedrops prior to treatment. Retrobulbar anesthesia was achieved with an injection of 2 ml xylocaine 2% and 2 ml carbostesine for immobilization and pain prevention. Postoperatively, 0.1% dexamethasone eyedrops were administered three times a day for five days. Follow-up examinations were performed at 4-week intervals until the tumor had regressed to a flat chorioretinal scar. When complete tumor regression was assumed, the follow-up interval was extended to 3 months. In cases of partial regression, additional treatment was performed after a period of 3 months. The minimum follow-up was 9 months.
Results The mean patient age at treatment was 60.5 years (range, 46 to 75 years). All patients were white; there were 8 women and 4 men. Evaluation for metastatic disease in all patients revealed no sign of metastasis at the time of treatment as well as during follow-up. The mean tumor thickness before treatment was 2.0 mm (range, 1.0 to 3.1 mm), the mean maximum basal diameter measured was 8.2 mm (range, 6.0 to 10.1 mm). Tumor location was below the fovea in 3 eyes, and one tumor touched the optic disc. The posterior margin of eight tumors touched the posterior pole, but did not involve the foveal area. Exudative retinal detachment was observed preoperatively in 4 eyes, In four eyes with amelanotic melanoma ICG-augmented TTT was used as first treatment modality. In five eyes insufficient regression during 9–13 months after ruthenium-106 brachytherapy was noted. Three eyes with hypopigmented melanoma recieved 2 sessions of TTT without ICG-enhancement and showed no significant tumor regression. In all cases further treatment was recommended because of presentation of known risk factors (19) for tumor regrowth and metastasis. Postoperatively 6 eyes revealed tumor regression to a completely flattened scar within 2–4 months after one treatment session. 3 eyes flattened after two sessions within 6–8 months. Mean treatment parameters at the first session included power at 500 mW (range, 450 to 600 mW) for 17 minutes (range, 6 to 26 minutes), and power at 600 mW in all cases for 21 minutes (range, 18 to 22 minutes) at the second session. The endpoint of treatment in all hypopigmented melanoma was a faint gray color for both sessions. Three eyes were judged as failures (two required ruthenium-106 radiotherapy because of insufficient regression after two sessions TTT and one eye was enucleated because of significant regrowth after previous radiotherapy and TTT). Visual acuity was unchanged or improved in 5 eyes. The reason for improvement of vision was the postoperative resolution of subretinal fluid. Visual acuity was decreased in 7 eyes, which is primarily due to the tumor location, requiring three eyes to be treated through the foveola for subfoveal tumors. In four eyes the development of severe maculopathy due to epiretinal gliosis in three and macular edema in one case were noted and accounted for a poorer visual outcome.
Indocyanine Green (ICG) Enhanced Transpupillary Thermotherapy
Epiretinal gliosis, macular edema as well as temporary retrobulbar pain in two cases were the only ocular side effects documented during follow-up. No signs of direct heat-related alterations were recorded in cornea, lens and vitreous. Fluorescein angiography postoperatively was performed in that nine eyes with complete tumor flattening during 3–8 months. In all cases the angiographic frames revealed a sharp demarcation of the treated area by a zone of pigment epithelium atrophy. A comparison with the surrounding normal tissue allowed to distinguish the heat treated area as nonfluorescent in seven, and as hypofluorescent in two cases. Choriocapillary vessels in 4 eyes remained perfused residually in several areas of the thermotherapy field. Only that four eyes, which recieved ruthenium-plaque therapy first, developed complete atrophy of the choriocapillary layer in the treatment zone.
Discussion Transpupillary thermotherapy is a recently developed technique for treating minimally raised choroidal melanoma (up to 4.5 mm). A diode laser of wavelength 810 nm is used, which is minimally absorbed by ocular media and produces tissue necrosis within the tumor by causing a rise in temperature to levels of approximately 65 °C. Several studies presented in the literature (6, 20, 22) showed a satisfactory local tumor control and minmal ocular side effects. The infrared wavelength (1, 7) is absorbed in melanin in the retinal pigment epithelium and choroid. Absence of pigmentation in amelanotic melanomas allows for increased penetration of infrared light into tissue and for a decreased volume uptake of light converted into heat. The mean energy required for the treatment of amelanotic melanomas was 15% higher than for pigmented tumors; the reduction of tumor height 3 months after TTT was 33% more in pigmented than in amelanotic tumors (15). Some amelanotic tumors showed quite no response even after repeated TTT (22). Indocyanine green (4) is a water-soluble tricarbocyanine dye that is mostly protein bound, with globulins (95%) being the principal carrier. The dye absorbs light maximally at 790 nm and fluorescence at 835 nm. The dye is taken up exclusively by hepatic parenchymal cells and is se-
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creted entirely into the bile. It has been approved by the Food and Drug Administration (FDA) for such indications as ophthalmic angiography and measurement of cardiac output and hepatic function. Indocyanine green enhances absorption of the infrared laser beam, a mechanism unrelated to photodynamic therapy. Indocyanine green-enhanced laser treatment has been used experimentally in other surgical specialties for tissue welding (3) and for superficial vein ablation (10, 12). In ophthalmology, ICG-enhanced laser treatment has been used to close subretinal neovascularization (1, 16) in animals and in humans. Based on a prior report (2) that demonstrated effectiveness of ICG to enhance the photocoagulative effects of the infrared diode laser for treatment of experimental ocular melanoma in Greene hamster eyes, we used ICG for enhancement of TTT. In every eye we started TTT for two minutes and then injected the indocyanine green dye. Our speculation was, that the initial heat would disturb the cellular integrity in the tumot tissue allowing for increased leakage and staining of the tumor with dye, thus providing improved uptake of infrared light converted into heat. Our results are preliminary because further investigations have to proof the influence of tumor vascularity on the treatment outcome and the mechanism of dye enhanced TTT. Possibly the ICG-effect can be developed by intravenous infusion of ICG or repetitive ICG-enhanced laser sessions. We also realize that our report contends a small group of patients with a rare tumor and a relative short follow-up.. Our results demonstrate, that combination of intravenous ICG and TTT could be very effective in treatment of primary hypopigmented choroidal melanoma as well as residual tumor prominences with secondary loss of pigmentation after brachytherapy or TTT. Longer follow-up is necessary for data regarding ultimate local tumor control and metastatic disease. Indozyaningrün (ICG) verstärkte transpupillare Thermotherapie (TTT) pigmentarmer Aderhautmelanome Hintergrund: Die transpupillare Thermotherapie unter Verwendung eines infraroten Diodenlasers bei 810 nm ist eine neue Behandlungsoption für kleine Aderhautmelanome, die wenig effektiv ist bei schwacher Tumorpigmentierung. Wir untersuchten die Wirksamkeit von intravenöser Gabe von Indozyaningrün (ICG)
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zur Absorptionssteigerung des Laserlichtes und dessen Auswirkung auf die Tumorregression. Material und Methoden: In einer prospektiven, nicht randomisierten Untersuchung wurden 12 Augen mit primären Aderhautmelanomen (pigmentarm, zentral des Äquators, Prominenz ≤ 4,5 mm) behandelt mit ICG verstärkter TTT (Diodenlaser bei 810 nm, Spotdurchmesser 2–3 mm, Leistung 0,5–1,0 Watt, Exposition 6–26 Minuten). Die Laserleistung wurde beginnend im Tumorzentrum bei 0,3 W in 50-Milliwattschritten für jeweils eine Minute langsam erhöht, bis eine Grauweißfärbung der Tumoroberfläche das Behandlungsende dieses Spots anzeigte. Die Spots wurden in konfluierender Überlappung gesetzt unter Einschluss eines 0,5 mm breiten Randsaumes im klinisch gesunden Gewebe. 2 Minuten nach Behandlungsbeginn wurden 100 mg ICG in 10cc wässriger Lösung intravenös über 20 Sekunden injiziert. 8 Tumoren hatten zuvor eine ungenügende Rückbildung nach TTT ohne Adjuvans oder Rutheniumbrachytherapie gezeigt. 4 amelanotische Tumoren wurden primär mit ICG verstärkter TTT behandelt. Die Nachbeobachtungszeit betrug minimal 9 Monate. Ergebnisse: 6 Augen zeigten eine komplette Rückbildung zu einer flachen Narbe im Verlauf von 2–4 Monaten nach einmaliger TTT. 3 Augen entwickelten eine flache Narbe nach 2 Behandlungen innerhalb von 6–8 Monaten. 3 Augen wurden als Therapieversager beurteilt (2 erhielten eine Rutheniumbrachytherapie wegen ungenügender Regression nach 2 Sitzungen TTT und ein Auge wurde enukleiert wegen rezidivierendem Tumorwachstum nach Brachytherapie und TTT). Die postoperative Sehschärfe war unverändert oder besser in 7 Augen. Oculäre Nebenwirkungen waren epiretinale Gliose (2), Maculaödem (1) und vorübergehender Retrobulbärschmerz (3). Metastasen traten während des Kontrollintervalls nicht auf. Diskussion: Indozyaningrün ist ein wirksames Adjuvans, um die in Hitze konvertierte Lichtaufnahme und damit die Effektivität der transpupillaren Thermotherapie zu verstärken für pigmentarme Aderhautmelanome oder tumoröse Restprominenzen mit sekundärem Pigmentverlust nach Brachytherapie oder TTT. Längere Nachkontrollen sind nötig zur Evaluierung der letztendlichen Tumorkontrolle und Metastasierungsrate.
Schlüsselwörter Aderhautmelanom, Transpupillare Thermotherapie, Indozyaningrün
References 1. BALLES MW, PULIAFITO CA, KLIMAN GH, et al.: Indocyanine green dye enhanced diode laser photocoagulation of subretinal neovasular membranes. Invest Ophthalmol Vis Sci 31 (suppl): 282, abstract (1990) 2. CHONG LP, ÖZLER SA, DE QUEIROZ JM, LIGGETT PE: Indocyanine green-enhanced diode laser treatment of melanoma in a rabbit model. Retina 13: 251–259 (1993) 3. CHUCK RS, OZ MC, DELOHERY TM, et al.: Dye-enhanced laser tissue welding. Laser Surg Med 9, 471–477 (1989) 4. DESMETTRE T, DEVOISELLE JM, MORDON S: Fluorescence properties and metabolic features of indocyanine green (ICG) as related to angiography. Survey of Ophthalmology 45 (1): (2000)
5. FINGER PT: Radiation therapy for choroidal melanoma. Surv of Ophthalmol 42 (3): 215–232 (1997) 6. GODFREY DG, WALDRON RG, CAPONE A jr: Transpupillary thermotherapy for small choroidal melanoma. Am J Ophthalmol 128 (1): 88–93 (1999) 7. JOURNÉE-DE KORVER JG, OOSTERHUIS JA, KAKEBEEKEKEMME HM, DE WOLFF-ROUENDAAL D: Transpupillary thermotherapy (TTT) by infrared irradiation of choroidal melanoma. Doc Ophthalmol 82: 185–191 (1992) 8. JOURNÉE-DE KORVER JG, OSTERHUIS JA, VRENSEN GFJM: Light and electron microscopic findings on experimental melanomas after hyperthermia at 50 °C. Melanoma Res 5: 393–402 (1995) 9. JOURNÉE-DE KORVER JG, OOSTERHUIS JA, DE WOLFF-ROUENDAAL D, KEMME H: Histopathological findings in human choroidal melanomas after transpupillary thermotherapy. Br J Ophthalmol 81: 234–239 (1997) 10. LIBUTTI SK, OZ MC, CHUCK RS, et al.: A preliminary study of dye-enhanced laser photosclerosis. Surgery 109: 163–168 (1991) 11. LOMMATZSCH PK, KIRSCH JH: Ru 106/Rh 106 plaque-radiotherapy for malignant melanomas of the choroid. Doc Ophthalmol 68: 225–238 (1988) 12. MOAZAMI N, OZ MC, BASS LS, TREAT MR: Reinforcement of colonic anastomoses with a laser and dye enhanced fibrinogen. Arch Surg 125: 1452–1454 (1990) 13. MEYER-SCHWICKERATH G, BORNFELD N: Photocoagulation of choroidal melanomas – thirty years´ experience. In: LOMMATZSCH PK, BLODI FC (eds): Intraocular tumours. Springer, New York 1983, 269–276 14. OOSTERHUIS JA, JOURNÉE-DE KORVER HG, KAKEBEEKEKEMME HM, BLEEKER JC: Transpupillary thermotherapy in choroidal melanomas. Arch Ophthamol 113: 315–321 (1995) 15. OOSTERHUIS JA, JOURNEE-DE KORVER HG, KEUNEN JEE: Transpupillary thermotherapy. Results in 50 patients with choroidal melanoma. Arch Ophthalmol 116: 157–162 (1998) 16. PULIAFITO CA, GUYER DR, MONES JM, WEAVER Y: Indocyanine green digital angiography and dye-enhanced diode laser photocoagulation of choroidal neovascularization. Invest Ophthalmol Vis Sci 32(suppl): 712, abstract (1991) 17. ROBERTSON DM, BUETTNER H, BENNETT SR: Transpupillary thermotherapy as primary treatment for small choroidal melanomas. Arch Ophthalmol 117: 1512–1519 (1999) 18. SCHNEIDER H, FISCHER K, FIETKAU R, GUTHOFF RF: Transpupillare Thermotherapie des malignen Aderhautmelanoms. Klin Monatsbl Augenheilkd 214 (2): 90–95 (1999) 19. SHIELDS CL, SHIELDS JA, KIRATLI H, et al.: Risk factors for growth and metastasis of small choroidal melanocytic lesions. Ophthalmology 102: 1351–1361 (1995) 20. SHIELDS CL, SHIELDS JA, CATER J, LOIS N, EDELSTEIN C, GÜNDÜZ K, MERCADO G: Transpupillary thermotherapy for choroidal melanoma. Ophthalmology 105 (4): 581–590 (1998) 21. STOFFELNS BM: Der infrarote Diodenlaser (810 nm) zur transpupillaren Thermotherapie des malignen Aderhautmelanoms. Lasermedizin 14: 99–105 (1999)
Indocyanine Green (ICG) Enhanced Transpupillary Thermotherapy 22. STOFFELNS BM, AUGUSTIN AJ, PFEIFFER N: Transpupillare Thermotherapie zur nichtadiuvanten Primärbehandlung des malignen Aderhautmelanoms. Der Ophthalmologe 96 (Suppl. 1): 152, abstract (1999)
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Correspondence address: Bernhard M. Stoffelns, M.D., Department of Ophthalmology, Johannes Gutenberg University Mainz, Langenbeckstrasse 1, D - 55131 Mainz, Germany Tel.: ++49-6131-177133; Fax: ++49-6131-176620; e-mail: [email protected]
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