- Email: [email protected]
Stereotactic radiotherapy in the treatment of juxtapapillary choroidal melanoma: 2-year follow-up
Stereotactic radiotherapy in the treatment of juxtapapillary choroidal melanoma: 2-year follow-up Sohel Somani,* MD; Arjun Sahgal,† MD; Hatem Krema,* MD; Mostafa Heydarian,‡ PhD; Hugh McGowan,* MD; David Payne,† MD; Wei Xu,§ PhD; Howard Michaels,‡ PhD; Norman Laperriere,† MD; E. Rand Simpson,* MD !"342!#4 s 2»35-» Objective: To evaluate the efficacy and complications of stereotactic radiotherapy in the management of patients with juxtapapillary choroidal melanoma. Design: Retrospective review. Participants: 64 patients with juxtapapillary choroidal melanoma. -ETHODS Consecutive patients with juxtapapillary choroidal melanomas located within 2 mm of the optic nerve, treated with stereotactic radiotherapy at Princess Margaret Hospital from October 1998 to January 2006, were reviewed for treatment effect and complication rates. Results: Median age was 63 years. Median tumor height was 4.2 mm, and median maximum tumor diameter was 9.8 mm. The prescribed radiation dose was 70 Gy in 5 fractions over 10 days, and the median follow-up was 26 months. After treatment, there was local tumor recurrence in 3 patients, and in 8 patients there was systemic progression. Actuarial rates of local tumor control, metastases, and survival at 26 months were 94%, 12%, and 94%, respectively. Rates of radiation-induced neovascular glaucoma, cataract, retinopathy, and optic neuropathy at 26 months were 28%, 45%, 80%, and 52%, respectively. Enucleation was necessary for 7 patients. #ONCLUSIONS Stereotactic radiotherapy offers a noninvasive alternative with acceptable ocular toxicity rates to enucleation and brachytherapy in the management of juxtapapillary choroidal melanoma. Objet : Évaluation de l’efficacité et des complications de la radiothérapie stéréotactique pour le traitement des patients ayant un mélanome choroïdien juxtapapillaire. Nature : Étude rétrospective Participants : 64 patients ayant un mélanome choroïdien juxtapapillaire. -£THODES : Étude des résultats des traitements et des taux de complication chez des patients consécutifs ayant un mélanome choroïdien juxtapapillaire situé à moins de 2 mm du nerf optique et soignés par radiothérapie stéréotactique à l’hôpital Princess Margret, entre les mois d’octobre 1998 et janvier 2006. 2£SULTATS : La moyenne d’âge était de 63 ans. La hauteur moyenne de la tumeur était de 4,2 mm et le diamètre moyen maximal était de 9,8 mm. La dose de radiation prescrite était de 70 Gy en 5 fractions sur 10 jours, la moyenne du suivi fut de 26 mois. Après le traitement, il y eut récurrence de tumeur locale chez 3 patients et progression systémique chez 8 patients. Les taux actuariels de contrôle de la tumeur locale, des métastases et de survivance après 26 mois furent de 94 %, 12 % et 94 % respectivement. Les taux de glaucome néovasculaire, cataracte, rétinopathie et neuropathie optique induites par radiation étaient à 26 mois de 28 %, 45 %, 80 % et 51 % respectivement. L’énucléation fut nécessaire pour 7 patients. #ONCLUSIONS : La radiothérapie stéréotactique offre une alternative non invasive avec des taux acceptables de toxicité oculaire pour l’énucléation et la brachythérapie dans le traitement du mélanome choroïdien juxtapapillaire.
U
veal melanoma, albeit rare, is the most common intraocular primary malignancy affecting the adult eye.1 According to recent large clinical trials, both enucleation and plaque brachytherapy have been found to be equally beneficial for overall survival. However, choroidal melanomas located adjacent to the optic nerve are typically excluded from such clinical trials. In the absence of a clearly accepted management strategy for juxtapapillary choroidal melanoma, various treatments have been described, including enucleation, notched plaque radiotherapy, charged
particle radiotherapy, and external beam stereotactic radiotherapy or radiosurgery.1–8 The challenge in dealing with juxtapapillary tumors lies in minimizing damage to the visually sensitive and radiation-sensitive adjacent optic nerve. Minimal long-term data exist in evaluating both the efficacy and the complications arising from stereotactic radiotherapy. Therefore, we report our updated experience, with 2-year follow-up data, in treating juxtapapillary choroidal melanoma tumor with fractionated stereotactic radiotherapy.
From *the Department of Ocular Oncology, †Radiation Oncology, ‡ Radiation Medicine, and §Biostatistics, Princess Margaret Hospital, University of Toronto, Toronto, Ont.
Correspondence to Sohel Somani, MD, Ocular Oncology Service 18-740, Princess Margaret Hospital, 610 University Ave., Toronto ON M5G 2M9; [email protected]
Presented in part at the Canadian Ophthalmological Society Annual Meeting in Toronto, Ont., June 21–24, 2006
This article has been peer-reviewed. Cet article a été évalué par les pairs.
Originally received Apr. 26, 2008. Revised July 19, 2008 Accepted for publication July 27, 2008 Published online Jan. 23, 2009
Can J Ophthalmol 2009;44:61–5 doi:10.3129/i08-177
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Juxtapapillary choroidal melanoma—Somani et al. METHODS Design
We conducted a retrospective chart review of all consecutive patients with juxtapapillary choroidal melanoma presenting from October 1998 to January 2006. Approval was obtained from the Princess Margaret Hospital Ethics Review Board for the chart review. All patients were treated with stereotactic radiotherapy by the Ocular Oncology Service, Princess Margaret Hospital, Toronto. Baseline patient data recorded included demographic information, past medical and ocular history, and findings from ophthalmological examination, colour fundus photography, and ultrasonography. A full systemic evaluation was also carried out at the initial baseline visit, demonstrating no evidence of metastases. Follow-up examinations included ophthalmological examination, colour fundus photography, ultrasonography, and screening metastatic surveillance with chest radiography and liver enzyme analysis. Visual acuity, tumor response, and complications were documented. The primary outcome measure was local tumor recurrence. This was defined as tumor growth of at least 30% over baseline measures of height and (or) maximal basal diameter detected clinically or by ultrasonography. Secondary outcome measures were metastatic rate, survival rate, enucleation rate, visual outcomes, and complication rates of cataract, neovascular glaucoma, tumor vasculopathy, retinopathy, maculopathy, vitreous hemorrhage, retinal detachment, and optic neuropathy. Radiation-induced cataract was defined as the development of any lens opacity that was not pre-existing. Neovascular glaucoma was diagnosed if neovascularization of the iris or angle occurred in conjunction with elevated intraocular pressure. Tumor vasculopathy was defined as retinal hemorrhage, exudates, or vascular occlusion occurring within a disc diameter of the tumor margin. Radiation retinopathy had similar findings but manifested 1 disc diameter outside the tumor margin. Radiation maculopathy was defined as similar vascular changes and included increased retinal thickness of any area within the anatomic macula. Radiation optic neuropathy was defined as optic disc pallor, optic disc swelling, and (or) peripapillary hemorrhages not pre-existing. Visual acuity was expressed in lines of vision: 0, enucleation; 1, no light perception; 2, light perception; 3, hand movements; and 4, counting fingers. Lines 5 to 16 correspond to Snellen visual acuity ranging from 20/400 to 20/20. Poor visual outcome was defined as a visual acuity of 20/200 or less, or a loss of 6 or more lines from pretreatment evaluation. Stereotactic radiotherapy
The prescribed dose was 70 Gy in 5 fractions treated every alternate day over 10 days. The stereotactic radiotherapy technique used has been previously well described,1 and a brief description follows.
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All patients were placed in the supine position and immobilized with a Radionics Gill-Thomas-Cosman stereotactic relocatable (or Tarbell-Loeffler Cosman relocatable head frame for pediatric patients) head frame (Integra Radionics, Burlington, Mass.) adapted with an in-house adjustable eye-fixation device. This device consists of an articulated arm to which a green light-emitting-diode (LED) and miniature camera are attached. Patients were then scanned by computerized axial tomography with their nonaffected eye staring at the green LED and a camera image taken to document eye position (reference image). The tumor with no applied margin was targeted. Treatment planning was accomplished using the Radionics XKnife-4, and more recently XKnife RT3, software (Integra Radionics). Multiple, converging non-coplanar arcs of radiation were employed to achieve the best dose distribution using circular collimators ranging from 10 to 27.5 mm. Radiotherapy was delivered by means of Radionics circular collimators and a Linac couch-mount assembly system on a Varian 2100C linear accelerator (Varian Inc, Palo Alto, Calif.) using 6 MV photons, and more recently on an Elekta “Synergy S” linear accelerator (Elekta Oncology Systems Ltd, Crawley, U.K.). During each fraction, eye position was continuously and meticulously monitored by the radiation therapist viewing the camera image on a television monitor at the radiation console. Eye position was compared with the eye position at the time of simulation, and treatment was interrupted if deviation of the eye position was observed. Alternatively, image-subtraction software developed at the Princess Margaret Hospital compared the eye position during treatment with the reference image, and treatment was interrupted automatically if deviation occurred. Typically, our 2 dedicated radiation therapists for stereotactic eye radiotherapy have preferred self-monitoring of eye position, and eye position has been steady with few incidences of treatment interruption. Statistical analysis
For continuous factors, summary statistics of the median and range were calculated; for categorical factors, the sample distributions were analyzed as counts within each category and corresponding proportions. A paired t test was applied to compare the difference in tumor height before and after radiotherapy. Patient overall survival was calculated on the basis of Kaplan–Meier estimates. Rates of complications were calculated using the cumulative incidence approach. Risk factors for metastasis were tested using the Cox proportional hazards model. To illustrate these associations, incidence curves were compiled. When the variables were continuous, they were dichotomized at the median. A Wilcox nonparametric test was applied to compare the initial and final visual acuity with other factors. Results were considered significant if the p value was less than or equal to 0.05. The statistical analyses were performed using the SAS system, v. 9.1 (SAS Institute, Cary, N.C.).
Juxtapapillary choroidal melanoma—Somani et al. RESULTS Demographic data
There were 64 patients included in this study. Median and mean age was 63 years. There were 36 male (56%) and 28 female (44%) patients. Of the eyes involved 33 were OS (52%) and 31 were OD (48%). Past medical history included hypertension (28%), cerebrovascular disease (6%), and diabetes (5%). Six percent of patients had pre-existing primary open-angle glaucoma, and 2 patients had a history of primary nonocular cancer. No patients were lost to follow-up. Tumor characteristics
All tumors were located in the juxtapapillary area (0–2 mm) with a median of 0 mm from the edge of the optic nerve (Table 1). The median distance of the posterior edge of the juxtapapillary tumor and the foveal avascular zone was 0.75 (range 0–4.5) mm. Median tumor height was 4.2 (range 1.5–11) mm. Median maximum tumor diameter was 9.8 (range 4.7–17) mm. In 12 patients (19%) there was a collar-button appearance on the ultrasound scan (Table 2). Thirty-one patients (48%) had a localized retinal detachment, and 2 patients presented with a more extensive (greater than half of the retina) retinal detachment. One patient had extrascleral extension on ultrasonography. Radiation data
Patients were treated with 70 Gy in 5 fractions over 10 days, with the exception of 1 patient whose treatment was delivered over 22 days because of a treatment delay secondary to comorbid medical complications; these were independent of the radiotherapy. The median prescription isodose was 95% (range 90%–100%). The median maximum and minimum dose to the tumor was 74.6 (range 47.2–78.6) Gy and 70.2 (range 40.7–74.7) Gy, respectively. The median maximum dose to the optic nerve was 72.9 (range 60.1–77.2) Gy. The median mean dose to the lens Table 1—Tumor characteristics Measurement T.ON T.Faz Tumor height Maximum basal tumor diameter
Mean (mm)
Median (mm)
Range (mm)
0.30 1.29 4.61 10.16
0.00 0.75 4.23 9.85
0.00–2.00 0.00–4.50 1.50–11.00 4.70–17.00
was 6.7 (1.0–67.5) Gy, and the median minimum dose to the lens was 2.1 (range 0.7–52.8) Gy. The median volume (in percent) of the eye exposed to 70 Gy (V70) was 14% (range 1%–54%). Tumor control
Median follow-up was 26 (range 6–72) months. Three patients had local (within the radiation field) tumor recurrence at 6, 7, and 23 months. Actuarial local tumor control was 94% at 26 months (Fig. 1). After radiotherapy, the mean tumor height decreased by 1.32 mm (p < 0.0001). Metastases developed in 8 patients (6 liver, 1 lung, 1 skull base), and the median time to metastasis was 17.5 (range 5–40) months. At 26 months, the actuarial metastatic rate was 12%. Initial tumor height (Fig. 2A) and maximum tumor diameter (Fig. 2B) were both associated with increased risk of metastasis (p value 0.04 and 0.002, respectively). Six patients died from liver metastasis and 1 patient from lung metastasis. Actuarial patient survival at 26 months after radiotherapy was 94% (Fig. 3). Complications
At 26 months after radiotheraphy, 45% of patients had a cataract. Cataract developed as early as 9 months and as late as 48 months, with a median of 18 months. A higher rate of cataract formation was associated with a greater lens minimum dose (p = 0.02), and a trend to a higher rate of cataract formation was associated with a greater lens mean dose (p = 0.07). The incidence of tumor vasculopathy was 83% at 26 months. The incidence of radiation retinopathy was 80% at 26 months. Radiation retinopathy developed as early as 2 months and as late as 31 months, with a median of 15 months. The incidence of radiation maculopathy was 49% at 26 months. A higher rate of radiation retinopathy was associated with a greater V70 (p = 0.01), and a trend to a higher rate of tumor vasculopathy was associated with a greater V70 (p = 0.07). The incidence of optic neuropathy was 52% at 26 months. The median onset of radiation optic neuropathy was 19 months. The incidence of neovascular glaucoma was 28% at 26 months. Neovascular glaucoma developed as early as 9 months and as late as 36 months, with a median of 20 months. A higher rate of neovascular glaucoma was associated with greater lens minimum dose
Note: T.ON, minimum distance between tumor margin and optic nerve; T.Faz, minimum distance between tumor margin and foveal avascular zone.
Table 2—Distribution of tumor characterisics Characteristic T.ON = 0 mm T.ON > 0 and ≤ 2 mm (1 disc diameter) Extrascleral extension of tumor Collar-button configuration Retinal detachment None Localized Subtotal (nonlocalized macula-off)
Patients, n (%) 48 (75) 16 (25) 1 (1.6) 12 (18.8) 31 (48.4) 31 (48.4) 2 (3.1)
Note: T.ON, minimum distance between tumor margin and optic nerve; Collar-button configuration, indicates a break through Bruch’s membrane.
Fig. 1—Kaplan–Meier curve of probability of tumor control (percentage) versus time (months), with actuarial local tumor control of 94% at 26 months. CAN J OPHTHALMOL—VOL. 44, NO. 1, 2009
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Juxtapapillary choroidal melanoma—Somani et al. (p = 0.001). Vitreous hemorrhage occurred in 17 patients, and 9 patients had worsening of their retinal detachment. Enucleation was necessary in 7 patients because of tumor recurrence (3/7) and painful neovascular glaucoma (4/7).
tance of the tumor to the foveal avascular zone was also significantly correlated with the decline in visual acuity (p = 0.004). There was no significant association between the V70 and decline in visual acuity.
Visual outcome
CONCLUSIONS
Initial median Snellen visual acuity was 20/100 (range 20/20 to hand motions). Fifteen patients had vision better than 20/40, 22 patients had vision between 20/40 and 20/200, and 27 patients had vision worse than 20/200. The median final vision was hand motions (range 20/25 to enucleation) with a median of 2 lines lost. There was a significant decrease in vision after radiotherapy (p < 0.0001). Initial vision was significantly correlated with distance of the tumor to the foveal avascular zone (p < 0.0001). Dis-
Fig. 2—(A) Kaplan–Meier curve demonstrating a higher probability of being metastasis free with tumor height less than 4.23 mm (solid line) than with tumor height greater than 4.23 mm (dashed line) (p = 0.04). (B) Kaplan-Meier curve demonstrating a higher probability of being metastasis free with tumor base diameter less than 9.85 mm (solid line) than with tumor base diameter greater than 9.85 mm (dashed line) (p = 0.002).
Fig. 3—Kaplan–Meier curve of patient survival (percentage) over time. Actuarial patient survival at 26 months was 94%.
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The Collaborative Ocular Melanoma Study (report number 28)9 and other studies6 have demonstrated no difference in survival in using irradiation versus enucleation in the management of medium-sized uveal melanoma; however, juxtapapillary melanomas were excluded in those analyses. Therefore, there is no clear consensus in the management of this type of choroidal melanoma. This retrospective study details the outcome of stereotactic radiotherapy as a management for juxtapapillary uveal melanoma, with a posterior margin located within 2 mm of the optic disc, for a median follow-up period of 26 months. Conventional plaque radiotherapy can be technically difficult in both insertion and placement when treating juxtapapillary tumors because of the proximity of the optic nerve. Williams et al.10 have reported cases in which the posterior edge of the juxtapapillary plaque was tilted away from the optic nerve, as demonstrated by magnetic resonance imaging, in cadaver eyes. Harbour et al.11 have reported that by using intraoperative echographic localization of plaque placement, there was 21% incomplete coverage of at least 1 margin of the posterior uveal melanomas treated by episcleral plaque when standard localization techniques were used. Notched plaques to accommodate the optic nerve may give a better localization advantage, but they still carry some theoretical risk of damage to both the optic nerve and its associated vasculature during insertion. Finger12 has recently reported the use of a “slotted eye plaque” as a solution to provide better coverage of juxtapapillary and circumpapillary melanomas. Stereotactic radiotherapy as an effective management of uveal melanoma has been reported in previous studies.1–3 This kind of irradiation allows steep dose gradients outside the target volume, thus minimizing the dose of radiation to surrounding structures. It also has the advantage over proton beam and helium ion radiotherapy in that it spares the patient 2 surgical procedures for insertion and removal of the tantalum rings, used for localization of the tumor margin. Stereotactic radiotherapy employs a higher dose per fraction method than plaque brachytherapy, which uses a lowdose radiation method allowing for relatively greater repair of neural tissue. However, this study has shown that the incidence of posterior segment complications such as radiation retinopathy was 80% and radiation papillopathy was 52%, which are similar to the results reported by De Potter et al.4 in their study using iodine-125 plaque brachytherapy in the management of juxtapapillary choroidal melanoma. Anterior segment complications, such as neovascular glaucoma and cataract, are frequently reported with all
Juxtapapillary choroidal melanoma—Somani et al. forms of radiotherapy. Our study demonstrated an incidence of neovascular glaucoma of 28%, peaking between 1 and 2.5 years after irradiation, which is comparable to the 31% incidence reported after helium ion radiotherapy at 5 to 10 year follow-up.13,14 However, Gragoudas et al.15 reported a lower incidence of neovascular glaucoma (15%) in their series of melanomas treated by proton beam irradiation. Perhaps the nature of proton beam radiotherapy with the Bragg peak effect, resulting in a sharp dose deposition at depth, reduces the risk of anterior segment complication. Similarly, the present study demonstrated the rate of radiation-induced cataract to be 45%, which approximates the incidence of 41% reported in the study of helium ion radiotherapy13 but is more than the rate of 33% with proton beam radiotherapy.15 A lower incidence of anterior segment complications has been reported with plaque brachytherapy than external beam radiotherapy. In 1 series of I-125 plaque brachytherapy and transpupillary thermotherapy for medium-sized melanoma, Shields et al.16 reported an incidence of neovascular glaucoma and radiation-induced cataract of 7% and 6%, respectively. In another series using Ru-106 plaque brachytherapy, Summanen et al.17 reported their incidence of neovascular glaucoma and radiation-induced cataract to be 12% and 26%, respectively. However, a study of larger melanomas (greater than 8 mm thickness) reported a higher incidence of neovascular glaucoma (21%) and cataract (66%) using I-125 plaque brachytherapy.18 The tumor control rate and the survival rate in this study were 94% at 26 months. Studies of other modalities with longer follow-up have found the tumor control rate and survival rate, at a median follow-up of 5 years, to be around 85% with brachytherapy treatment4,5,19 and 83% with helium ion irradiation13 of juxtapapillar melanoma. We conclude that stereotactic radiotherapy offers a noninvasive, relatively economic management option in the treatment of juxtapapillary uveal melanoma. It provides a high local tumor control rate, similar to the rate reported with other irradiation modalities at a similar median follow-up period. Furthermore, it carries a similar incidence of anterior segment complications in comparison to other external beam radiotherapy options, and a higher incidence in comparison to brachytherapy. We would like to acknowledge Sharon McKinon and Shenaz Ladak as our dedicated radiation therapists on the stereotactic eye radiotherapy team. We would also like to thank Allan Connor for figure preparation. The authors have no proprietary or commercial interest in any materials discussed in this article.
REFERENCES 1. Emara K, Weisbrod DJ, Shagal A, et al. Stereotactic radiotherapy in the treatment of juxtapapillary choroidal melanoma: preliminary results. Int J Radiat Oncol Biol Phys 2004;59:94–100. 2. Bellman C, Fuss M, Holz FG, et al. Stereotactic radiation therapy for malignant choroidal tumors. Ophthalmology 2000;107:358–65.
3. Dieckmann K, George D, Bogner J, et al. Optimizing Linacbased stereotactic radiotherapy of uveal melanomas: 7 years’ clinical experience. Int J Radiat Oncol Biol Phys 2006;66:S47–52. 4. De Potter P, Shields CL, Shields JA, Cater JR, Brady LW. Plaque radiotherapy for juxtapapillary choroidal melanoma: visual acuity and survival outcome. Arch Ophthalmol 1996;114:1357–65. 5. Lommatstzsch PK, Alberti W, Lommatzsch R, Rohrwacher F. Radiation effects on the optic nerve observed after brachytherapy of choroidal melanomas with 106Ru/106Rh plaques. Graefes Arch Clin Exp Ophthalmol 1994;232:482–7. 6. De Potter P, Shields CL, Shields JA, Cater JR, Tardio DJ. Impact of enucleation versus plaque radiotherapy in the management of juxtapapillary choroidal melanoma on patient survival. Br J Ophthalmol 1994;78:109–14. 7. Lommatstzsch PK, Lommatzsch R. Treatment of juxtapapillary melanomas. Br J Ophthalmol 1991;75:715–7. 8. Seddon JM, Gragoudas ES, Egan KM et al. Uveal melanomas near the optic disc or fovea: visual results after proton beam irradiation. Ophthalmology 1987;94;354–62. 9. The Collaborative Ocular Melanoma Study Group. The COMS randomized trial of iodine 125 brachytherapy for choroidal melanoma. V. Twelve-year mortality rates and prognostic factors: COMS report No. 28. Arch Ophthalmol 2006;124:1684–93. 10. Williams D, Mieler W, Jaffe G, Robertson DM, Hendrix L. Magnetic resonance imaging of juxtapapillary plaques in cadaver eyes. Br J Ophthalmol 1990;74:43–6. 11. Harbour JW, Murray TG, Byrne SF, et al. Intraoperative echographic localization of iodine 125 episcleral radioactive plaques for posterior uveal melanoma. Retina 1996;16:129–34. 12. Finger PT. Finger’s “slotted” eye plaque for radiation therapy: treatment of juxtapapillary and circumpapillary intraocular tumors. Br J Ophthalmol 2007;91:891–4. 13. Char DH, Castro JR, Kroll SM, Irvine AR, Quivey JM, Stone RD. Five-year follow-up of helium ion therapy for uveal melanoma. Arch Ophthalmol 1990;108:209–14. 14. Char DH, Kroll SM, Castro J. Ten-year follow-up of helium ion therapy for uveal melanoma. Am J Ophthalmol 1998;125:81–9. 15. Gragoudas ES, Seddon JM, Egan K, et al. Long-term results of proton beam irradiated uveal melanomas. Ophthalmology 1987;94:349–53. 16. Shields CL, Cater J, Shields JA, et al. Combined plaque radiotherapy and transpupillary thermotherapy for choroidal melanoma: tumor control and treatment complications in 270 consecutive patients. Arch Ophthalmol 2002;120:933–40. 17. Summanen P, Immonen I, Kivela T, Tommila P, Heikkonen J, Tarkkanen A. Radiation related complications after ruthenium plaque radiotherapy of uveal melanoma. Br J Ophthalmol 1996;80:732–9. 18. Shields CL, Naseripour M, Cater J, et al. Plaque radiotherapy for large posterior uveal melanomas (≥8-mm thick) in 354 consecutive patients. Ophthalmology 2002;109:1838–49. 19. Karlsson UL, Augsburger JJ, Shields JA, Markoe AM, Brady LW, Woodleigh R. Recurrence of posterior uveal melanoma after 60Co episcleral plaque therapy. Ophthalmology 1998;96;382–8.
Keywords: choroidal melanoma, stereotactic radiation, complications CAN J OPHTHALMOL—VOL. 44, NO. 1, 2009
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U
veal melanoma, albeit rare, is the most common intraocular primary malignancy affecting the adult eye.1 According to recent large clinical trials, both enucleation and plaque brachytherapy have been found to be equally beneficial for overall survival. However, choroidal melanomas located adjacent to the optic nerve are typically excluded from such clinical trials. In the absence of a clearly accepted management strategy for juxtapapillary choroidal melanoma, various treatments have been described, including enucleation, notched plaque radiotherapy, charged
particle radiotherapy, and external beam stereotactic radiotherapy or radiosurgery.1–8 The challenge in dealing with juxtapapillary tumors lies in minimizing damage to the visually sensitive and radiation-sensitive adjacent optic nerve. Minimal long-term data exist in evaluating both the efficacy and the complications arising from stereotactic radiotherapy. Therefore, we report our updated experience, with 2-year follow-up data, in treating juxtapapillary choroidal melanoma tumor with fractionated stereotactic radiotherapy.
From *the Department of Ocular Oncology, †Radiation Oncology, ‡ Radiation Medicine, and §Biostatistics, Princess Margaret Hospital, University of Toronto, Toronto, Ont.
Correspondence to Sohel Somani, MD, Ocular Oncology Service 18-740, Princess Margaret Hospital, 610 University Ave., Toronto ON M5G 2M9; [email protected]
Presented in part at the Canadian Ophthalmological Society Annual Meeting in Toronto, Ont., June 21–24, 2006
This article has been peer-reviewed. Cet article a été évalué par les pairs.
Originally received Apr. 26, 2008. Revised July 19, 2008 Accepted for publication July 27, 2008 Published online Jan. 23, 2009
Can J Ophthalmol 2009;44:61–5 doi:10.3129/i08-177
CAN J OPHTHALMOL—VOL. 44, NO. 1, 2009
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Juxtapapillary choroidal melanoma—Somani et al. METHODS Design
We conducted a retrospective chart review of all consecutive patients with juxtapapillary choroidal melanoma presenting from October 1998 to January 2006. Approval was obtained from the Princess Margaret Hospital Ethics Review Board for the chart review. All patients were treated with stereotactic radiotherapy by the Ocular Oncology Service, Princess Margaret Hospital, Toronto. Baseline patient data recorded included demographic information, past medical and ocular history, and findings from ophthalmological examination, colour fundus photography, and ultrasonography. A full systemic evaluation was also carried out at the initial baseline visit, demonstrating no evidence of metastases. Follow-up examinations included ophthalmological examination, colour fundus photography, ultrasonography, and screening metastatic surveillance with chest radiography and liver enzyme analysis. Visual acuity, tumor response, and complications were documented. The primary outcome measure was local tumor recurrence. This was defined as tumor growth of at least 30% over baseline measures of height and (or) maximal basal diameter detected clinically or by ultrasonography. Secondary outcome measures were metastatic rate, survival rate, enucleation rate, visual outcomes, and complication rates of cataract, neovascular glaucoma, tumor vasculopathy, retinopathy, maculopathy, vitreous hemorrhage, retinal detachment, and optic neuropathy. Radiation-induced cataract was defined as the development of any lens opacity that was not pre-existing. Neovascular glaucoma was diagnosed if neovascularization of the iris or angle occurred in conjunction with elevated intraocular pressure. Tumor vasculopathy was defined as retinal hemorrhage, exudates, or vascular occlusion occurring within a disc diameter of the tumor margin. Radiation retinopathy had similar findings but manifested 1 disc diameter outside the tumor margin. Radiation maculopathy was defined as similar vascular changes and included increased retinal thickness of any area within the anatomic macula. Radiation optic neuropathy was defined as optic disc pallor, optic disc swelling, and (or) peripapillary hemorrhages not pre-existing. Visual acuity was expressed in lines of vision: 0, enucleation; 1, no light perception; 2, light perception; 3, hand movements; and 4, counting fingers. Lines 5 to 16 correspond to Snellen visual acuity ranging from 20/400 to 20/20. Poor visual outcome was defined as a visual acuity of 20/200 or less, or a loss of 6 or more lines from pretreatment evaluation. Stereotactic radiotherapy
The prescribed dose was 70 Gy in 5 fractions treated every alternate day over 10 days. The stereotactic radiotherapy technique used has been previously well described,1 and a brief description follows.
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All patients were placed in the supine position and immobilized with a Radionics Gill-Thomas-Cosman stereotactic relocatable (or Tarbell-Loeffler Cosman relocatable head frame for pediatric patients) head frame (Integra Radionics, Burlington, Mass.) adapted with an in-house adjustable eye-fixation device. This device consists of an articulated arm to which a green light-emitting-diode (LED) and miniature camera are attached. Patients were then scanned by computerized axial tomography with their nonaffected eye staring at the green LED and a camera image taken to document eye position (reference image). The tumor with no applied margin was targeted. Treatment planning was accomplished using the Radionics XKnife-4, and more recently XKnife RT3, software (Integra Radionics). Multiple, converging non-coplanar arcs of radiation were employed to achieve the best dose distribution using circular collimators ranging from 10 to 27.5 mm. Radiotherapy was delivered by means of Radionics circular collimators and a Linac couch-mount assembly system on a Varian 2100C linear accelerator (Varian Inc, Palo Alto, Calif.) using 6 MV photons, and more recently on an Elekta “Synergy S” linear accelerator (Elekta Oncology Systems Ltd, Crawley, U.K.). During each fraction, eye position was continuously and meticulously monitored by the radiation therapist viewing the camera image on a television monitor at the radiation console. Eye position was compared with the eye position at the time of simulation, and treatment was interrupted if deviation of the eye position was observed. Alternatively, image-subtraction software developed at the Princess Margaret Hospital compared the eye position during treatment with the reference image, and treatment was interrupted automatically if deviation occurred. Typically, our 2 dedicated radiation therapists for stereotactic eye radiotherapy have preferred self-monitoring of eye position, and eye position has been steady with few incidences of treatment interruption. Statistical analysis
For continuous factors, summary statistics of the median and range were calculated; for categorical factors, the sample distributions were analyzed as counts within each category and corresponding proportions. A paired t test was applied to compare the difference in tumor height before and after radiotherapy. Patient overall survival was calculated on the basis of Kaplan–Meier estimates. Rates of complications were calculated using the cumulative incidence approach. Risk factors for metastasis were tested using the Cox proportional hazards model. To illustrate these associations, incidence curves were compiled. When the variables were continuous, they were dichotomized at the median. A Wilcox nonparametric test was applied to compare the initial and final visual acuity with other factors. Results were considered significant if the p value was less than or equal to 0.05. The statistical analyses were performed using the SAS system, v. 9.1 (SAS Institute, Cary, N.C.).
Juxtapapillary choroidal melanoma—Somani et al. RESULTS Demographic data
There were 64 patients included in this study. Median and mean age was 63 years. There were 36 male (56%) and 28 female (44%) patients. Of the eyes involved 33 were OS (52%) and 31 were OD (48%). Past medical history included hypertension (28%), cerebrovascular disease (6%), and diabetes (5%). Six percent of patients had pre-existing primary open-angle glaucoma, and 2 patients had a history of primary nonocular cancer. No patients were lost to follow-up. Tumor characteristics
All tumors were located in the juxtapapillary area (0–2 mm) with a median of 0 mm from the edge of the optic nerve (Table 1). The median distance of the posterior edge of the juxtapapillary tumor and the foveal avascular zone was 0.75 (range 0–4.5) mm. Median tumor height was 4.2 (range 1.5–11) mm. Median maximum tumor diameter was 9.8 (range 4.7–17) mm. In 12 patients (19%) there was a collar-button appearance on the ultrasound scan (Table 2). Thirty-one patients (48%) had a localized retinal detachment, and 2 patients presented with a more extensive (greater than half of the retina) retinal detachment. One patient had extrascleral extension on ultrasonography. Radiation data
Patients were treated with 70 Gy in 5 fractions over 10 days, with the exception of 1 patient whose treatment was delivered over 22 days because of a treatment delay secondary to comorbid medical complications; these were independent of the radiotherapy. The median prescription isodose was 95% (range 90%–100%). The median maximum and minimum dose to the tumor was 74.6 (range 47.2–78.6) Gy and 70.2 (range 40.7–74.7) Gy, respectively. The median maximum dose to the optic nerve was 72.9 (range 60.1–77.2) Gy. The median mean dose to the lens Table 1—Tumor characteristics Measurement T.ON T.Faz Tumor height Maximum basal tumor diameter
Mean (mm)
Median (mm)
Range (mm)
0.30 1.29 4.61 10.16
0.00 0.75 4.23 9.85
0.00–2.00 0.00–4.50 1.50–11.00 4.70–17.00
was 6.7 (1.0–67.5) Gy, and the median minimum dose to the lens was 2.1 (range 0.7–52.8) Gy. The median volume (in percent) of the eye exposed to 70 Gy (V70) was 14% (range 1%–54%). Tumor control
Median follow-up was 26 (range 6–72) months. Three patients had local (within the radiation field) tumor recurrence at 6, 7, and 23 months. Actuarial local tumor control was 94% at 26 months (Fig. 1). After radiotherapy, the mean tumor height decreased by 1.32 mm (p < 0.0001). Metastases developed in 8 patients (6 liver, 1 lung, 1 skull base), and the median time to metastasis was 17.5 (range 5–40) months. At 26 months, the actuarial metastatic rate was 12%. Initial tumor height (Fig. 2A) and maximum tumor diameter (Fig. 2B) were both associated with increased risk of metastasis (p value 0.04 and 0.002, respectively). Six patients died from liver metastasis and 1 patient from lung metastasis. Actuarial patient survival at 26 months after radiotherapy was 94% (Fig. 3). Complications
At 26 months after radiotheraphy, 45% of patients had a cataract. Cataract developed as early as 9 months and as late as 48 months, with a median of 18 months. A higher rate of cataract formation was associated with a greater lens minimum dose (p = 0.02), and a trend to a higher rate of cataract formation was associated with a greater lens mean dose (p = 0.07). The incidence of tumor vasculopathy was 83% at 26 months. The incidence of radiation retinopathy was 80% at 26 months. Radiation retinopathy developed as early as 2 months and as late as 31 months, with a median of 15 months. The incidence of radiation maculopathy was 49% at 26 months. A higher rate of radiation retinopathy was associated with a greater V70 (p = 0.01), and a trend to a higher rate of tumor vasculopathy was associated with a greater V70 (p = 0.07). The incidence of optic neuropathy was 52% at 26 months. The median onset of radiation optic neuropathy was 19 months. The incidence of neovascular glaucoma was 28% at 26 months. Neovascular glaucoma developed as early as 9 months and as late as 36 months, with a median of 20 months. A higher rate of neovascular glaucoma was associated with greater lens minimum dose
Note: T.ON, minimum distance between tumor margin and optic nerve; T.Faz, minimum distance between tumor margin and foveal avascular zone.
Table 2—Distribution of tumor characterisics Characteristic T.ON = 0 mm T.ON > 0 and ≤ 2 mm (1 disc diameter) Extrascleral extension of tumor Collar-button configuration Retinal detachment None Localized Subtotal (nonlocalized macula-off)
Patients, n (%) 48 (75) 16 (25) 1 (1.6) 12 (18.8) 31 (48.4) 31 (48.4) 2 (3.1)
Note: T.ON, minimum distance between tumor margin and optic nerve; Collar-button configuration, indicates a break through Bruch’s membrane.
Fig. 1—Kaplan–Meier curve of probability of tumor control (percentage) versus time (months), with actuarial local tumor control of 94% at 26 months. CAN J OPHTHALMOL—VOL. 44, NO. 1, 2009
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Juxtapapillary choroidal melanoma—Somani et al. (p = 0.001). Vitreous hemorrhage occurred in 17 patients, and 9 patients had worsening of their retinal detachment. Enucleation was necessary in 7 patients because of tumor recurrence (3/7) and painful neovascular glaucoma (4/7).
tance of the tumor to the foveal avascular zone was also significantly correlated with the decline in visual acuity (p = 0.004). There was no significant association between the V70 and decline in visual acuity.
Visual outcome
CONCLUSIONS
Initial median Snellen visual acuity was 20/100 (range 20/20 to hand motions). Fifteen patients had vision better than 20/40, 22 patients had vision between 20/40 and 20/200, and 27 patients had vision worse than 20/200. The median final vision was hand motions (range 20/25 to enucleation) with a median of 2 lines lost. There was a significant decrease in vision after radiotherapy (p < 0.0001). Initial vision was significantly correlated with distance of the tumor to the foveal avascular zone (p < 0.0001). Dis-
Fig. 2—(A) Kaplan–Meier curve demonstrating a higher probability of being metastasis free with tumor height less than 4.23 mm (solid line) than with tumor height greater than 4.23 mm (dashed line) (p = 0.04). (B) Kaplan-Meier curve demonstrating a higher probability of being metastasis free with tumor base diameter less than 9.85 mm (solid line) than with tumor base diameter greater than 9.85 mm (dashed line) (p = 0.002).
Fig. 3—Kaplan–Meier curve of patient survival (percentage) over time. Actuarial patient survival at 26 months was 94%.
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The Collaborative Ocular Melanoma Study (report number 28)9 and other studies6 have demonstrated no difference in survival in using irradiation versus enucleation in the management of medium-sized uveal melanoma; however, juxtapapillary melanomas were excluded in those analyses. Therefore, there is no clear consensus in the management of this type of choroidal melanoma. This retrospective study details the outcome of stereotactic radiotherapy as a management for juxtapapillary uveal melanoma, with a posterior margin located within 2 mm of the optic disc, for a median follow-up period of 26 months. Conventional plaque radiotherapy can be technically difficult in both insertion and placement when treating juxtapapillary tumors because of the proximity of the optic nerve. Williams et al.10 have reported cases in which the posterior edge of the juxtapapillary plaque was tilted away from the optic nerve, as demonstrated by magnetic resonance imaging, in cadaver eyes. Harbour et al.11 have reported that by using intraoperative echographic localization of plaque placement, there was 21% incomplete coverage of at least 1 margin of the posterior uveal melanomas treated by episcleral plaque when standard localization techniques were used. Notched plaques to accommodate the optic nerve may give a better localization advantage, but they still carry some theoretical risk of damage to both the optic nerve and its associated vasculature during insertion. Finger12 has recently reported the use of a “slotted eye plaque” as a solution to provide better coverage of juxtapapillary and circumpapillary melanomas. Stereotactic radiotherapy as an effective management of uveal melanoma has been reported in previous studies.1–3 This kind of irradiation allows steep dose gradients outside the target volume, thus minimizing the dose of radiation to surrounding structures. It also has the advantage over proton beam and helium ion radiotherapy in that it spares the patient 2 surgical procedures for insertion and removal of the tantalum rings, used for localization of the tumor margin. Stereotactic radiotherapy employs a higher dose per fraction method than plaque brachytherapy, which uses a lowdose radiation method allowing for relatively greater repair of neural tissue. However, this study has shown that the incidence of posterior segment complications such as radiation retinopathy was 80% and radiation papillopathy was 52%, which are similar to the results reported by De Potter et al.4 in their study using iodine-125 plaque brachytherapy in the management of juxtapapillary choroidal melanoma. Anterior segment complications, such as neovascular glaucoma and cataract, are frequently reported with all
Juxtapapillary choroidal melanoma—Somani et al. forms of radiotherapy. Our study demonstrated an incidence of neovascular glaucoma of 28%, peaking between 1 and 2.5 years after irradiation, which is comparable to the 31% incidence reported after helium ion radiotherapy at 5 to 10 year follow-up.13,14 However, Gragoudas et al.15 reported a lower incidence of neovascular glaucoma (15%) in their series of melanomas treated by proton beam irradiation. Perhaps the nature of proton beam radiotherapy with the Bragg peak effect, resulting in a sharp dose deposition at depth, reduces the risk of anterior segment complication. Similarly, the present study demonstrated the rate of radiation-induced cataract to be 45%, which approximates the incidence of 41% reported in the study of helium ion radiotherapy13 but is more than the rate of 33% with proton beam radiotherapy.15 A lower incidence of anterior segment complications has been reported with plaque brachytherapy than external beam radiotherapy. In 1 series of I-125 plaque brachytherapy and transpupillary thermotherapy for medium-sized melanoma, Shields et al.16 reported an incidence of neovascular glaucoma and radiation-induced cataract of 7% and 6%, respectively. In another series using Ru-106 plaque brachytherapy, Summanen et al.17 reported their incidence of neovascular glaucoma and radiation-induced cataract to be 12% and 26%, respectively. However, a study of larger melanomas (greater than 8 mm thickness) reported a higher incidence of neovascular glaucoma (21%) and cataract (66%) using I-125 plaque brachytherapy.18 The tumor control rate and the survival rate in this study were 94% at 26 months. Studies of other modalities with longer follow-up have found the tumor control rate and survival rate, at a median follow-up of 5 years, to be around 85% with brachytherapy treatment4,5,19 and 83% with helium ion irradiation13 of juxtapapillar melanoma. We conclude that stereotactic radiotherapy offers a noninvasive, relatively economic management option in the treatment of juxtapapillary uveal melanoma. It provides a high local tumor control rate, similar to the rate reported with other irradiation modalities at a similar median follow-up period. Furthermore, it carries a similar incidence of anterior segment complications in comparison to other external beam radiotherapy options, and a higher incidence in comparison to brachytherapy. We would like to acknowledge Sharon McKinon and Shenaz Ladak as our dedicated radiation therapists on the stereotactic eye radiotherapy team. We would also like to thank Allan Connor for figure preparation. The authors have no proprietary or commercial interest in any materials discussed in this article.
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3. Dieckmann K, George D, Bogner J, et al. Optimizing Linacbased stereotactic radiotherapy of uveal melanomas: 7 years’ clinical experience. Int J Radiat Oncol Biol Phys 2006;66:S47–52. 4. De Potter P, Shields CL, Shields JA, Cater JR, Brady LW. Plaque radiotherapy for juxtapapillary choroidal melanoma: visual acuity and survival outcome. Arch Ophthalmol 1996;114:1357–65. 5. Lommatstzsch PK, Alberti W, Lommatzsch R, Rohrwacher F. Radiation effects on the optic nerve observed after brachytherapy of choroidal melanomas with 106Ru/106Rh plaques. Graefes Arch Clin Exp Ophthalmol 1994;232:482–7. 6. De Potter P, Shields CL, Shields JA, Cater JR, Tardio DJ. Impact of enucleation versus plaque radiotherapy in the management of juxtapapillary choroidal melanoma on patient survival. Br J Ophthalmol 1994;78:109–14. 7. Lommatstzsch PK, Lommatzsch R. Treatment of juxtapapillary melanomas. Br J Ophthalmol 1991;75:715–7. 8. Seddon JM, Gragoudas ES, Egan KM et al. Uveal melanomas near the optic disc or fovea: visual results after proton beam irradiation. Ophthalmology 1987;94;354–62. 9. The Collaborative Ocular Melanoma Study Group. The COMS randomized trial of iodine 125 brachytherapy for choroidal melanoma. V. Twelve-year mortality rates and prognostic factors: COMS report No. 28. Arch Ophthalmol 2006;124:1684–93. 10. Williams D, Mieler W, Jaffe G, Robertson DM, Hendrix L. Magnetic resonance imaging of juxtapapillary plaques in cadaver eyes. Br J Ophthalmol 1990;74:43–6. 11. Harbour JW, Murray TG, Byrne SF, et al. Intraoperative echographic localization of iodine 125 episcleral radioactive plaques for posterior uveal melanoma. Retina 1996;16:129–34. 12. Finger PT. Finger’s “slotted” eye plaque for radiation therapy: treatment of juxtapapillary and circumpapillary intraocular tumors. Br J Ophthalmol 2007;91:891–4. 13. Char DH, Castro JR, Kroll SM, Irvine AR, Quivey JM, Stone RD. Five-year follow-up of helium ion therapy for uveal melanoma. Arch Ophthalmol 1990;108:209–14. 14. Char DH, Kroll SM, Castro J. Ten-year follow-up of helium ion therapy for uveal melanoma. Am J Ophthalmol 1998;125:81–9. 15. Gragoudas ES, Seddon JM, Egan K, et al. Long-term results of proton beam irradiated uveal melanomas. Ophthalmology 1987;94:349–53. 16. Shields CL, Cater J, Shields JA, et al. Combined plaque radiotherapy and transpupillary thermotherapy for choroidal melanoma: tumor control and treatment complications in 270 consecutive patients. Arch Ophthalmol 2002;120:933–40. 17. Summanen P, Immonen I, Kivela T, Tommila P, Heikkonen J, Tarkkanen A. Radiation related complications after ruthenium plaque radiotherapy of uveal melanoma. Br J Ophthalmol 1996;80:732–9. 18. Shields CL, Naseripour M, Cater J, et al. Plaque radiotherapy for large posterior uveal melanomas (≥8-mm thick) in 354 consecutive patients. Ophthalmology 2002;109:1838–49. 19. Karlsson UL, Augsburger JJ, Shields JA, Markoe AM, Brady LW, Woodleigh R. Recurrence of posterior uveal melanoma after 60Co episcleral plaque therapy. Ophthalmology 1998;96;382–8.
Keywords: choroidal melanoma, stereotactic radiation, complications CAN J OPHTHALMOL—VOL. 44, NO. 1, 2009
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