Ocular Response of Choroidal Melanoma With Monosomy 3 Versus Disomy 3 After Iodine-125 Brachytherapy

Int. J. Radiation Oncology Biol. Phys., Vol. 81, No. 4, pp. 1046–1048, 2011 Copyright Ó 2011 Elsevier Inc. Printed in the USA. All rights reserved 0360-3016/$ - see front matter

doi:10.1016/j.ijrobp.2010.07.016

CLINICAL INVESTIGATION

Eye

OCULAR RESPONSE OF CHOROIDAL MELANOMA WITH MONOSOMY 3 VERSUS DISOMY 3 AFTER IODINE-125 BRACHYTHERAPY OMKAR S. MARATHE,* JEFFREY WU, M.D.,y STEVE P. LEE, M.D., PH.D.,y FEI YU, PH.D.,z BARRY L. BURGESS,z MIN LEU, PH.D.,y BRADLEY R. STRAATSMA, M.D., J.D.,z AND TARA A. MCCANNEL, M.D., PH.D.zx *David Geffen School of Medicine, yDepartment of Radiation Oncology, zDepartment of Ophthalmology, The Jules Stein Eye Institute, and xJonsson Comprehensive Cancer Center, University of Los Angeles, Los Angeles, CA Purpose: To report the ocular response of choroidal melanoma with monosomy 3 vs. disomy 3 after 125I brachytherapy. Methods and Materials: We evaluated patients with ciliochoroidal melanoma managed with fine needle aspiration biopsy immediately before plaque application for 125I brachytherapy between January 1, 2005 and December 31, 2008. Patients with (1) cytopathologic diagnosis of melanoma, (2) melanoma chromosome 3 status identified by fluorescence in situ hybridization, and (3) 6 or more months of follow-up after brachytherapy were sorted by monosomy 3 vs. disomy 3 and compared by Kruskal-Wallis test. Results: Among 40 ciliochoroidal melanomas (40 patients), 15 had monosomy 3 and 25 had disomy 3. Monosomy 3 melanomas had a median greatest basal diameter of 12.00 mm and a median tumor thickness of 6.69 mm before brachytherapy; at a median of 1.75 years after brachytherapy, median thickness was 3.10 mm. Median percentage decrease in tumor thickness was 48.3%. Disomy 3 melanomas had a median greatest basal diameter of 10.00 mm and median tumor thickness of 3.19 mm before brachytherapy; at a median of 2.00 years after brachytherapy, median tumor thickness was 2.37 mm. The median percentage decrease in tumor thickness was 22.7%. Monosomy 3 melanomas were statistically greater in size than disomy 3 melanomas (p < 0.001) and showed a greater decrease in tumor thickness after brachytherapy (p = 0.006). Conclusion: In this study, ciliochoroidal melanomas with monosomy 3 were significantly greater in size than disomy 3 melanoma and showed a significantly greater decrease in thickness at a median of 1.75 years after brachytherapy. The greater decrease in monosomy 3 melanoma thickness after brachytherapy is consistent with other malignancies in which more aggressive pathology has been shown to be associated with a greater initial response to radiotherapy. Ó 2011 Elsevier Inc. Ciliochoroidal melanoma, Choroidal melanoma, Uveal melanoma, Monosomy 3, 125I brachytherapy.

INTRODUCTION

(2, 3). Studies of ciliochoroidal melanoma have shown that patients with an early rapid tumor response to radiation have a greater likelihood to develop metastatic disease (4–6). It remains unclear whether the finding of monosomy 3 would necessarily predict a differential degree of local tumor response as compared with tumors without monosomy 3. In this study, we sought to evaluate the response of ciliochoroidal melanoma with known chromosome 3 status after treatment with 125I brachytherapy.

Melanoma arising from the ciliary body and the choroid is the most common primary intraocular malignancy of adults. The Collaborative Ocular Melanoma Study randomized clinical trial of 125I brachytherapy vs. enucleation for medium-sized melanoma showed that, for patients who met eligibility criteria, there was no statistically significant difference in allcause mortality between 125I brachytherapy and enucleation 5, 10, and 12 years after treatment (1). Therefore, 125I brachytherapy alone is the standard of care for globe-sparing local treatment of ciliochoroidal melanoma. Testable with cytogenetic studies, loss of one copy of chromosome 3, or monosomy 3, in tumor tissue is detected in approximately half of ciliochoroidal melanomas and is the risk factor most strongly associated with metastatic death

METHODS AND MATERIALS A retrospective review of all patients with a clinical diagnosis of ciliochoroidal melanoma who underwent 125I brachytherapy and evaluation of chromosome 3 status by fluorescence in situ

Reprint requests to: Tara A. McCannel, M.D., Ph.D., Department of Ophthalmology, University of Los Angeles, 100 Stein Plaza, Los Angeles, CA 90095. Tel: (310) 206-7484; Fax: (310) 794-7904; E-mail: [email protected]

Supported by the George and Ruth E. Moss Trust and an unrestricted grant from Research to Prevent Blindness. Conflict of interest: none. Received April 19, 2010, and in revised form July 4, 2010. Accepted for publication July 5, 2010. 1046

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I brachytherapy response of monosomy 3 ciliochoroidal melanoma d O. S. MARATHE et al.

hybridization were included. Intraoperative fine needle aspiration biopsy, described elsewhere (7, 8), was performed with a 30gauge needle via a transscleral approach immediately before 125I plaque placement for brachytherapy. Patients with (1) cytopathologic diagnosis of melanoma, (2) melanoma chromosome 3 status identified by fluorescence in situ hybridization, and (3) 6 months or more of follow-up after brachytherapy were sorted into two groups according to chromosome 3 status of monosomy 3 or disomy 3 and compared by Kruskal-Wallis test. Follow-up evaluations, which included ultrasound by a single ultrasonographer, were performed every 6 months. Chromosome 3 status was evaluated at the University of California, Los Angeles Clinical Cytogenetics Laboratory with a centromeric probe, CEP-3 Spectrum Orange (Vysis, Downers Grove, IL). This research was approved by the Institutional Review Board of the University of California, Los Angeles, and work was in compliance with the Health Insurance Portability and Accountability Act of 1996.

RESULTS Forty eyes (40 patients) with ciliochoroidal melanoma had fine needle aspiration biopsy samples sufficient for chromosome 3 testing (monosomy 3 or disomy 3); 15 had monosomy 3 and 25 had disomy 3. Mean patient age for monosomy 3 was 60.73 years (median, 65 years) and for disomy 3 was 55.5 years (median, 58 years). The age of patients ranged from 28 to 82 years. Monosomy 3 melanoma had a median greatest basal diameter of 12.00 mm and a median tumor thickness of 6.69 mm before brachytherapy. The median dose was 85.2 Gy to tumor apex and 254.8 Gy at the base. At a median of 1.75 years after brachytherapy, median thickness was 3.10 mm. Median percentage decrease in tumor thickness was 48.3%. Disomy 3 melanoma had a median greatest basal diameter of 10 mm and median tumor thickness of 3.19 mm before brachyther-

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apy. The median dose was 85.6 Gy to tumor apex and 181.5 Gy at the base. At a median of 2.0 years after brachytherapy, median tumor thickness was 2.37 mm. The median percentage decrease in tumor thickness was 22.7% (Table 1). No patient had local recurrence of the tumor during the follow-up period. Before brachytherapy, monosomy 3 melanomas were statistically greater in size than disomy 3 melanomas (p < 0.001). After brachytherapy, monosomy 3 melanomas showed a greater decrease in tumor thickness than disomy 3 melanomas over a median of 1.75 years (p = 0.006).

DISCUSSION In this study, we have shown that ciliochoroidal melanomas with monosomy 3 treated with 125I brachytherapy without adjunctive therapy had a greater response with respect to decrease in tumor size compared with tumors with disomy 3. Furthermore, we observed that monosomy 3 tumors were larger in size at diagnosis compared with tumors with disomy 3. Shields et al. (9) reported a series of tumors treated with 125 I brachytherapy and adjuvant transpupillary thermotherapy (TTT) and observed that tumors with known monosomy 3 status had a faster tumor thickness regression than tumors with disomy 3. The major difference between the Shields’ study and ours involved the strikingly different approach to local treatment: Shields et al. used TTT sessions as an adjuvant to 125I brachytherapy. In addition, for Shields et al. the mean pretreatment tumor height of the monosomy 3 group (4.0 mm) was smaller than for our baseline monosomy 3 group (6.69 mm). Furthermore, we found that the difference in tumor regression in our series at 1.75 years between monosomy 3 and disomy 3 melanoma, 48.3% and 22.7%, respectively, was greater than the Shields report of 47.7%

Table 1. Tumor characteristics of patients before and after 125I brachytherapy Characteristic Tumor size Baseline thickness (mm) Mean  SD Median (range) End of follow-up thickness (mm) Mean  SD Median (range) Change Mean  SD (mm) Median (range) (mm) Decrease in median (%) Change in thickness (%) Mean  SD Median (range) Duration of follow-up (y) Mean  SD Median (range)

Monosomy 3 (n = 15)

Disomy 3 (n = 25)

p* 0.0008

6.69  2.70 6.80 (2.32–10.31)

3.77  1.86 3.19 (1.00–8.13)

3.57  1.55 3.10 (1.70–7.22)

2.76  1.27 2.37 (1.41–7.51)

3.12  1.79 2.90 (0.15–6.00) 42.6

1.01  1.30 0.78 (0.94 to 4.41) 24.5

44.0  15.8 48.3 (6.5–68.7)

19.4  31.2 22.7 (79.0 to 66.7)

1.73  0.51 1.75 (0.75–2.50)

1.94  0.71 2.00 (0.50–3.33)

0.054 <0.001

0.006 0.31

A significant difference between monosomy 3 and disomy 3 tumors was noted in baseline tumor thickness and in the percentage decrease in tumor thickness after treatment with 125I brachytherapy. * Kruskal-Wallis test.

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and 40.1% regression for monosomy 3 and disomy 3, respectively, at 18 months. Their greater regression in the disomy 3 group is likely attributable to their use of adjuvant TTT in the treatment of all melanomas, which is not a standard practice in most ophthalmic oncology centers. Their use of TTT in all tumors may introduce a bias in their tumor shrinkage analysis. We consider a successful local tumor response to brachytherapy to be ultrasonographic evidence of cessation of tumor growth, or a decrease in tumor size compared with baseline. Although primary treatment failure is evident if tumor growth continues and tumor size increases after treatment, there is no evidence to suggest that the degree of shrinkage correlates with either a more successful rate of local recurrence or improved patient mortality. Our findings support the concept that the cytogenetic features of the tumor determine local tumor response to radiation, in addition to metastatic mortality. As observed by Kaiserman et al. (4), Augsburger et al. (5), and Glynn et al. (6), regression rates of melanomas after local radiation correlate with increased mortality. In this report, we

Volume 81, Number 4, 2011

found that monosomy 3 melanomas have a greater tumor regression response after 125I brachytherapy than disomy 3 melanomas. The monosomy 3 biology may be related to a more pathologically aggressive nature and increased mitotic activity conferring a greater response to radiation treatment. Since the early beginnings of classical radiation biology, it has been known that poorly differentiated neoplasms have a stronger response to radiation than differentiated tumors. Thus, ciliochoroidal melanomas with monosomy 3, known to be more aggressive tumors than tumors with disomy 3, may have particular tumor biological factors that make them more responsive to radiation. Our study demonstrated that ciliochoroidal melanomas with monosomy 3 are generally larger in size at diagnosis than disomy 3 melanomas and have a significantly greater decrease in size after 125I brachytherapy than disomy 3 melanomas. Determination of specific cytogenetic characteristics of these tumors may thus yield both clinically useful prognostic and predictive information regarding local treatment response to radiation.

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6. Glynn RJ, Seddon JM, Gragoudas ES, et al. Evaluation of tumor regression and other prognostic factors for early and late metastasis after proton irradiation of uveal melanoma. Ophthalmology 1989;96:1566–1573. 7. Young TA, Rao NP, Glasgow BJ, et al. Fluorescent in situ hybridization for monosomy 3 via 30-gauge fine-needle aspiration biopsy of choroidal melanoma in vivo. Ophthalmology 2007;1: 142–146. 8. Young TA, Burgess BL, Rao NP, et al. Transscleral fine-needle aspiration biopsy of macular choroidal melanoma. Am J Ophthalmol 2008;145:297–302. 9. Shields CL, Bianciotto C, Rudich D, et al. Regression of uveal melanoma after plaque radiotherapy and thermotherapy based on chromosome 3 status. Retina 2008;28: 1289–1295.