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Clinical science
Recurrence of iris melanoma after proton beam therapy Maria T Sandinha,1,2 Andrzej Kacperek,3 R Douglas Errington,3 Sarah E Coupland,1 Bertil Damato1,4 1 St Paul’s Eye Unit, Liverpool Ocular Oncology Centre, Liverpool, UK 2 Sunderland Eye Infirmary, Sunderland, UK 3 Douglas Cyclotron Unit, Clatterbridge Cancer Centre, Liverpool, UK 4 Ocular Oncology Service, Departments of Ophthalmology and Radiation Oncology, University of California San Francisco, San Francisco, USA
Correspondence to Dr Maria T Sandinha, Vitreoretinal Service, Sunderland Eye Infirmary, Queen Alexandra Road, Sunderland, Tyne and Wear SR2 9HP, UK; [email protected] Received 14 April 2013 Revised 16 November 2013 Accepted 11 December 2013 Published Online First 10 January 2014
To cite: Sandinha MT, Kacperek A, Errington RD, et al. Br J Ophthalmol 2014;98:484–487. 484
ABSTRACT Background/Aims A retrospective service evaluation to report on recurrence of iris melanoma after proton beam therapy (PBT). Methods The cohort comprised 150 consecutive eyes with iris melanoma treated with proton beam radiotherapy. Treatment consisted of 53.1 Gy of proton beam irradiation delivered in four fractions over four consecutive days. Main outcome measures were local tumour control and tumour-related mortality. Results A total of 150 patients were treated. The median follow-up time was 66 months (range, 12– 108 months). The tumour ultrasound thickness ranged from 1.1 mm to 4.9 mm, with a median of 2.4 mm. The tumours in these patients had a median largest basal diameter of 6.7 mm (range, 2.9–8.4 mm), involving more than two clock hours of iris or angle in five patients. The ciliary body was involved in three patients. Eight patients (5.3%) presented with local recurrence, diagnosed after a median follow-up of 24 months (range, 12–84 months). The recurrence was focal in two patients and diffuse in six. Six eyes were enucleated whereas one eye underwent iridocyclectomy and one received a second course of PBT. Conclusions PBT provides excellent local tumour control and ocular preservation with good retention of vision. Most recurrences occur because the extent of the tumour is clinically underestimated but some tumours are radioresistant. Recurrence can occur several years after treatment. These findings indicate the need for wide safety margins and even radiotherapy of the entire anterior segment in patients with diffuse disease. Surveillance after treatment needs to be lifelong.
Iris melanomas account for approximately 3–5% of all uveal melanomas.1 No single characteristic conclusively differentiates these from naevi, but suspicious features include: young age, hyphaema, inferior iris location and diffuse growth and larger tumour size.2 Nodular iris melanomas tend to behave in an indolent fashion and have a better survival prognosis than ciliary body (CB) and choroidal melanomas; however, diffuse iris melanomas are more lethal.3 4 Enucleation is indicated if the tumour is considered too advanced for surgical resection or radiotherapy.5 6 Case series of patients treated with proton beam irradiation have been reported, with good results.7–11 Local recurrence is rare but can be life threatening and can result in loss of the eye.7 There is scope for a better understanding of the complication so that this outcome can be prevented and treated appropriately. To our knowledge, no previous studies have focused on this problem.
The aims of this study were to understand the nature of local recurrence of iris melanoma after proton beam radiotherapy and to determine how this complication might be avoided.
MATERIALS AND METHODS The study was a retrospective review of all patients with iris melanoma treated with proton beam therapy (PBT) as a primary treatment from January 1994 until December 2010. Patient details, which had been recorded prospectively, were obtained from the Liverpool Ocular Oncology Centre database. The tumours had been diagnosed as melanoma, either clinically, according to a variety of features (see Discussion), or histologically, and all were considered to have arisen in the iris. Patients with CB melanoma with iris involvement or with a tumour showing extrascleral spread were excluded. This study adhered to the tenets of the Declaration of Helsinki. Consent for the use of data, tissues, and images for research, tissue, and audit had routinely been obtained prospectively from patients. Institutional board approval was not required because this was a service evaluation. Pretreatment assessment included measurement of visual acuity with a Snellen chart (before 2006) or logarithm of the minimal angle of resolution chart (after 2005); slit-lamp examination, with measurement of longitudinal and transverse tumour diameters, prior to mydriasis; and gonioscopy, determining the circumferential extent of increased pigmentation in the angle, in clock hours. High-frequency B-scan ultrasonography was performed with an Eyecubed ultrasound machine (Ellex Ltd, I3 System) using a water bath filled with 2% hypromellose. Patients were treated according to a standard protocol.1 In summary, all patients received a dose of 53.1 Gy delivered in four fractions over four consecutive days. No localising markers were required. The eyelids were retracted out of the radiation field and the pupil was dilated to reduce the treatment volume. A 2.5–3.0 mm safety margin was planned around the tumour volume (this tumour volume included pigment seeding in the iridocorneal angle, when present at the time of diagnosis). Patients were reviewed approximately 6 months after the proton beam radiotherapy, then 6 monthly for 5 years, and then annually. For patients from outside the region, arrangements were made for consultations to alternate between the referring hospital and our clinic until the ocular condition appeared stable. At that point patients were discharged from our care for lifelong monitoring at their local hospital. Follow-up information on these
Sandinha MT, et al. Br J Ophthalmol 2014;98:484–487. doi:10.1136/bjophthalmol-2013-303321
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Clinical science patients was obtained from the referring ophthalmologist or general practitioner.
RESULTS A total of 150 patients with iris melanoma were treated with proton beam radiotherapy between 1994 and 2011. The median follow-up time of all 150 patients was 66 months (range, 24–108 months). Eight patients (5.3%) presented with local recurrence, indicated by an increase in tumour size after an initial response to the treatment, or the appearance of tumour in a different location from when first diagnosed. Recurrences occurred after a median time of 24 months (range, 12–84 months) after initial treatment. At the initial diagnosis, the largest basal diameter of these tumours ranged from 2.9 mm to 8.4 mm with a median of 6.6 mm and the thickness ranged from 1.1 mm to 4.9 mm, with a median of 2.4 mm.
Case reports Patient 1 presented with a superior nodular iris melanoma in the right eye. The tumour measured 6.6×5.0×1.5 mm, involving three clock hours of iris (ie, 1–4 o’clock) and three clock hours of the angle. There was no CB involvement. The recurrence occurred 24 months after proton beam radiotherapy and showed annular spread around the anterior chamber and angle. The patient was treated by enucleation. The tumour was of mixed type. The patient was well in May 2011, 36 months after initial therapy. Patient 2 was treated for a nodular iris melanoma in the inferotemporal quadrant of the right eye. The tumour measured 3.3×3.0 × 1.1 mm and involved two clock hours of iris (6 to 8 o’clock) and four clock hours of the angle. The tumour recurrence occurred 12 months after radiotherapy with invasion of the angle and anterior chamber in a ring pattern. The patient was treated by enucleation. The tumour was of spindle type. The patient was well when this study was undertaken, 108 months after initial ocular therapy. Patient 3 had an inferonasal nodular iris melanoma in the left eye. The tumour measured 6.7×5.0×5.0 mm and involved three clock hours of iris (6–9), angle and CB (figure 1A). The recurrence occurred 60 months after initial therapy with annular spread in the anterior chamber and angle. The patient was treated by enucleation. The tumour was of mixed type. The patient died of metastasis 72 months after diagnosis. Patient 4 presented with an inferior nodular iris melanoma in the right eye. The tumour involved the two clock hours of the iris, from the 5 to the 7 o’clock meridians, measuring 2.8×2.3×1.2 mm. The recurrence in the form of annular spread around the anterior chamber and angle occurred 24 months after radiotherapy. The patient was treated by enucleation. The tumour was of mixed cell type. The patient was well on the date of this audit, 36 months after initial treatment. Patient 5 was treated for a nodular iris melanoma in the inferonasal quadrant of the right eye (figure 1B). The tumour measured 8.2×6.1×3.0 mm and involved four clock hours of iris (2–6), 6 h of the angle and 4 h of the CB. The patient required glaucoma drainage surgery 12 months after treatment. Twenty-four months after radiotherapy, she presented with limited recurrence (one clock hour), centred in the superior quadrant, adjacent to the trabeculectomy wound. The patient was treated with further PBT, localised to the recurrence. At the close of this study, 60 months after initial treatment, this patient was doing well.
Patient 6 presented with a nodular iris melanoma in the inferotemporal quadrant of the right eye. The tumour measured 7.0×6.0×4.0 mm and involved one clock hour of the iris (6–7), 4 h of the angle and 3 h of the CB. The patient underwent augmented trabeculectomy 24 months after treatment. The recurrence, 36 months after first PBT, showed extensive angle involvement in a ring pattern but the patient declined enucleation. The patient was treated with further proton beam radiation delivered to the entire anterior segment and although no further growth was noted, the eye became painful from neovascular glaucoma and this patient underwent enucleation 4 months after her second PBT. The tumour was of mixed cell type. The patient died 96 months after the initial treatment, of breast cancer metastasis. Patient 7 presented with a temporal nodular iris melanoma in the right eye (figure 1C). The tumour involved two clock hours of iris (8–10) and measured 5.6×3.3×1.8 mm. Eighty-four months after initial PBT (figure 1D), there was recurrence of the tumour within the irradiated field (figure 1E). The patient was treated by iridocyclectomy. The tumour was of mixed cell type. He subsequently had cataract surgery (figure 1F), which improved the visual acuity to 6/9 unaided. At the close of this study, 96 months after initial treatment, this patient was doing well. Patient 8 presented with a nodular iris melanoma in the inferonasal quadrant of the right eye. The tumour measured 8.4×6.8×4.9 mm, involving three and a half clock hours of iris (3–6.30), 6 h of the angle and 3 h of the CB. Although most of the anterior segment was irradiated with initial PBT, the patient was enucleated 24 months later because of diffuse annular spread, with extraocular extension subconjunctivally. The tumour was of spindle type. The patient died of metastatic disease 36 months after initial therapy. In summary, all patients with recurrent tumour presented initially with a nodular iris melanoma, with six showing angle involvement and three also having CB involvement. Two patients (Patients 2 and 4) with diffuse recurrence presented initially with tumours of only 3.3 mm and 2.8 mm diameter, respectively. Seven patients required enucleation, for recurrence in six patients and because of painful neovascular glaucoma in one case. Three patients had glaucoma and one patient developed cataract. No patients developed keratopathy or madarosis from the radiotherapy.
DISCUSSION Herein, we report eight recurrent iris melanomas after proton beam radiotherapy of 150 patients. The recurrences were diagnosed a median of 2 years (range, 1–7 years) after initial treatment. Seven recurrent tumours were marginal and one developed within the irradiated field. To our knowledge, such a central recurrence has not previously been reported after proton beam radiotherapy of iris melanoma. The main strength of this study is the large number of patients treated with PBT at a single centre. The main weakness is the short follow-up, so that the long-term recurrence rate may be underestimated. Another weakness is that most patients did not have histological confirmation of the diagnosis so that some of the tumours may have been naevi, in which case the incidence of recurrence would be higher than 5.3%. Tumours involving iris and CB were categorised according to location of their ‘centre of gravity’. Although it is possible that some tumours located predominantly in iris originated in the CB, excluding tumours with any CB involvement would have biased our results by excluding more aggressive iris melanomas.
Sandinha MT, et al. Br J Ophthalmol 2014;98:484–487. doi:10.1136/bjophthalmol-2013-303321
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Clinical science Figure 1 Iris melanoma at presentation involving respectively three clock hours of iris, angle and ciliary body in Patient 3 (A) and four clock hours of iris, ciliary body and six of angle in Patient 5 (B). Iris melanoma at presentation in Patient 7 involving two clock hours of iris (C); the treatment plan showing 20%, 50% and 90% isodose curves for this patient (D). The tumour recurred in the irradiated field (E) and successful iridocyclectomy followed by cataract extraction and lens implant was carried out (F).
It is noteworthy that tumour recurrence with diffuse growth and seeding was seen in two patients after treatment of tumours having basal diameters of only 3.3 mm and 2.8 mm, respectively. Small tumour size does not guarantee that a melanocytic iris tumour is benign and that it will not recur after treatment. Most recurrences developed because the extent of diffuse tumours was underestimated when planning initial treatment. We now treat such tumours with very wide safety margins, in some cases including the entire anterior segment in the radiation field with good results, albeit having to treat glaucoma in most patients.11 12 Others report similar results after whole anterior segment irradiation.10 The central tumour recurrence in one patient raises the possibility of radioresistance. As most iris melanomas behave in an indolent fashion, with a low mitotic rate and slow growth, one would expect these tumours to be relatively radioresistant in comparison with melanomas in other parts of the eye. Higher doses of radiation would eliminate this problem but would increase the incidence of limbal stem cell deficiency and other ocular complications. Further studies are indicated to determine the long-term rates of central tumour recurrence and whether such cases can be satisfactorily treated by local resection or further radiotherapy. Although it is not possible to perform meaningful comparisons between our study and previous investigations by other workers, our local tumour control rate of 94.7% compares favourably with those achieved with brachytherapy and conservative surgery. Shields et al6 treated 38 patients with custommade plaques with a variety of isotopes and showed a local control rate of 92%. The same group also used 125I radioactive plaques for iris tumours for which surgery was not indicated or 486
after a first recurrence.6 They reported a local recurrence rate of 8% at 5 years and 15% at 10 years. Conway et al5 in their study of outcomes of conservative surgical treatment included 44 patients who underwent local resection and reported four recurrences (9%), three of which occurred within the first 3 years of primary ocular treatment. The metastatic rate of diffuse iris melanoma has been reported to be as high as 13% over 6 years13 compared with 3% after 5 years for circumscribed iris melanoma.14 The 10-year survival probability is about 95%.6 Iris melanomas in the presence of raised intraocular pressure or glaucoma are more likely to be diffuse and therefore present a higher risk for metastasis.13–17 In our series two patients died of metastatic disease; the time between treatment and death was 3 years and 6 years, respectively. Other groups do not report any deaths from metastasis. For example, Pe’er et al18 described 558 treated uveal melanomas, 2.1% of which were isolated iris melanoma, which did not metastasise. In Lumbroso-Le Rouic series8 of 21 patients with iris melanomas treated with PBT, the iridocorneal angle was involved in 71.4% of the patients but none of the patients developed confirmed metastasis. Concerns have been raised regarding the safety of trabeculectomy in cases where the intraocular pressure is not medically controlled after treatment of iris melanoma.19 However, none of the two patients undergoing trabeculectomy after proton beam radiotherapy developed metastasis. Case reports of recurrence of CB and iris melanoma following trabeculectomy have been described in the literature.20 21 There are concerns that tumour cells might seed though the drainage fistula and metastasise to other parts of the body. We consider these risks to be very small. Moreover, metastatic disease occurs
Sandinha MT, et al. Br J Ophthalmol 2014;98:484–487. doi:10.1136/bjophthalmol-2013-303321
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Clinical science haematogenously and there is growing evidence dissemination starts at a very early stage.19 For this reason, it is unlikely that glaucoma drainage surgery would enhance the risk of metastatic spread to the rest of the body by providing an exit route from the eye. In conclusion, we describe eight patients with recurrent iris melanomas after PBT. Most recurrences were marginal, occurring as a result of underestimation of the extent of spread; however, one tumour seems to have been radioresistant. The risk of local tumour recurrence should be considered when planning proton beam radiotherapy for iris melanoma and subsequent long-term surveillance. Contributors MTS wrote the paper and was responsible for the acquisition and interpretation of data. AK and RDE revised the manuscript critically for important intellectual content. SEC and BD contributed to the analysis of data and to the revision of the article. All five authors were responsible for editing the final version. Competing interests None. Provenance and peer review Not commissioned; externally peer reviewed.
REFERENCES 1 2 3 4 5
Damato BE, Coupland SE. Differences in uveal melanomas between men and women from the British Isles. Eye (Lond) 2012;26:292–9. Shields CL, Kaliki S, Hutchinson A, et al. Iris Nevus Growth into Melanoma: analysis of 1611 consecutive eyes: the ABCDEF guide. Ophthalmology 2013;120:766–72. Demirci H, Shields CL, Shields JA, et al. Diffuse iris melanoma: a report of 25 cases. Ophthalmology 2002;109:1553–60. Shields CL, Kaliki S, Shah SU, et al. Iris melanoma: features and prognosis in 317 children and adults. J AAPOS 2012;16:10–16. Conway RM, Chua WC, Qureshi C, et al. Primary iris melanoma: diagnostic features and outcome of conservative surgical treatment. Br J Ophthalmol 2001;85:848–54.
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Shields CL, Naseripour M, Shields JA, et al. Custom-designed plaque radiotherapy for nonresectable iris melanoma in 38 patients: tumour control and ocular complications. Am J Ophthalmol 2003;135:648–56. Damato B, Kacperek A, Chopra M, et al. Proton Beam Radiotherapy of Iris Melanoma. Int J Radiation Oncology Biol Phys 2005;63:109–15. Lumbroso-Le Rouic L, Delacroix S, Dendale R, et al. Proton beam therapy for iris melanomas. Eye (Lond) 2006;20:1300–5. Rundle P, Singh AD, Rennie I. Proton beam therapy for iris melanoma: a review of 15 cases. Eye (Lond) 2007;21:79–82. Sharkawi E, Oleszczuk JD, Bergin C, et al. Baerveldt shunts in the treatment of glaucoma secondary to anterior uveal melanoma and proton beam radiotherapy. The Br J Ophthalmol 2012;96:1104–7. Konstantinidis L, Roberts D, Errington RD, et al. Whole anterior segment proton beam radiotherapy for diffuse iris melanoma. Br J Ophthalmol 2013;97:471–4. Tan AN, Hoevenaars JG, Webers CA, et al. Baerveldt implant for secondary glaucoma due to iris melanoma. Clin Ophthalmol 2010;4:407–9. Demirci H, Shields CL, Shields JA, et al. Diffuse iris melanoma. Ophthalmology 2002;109:1553–60. Shields CL, Shields JA, Materin M, et al. Iris melanoma; risk factors for metastasis in 169 consecutive patients. Ophthalmology 2001;108:172–8. Brown D, Boniuk M, Font RL. Diffuse malignant melanoma of iris with metastases. Surv Ophthalmol 1990;34:357–64. Rones B, Zimmerman LE. The prognosis of primary tumors of the iris treated by iridectomy. Arch Ophthalmol 1958;60:193–205. Sunba MS, Rahi AH, Morgan G. Tumours of the anterior uvea. I. Metastasizing malignant melanoma of the iris. Arch Ophthalmol 1980;98:82–5. Frenkel S, Hendler K, Pe’er J. Uveal melanoma in Israel in the last two decades: characterization, treatment and prognosis. Isr Med Assoc J 2009;11:280–85. Tan AN, Hoevenaars JGMM, Webers CAB, et al. Baerveldt implant for secondary glaucoma due to iris melanoma. Clin Ophthalmol 2010;4:407–9. Grossniklaus HE, Brown RH, Stulting RD, et al. Iris melanoma seeding through a trabeculectomy site. Arch Ophthalmol 1990;108:1287–90. Tay E, Cree IA, Hungerford J, et al. Recurrence of treated ciliary body melanoma following trabeculectomy. Clin Experiment Ophthalmol 2009;37:503–5.
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Recurrence of iris melanoma after proton beam therapy Maria T Sandinha, Andrzej Kacperek, R Douglas Errington, et al. Br J Ophthalmol 2014 98: 484-487 originally published online January 10, 2014
doi: 10.1136/bjophthalmol-2013-303321
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Clinical science
Recurrence of iris melanoma after proton beam therapy Maria T Sandinha,1,2 Andrzej Kacperek,3 R Douglas Errington,3 Sarah E Coupland,1 Bertil Damato1,4 1 St Paul’s Eye Unit, Liverpool Ocular Oncology Centre, Liverpool, UK 2 Sunderland Eye Infirmary, Sunderland, UK 3 Douglas Cyclotron Unit, Clatterbridge Cancer Centre, Liverpool, UK 4 Ocular Oncology Service, Departments of Ophthalmology and Radiation Oncology, University of California San Francisco, San Francisco, USA
Correspondence to Dr Maria T Sandinha, Vitreoretinal Service, Sunderland Eye Infirmary, Queen Alexandra Road, Sunderland, Tyne and Wear SR2 9HP, UK; [email protected] Received 14 April 2013 Revised 16 November 2013 Accepted 11 December 2013 Published Online First 10 January 2014
To cite: Sandinha MT, Kacperek A, Errington RD, et al. Br J Ophthalmol 2014;98:484–487. 484
ABSTRACT Background/Aims A retrospective service evaluation to report on recurrence of iris melanoma after proton beam therapy (PBT). Methods The cohort comprised 150 consecutive eyes with iris melanoma treated with proton beam radiotherapy. Treatment consisted of 53.1 Gy of proton beam irradiation delivered in four fractions over four consecutive days. Main outcome measures were local tumour control and tumour-related mortality. Results A total of 150 patients were treated. The median follow-up time was 66 months (range, 12– 108 months). The tumour ultrasound thickness ranged from 1.1 mm to 4.9 mm, with a median of 2.4 mm. The tumours in these patients had a median largest basal diameter of 6.7 mm (range, 2.9–8.4 mm), involving more than two clock hours of iris or angle in five patients. The ciliary body was involved in three patients. Eight patients (5.3%) presented with local recurrence, diagnosed after a median follow-up of 24 months (range, 12–84 months). The recurrence was focal in two patients and diffuse in six. Six eyes were enucleated whereas one eye underwent iridocyclectomy and one received a second course of PBT. Conclusions PBT provides excellent local tumour control and ocular preservation with good retention of vision. Most recurrences occur because the extent of the tumour is clinically underestimated but some tumours are radioresistant. Recurrence can occur several years after treatment. These findings indicate the need for wide safety margins and even radiotherapy of the entire anterior segment in patients with diffuse disease. Surveillance after treatment needs to be lifelong.
Iris melanomas account for approximately 3–5% of all uveal melanomas.1 No single characteristic conclusively differentiates these from naevi, but suspicious features include: young age, hyphaema, inferior iris location and diffuse growth and larger tumour size.2 Nodular iris melanomas tend to behave in an indolent fashion and have a better survival prognosis than ciliary body (CB) and choroidal melanomas; however, diffuse iris melanomas are more lethal.3 4 Enucleation is indicated if the tumour is considered too advanced for surgical resection or radiotherapy.5 6 Case series of patients treated with proton beam irradiation have been reported, with good results.7–11 Local recurrence is rare but can be life threatening and can result in loss of the eye.7 There is scope for a better understanding of the complication so that this outcome can be prevented and treated appropriately. To our knowledge, no previous studies have focused on this problem.
The aims of this study were to understand the nature of local recurrence of iris melanoma after proton beam radiotherapy and to determine how this complication might be avoided.
MATERIALS AND METHODS The study was a retrospective review of all patients with iris melanoma treated with proton beam therapy (PBT) as a primary treatment from January 1994 until December 2010. Patient details, which had been recorded prospectively, were obtained from the Liverpool Ocular Oncology Centre database. The tumours had been diagnosed as melanoma, either clinically, according to a variety of features (see Discussion), or histologically, and all were considered to have arisen in the iris. Patients with CB melanoma with iris involvement or with a tumour showing extrascleral spread were excluded. This study adhered to the tenets of the Declaration of Helsinki. Consent for the use of data, tissues, and images for research, tissue, and audit had routinely been obtained prospectively from patients. Institutional board approval was not required because this was a service evaluation. Pretreatment assessment included measurement of visual acuity with a Snellen chart (before 2006) or logarithm of the minimal angle of resolution chart (after 2005); slit-lamp examination, with measurement of longitudinal and transverse tumour diameters, prior to mydriasis; and gonioscopy, determining the circumferential extent of increased pigmentation in the angle, in clock hours. High-frequency B-scan ultrasonography was performed with an Eyecubed ultrasound machine (Ellex Ltd, I3 System) using a water bath filled with 2% hypromellose. Patients were treated according to a standard protocol.1 In summary, all patients received a dose of 53.1 Gy delivered in four fractions over four consecutive days. No localising markers were required. The eyelids were retracted out of the radiation field and the pupil was dilated to reduce the treatment volume. A 2.5–3.0 mm safety margin was planned around the tumour volume (this tumour volume included pigment seeding in the iridocorneal angle, when present at the time of diagnosis). Patients were reviewed approximately 6 months after the proton beam radiotherapy, then 6 monthly for 5 years, and then annually. For patients from outside the region, arrangements were made for consultations to alternate between the referring hospital and our clinic until the ocular condition appeared stable. At that point patients were discharged from our care for lifelong monitoring at their local hospital. Follow-up information on these
Sandinha MT, et al. Br J Ophthalmol 2014;98:484–487. doi:10.1136/bjophthalmol-2013-303321
Downloaded from bjo.bmj.com on April 23, 2014 - Published by group.bmj.com
Clinical science patients was obtained from the referring ophthalmologist or general practitioner.
RESULTS A total of 150 patients with iris melanoma were treated with proton beam radiotherapy between 1994 and 2011. The median follow-up time of all 150 patients was 66 months (range, 24–108 months). Eight patients (5.3%) presented with local recurrence, indicated by an increase in tumour size after an initial response to the treatment, or the appearance of tumour in a different location from when first diagnosed. Recurrences occurred after a median time of 24 months (range, 12–84 months) after initial treatment. At the initial diagnosis, the largest basal diameter of these tumours ranged from 2.9 mm to 8.4 mm with a median of 6.6 mm and the thickness ranged from 1.1 mm to 4.9 mm, with a median of 2.4 mm.
Case reports Patient 1 presented with a superior nodular iris melanoma in the right eye. The tumour measured 6.6×5.0×1.5 mm, involving three clock hours of iris (ie, 1–4 o’clock) and three clock hours of the angle. There was no CB involvement. The recurrence occurred 24 months after proton beam radiotherapy and showed annular spread around the anterior chamber and angle. The patient was treated by enucleation. The tumour was of mixed type. The patient was well in May 2011, 36 months after initial therapy. Patient 2 was treated for a nodular iris melanoma in the inferotemporal quadrant of the right eye. The tumour measured 3.3×3.0 × 1.1 mm and involved two clock hours of iris (6 to 8 o’clock) and four clock hours of the angle. The tumour recurrence occurred 12 months after radiotherapy with invasion of the angle and anterior chamber in a ring pattern. The patient was treated by enucleation. The tumour was of spindle type. The patient was well when this study was undertaken, 108 months after initial ocular therapy. Patient 3 had an inferonasal nodular iris melanoma in the left eye. The tumour measured 6.7×5.0×5.0 mm and involved three clock hours of iris (6–9), angle and CB (figure 1A). The recurrence occurred 60 months after initial therapy with annular spread in the anterior chamber and angle. The patient was treated by enucleation. The tumour was of mixed type. The patient died of metastasis 72 months after diagnosis. Patient 4 presented with an inferior nodular iris melanoma in the right eye. The tumour involved the two clock hours of the iris, from the 5 to the 7 o’clock meridians, measuring 2.8×2.3×1.2 mm. The recurrence in the form of annular spread around the anterior chamber and angle occurred 24 months after radiotherapy. The patient was treated by enucleation. The tumour was of mixed cell type. The patient was well on the date of this audit, 36 months after initial treatment. Patient 5 was treated for a nodular iris melanoma in the inferonasal quadrant of the right eye (figure 1B). The tumour measured 8.2×6.1×3.0 mm and involved four clock hours of iris (2–6), 6 h of the angle and 4 h of the CB. The patient required glaucoma drainage surgery 12 months after treatment. Twenty-four months after radiotherapy, she presented with limited recurrence (one clock hour), centred in the superior quadrant, adjacent to the trabeculectomy wound. The patient was treated with further PBT, localised to the recurrence. At the close of this study, 60 months after initial treatment, this patient was doing well.
Patient 6 presented with a nodular iris melanoma in the inferotemporal quadrant of the right eye. The tumour measured 7.0×6.0×4.0 mm and involved one clock hour of the iris (6–7), 4 h of the angle and 3 h of the CB. The patient underwent augmented trabeculectomy 24 months after treatment. The recurrence, 36 months after first PBT, showed extensive angle involvement in a ring pattern but the patient declined enucleation. The patient was treated with further proton beam radiation delivered to the entire anterior segment and although no further growth was noted, the eye became painful from neovascular glaucoma and this patient underwent enucleation 4 months after her second PBT. The tumour was of mixed cell type. The patient died 96 months after the initial treatment, of breast cancer metastasis. Patient 7 presented with a temporal nodular iris melanoma in the right eye (figure 1C). The tumour involved two clock hours of iris (8–10) and measured 5.6×3.3×1.8 mm. Eighty-four months after initial PBT (figure 1D), there was recurrence of the tumour within the irradiated field (figure 1E). The patient was treated by iridocyclectomy. The tumour was of mixed cell type. He subsequently had cataract surgery (figure 1F), which improved the visual acuity to 6/9 unaided. At the close of this study, 96 months after initial treatment, this patient was doing well. Patient 8 presented with a nodular iris melanoma in the inferonasal quadrant of the right eye. The tumour measured 8.4×6.8×4.9 mm, involving three and a half clock hours of iris (3–6.30), 6 h of the angle and 3 h of the CB. Although most of the anterior segment was irradiated with initial PBT, the patient was enucleated 24 months later because of diffuse annular spread, with extraocular extension subconjunctivally. The tumour was of spindle type. The patient died of metastatic disease 36 months after initial therapy. In summary, all patients with recurrent tumour presented initially with a nodular iris melanoma, with six showing angle involvement and three also having CB involvement. Two patients (Patients 2 and 4) with diffuse recurrence presented initially with tumours of only 3.3 mm and 2.8 mm diameter, respectively. Seven patients required enucleation, for recurrence in six patients and because of painful neovascular glaucoma in one case. Three patients had glaucoma and one patient developed cataract. No patients developed keratopathy or madarosis from the radiotherapy.
DISCUSSION Herein, we report eight recurrent iris melanomas after proton beam radiotherapy of 150 patients. The recurrences were diagnosed a median of 2 years (range, 1–7 years) after initial treatment. Seven recurrent tumours were marginal and one developed within the irradiated field. To our knowledge, such a central recurrence has not previously been reported after proton beam radiotherapy of iris melanoma. The main strength of this study is the large number of patients treated with PBT at a single centre. The main weakness is the short follow-up, so that the long-term recurrence rate may be underestimated. Another weakness is that most patients did not have histological confirmation of the diagnosis so that some of the tumours may have been naevi, in which case the incidence of recurrence would be higher than 5.3%. Tumours involving iris and CB were categorised according to location of their ‘centre of gravity’. Although it is possible that some tumours located predominantly in iris originated in the CB, excluding tumours with any CB involvement would have biased our results by excluding more aggressive iris melanomas.
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Clinical science Figure 1 Iris melanoma at presentation involving respectively three clock hours of iris, angle and ciliary body in Patient 3 (A) and four clock hours of iris, ciliary body and six of angle in Patient 5 (B). Iris melanoma at presentation in Patient 7 involving two clock hours of iris (C); the treatment plan showing 20%, 50% and 90% isodose curves for this patient (D). The tumour recurred in the irradiated field (E) and successful iridocyclectomy followed by cataract extraction and lens implant was carried out (F).
It is noteworthy that tumour recurrence with diffuse growth and seeding was seen in two patients after treatment of tumours having basal diameters of only 3.3 mm and 2.8 mm, respectively. Small tumour size does not guarantee that a melanocytic iris tumour is benign and that it will not recur after treatment. Most recurrences developed because the extent of diffuse tumours was underestimated when planning initial treatment. We now treat such tumours with very wide safety margins, in some cases including the entire anterior segment in the radiation field with good results, albeit having to treat glaucoma in most patients.11 12 Others report similar results after whole anterior segment irradiation.10 The central tumour recurrence in one patient raises the possibility of radioresistance. As most iris melanomas behave in an indolent fashion, with a low mitotic rate and slow growth, one would expect these tumours to be relatively radioresistant in comparison with melanomas in other parts of the eye. Higher doses of radiation would eliminate this problem but would increase the incidence of limbal stem cell deficiency and other ocular complications. Further studies are indicated to determine the long-term rates of central tumour recurrence and whether such cases can be satisfactorily treated by local resection or further radiotherapy. Although it is not possible to perform meaningful comparisons between our study and previous investigations by other workers, our local tumour control rate of 94.7% compares favourably with those achieved with brachytherapy and conservative surgery. Shields et al6 treated 38 patients with custommade plaques with a variety of isotopes and showed a local control rate of 92%. The same group also used 125I radioactive plaques for iris tumours for which surgery was not indicated or 486
after a first recurrence.6 They reported a local recurrence rate of 8% at 5 years and 15% at 10 years. Conway et al5 in their study of outcomes of conservative surgical treatment included 44 patients who underwent local resection and reported four recurrences (9%), three of which occurred within the first 3 years of primary ocular treatment. The metastatic rate of diffuse iris melanoma has been reported to be as high as 13% over 6 years13 compared with 3% after 5 years for circumscribed iris melanoma.14 The 10-year survival probability is about 95%.6 Iris melanomas in the presence of raised intraocular pressure or glaucoma are more likely to be diffuse and therefore present a higher risk for metastasis.13–17 In our series two patients died of metastatic disease; the time between treatment and death was 3 years and 6 years, respectively. Other groups do not report any deaths from metastasis. For example, Pe’er et al18 described 558 treated uveal melanomas, 2.1% of which were isolated iris melanoma, which did not metastasise. In Lumbroso-Le Rouic series8 of 21 patients with iris melanomas treated with PBT, the iridocorneal angle was involved in 71.4% of the patients but none of the patients developed confirmed metastasis. Concerns have been raised regarding the safety of trabeculectomy in cases where the intraocular pressure is not medically controlled after treatment of iris melanoma.19 However, none of the two patients undergoing trabeculectomy after proton beam radiotherapy developed metastasis. Case reports of recurrence of CB and iris melanoma following trabeculectomy have been described in the literature.20 21 There are concerns that tumour cells might seed though the drainage fistula and metastasise to other parts of the body. We consider these risks to be very small. Moreover, metastatic disease occurs
Sandinha MT, et al. Br J Ophthalmol 2014;98:484–487. doi:10.1136/bjophthalmol-2013-303321
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Clinical science haematogenously and there is growing evidence dissemination starts at a very early stage.19 For this reason, it is unlikely that glaucoma drainage surgery would enhance the risk of metastatic spread to the rest of the body by providing an exit route from the eye. In conclusion, we describe eight patients with recurrent iris melanomas after PBT. Most recurrences were marginal, occurring as a result of underestimation of the extent of spread; however, one tumour seems to have been radioresistant. The risk of local tumour recurrence should be considered when planning proton beam radiotherapy for iris melanoma and subsequent long-term surveillance. Contributors MTS wrote the paper and was responsible for the acquisition and interpretation of data. AK and RDE revised the manuscript critically for important intellectual content. SEC and BD contributed to the analysis of data and to the revision of the article. All five authors were responsible for editing the final version. Competing interests None. Provenance and peer review Not commissioned; externally peer reviewed.
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Recurrence of iris melanoma after proton beam therapy Maria T Sandinha, Andrzej Kacperek, R Douglas Errington, et al. Br J Ophthalmol 2014 98: 484-487 originally published online January 10, 2014
doi: 10.1136/bjophthalmol-2013-303321
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