Purpose
To evaluate survival and ocular outcome in recurrent uveal melanoma treated with proton beam therapy as salvage therapy.
Design
Retrospective, interventional case series.
Methods
We evaluated 48 patients with local recurrence of uveal melanoma after primary treatment with brachytherapy, transpupillary thermotherapy, proton beam therapy, laser photocoagulation, CyberKnife radiation, or photodynamic therapy. All patients received proton beam therapy as a salvage therapy at the Helmholtz Zentrum Berlin between July 2000 and December 2010. Kaplan-Meier analysis was used to obtain survival rates.
Results
The Kaplan-Meier estimator for local tumor control was 92.1% at 10 years after secondary treatment with proton beam therapy. Local recurrence developed in 3 patients; 1 of them underwent enucleation. During follow-up, 20.8% of the patients died (16.7% of metastasis, 4.1% of other causes or not specified). The most frequent surgical interventions were phacoemulsification (20.8%) and pars plana vitrectomy (10.4%). The Kaplan-Meier estimators were 77.4% for survival and 70.1% for the absence of metastasis 10 years after the primary treatment.
Conclusions
Proton beam therapy as a salvage treatment resulted in high local tumor control rates in recurrent uveal melanoma, especially if the primary therapy was transpupillary thermotherapy or plaque brachytherapy. Preservation of the globe was possible in most patients. Enucleations were indicated only in case of re-recurrences of uveal melanoma, but not because of secondary complications like intractable pain or secondary glaucoma. Retreatment was associated with vision deterioration, but loss of vision remained exceptional. Further larger prospective studies are needed to confirm the presented results of our retrospective analysis.
Uveal melanoma is the most common primary malignant ocular tumor in adults. Beyond the means of enucleation, different treatment methods for local tumor control have been developed during recent decades with the goal of preservation of the globe and its function. Today, the most accepted therapies are based on radiation, including brachytherapy with episcleral plaques (eg, 125 I or 106 Ru), teletherapy with heavy charged particles (proton beam therapy, helium ion therapy), and CyberKnife radiotherapy. In the end, all treatment methods bear the risk of local recurrence.
Depending on the technique, tumor size, and location, recurrence rates range between 3.2% to 22% in large studies. The type of recurrence usually is not specified further in most studies. Recurrence may take the form of marginal recurrence, diffuse recurrence, distant recurrence, or extrascleral extension. Large tumor diameter, small tumor volume, iris root involvement, and safety margins inferior to 1 mm have been identified as risk factors for local recurrence after proton beam therapy. Patients with tumors abutting or overhanging the optic disc and those requiring more than 3 sessions for tumor control had a much higher risk for recurrence after primary transpupillary thermotherapy (TTT). A specific issue of plaque therapy is the treatment of peripapillary tumors because the optic nerve is a mechanical barrier. Notched plaques are a possibility for juxtapapillary melanomas, but the correct placement for postequatorial plaques is challenging and can result in malpositioning or tilting. To spare critical structures, eccentric plaque placement has been practiced in some centers, which can result in higher recurrence rates.
Currently, enucleation is the most frequently used treatment for recurrent melanoma. This may be a consequence of the unclear prognostic impact of local recurrence. Several studies suggest that local recurrence is associated with a reduced outcome regarding the development of metastases and survival. As there is no consent for retreatment, the way of retreatment remains a single case decision. The treatment approach depends on the extent and the location of the recurrence. Only a few studies have analyzed the salvage treatment of recurrent choroidal melanoma with proton beam therapy. The goal of our study was to evaluate the survival rate and functional outcome of patients with local recurrence of choroidal melanoma retreated with proton beam therapy.
Methods
The study was approved by the institutional review board of the Charité-Universitätsmedizin Berlin, Berlin, Germany, and was in accordance with the tenets of the Declaration of Helsinki. We performed a retrospective chart analysis of consecutive patients receiving proton beam therapy as salvage therapy for recurrent choroidal melanoma between July 2000 and December 2010 in the Department of Ophthalmology, Charité, Berlin, Germany. Previous treatments comprised brachytherapy, TTT, photodynamic therapy (PDT), CyberKnife therapy, or proton beam therapy (See Tables 1,2, and 3 ). Of all cases of choroidal melanoma, 6.25% initially had an additional ciliary body involvement. Seventeen (35.4%) patients previously had been treated with ruthenium-plaque brachytherapy as primary treatment. Four patients (8.3%) had been treated with ruthenium-plaque brachytherapy in combination with TTT. The ruthenium plaque had been relocated in 2 patients because of a 2-peaked tumor. Nineteen patients (39.6%) were treated only with TTT, ranging from 1 to 4 applications, with an average of 2.4 applications. Most of the tumors treated with TTT were from external hospitals, and information regarding the applied energy is irreproducible in most cases. Four patients (8.3%) were treated with proton beam therapy, 2 patients (4.2%) were treated with multiple laser coagulations, 1 patient (2.1%) was treated with CyberKnife radiosurgery, and 1 patient (2.1%) was treated with PDT. Four patients already had a second relapse when they were included in our study. Two of those patients had been treated twice with ruthenium-plaque brachytherapy and 2 had been treated with TTT 3 times for each case.
| Patient No. | Primary Therapy | Comment | Kind of Relapse Before Salvage PBT | Time to Relapse Before Salvage PBT (mo) | Time to Relapse After Salvage PBT (mo) | Initial Prominence (mm) | Prominence Before Salvage PBT (mm) | Clinical Target Volume (mm 3 ) | Tumor Location |
|---|---|---|---|---|---|---|---|---|---|
| 1 | 106 Ru | Central margin | 11.4 | 3.5 | 4.0 | 200 | Parafoveal/circumpapillary | ||
| 2 | 106 Ru | Central margin | 22.7 | 8.1 | 3.3 | 240 | Parafoveal/parapapillary | ||
| 3 | 106 Ru | Central margin | 8.5 | 2.7 | 2.3 | 160 | Juxtafoveal/juxtapapillary | ||
| 4 | 106 Ru | Diffuse growth | 6.7 | 5.0 | 6.2 | 890 | Subfoveal/parapapillary | ||
| 5 | 106 Ru | Central margin | 18.8 | 1.7 | 2.7 | 229 | Parafoveal/parapapillary | ||
| 6 | 106 Ru | Central margin | 57.7 | 6.7 | 4.8 | 272 | Juxtafoveal/parapapillary | ||
| 7 | 106 Ru | Central margin | 15.6 | 1.7 | 1.1 | 145 | Parafoveal/parapapillary | ||
| 8 | 106 Ru | Central margin | 23.7 | 3.0 | 3.2 | 578 | Parafoveal/parapapillary | ||
| 9 | 106 Ru | Diffuse growth | 8.4 | 6.3 | 8.9 | 1148 | Subfoveal/parapapillary | ||
| 10 | 106 Ru | Diffuse growth | 15.6 | 1.8 | 1.9 | 57 | Subfoveal/parapapillary | ||
| 11 | 106 Ru | Central margin | 30 | 2.8 | 3.0 | 439 | Subfoveal/parapapillary | ||
| 12 | 106 Ru | Central margin | 15.6 | 6.0 | 8.1 | 1230 | Juxtafoveal/parapapillary | ||
| 13 | 106 Ru | Plaque was relocated because of the shape of the tumor | Central margin | 13.6 | 4.9 | 3.9 | 212 | Parafoveal/parapapillary | |
| 14 | 106 Ru | Plaque was relocated because of the shape of the tumor | Central margin | 21.8 | 7.1 | 8.8 | 1473 | Parafoveal/juxtapapillary | |
| 15 | 106 Ru (×2) | Local recurrence 36 mo after first treatment | Peripheral margin | 56.1 | 4.6 | 2.1 | ∼50 | Anterior | |
| 16 | 106 Ru (×2) | Two applications; insufficient radiation had been noted 2 mo after first treatment | Central margin | 5.8 | 6.8 | 5.4 | 207 | Parafoveal/juxtapapillary | |
| 17 | 106 Ru (×2) | Local recurrence 19 mo after the first treatment | Central margin | 31.5 | 4.1 | 2.6 | 351 | Parafoveal/juxtapapillary | |
| 18 | 106 Ru, TTT | Central margin | 9.9 | 7.5 | 9.3 | 530 | Parafoveal/juxtapapillary | ||
| 19 | 106 Ru, TTT | Diffuse growth | 16.3 | 6.0 | NA | ∼50 | Anterior | ||
| 20 | 106 Ru, TTT | Central margin | 46.7 | 4.9 | 3.5 | 302 | Parafoveal/parapapillary | ||
| 21 | 106 Ru, TTT (×3) | Central margin | 76.8 | 3.7 | 1.3 | 92 | Parafoveal/juxtapapillary |
| Patient No. | Primary Therapy | Comment | Kind of Relapse Before Salvage PBT | Time to Relapse Before Salvage PBT (mo) | Time to Relapse After Salvage PBT (mo) | Initial Prominence (mm) | Prominence Before Salvage PBT (mm) | Clinical Target Volume (mm 3 ) | Tumor Location |
|---|---|---|---|---|---|---|---|---|---|
| 22 | TTT | Diffuse growth | 6.1 | 2.2 | 2.6 | 160 | Subfoveal/juxtapapillary | ||
| 23 | TTT | No regression | 20.6 | NA | 3.5 | 140 | Parafoveal/juxtapapillary | ||
| 24 | TTT | Central margin | 3.6 | 40.5 a | 2.3 | 2.4 | 63 | Parafoveal/parapapillary | |
| 25 | TTT | Central margin | 14.3 | 3.2 | 3.3 | 126 | Juxtafoveal/parapapillary | ||
| 26 | TTT | Central margin | 54.4 | NA | 4.4 | 210 | Subfoveal/parapapillary | ||
| 27 | TTT (×2) | Single-eye situation, enucleation because of a choroidal melanoma approximately 18 y before | Central margin | 59.4 | 2.0 | 5.4 | 350 | Parafoveal/juxtapapillary | |
| 28 | TTT (×2) | Central margin | 53.1 | 1.7 | 1.5 | 140 | Subfoveal/parapapillary | ||
| 29 | TTT (×2) | Peripheral margin | 90.6 | 2.0 | 3.7 | 200 | Subfoveal/parapapillary | ||
| 30 | TTT (×2) | Central margin | 55.2 | 1.4 | 1.2 | 72 | Subfoveal/circumpapillary | ||
| 31 | TTT (×2) | Central margin | 130.4 | 2.6 | 1.2 | 185 | Subfoveal/parapapillary | ||
| 32 | TTT (×3) | Central margin | 9.4 | 3.1 | 2.0 | 100 | Subfoveal/circumpapillary | ||
| 33 | TTT (×3) | Central margin | 14.9 | 1.4 | 3.2 | 130 | Parafoveal/juxtapapillary | ||
| 34 | TTT (×3) | Local recurrence 28 mo after the first treatment, extraocular growth | Central margin | 34.7 | 2.1 | 2.5 | 500 | Parafoveal/juxtapapillary | |
| 35 | TTT (×3) | Local recurrence 14 mo after the first treatment | Central margin | 48.8 | 1.9 | 1.0 | 50 | Parafoveal/parapapillary | |
| 36 | TTT (×3) | Central margin | 106.1 | 1.4 | 0.7 | 125 | Parafoveal/juxtapapillary | ||
| 37 | TTT (×3) | Central margin | 112.1 | 1.9 | 2.8 | 91 | Juxtafoveal/juxtapapillary | ||
| 38 | TTT (×4) | Central margin | 14.5 | 2.3 | 1.9 | 80 | Parafoveal/juxtapapillary | ||
| 39 | TTT (×4) | Central margin | 4.2 | 4.2 | 5.3 | 440 | Subfoveal/circumpapillary | ||
| 40 | TTT (×4) | Central margin | 59.9 | 2.5 | 2.2 | 80 | Parafoveal/juxtapapillary |
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