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Efficacy and safety of proton radiotherapy in treating choroidal melanoma: a systematic review and meta-analysis

Radiation Oncology volume 20, Article number: 7 (2025) Cite this article

Abstract

Background

Proton beam therapy (PBT) has been gradually introduced for treating choroidal melanoma. This study systematically reviewed clinical reports to evaluate the efficacy and safety of PBT in choroidal melanoma patients.

Methods

This systematic review included all the primary studies involving PBT for choroidal melanoma patients through April 2024. Four publicly accessible databases were searched, and the statistical data were analyzed using STATA 15.0. The outcomes of interest included overall survival (OS), metastasis-free survival, local control rate, and adverse reactions.

Results

A total of six case series involving 1059 patients with choroidal melanoma were included. The random effect model meta-analysis showed that the 2-, 3-, 5-, and 10-year OS rates of patients with choroidal melanoma treated with PBT were 97%, 92%, 73%, and 39%, respectively. The metastasis-free survival rates at 2, 3, and 5 years were 92%, 89%, and 76%, respectively, and the local control rates at 1, 3, 5, and 10 years were 98%, 92%, 94%, and 88%, respectively. Four studies reported adverse reactions. The most common adverse reactions after PBT were glaucoma, optic neuropathy, and cataracts, with incidence rates ranging from 17.9 to 27%, 12.8–64%, and 29.6–39.8%, respectively.

Conclusions

This meta-analysis identified PBT as a vital local treatment strategy against choroidal melanoma. Both OS and local control rates showed excellent results. However, more prospective trials can help compare the efficacy of PBT with typical therapy.

Introduction

The most prevalent original intraocular malignant tumor, choroidal melanoma, is derived from choroid melanocytes and ranks second among all malignant melanomas, with a global average incidence of 9–80 per 10,000 people [1, 2]. The metastasis and mortality rates of choroidal melanoma are high, with approximately 50% of patients eventually developing hematologic metastasis. The liver is one of the most commonly metastasized organs [3]. Choroidal melanoma patients and liver metastases had a 50–80% 5-year survival rate and a 1-year median overall survival [4, 5].

Once, eye removal was the only effective treatment for choroidal melanoma patients [6]. However, the surgical treatment of choroidal tumors is often accompanied by a higher risk of early and late postoperative complications. Hence, surgery is more challenging than other treatment modalities [7]. Radiation therapy (RT) is necessary for treating choroidal melanoma, particularly inoperable choroidal melanomas or those with persistent tumors [8]. Choroidal melanoma has poor radiosensitivity, and the high irradiation doses needed are difficult to achieve with conventional photon therapy. Multiple retrospective investigations indicated that the survival outcomes of enucleation and RT remain comparable, suggesting a potential equivalence in their effectiveness [9,10,11]. The Collaborative Ocular Melanoma Study (COMS) prospective trial comparing eye removal and iodine-125 (125I) episcleral plaque brachytherapy (EPB) found no survival difference between patients treated with 125I brachytherapy and those treated with eye removal [12]. Therefore, EPB is the most common treatment modality for choroidal melanoma [13]. Many radioisotopes have been utilized for brachytherapy, including cobalt-60 [14], palladium103 [15], 125I [16], iridium-192, and ruthenium-106 [17]. However, studies involving 125I brachytherapy indicated a significantly higher late recurrence rate than charged particle radiation therapy [18].

Over the past few decades, proton beam therapy (PBT), such as particle RT techniques, has emerged. PBT has special physical and biological benefits over traditional RT using X-rays. The proton beam can produce a more even dose distribution because accelerating ions can discharge their maximum energy near their trajectory end, producing a Bragg peak [19]. Thus, PBT allows for increased doses to the tumor site while lessening damage to healthy tissue. Because of the exact dosing and targeting, proton RT causes lesser damage to tissues around the malignancy [20]. It is better suited for treating these challenging tumors near the macula or optic disc [21, 22]. Proton therapy has more advantages than photon therapy in terms of patient prognosis, as well as vision enhancement [23].

The application of PBT for treating choroidal melanoma is a rapidly expanding field of research. In recent years, more clinical trials have been conducted using PBT to treat choroidal melanoma. Therefore, assessing the OS, local control rates (LCR), and adverse effects in choroidal melanoma patients has become feasible after PBT. Numerous investigations have proven the effective disease management and favorable toxicity of PBT for choroidal melanoma [24,25,26]. However, the sample size was tiny in most studies, with ambiguous or debatable findings. Research grounded in evidence can enhance clinical practice [27]. Therefore, a solid meta-analysis would comprise a body of information beneficial for developing future applications and concepts in this domain. A meta-analysis published in 2013 [28] examined the effectiveness and side effects of charged particles in treating uveal melanoma (UM). However, this analysis included low-quality studies without accounting for differences in the treatment efficacy of different charged particles for UM.

Thus, this systematic review and meta-analysis intended to gather and examine most existing research on the efficacy and adverse effects of PBT used to treat choroidal melanoma, identify relevant studies, and describe evidence that would benefit both future highly qualified research and therapeutic practice.

Materials and methods

This review adhered to several other methodological studies [29,30,31] and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) [32]. The protocol was registered on the PROSPERO website. (PROSPERO registration number: CRD42023486142).

Literature search

Computerized searches of PubMed, Embase, Web of Science, and the Cochrane Library were performed to obtain studies published on proton therapy for choroidal melanoma from library inception to April 1, 2024. The references in the included studies and related reviews were assessed to obtain relevant studies not identified using the above searches. Keywords and mesh searches were combined to search. The main search terms included “choroidal melanoma,” “choroidal melanomas,” “proton therapy,” “proton beam,” “proton beam radiation therapy,” and “radiation therapy.”

Inclusion and exclusion criteria

Inclusion criteria

The inclusion criteria were (a) English literature, (b) study populations that included patients (no age limit) diagnosed with choroidal melanoma (any stage) for which independent data were available, (c) interventions, such as proton therapy, without other combined therapeutic measures, (d) comparators: unlimited control measures of treatment, and (e) studies that reported at least two of the following outcomes: OS, LCR, metastasis-free survival, and the incidence of ocular adverse reactions.

Exclusion criteria

The exclusion criteria were (a) a sample size of < 10 patients; (b) duplicate publications; (c) letters, reviews, protocols, and editorials; (d) studies on cells and animal models; (e) re-irradiation studies; and (f) studies lacking detailed data.

Data extraction

The data were extracted independently by two reviewers, and another reviewer validated the findings. The following information was obtained: (a) general details, such as the author, year of publication, and country of publication; (b) PICOS characteristics, such as tumor stage, length of treatment, overall dosage, times of segmentation, outcomes (OS, LCR, metastasis-free survival, and the incidence of ocular adverse reactions), and study design; and (e) details on the pertinent quality assessment items.

Quality and bias assessments

The risk of bias in the included case series [33,34,35,36,37,38] was assessed using the Institute of Health Economics (IHE) evaluation tool [39]. The tool was categorized into eight domains and 20 items. More than 70% of the items had an acceptable risk of bias.

Statistical analysis

Descriptive statistics helped analyze the adverse reaction rates and baseline factors. Frequencies and percentages described dichotomous data, while means with deviation from the mean or medians with interquartile ranges were for continuous data. We employed a random effects model to generate an overall pooled estimate for the case series investigations. The effect sizes for dichotomous outcomes were estimated by computing proportions with 95% confidence intervals (CIs). Each study was analyzed using STATA version 15.0 (StataCorp, College Station, TX, USA). A funnel plot assessed publication bias when 10 or more factors were pooled.

Results

Search strategy

The systematic literature search yielded 1,225 candidate papers, vetted based on the exclusion criteria (Fig. 1). We screened 116 relevant documents and excluded another 110 irrelevant studies (Fig. 1). Finally, six studies were included in the retrospective analysis.

Basic characteristics of included studies

As shown in Table 1, proton radiotherapy was administered to 1059 patients with choroidal melanoma across six different study sites. All six studies [33,34,35,36,37,38] reported survival rates after proton radiotherapy [34,35,36,37,38]. reported LCRs after proton radiotherapy and four [35,36,37,38] reported adverse events after proton radiotherapy. Table 1 includes the primary patient baseline characteristics from all included trials.

Fig. 1
figure 1

The flowchart of literature screening

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Table 1 The baseline characteristics of all the included studies
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The risk of bias assessment of the included studies

All the included studies were case series. According to Table 2, the IHE quality assessment results depicted the low overall quality of the included case series studies. This is mainly because the studies are blinded to the outcome assessors.

Table 2 Risk of bias evaluation of the involved case series studies
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Meta-analysis results

Overall survival

After 2, 3, 5, and 10 years of PBT treatment, the OS rates of patients with choroidal melanoma were 97% (95% CI: 0.88–0.99), 92% (95% CI: 0.85–0.97, I2 = 0%), 73% (95% CI: 0.61–0.83, I2 = 0%), and 39% (95% CI: 0.34–0.45) (Fig. 2) [33, 35,36,37,38].

Fig. 2
figure 2

The pooled incidences of OS post-PBT for choroidal melanoma

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Metastasis-free survival and local control rate

After 2, 3, and 5 years of PBT, choroidal melanoma patients had metastasis-free survival rates of 92% (95% CI: 0.82–0.96), 89% (95% CI: 0.82–0.95, I2 = 0%), and 76% (95% CI: 0.70–0.82, I2 = 0%), respectively (Fig. 3) [33, 34, 37, 38].

Fig. 3
figure 3

The pooled incidences of metastasis-free survival post-PBT for choroidal melanoma patients

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After 1, 3, 5, and 10 years of PBT, the LCRs in choroidal melanoma patients were 98% (95% CI: 0.95–0.99), 92% (95% CI: 0.86–0.97, I2 = 0%), 94% (95% CI: 0.92–0.95, I2 = 0%), and 88% (95% CI: 0.84–0.91) (Fig. 4) [33,34,35,36,37,38].

Fig. 4
figure 4

The pooled incidences of LCR post-PBT for choroidal melanoma patients

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Adverse reactions

Four studies reported adverse reactions [35,36,37,38]. Our systematic review observed that the main adverse reactions after proton RT were glaucoma, optic neuropathy, and cataracts. The incidence of glaucoma after proton therapy ranged from 17.9 to 27%. One study [37] compared events in patients with different disease states and identified that the prevalence of neovascular glaucoma was 23% in patients with stages T1 and T2 and 68% in patients with T3 stage after proton therapy. Papakostas et al. [35] found that the 10-year incidence of neovascular glaucoma was 44.8% in patients whose tumors near the optic nerve and/or macula were within two disc diameters (DD). In contrast, for patients with tumors > 2 DD from the optic nerve and/or macula, the occurrence of neovascular glaucoma was 20.6% over 10 years. Previous studies reported incidences of optic neuropathy from 12.8 to 64% and cataract incidences ranging from 29.6 to 39.8% [36, 37].

Publication bias and subgroup analysis

When assessing publication bias, if the number of included studies with the same outcome indicator is ≥ 10, the risk of publication bias should be detected with an “inverted funnel plot.” Considering the limited quantity of studies involved in the outcome indicators in this study, the inverted funnel plot and subgroup analyses were not performed.

Discussion

Choroidal melanoma is a radiotherapy-insensitive tumor and is highly resistant to conventional radiotherapy. Therefore, conventional radiotherapy is limited to the clinical application of melanoma. Compared with conventional radiotherapy, proton radiation therapy (PBT) has the Bragg peak property, delivering a higher dose to the target area without elevating the dose to the surrounding tissues and organs. Therefore, PBT will preferentially affect the targeted tumor cells and improve the local control rates (LCRs) while reducing the harm to the surrounding tissues [40,41,42,43,44]. The Bragg peak area (tumor target area) has a high relative biological effectiveness (RBE). Killing cancer cells is dominated by clustered DNA damage, independent of the cell cycle or the oxygen enhancement ratio, and is virtually unrepairable. PBT in cancer therapy is promising due to its superior biological dose distribution. Thus, proton therapy can treat various malignancies [45]. Although the alleged reduced toxicity and better therapeutic efficacy of proton therapy remain unconfirmed, this claim is strongly supported based on dosimetric comparisons [46].

Enucleation is the only viable treatment for choroidal melanoma. The NCCN guidelines for uveal melanoma suggest that radiotherapy is the most common first-line treatment for choroidal melanoma [3, 47]. For all choroidal melanomas with a maximum diameter of ≥ 5 mm but no more than 18 mm with a thickness of no more than 10 mm, plaque brachytherapy is the recommended first-line choice, based on the results from a large prospective randomized Collaborative Ocular Melanoma Study (COMS) trial [12, 48]. This trial showed no significant difference in long-term outcomes between plaque brachytherapy and enucleation in patients with small- to medium-sized choroidal melanomas. However, plaque brachytherapy does not obtain adequate margin coverage in tumors near the optic nerve. A prospective study revealed that plaque brachytherapy provides local control of choroidal melanoma near the optic nerve but has a high risk of radiation optic neuropathy [49]. For diametrically large tumors or those too close to the optic nerve that requires effective treatment with brachytherapy, particle beam therapy (proton, carbon ion, or helium ion) is the preferred radiation therapy method [47].

Common particle beam therapies include proton, carbon, and helium ions. The clinical application of proton radiation therapy for choroidal melanoma has a rich experience [40]. This is the first English-language meta-analysis study of PBT for choroidal melanoma patients. Six published studies were identified with a total of 1059 patients. Based on the combined results, the 2-, 3-, 5-, and 10-year OS rates for choroidal melanoma patients treated using PBT were 97%, 92%, 73%, and 39%, respectively. The 2-, 3-, and 5-year metastasis-free survival rates for choroidal melanoma patients treated using PBT were 92%, 89%, and 76%. The 1-, 3-, 5-, and 10-year local control rates of choroidal melanoma patients treated using PBT were 98%, 92%, 94%, and 88%, respectively. This indicates that proton beam therapy for choroidal melanoma results in good LCRs with unsatisfactory long-term OS. The quality of the included studies was low, with low certainty of evidence.

A multivariate analysis of the National Cancer Database observed that patients treated with proton therapy showed a lower overall survival rate than those receiving plaque brachytherapy [50]. A retrospective study published in 2014 indicated a 5-year overall survival rate of 81.5% in uveal melanoma patients treated with 106Ru plaque brachytherapy based on the COMS planning technique [51]. A randomized, multicenter clinical trial of COMS highlighted a 5-year overall survival rate of 90% for choroidal melanoma patients treated with 125I brachytherapy [12]. Thus, PBT for choroidal melanoma patients is inferior to plaque brachytherapy in OS. Gamma knife radiosurgery is commonly used to treat intracranial tumors and has been extended to treating ocular malignancies. Parker et al. conducted a meta-analysis and reported that the 3-year and 5-year survival rates of choroidal melanoma patients treated using Gamma knife radiation therapy were 92% and 76% [52]. Our pooled results observed 3- and 5-year OS rates of 92% and 73% for patients treated with choroidal melanoma. Thus, the PBT ineffectiveness for choroidal melanoma is like Gamma knife radiosurgery. However, further studies can confirm this due to the low evidence from the included studies, and most were retrospective clinical studies. The originally included studies reported overall survival rates at different times, diminishing the likelihood of obtaining results with meta-analysis.

Local tumor recurrence has been reported in nearly 16% of cases post-plaque brachytherapy [53,54,55]. A 2002 study showed a 3-year local control rate of 86.9% in choroidal melanoma patients treated with 125I episcleral plaque designed by COMS [56]. This is inconsistent with the standard treatment. The efficacy of 106Ru brachytherapy for uveal melanoma varies widely. Moreover, reported local control rates ranged between 59.0% and 98.0%. Factors impacting outcome include tumor size, thickness, anatomical location, and radiation dose to the tumor tip. The data included larger and thicker tumors that could exhibit responses with higher complication rates [57]. The present study observed that the 3- and 5-year LCRs of choroidal melanoma patients treated with PBT were 92% and 94%, respectively. Hence, the local control rate of PBT is superior to that of plaque radiation therapy in choroidal melanoma patients. Another meta-analysis published in 2021 showed a 5-year LCR of 84% in patients with UM treated with 106Ru brachytherapy [58]. A meta-analysis of Gallo et al. in 2024 showed a 5-year LCR of 83% for 106Ru brachytherapy for small choroidal melanomas [59]. In 2022, a systematic evaluation revealed a 5-year LCR of 91% after plaque brachytherapy for uveal melanoma [60]. A meta-analysis by Kosydar et al. found that patients with UM treated with photon stereotactic radiosurgery versus photon fractionated stereotactic radiotherapy had 5-year LCRs of 89% and 90%, respectively [61]. A systematic review found that choroidal melanoma patients treated with particle beam radiation had similar or better disease-specific survival than plaque brachytherapy [28]. Thus, LCR post-PBT treatment could be superior to different modalities. However, the conclusion may not be dependable enough because of the small sample size.

Adverse reactions are a common problem after choroidal melanoma radiotherapy. Nearly half of the patients develop ocular complications after proton irradiation, with cataracts and glaucoma being the most common complications [62,63,64]. Neovascular glaucoma is considered to be the primary cause of secondary eye removal after radiotherapy [65]. PBT is more effective than other treatment modalities in reducing the dose to the target tumor because it has a significant dose distribution there. Some studies demonstrated [22] that the impact of proton beam radiation on the retina’s outer layer is less than that of plaque brachytherapy, thus enabling patients to maintain better visual function. For PBT to reach a posterior tumor, the anterior portion must be radiated. Thus, the degree of anterior chamber and lens involvement are closely associated with the development of neovascular glaucoma [66, 67]. In addition to the RT technique and dose, unfavorable effects can differ according to the tumor’s size and location [68]. A meta-analysis by Karimi et al. [58] reported that the incidence of retinopathy after 106Ru brachytherapy in patients with UM ranged from 20 to 53%, and the incidence of cataracts ranged from 4.2 to 53.8%. A review in 2024 [69] reported that 7–28.6% of patients with UM treated with PBT developed neovascular glaucoma. In this study, the incidence of glaucoma after PBT treatment was 17.9–27%, the optic neuropathy incidence was 12.8–64%, and that of cataracts was 29.6–39.8%.

One report included [37] observed that the incidence of neovascular glaucoma post-irradiation was linked with the patient tumor stage. This could be related to the different irradiation doses patients receive across different disease stages. Another study showed [70] that radiation exposure to the optic disc was an independent risk factor for adverse effects, such as secondary glaucoma, radiation optic neuropathy, and iris neovascularization. Some studies reported [70,71,72,73] that the incidence of complications after proton irradiation was related to the irradiation exposure area of the macula or optic disc and increased as the area increased. Thus, exploring the relationship between irradiation dose and the incidence of adverse effects should be the next research goal for PBT.

Although this systematic review and meta-analysis demonstrated that PBT is an effective treatment for choroidal melanoma, the results of the study must be cautiously interpreted and applied because of some significant limitations. First, in terms of LCRs, this study found that the pooled 3-year LCR was lower than the pooled 5-year LCR, which may have been due to the lower quality of the studies in this meta-analysis and the smaller number of studies. Further research is needed to explore this idea. Second, some studies reported incomplete data, which could reduce the credibility of this study’s results. Third, because most of the included studies were retrospective, and very few comprehensively reported adverse reactions, they could not be combined for analysis. Fourth, many studies did not clearly describe UM versus choroidal melanoma, confounding the conclusions. Although PBT is a novel clinical treatment, more prospective studies with bigger sample sizes will be needed to determine its effectiveness as it gains popularity.

Conclusions

This meta-analysis identified PBT as a vital local treatment strategy against choroidal melanoma. Both OS and local control rates showed excellent results. However, more prospective trials can help compare the efficacy of PBT with typical therapy.

Data availability

No datasets were generated or analysed during the current study.

Abbreviations

PBT:

Proton beam therapy

OS:

Overall survival

RT:

Radiation therapy

LCR:

Local control rate

UM:

Uveal melanoma

PDT:

Photodynamic therapy

106Ru:

Ruthenium-106

SRS:

Stereotactic radiosurgery

fSRT:

Fractionated stereotactic radiotherapy

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Acknowledgements

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Funding

Supported by the Natural Science Foundation of Gansu Province (No. 23JRRA1291).

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Authors and Affiliations

  1. The First School of Clinical Medical, Gansu University of Chinese Medicine, Lanzhou, 730000, China

    Yuxin Miao, Tingwei Zheng, Qihang Lei, Qin Liu & Huiling Bai

  2. Gansu Provincial Hospital, Lanzhou, 730000, Gansu, China

    Yuxin Miao, Tingwei Zheng, Qihang Lei, Qin Liu & Huiling Bai

  3. Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, China

    Qiuning Zhang

  4. Evidence-based Medicine Center, School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu, China

    Meixuan Li

  5. Gansu Provincial Hospital of TCM, Lanzhou, Gansu, China

    Hongtao Luo

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Contributions

Conception/design: YM and QL. Provision of study materials and patients: YM, TZ, and QL. Data collection and/or assembly: YM, TZ, HB, and HL. Data analysis and interpretation: YM, TZ, HL, QL, HB, QZ, ML, QL. Manuscript writing: YM. Final approval of the manuscript: QL and HB.

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Miao, Y., Zheng, T., Zhang, Q. et al. Efficacy and safety of proton radiotherapy in treating choroidal melanoma: a systematic review and meta-analysis. Radiat Oncol 20, 7 (2025). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s13014-024-02580-w

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Keywords

Radiation Oncology

ISSN: 1748-717X

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