What neoadjuvant treatment options are available to downsize a large choroidal melanoma before definitive local therapy or enucleation?

Neoadjuvant Treatment for Choroidal Melanoma

Neoadjuvant therapy is not a standard treatment approach for choroidal melanoma, as the evidence base is extremely limited and current management focuses on primary local therapies (plaque brachytherapy, proton beam radiotherapy, or enucleation) without downsizing strategies.

Critical Distinction: Cutaneous vs. Uveal Melanoma

The available guideline evidence addresses cutaneous melanoma, not choroidal (uveal) melanoma, which are biologically distinct diseases with different treatment paradigms 1:

• Cutaneous melanoma responds to immune checkpoint inhibitors and BRAF/MEK inhibitors, with robust neoadjuvant data 1
• Choroidal/uveal melanoma has fundamentally different biology, lacks response to standard immunotherapy, and has no established neoadjuvant protocols 2, 3

Limited Evidence for Choroidal Melanoma Neoadjuvant Approaches

Photodynamic Therapy (PDT)

The only specific neoadjuvant data for choroidal melanoma involves PDT before brachytherapy 4:

• PDT reduced tumor height in 73.4% of amelanotic choroidal melanomas before brachytherapy 4
• This resulted in 17.26% reduction in macular radiation dose and 21.22% reduction in optic nerve dose 4
• Visual outcomes were significantly better (mean loss of 5 ETDRS letters vs. 14 letters with brachytherapy alone at 24 months) 4
• This approach is limited to amelanotic tumors and represents the only published neoadjuvant strategy specific to choroidal melanoma 4

Current Standard Management

Primary treatment for choroidal melanoma remains local therapy without neoadjuvant downsizing 2, 3:

• Plaque brachytherapy (typically iodine-125) for medium-sized tumors 5
• Proton beam radiotherapy for larger or posterior tumors
• Enucleation for very large tumors or those with complications 5
• Transpupillary thermotherapy as adjunctive therapy in selected cases 5

Why Systemic Neoadjuvant Therapy Is Not Used

Uveal melanoma is immunologically "cold" and does not respond to checkpoint inhibitors that work in cutaneous melanoma 2, 3:

• Different molecular drivers (BAP1, SF3B1, EIF1AX mutations rather than BRAF) 3
• Lack of response to anti-PD-1/PD-L1 therapy 2
• No established role for targeted therapy in primary disease management 2, 3
• Metastatic uveal melanoma trials show minimal benefit from immunotherapy 2, 3

Clinical Approach to Large Choroidal Melanomas

For large choroidal melanomas where globe preservation is desired:

1. Consider plaque brachytherapy with notched plaque design for tumors encircling the optic disc, which achieved 75% globe retention 5
2. Accept that visual outcomes may be poor (62% with vision ≤20/200) but local control is achievable (86% without recurrence) 5
3. Enucleation remains appropriate for very large tumors (>10mm thickness) or those with complications 5, 6
4. Molecular prognostication should be performed via biopsy to assess metastatic risk, not to guide neoadjuvant therapy 3

Common Pitfalls

• Do not extrapolate cutaneous melanoma neoadjuvant data to choroidal melanoma—these are different diseases 1, 2
• Do not delay definitive local therapy waiting for systemic downsizing that will not occur 2, 3
• PDT is only applicable to amelanotic tumors and requires specialized expertise 4
• Tumor size alone should not dictate enucleation—circumpapillary tumors up to 14.8mm thickness have been successfully treated with plaque radiotherapy 5