(NCCN

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NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines

)

Melanoma: Uveal

Version 2.2021 — June 25, 2021

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NCCN Guidelines Version 2.2021

Melanoma: Uveal

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

NCCN Guidelines Index

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NCCN Guidelines Panel Disclosures

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ϖ Dermatology

‡ Hematology/

Hematology oncology

Þ Internal medicine

† Medical oncology

۞ Ophthalmology

≠ Pathology

¥ Patient advocacy

§ Radiotherapy/

Radiation oncology

¶ Surgery/Surgical

oncology

* Discussion Section

Writing Committee

NCCN

Nicole McMillian, MS

Mai Nguyen, PhD

Brian Gastman, MD ¶

Case Comprehensive Cancer Center/

University Hospitals Seidman Cancer

Center and Cleveland Clinic Taussig

Cancer Institute

Kenneth Grossmann, MD, PhD †

Huntsman Cancer Institute

at the University of Utah

Samantha Guild ¥

AIM at Melanoma

Ashley Holder, MD ¶

O'Neal Comprehensive

Cancer Center at UAB

Douglas Johnson, MD, MSCI †

Vanderbilt-Ingram Cancer Center

Richard W. Joseph, MD ‡ †

Mayo Clinic Cancer Center

Giorgos Karakousis, MD ¶

Abramson Cancer Center at the

University of Pennsylvania

Kari Kendra, MD, PhD †

The Ohio State University Comprehensive

Cancer Center - James Cancer Hospital

and Solove Research Institute

Julie R. Lange, MD, ScM ¶

The Sidney Kimmel Comprehensive

Cancer Center at Johns Hopkins

Ryan Lanning, MD, PhD §

University of Colorado Cancer Center

Kim Margolin, MD †

City of Hope National Medical Center

*Susan M. Swetter, MD/Chair ϖ

Stanford Cancer Institute

*John A. Thompson, MD ‡ †/Vice-Chair

Fred Hutchinson Cancer Research Center/

Seattle Cancer Care Alliance

Mark R. Albertini, MD †

University of Wisconsin

Carbone Cancer Center

Christopher A. Barker, MD §

Memorial Sloan Kettering Cancer Center

Joel Baumgartner, MD ¶

UC San Diego Moores Cancer Center

Genevieve Boland, MD, PhD ¶

Massachusetts General Hospital

Cancer Center

Bartosz Chmielowski, MD, PhD ‡ †

UCLA Jonsson Comprehensive

Cancer Center

Dominick DiMaio, MD ≠

Fred & Pamela Buffett Cancer Center

Alison Durham, MD ϖ

University of Michigan

Rogel Cancer Center

Ryan C. Fields, MD ¶

Siteman Cancer Center at Barnes-

Jewish Hospital and Washington

University School of Medicine

Martin D. Fleming, MD ¶

The University of Tennessee

Health Science Center

Anjela Galan, MD ≠

Yale Cancer Center/

Smilow Cancer Hospital

Miguel Materin, MD ۞

Duke Cancer Institute

Anthony J. Olszanski, MD, RPh †

Fox Chase Cancer Center

Patrick A. Ott, MD, PhD † ‡ Þ

Dana-Farber/Brigham and Women's

Cancer Center

*P. Kumar Rao, MD ۞

Siteman Cancer Center at Barnes-

Jewish Hospital and Washington

University School of Medicine

Ramesh Rengan, MD, PhD §

Fred Hutchinson Cancer Research Center/

Seattle Cancer Care Alliance

Merrick I. Ross, MD ¶

The University of Texas

MD Anderson Cancer Center

April K. Salama, MD †

Duke Cancer Institute

Rohit Sharma, MD ¶

UT Southwestern Simmons

Comprehensive Cancer Center

Joseph Skitzki, MD ¶

Roswell Park Cancer Institute

Jeffrey Sosman, MD ‡

Robert H. Lurie Comprehensive Cancer

Center of Northwestern University

Katy Tsai, MD †

UCSF Helen Diller Family Comprehensive

Cancer Center

Evan Wuthrick, MD §

Moffitt Cancer Center

NCCN Guidelines Version 2.2021

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NCCN Guidelines Panel Disclosures

*P. Kumar Rao, MD/Lead ۞

Siteman Cancer Center at Barnes-Jewish

Hospital and Washington University School of

Medicine

Christopher A. Barker, MD §

Memorial Sloan Kettering Cancer Center

Samantha Guild ¥

AIM at Melanoma

Richard Joseph, MD ‡ †

Mayo Clinic Cancer Center

Miguel Materin, MD ۞

Duke Cancer Institute

Ramesh Rengan, MD, PhD §

Fred Hutchinson Cancer Research Center/

Seattle Cancer Care Alliance

Jeffrey Sosman, MD ‡

Robert H. Lurie Comprehensive Cancer

Center of Northwestern University

*Susan Swetter, MD ϖ

Stanford Cancer Institute

*John A. Thompson, MD ‡ †

Fred Hutchinson Cancer Research

Center/Seattle Cancer Care Alliance

Evan Wuthrick, MD §

Moffitt Cancer Center

ϖ Dermatology

‡ Hematology/Hematology oncology

† Medical oncology

۞ Ophthalmology

¥ Patient advocacy

§ Radiotherapy/Radiation oncology

* Discussion Section Writing Committee

UVEAL MELANOMA SUBCOMMITTEE

NCCN Guidelines Version 2.2021

Melanoma: Uveal

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NCCN Guidelines Index

Table of Contents

Discussion

NCCN Uveal Melanoma Panel Members

NCCN Uveal Melanoma Subcommittee Members

Summary of the Guidelines Updates

Clinical Presentation, Workup and Diagnosis, Clinical Staging (UM-1)

Workup and Staging, Tumor Size, Primary Treatment (UM-2)

Additional Primary Treatment (UM-3)

Systemic Imaging Based on Risk Stratication (UM-4)

Treatment for Recurrence (UM-5)

Treatment of Metastatic Disease (UM-6)

Risk Factors for Development of Uveal Melanoma (UM-A)

Principles of Radiation Therapy (UM-B)

Systemic Therapy for Distant Metastatic Disease (UM-C)

Staging (ST-1)

Clinical Trials: NCCN believes that

the best management for any patient

with cancer is in a clinical trial.

Participation in clinical trials is

especially encouraged.

Find an NCCN Member Institution:

https://www.nccn.org/home/member-

institutions.

NCCN Categories of Evidence and

Consensus: All recommendations

are category 2A unless otherwise

indicated.

See NCCN Categories of Evidence

and Consensus.

NCCN Categories of Preference:

All recommendations are considered

appropriate.

See NCCN Categories of Preference.

The NCCN Guidelines

are a statement of evidence and consensus of the authors regarding their views of currently accepted approaches to

treatment. Any clinician seeking to apply or consult the NCCN Guidelines is expected to use independent medical judgment in the context of individual

clinical circumstances to determine any patient’s care or treatment. The National Comprehensive Cancer Network

(NCCN

) makes no representations

or warranties of any kind regarding their content, use or application and disclaims any responsibility for their application or use in any way. The NCCN

Guidelines are copyrighted by National Comprehensive Cancer Network

NCCN Guidelines Version 2.2021

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UPDATES

UM-1

• Workup and Diagnosis, First bullet:

First arrow sub-bullet revised: "H&P, including personal/family

history of prior or current cancers (outside the eye)" and footnote

b added.

Third arrow sub-bullet revised: Ocular ultrasound of eye and orbit

• Footnote d revised: "...Biopsy of the primary tumor does not impact

outcome, but may provide prognostic information that can help

inform frequency of follow-up and may be needed for eligibility

for clinical trials. If biopsy is performed, molecular/chromosomal

testing for prognostication (chromosome analysis or gene

expression proling [GEP]) is preferred over cytology alone..."

(Also for UM-2A)

UM-2

• Tumor size: The largest diameter was revised as follows:

Largest diameter 5–18

5–19 mm and thickness <2.5 mm

Largest diameter ≤18

≤19 mm and thickness 2.5–10 mm

Largest diameter >18

>19 mm [any thickness] or Thickness >10

mm...

UM-2A

• Footnote u is new: Pathologic evaluation should follow the uveal

melanoma synoptic report recommendations by the College of

American Pathologists. Available at: https://documents.cap.org/

protocols/cp-uveal-melanoma-17protocol-4000.pdf

• Footnote p revised: "...The largest commercially available

brachytherapy plaque is 22

23 mm in diameter; thus, plaque

brachytherapy is recommended only for tumors with largest basal

diameter ≤18

≤19 mm.

UM-3

• Footnote v regarding "Extraocular extension at the time of

enucleation" is new: This is a relatively rare occurrence; data are

limited for these recommendations.

UM-4

• First column recommendation revised: Systemic imaging ± blood

tests based on risk stratication by genetic testing ± tumor size and

histology (at presentation).

• Risk of Distant Metastasis: Under High risk, the following were

removed:

Extraocular extension

Ciliary body involvement

• Footnote dd revised: "... Additional imaging modalities may include

chest/abdominal/pelvic CT with contrast, or dual energy subtraction

chest x-ray. However, screening should..."

• Footnote ee is new: 8q gain, especially when numerous copies are

found portends greater risk for metastasis.

UM-6

• Treatment of Metastatic Disease:

After "No evidence of disease" revised: Clinical trial, if available

(preferred)

After "Residual or progressive disease" the arrow was redrawn for

clarity.

Continued

Updates in Version 1.2021 of the NCCN Guidelines for Melanoma: Uveal from Version 3.2020 include:

General

• The Guideline name changed from Uveal Melanoma to Melanoma: Uveal.

Updates in Version 2.2021 of the NCCN Guidelines for Melanoma: Uveal from Version 1.2021 include:

MS-1

• The Discussion has been updated to reect the changes in the algorithm.

NCCN Guidelines Version 2.2021

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UM-A Risk Factors for Development of Uveal Melanoma

• First bullet:

Third arrow sub-bullet revised: Familial uveal melanoma (eg,

germline mutations in BAP1 mutation,

PALB-2, MBD4, or NF-1

(neurobromatosis) [NF-1], dysplastic nevus

syndrome [BK-mole])

Three new arrow sub-bullets added:

◊ Higher numbers of atypical cutaneous nevi, common cutaneous

nevi, and/or cutaneous freckles

◊ Light skin color, propensity to sunburn, and/or light eye (iris)

color

◊ Strong personal or family history of cancer

• Footnote b is new:

Evaluate for evidence of hereditary syndrome and refer for genetic

counseling and testing if indicated:

◊ Early age of diagnosis (<30 years of age)

◊ History of other primary cancers in the patient

◊ Family or personal history of other cancers known to be

associated with a hereditary syndrome:

– BAP1: RCC, mesothelioma, cutaneous melanoma,

cholangiocarcinoma, meningioma

– BRCA, PALB2: breast, ovarian, or pancreatic cancers

• New references were added.

UM-B Principles of Radiation Therapy

1 of 3

• Treatment Information

Second arrow sub-bullet revised: Plaque brachytherapy is

appropriate for patients with tumors ≤18

≤19 mm in largest base

diameter, ≤10 mm in thickness

Fifth arrow sub-bullet revised: "...MRI or CT may be used for

preoperative planning."

Sixth arrow sub-bullet revised: Round or custom plaques are most

commonly used,

. although non-round plaques (eg, notched) can

be considered for tumors in specic locations (eg, peripapillary).

Custom plaques, such as notched plaques, are commonly used for

tumors in specic locations (peripapillary).

• Treatment Dosing Information, rst arrow sub-bullet revised: "...The

largest commercially available brachytherapy plaque is 22

23 mm

in diameter; thus, plaque brachytherapy is recommended only for

tumors with largest basal diameter ≤18

≤19 mm.

2 of 3

• Radioembolization, rst bullet revised: Selective internal radiation

therapy for patients with liver metastases using yttrium-90 has been

reported in retrospective studies and in one prospective study.

3 of 3

• References updated.

UM-C Systemic Therapy for Distant Metastatic Disease

• Preferred regimens revised:

Clinical trial

When available and clinically appropriate, enrollment

in a clinical trial is recommended.

• Footnote a revised: When available and clinically appropriate,

enrollment in a clinical trial is recommended. The literature is not

directive regarding the specic systemic agent(s) oering superior

outcomes, but does provide evidence that uveal melanoma is

sensitive to some of the same systemic therapies used to treat

cutaneous melanoma. Although there are no systemic therapies

that have reliably improved the overall survival in patients with

metastatic uveal melanoma, individual patients may derive

substantial

benet on occasion. Given the lack of positive phase III

studies, clinical trials are preferred.

• New references were added for nivolumab/ipilimumab.

UPDATES

Updates in Version 1.2021 of the NCCN Guidelines for Melanoma: Uveal from Version 3.2020 include:

NCCN Guidelines Version 2.2021

Melanoma: Uveal

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

NCCN Guidelines Index

Table of Contents

Discussion

• Clinical evaluation, including:

H&P, including personal/family history of prior

or current cancers (outside the eye)

Color fundus photography

Ocular ultrasound

Comprehensive eye exam: Examine the front

and back of eye (biomicroscopy)

◊ Dilated fundus exam

(indirect ophthalmoscopy)

◊ Measure visual acuity

◊ Measure and document location and the size

of the tumor (diameter, thickness), distance

from disc and fovea, and ciliary body

involvement

◊ Assess and document if present:

– Subretinal uid

– Orange pigment

• Additional testing options include:

Autouorescence of the ocular fundus

Optical coherence tomography

Retinal uorescein angiography of the ocular

fundus

Transillumination

MRI occasionally needed to conrm diagnosis

• Consider biopsy if needed to conrm diagnosis

or for prognostic analysis for risk stratication

UM-1

CLINICAL

PRESENTATION

WORKUP AND DIAGNOSIS CLINICAL STAGING

This guideline does not include the management of iris melanoma.

See Risk Factors for Development of Uveal Melanoma (UM-A).

Biopsy is usually not necessary for initial diagnosis of uveal melanoma and

selection of first-line treatment, but may be useful in cases of uncertainty

regarding diagnosis, such as for amelanotic tumors, or retinal detachment.

Biopsy of the primary tumor may provide prognostic information that can help

inform frequency of follow-up and may be needed for eligibility for clinical trials.

If biopsy is performed, molecular/chromosomal testing for prognostication is

preferred over cytology alone. The risks/benefits of biopsy for prognostic analysis

should be carefully considered and discussed.

Risk factors for growth of small melanocytic tumors: presence of symptoms,

tumor thickness >2 mm, tumor diameter >5 mm, presence of subretinal fluid and

orange pigment, tumor margin within 3 mm of optic disk, ultrasound hollowness,

absence of halo.

The recommendation to "observe and re-evaluate" consists of tests listed under

"Workup and Diagnosis" that would help to clarify if there is progression and

determine the natural history of the indeterminate lesion.

Frequency of evaluation should depend on index of suspicion, patient age, and

medical frailty.

• Suspicious pigmented

uveal tumor of ciliary

body and/or choroid

Symptoms may

include:

◊ Vision loss

◊ Vision changes

(eg, blurred vision,

photopsia, oaters,

metamorphopsia)

May be asymptomatic

Assessment of risk

factors for developing

uveal melanoma

Uveal melanoma

Observe and

re-evaluate for growth or

features of malignancy

• Every 2–4 months

clinically indicated

• Then close follow-up

for 5 years

• Then annually

thereafter

See Workup and

Staging for uveal

melanoma (UM-2)

Diagnosis uncertain

and/or <3 risk factors

for growth

NCCN Guidelines Version 2.2021

Melanoma: Uveal

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

NCCN Guidelines Index

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Discussion

UM-2

WORKUP AND STAGING

PRIMARY TREATMENT

m,n

• Ocular imaging if not previously

done:

If large tumor, close to nerve

or suspicion of extraocular

involvement, MRI of orbit with and

without IV contrast

• Assess and document, if present:

Ciliary body involvement

Extraocular extension

• Extraocular imaging:

Baseline imaging to screen for

distant disease

h,i,j

• Consider biopsy of primary tumor

for prognostic analysis

Largest diameter 5–19 mm

and

thickness <2.5 mm

Largest diameter ≤19 mm

and thickness 2.5–10 mm

Largest diameter >19 mm

[any thickness]

or Thickness >10 mm [any diameter]

or Thickness >8 mm with optic nerve

involvement [any diameter]

Metastasis

• Options:

Brachytherapy plaque

o,p,q

Particle beam radiation

• Other options in highly select

patients

Options:

• Brachytherapy plaque

o,p,q,s

• Particle beam radiation

o,s

• Enucleation

t,u

Options:

• RT

Particle beam radiation

o,s

Stereotactic radiosurgery (SRS)

• Enucleation

t,u

See UM-6

See

Additional

Primary

Treatment

(UM-3)

TUMOR SIZE

See Footnotes on UM-2A

NCCN Guidelines Version 2.2021

Melanoma: Uveal

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

NCCN Guidelines Index

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Discussion

Biopsy of the primary tumor may provide prognostic information that can help inform frequency of follow-up and may be needed for eligibility for clinical trials. If biopsy

is performed, molecular/chromosomal testing for prognostication is preferred over cytology alone. The risks/benefits of biopsy for prognostic analysis should be

carefully considered and discussed.

Unless there is a specific contraindication to the administration of IV contrast (ie, renal impairment or history of a severe allergy), all cross-sectional imaging studies

should be performed with and without IV contrast.

Despite lack of treatment options for patients with distant metastatic disease, NCCN favors staging before primary treatment. For small, low-risk tumors, imaging after

primary treatment can be considered.

The most frequent sites of metastasis are liver, lungs, skin/soft tissue, and bones. At minimum, all patients should have contrast-enhanced MR or ultrasound of the

liver, with modality preference determined by expertise at the treating institution. Additional imaging modalities may include chest/abdominal/pelvic CT with contrast.

However, screening should limit radiation exposure whenever possible.

The cutoff for largest basal diameter depends on the dimensions of the largest brachytherapy plaque available, so may depend on the type of plaque and isotope

selected if brachytherapy is used.

Patients may be considered for palliative local therapy to the primary tumor in the setting of metastatic disease. Patients who present with advanced metastatic disease

and limited life expectancy may elect to have no treatment to their primary tumor.

An essential feature of high-quality care is that clinical decisions are informed by a variety of case-specific factors (eg, patient characteristics and preferences like age,

status of the other eye among others, disease characteristics, medical history), such that for some patients the best clinical approach may be other than one of the

listed options.

For small ciliary body and iris tumors (less than 3 clock hours), surgical excision may be considered.

See Principles of Radiation Therapy (UM-B).

The plaque should cover the tumor with a ≥2-mm circumferential margin. The exception is for tumors near the optic nerve where it may be impossible to achieve

adequate coverage of the margins. The largest commercially available brachytherapy plaque is 23 mm in diameter; thus, plaque brachytherapy is recommended only

for tumors with largest basal diameter ≤19 mm.

Brachytherapy with scleral patch graft for cases with limited extraocular extension.

Consider laser ablation or enucleation for patients who are not good candidates for brachytherapy or particle beam radiation.

Consider additional treatment with resection, laser ablation, transpupillary thermotherapy, or cryotherapy if concerned that adequate response was not achieved from

initial radiation.

While there is a trend toward avoiding enucleation, it is recommended for patients with neovascular glaucoma, tumor replacing >50% of globe, or blind, painful eyes.

Consider enucleation in cases of extensive extraocular extension.

Pathologic evaluation should follow the uveal melanoma synoptic report recommendations by the College of American Pathologists.

Available at: https://documents.cap.org/protocols/cp-uveal-melanoma-17protocol-4000.pdf

UM-2A

FOOTNOTES

NCCN Guidelines Version 2.2021

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and this illustration may not be reproduced in any form without the express written permission of NCCN.

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Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

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Discussion

UM-3

See Principles of Radiation Therapy (UM-B).

This is a relatively rare occurrence; data are limited for these recommendations.

ADDITIONAL PRIMARY TREATMENT

Extraocular

extension

at the time of

enucleation

All others

See Follow-up

(UM-4)

Microscopically positive or close

margins after enucleation (but no clinical,

intraoperative, or radiographic evidence of

gross residual disease in the orbit)

Observe

Map biopsy

and/or

Consider RT to orbit

(particle beam or photon beam)

Visible extraocular tumor or

suspicion of gross disease in the orbit

Biopsy extraocular tissue if possible

and consider one or more of the

following:

• Intraoperative cryotherapy

• Orbital exenteration

• RT to orbit (particle beam or

photon beam)

NCCN Guidelines Version 2.2021

Melanoma: Uveal

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

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Discussion

RISK OF DISTANT METASTASIS

SYSTEMIC IMAGING BASED ON RISK STRATIFICATION

Low risk:

• Class 1A

• Disomy 3

• Gain of chromosome 6p

• EIF1AX mutation

• T1 (AJCC) (See ST-1 and ST-2)

Medium risk:

• Class 1B

• SF3B1 mutation

• T2 and T3 (AJCC) (See ST-1 and ST-2)

High risk:

• Class 2

• Monosomy 3

• Gain of chromosome 8q

• BAP1 mutation

• PRAME expression

• T4 (AJCC) (See ST-1 and ST-2)

• Imaging to evaluate signs or symptoms

as clinically indicated

• Consider surveillance imaging

every

12 months

• Imaging to evaluate signs or symptoms

• Consider surveillance imaging

every 6–12 months for 10 years,

then as clinically indicated

• Imaging to evaluate signs or symptoms

• Consider surveillance imaging

every 3–6 months for 5 years,

then every 6–12 months for years 6–10,

then as clinically indicated

Recurrence

(See UM-5)

UM-4

Standard follow-

up for aected

eye

w,x,y

and

Systemic imaging

± blood tests

based on risk

stratication by

genetic testing

± tumor size

(at presentation)

Risk stratification to determine the frequency of follow-up should be based on the highest risk factor present.

The affected eye should be imaged with color fundus photography and

ultrasonography every 3–6 months for 3–5 years, then every 6–12 months

thereafter, if stable. The frequency of follow-up should depend on the size

and location (eg, juxtapapillary location, ciliary body involvement) of the

tumor at presentation. Radiation-related retinopathy and other treatment-

related complications may occur at any time following treatment.

The contralateral eye is not at increased risk of uveal melanoma, and can

be followed with routine ophthalmologic care.

Additional risk factors for recurrence: Juxtapapillary location and ciliary

body involvement.

Liver function tests (LFTs) may be considered as part of follow-up,

although some studies showed poor sensitivity for early detection of liver

metastases.

If biopsy not performed, then follow medium- or high-risk pathways,

depending on whether any high-risk features are present.

Onken MD, Worley LA, Char DH, et al. Collaborative ocular oncology group report

number 1: prospective validation of a multi-gene prognostic assay in uveal melanoma.

Ophthalmology 2012;119:1596-1603.

The most frequent sites of metastasis are liver, lungs, skin/soft tissue, and bones. For

patients who elect to have surveillance imaging, options include: contrast-enhanced

MR or ultrasound of the liver, with modality preference determined by expertise at

the treating institution. Additional imaging modalities may include chest/abdominal/

pelvic CT with contrast, or dual energy subtraction chest x-ray. However, screening

should limit radiation exposure whenever possible. Scans should be performed with IV

contrast unless contraindicated. Recognizing that there are limited options for systemic

recurrence, and that regular imaging may cause patient anxiety, patients should discuss

with their treating physician the benefits of surveillance imaging, and some patients may

elect to forgo surveillance imaging. Participation in a clinical trial is strongly encouraged.

8q gain, especially when numerous copies are found, portends greater risk for

metastasis.

NCCN Guidelines Version 2.2021

Melanoma: Uveal

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

NCCN Guidelines Index

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Discussion

UM-5

Recurrence

• H&P

• Biopsy if clinically

appropriate

,gg

• Ocular orbital

imaging if not

previously done

• Imaging to evaluate

extent of local

recurrence and/or for

baseline staging

Distant metastatic disease

TREATMENT FOR

RECURRENCE

WORKUP

RT (plaque brachytherapy or particle beam)

Enucleation

Laser ablation

(See UM-6)

Intraocular recurrence

(limited to eye, no orbital

involvement)

Extraocular involvement

Surgical resection

± RT to orbit (particle beam or photon beam)

± cryotherapy to orbital tumor

Surgical resection

or Cryotherapy to orbital tumor

and/or

RT to orbit (particle beam or photon beam)

Orbital involvement in patients

with prior enucleation

See Principles of Radiation Therapy (UM-B).

Extraocular recurrence or metastasis should be confirmed histologically whenever possible or if clinically indicated. Biopsy techniques may include FNA or core.

Obtain tissue for genetic analysis (screening for mutations that may be potential targets for treatment or determine eligibility for a clinical trial) from either biopsy of

the metastasis (preferred) or archival material if the patient is being considered for targeted therapy. Consider broader genomic profiling if the test results might guide

future decisions or eligibility for participation in a clinical trial.

Intraocular recurrence can often be diagnosed and managed without a biopsy. Additional prognostic FNA biopsy may be valuable.

The most frequent sites of metastasis are liver, lungs, skin/soft tissue, and bones. Imaging options include: contrast-enhanced MR or ultrasound of the liver, with

modality preference determined by expertise at the treating institution. Additional imaging may include chest/abdominal/pelvic CT with contrast and/or whole-body FDG

PET/CT; however, screening should limit radiation exposure whenever possible. Brain MRI with IV contrast may be performed if neurologic symptoms are present, but

routine CNS imaging is not recommended. Scans should be performed with IV contrast unless contraindicated.

For small recurrences in patients who cannot undergo RT or surgery, transpupillary thermotherapy is recommended.

NCCN Guidelines Version 2.2021

Melanoma: Uveal

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

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Discussion

UM-6

• Biopsy if clinically

appropriate



• Imaging

for

baseline staging

and to evaluate

specic signs and

symptoms

• Consider LFTs,

including LDH

WORKUP TREATMENT OF METASTATIC DISEASE

Distant

metastatic

disease

No evidence

of disease

Residual or

progressive

disease

Clinical trial,

if available

Observation

(See Follow-up

UM-4)

Imaging

to assess

response or

progression

Clinical trial (preferred)

Consider one or more of the following:

• Liver-directed therapies

Regional isolation perfusion of the liver

Embolization (chemotherapy,

radiation,

immunotherapy)

Ablative procedures (thermal ablation,

cryotherapy)

Consider resection and/or RT

(photon beam or SRS)

for limited or

symptomatic disease in the liver

• Systemic therapies

Systemic therapy

Consider resection and/or RT

(photon beam or SRS)

for limited or

symptomatic extrahepatic disease

• Best supportive/palliative care

(See NCCN Guidelines for Palliative

Care)

See Principles of Radiation Therapy (UM-B).

Extraocular recurrence or metastasis should be confirmed histologically whenever

possible or if clinically indicated. Biopsy techniques may include FNA or core. Obtain

tissue for genetic analysis (screening for mutations that may be potential targets for

treatment or determine eligibility for a clinical trial) from either biopsy of the metastasis

(preferred) or archival material if the patient is being considered for targeted therapy.

Consider broader genomic profiling if the test results might guide future decisions or

eligibility for participation in a clinical trial.

The most frequent sites of metastasis are liver, lungs, skin/soft tissue, and bones.

Imaging options include: contrast-enhanced MR or ultrasound of the liver, with modality

preference determined by expertise at the treating institution. Additional imaging may

include chest/abdominal/pelvic CT with contrast and/or whole-body FDG PET/CT;

however, screening should limit radiation exposure whenever possible. Brain MRI with IV

contrast may be performed if neurologic symptoms are present, but routine CNS imaging

is not recommended. Scans should be performed with IV contrast unless contraindicated.

LDH is a validated prognostic indicator in cutaneous melanoma.

However, its role in risk stratification of metastatic uveal melanoma is

unknown.

In general, there are no systemic therapies that have reliably

improved the overall survival in patients with metastatic uveal

melanoma; however, individual patients may derive substantial

benefit on occasion. If disease is confined to the liver, regionally

hepatic-directed therapies such as chemoembolization,

radioembolization, or immunoembolization should be considered. See

Systemic Therapy for Metastatic or Unresectable Disease (UM-C).

See Principles of Radiation for Metastatic Disease (ME-H 3 of 7) in

the NCCN Guidelines for Melanoma: Cutaneous.

NCCN Guidelines Version 2.2021

Melanoma: Uveal

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

NCCN Guidelines Index

Table of Contents

Discussion

UM-A

1 OF 2

• Patients with the following risk factors are at increased risk of developing uveal melanoma:

Choroidal nevi

Ocular/oculodermal melanocytosis (hyperpigmentation of episclera, uvea, and skin)

Familial uveal melanoma (eg, germline mutations in BAP1, PALB-2, MBD4, or NF-1 [neurobromatosis])

1-6

Higher numbers of atypical cutaneous nevi, common cutaneous nevi, and/or cutaneous freckles

Light skin color, propensity to sunburn, and/or light eye (iris) color

Strong personal or family history of cancer

• The presence of cutaneous melanoma does not increase the risk of uveal melanoma. Among patients with cutaneous melanoma, routine

screening for uveal melanoma is not required.

RISK FACTORS FOR DEVELOPMENT OF UVEAL MELANOMA

Risk factors for growth of small melanocytic tumors: presence of symptoms, tumor thickness >2 mm, tumor diameter >5 mm, presence of subretinal fluid and orange

pigment, tumor margin within 3 mm of optic disk, ultrasound hollowness, absence of halo.

Evaluate for evidence of hereditary syndrome and refer for genetic counseling and testing if indicated:

• Early age of diagnosis (<30 years of age)

• History of other primary cancers in the patient

• Family or personal history of other cancers known to be associated with a hereditary syndrome:

 BAP1: RCC, mesothelioma, cutaneous melanoma, cholangiocarcinoma, meningioma

 BRCA, PALB2: breast, ovarian, or pancreatic cancers

References

NCCN Guidelines Version 2.2021

Melanoma: Uveal

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

NCCN Guidelines Index

Table of Contents

Discussion

Walpole S, Pritchard AL, Cebulla CM, et al. Comprehensive Study of the Clinical Phenotype of Germline BAP1 Variant-Carrying Families Worldwide. J Natl Cancer Inst

2018;110:1328-1341.

Abdel-Rahman MH, Pilarski R, Cebulla CM, et al. Germline BAP1 mutation predisposes to uveal melanoma, lung adenocarcinoma, meningioma, and other cancers. J

Med Genet 2011;48:856-859.

Pilarski R, Carlo M, Cebulla C, Abdel-Rahman M. BAP1 Tumor Predisposition Syndrome. In: Adam MP, Ardinger HH, Pagon RA, et al. eds. GeneReviews. Seattle, WA:

Derrien AC, Rodrigues M, Eeckhoutte A, et al. Germline MBD4 mutations and predisposition to uveal melanoma. J Natl Cancer Inst 2021;113:80-87.

Abdel-Rahman MH, Sample KM, Pilarski R, et al. Whole exome sequencing identifies candidate genes associated with hereditary predisposition to uveal melanoma.

Ophthalmology 2020;127:668-678.

Abdel-Rahman MH, Pilarski R, Ezzat S, et al. Cancer family history characterization in an unselected cohort of 121 patients with uveal melanoma. Fam Cancer

2010;9:431-438.

Singh N, Singh R, Bowen RC, et al. Uveal Melanoma in BAP1 Tumor Predisposition Syndrome: Estimation of Risk. Am J Ophthalmol 2020;224:172-177.

RISK FACTORS FOR DEVELOPMENT OF UVEAL MELANOMA

REFERENCES

UM-A

2 OF 2

NCCN Guidelines Version 2.2021

Melanoma: Uveal

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

NCCN Guidelines Index

Table of Contents

Discussion

UM-B

1 OF 3

Plaque Brachytherapy

• Treatment Information

Plaque brachytherapy is a common form of denitive radiotherapy for the primary tumor.

A prospective trial found no dierence in cause-

specic survival among patients with tumors 2.5–10 mm in apical height (2.5–8 mm if peripapillary) and ≤16 mm in maximum basal diameter

randomized to plaque brachytherapy or enucleation.

Plaque brachytherapy is appropriate for patients with tumors ≤19 mm

in largest base diameter, ≤10 mm in thickness.

Plaque brachytherapy is appropriate as an upfront therapy after initial diagnosis, or after local recurrence following a prior local therapy.

Plaque brachytherapy should be performed by an experienced multidisciplinary team including an ophthalmic oncologist, radiation

oncologist, and brachytherapy physicist.

Tumor localization for brachytherapy may be performed using indirect ophthalmoscopy, transillumination, light pipe diathermy,

and/or ultrasound (intraoperative and/or preoperative).

MRI or CT may be used for preoperative planning.

Round or custom plaques are most commonly used. Custom plaques, such as notched plaques, are commonly used for tumors in specic

locations (peripapillary).

• Treatment Dosing Information

Using iodine-125 Collaborative Ocular Melanoma Study (COMS) plaques, 85 Gy should be prescribed to the apex of the tumor at low dose

rate (≥0.6 Gy/h). Dose adjustments may need to be made for non-COMS plaques.

The plaque margin on the tumor border should be

≥2 mm when feasible (diameter of plaque ≥4 mm larger than largest base diameter of tumor). The exception is for tumors near the optic

nerve where it may be impossible to achieve adequate coverage of the margins. The largest commercially available brachytherapy plaque

is 23 mm

in diameter; thus, plaque brachytherapy is recommended only for tumors with largest basal diameter ≤19 mm.

Using other radioisotopes (eg, ruthenium-106, palladium-103, strontium-90, cobalt-60, cesium-131), or non-COMS iodine-125 plaques,

60–100 Gy may be prescribed at low dose rate to the tumor apex; alternatively, a minimum dose may be prescribed to the base of the tumor.

The plaque margin on the tumor border may vary for other radioisotopes.

Particle Beam Therapy

• Treatment Information

Particle beam therapy is a common form of denitive radiotherapy for the primary tumor.

A prospective trial found no dierence in cause-

specic survival among patients with tumors ≤15 mm in maximum basal diameter and ≤11 mm in apical height randomized to plaque

brachytherapy or particle beam therapy.

Particle beam therapy is appropriate as upfront therapy after initial diagnosis, after margin-positive enucleation, or for intraocular or orbital

recurrence.

Particle beam therapy should be performed by an experienced multidisciplinary team including an ophthalmic oncologist, radiation

oncologist, and particle beam physicist.

Tumor localization for particle beam therapy may be performed using indirect ophthalmoscopy, transillumination, and/or ultrasound

(intraoperative and/or preoperative), MRI, and/or CT.

PRINCIPLES OF RADIATION THERAPY

Continued

References

The cutoff for largest basal diameter depends on the dimensions of the largest brachytherapy plaque available, so may depend on the type

of plaque and isotope selected if brachytherapy is used.

NCCN Guidelines Version 2.2021

Melanoma: Uveal

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

NCCN Guidelines Index

Table of Contents

Discussion

Particle Beam Therapy (continued)

• Treatment Dosing Information

For intraocular tumors:

◊ Using protons, 50–70 cobalt Gray equivalent (CGyE) in 4–5 fractions should be prescribed to encompass the planning target volume

surrounding the tumor.

7-9

◊ Using carbon ions, 60–85 CGyE in 5 fractions should be prescribed to encompass the planning target volume surrounding the tumor.

◊ Fiducial markers (tantalum clips) are encouraged to permit eye and tumor position verication for image-guided radiotherapy delivery.

◊ Volumetric planning in 3 dimensions (with or without CT and/or MRI) is encouraged to maximize radiation delivery to tumor and minimize

radiation delivery to organs and tissues at risk of injury from radiation.

Stereotactic Radiosurgery (SRS)

• Treatment Information

SRS is the least often used form of denitive radiotherapy for the treatment of primary or recurrent intraocular tumors.

11,12

Few prospective studies have assessed the ecacy and safety of radiosurgery.

13,14

Tumor localization, ducial marker use, and planning for SRS are generally consistent with particle beam therapy approaches.

• Treatment Dosing Information

Using fractionated SRS: 45–70 Gy in 2–5 fractions should be prescribed.

Using single-fraction SRS: 18–45 Gy in 1 fraction should be prescribed.

Photon Beam Radiotherapy

• Treatment/Dosing Information

Photon beam radiotherapy is a preferred option as an adjuvant to surgery for orbital involvement.

◊ Adjuvant radiotherapy can be used in patients at risk for local recurrence (margin-positive enucleation or exenteration) or regional

recurrence (resected regional metastases).

– Adjuvant RT Dosing

▪ A dose of 20–30 Gy in 5 fractions should be prescribed to the clinical target volume at risk for recurrence

15,16

using intensity-

modulated techniques with image guidance.

Photon beam radiotherapy can be used for treatment of distant metastases at risk for causing symptoms or for palliation of symptomatic

distant metastases.

– RT Dosing for Distant Metastases

▪ Doses of 8–30 Gy in 1–10 fractions should be prescribed to the appropriate target volume

using appropriate 3-D or intensity-

modulated radiation therapy (IMRT) techniques with or without image guidance.

Radioembolization

• Selective internal radiation therapy for patients with liver metastases using yttrium-90 has been reported in retrospective studies and in one

prospective study.

18,19

• Further study is required to determine the appropriate patients for and risks and benets of this approach.

UM-B

2 OF 3

PRINCIPLES OF RADIATION THERAPY

References

NCCN Guidelines Version 2.2021

Melanoma: Uveal

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

NCCN Guidelines Index

Table of Contents

Discussion

UM-B

3 OF 3

Abrams MJ, Gagne NL, Melhus CS, Mignano JE. Brachytherapy vs. external beam radiotherapy for choroidal melanoma: Survival and patterns-of-care analyses.

Brachytherapy 2016;15:216-223.

Collaborative Ocular Melanoma Study Group. The COMS randomized trial of iodine 125 brachytherapy for choroidal melanoma: V. Twelve-year mortality rates and

prognostic factors: COMS report No. 28. Arch Ophthalmol 2006;124:1684-1693.

American Brachytherapy Society - Ophthalmic Oncology Task Force. The American Brachytherapy Society consensus guidelines for plaque brachytherapy of uveal

melanoma and retinoblastoma. Brachytherapy 2014;13:1-14.

Almony A, Breit S, Zhao H, et al. Tilting of radioactive plaques after initial accurate placement for treatment of uveal melanoma. Arch Ophthalmol 2008;126:65-70.

Rivard MJ, Chiu-Tsao ST, Finger PT, et al. Comparison of dose calculation methods for brachytherapy of intraocular tumors. Med Phys 2011;38:306-316.

Mishra KK, Quivey JM, Daftari IK, et al. Long-term results of the UCSF-LBNL randomized trial: Charged particle with helium ion versus iodine-125 plaque therapy for

choroidal and ciliary body melanoma. Int J Radiat Oncol Biol Phys 2015;92:376-383.

Hrbacek J, Mishra KK, Kacperek A, et al. Practice patterns analysis of ocular proton therapy centers: The International OPTIC Survey. Int J Radiat Oncol Biol Phys

2016;95:336-343.

Hartsell WF, Kapur R, Hartsell SO, et al. Feasibility of proton beam therapy for ocular melanoma using a novel 3D treatment planning technique. Int J Radiat Oncol Biol

Phys 2016;95:353-359.

Gragoudas ES, Lane AM, Regan S, et al. A randomized controlled trial of varying radiation doses in the treatment of choroidal melanoma. Arch Ophthalmol

2000;118:773-778.

Tsuji H, Ishikawa H, Yanagi T, et al. Carbon-ion radiotherapy for locally advanced or unfavorably located choroidal melanoma: a phase I/II dose-escalation study. Int J

Radiat Oncol Biol Phys 2007;67:857-862.

Muller K, Naus N, Nowak PJ, et al. Fractionated stereotactic radiotherapy for uveal melanoma, late clinical results. Radiother Oncol 2012;102:219-224.

Dunavoelgyi R, Georg D, Zehetmayer M, et al. Dose-response of critical structures in the posterior eye segment to hypofractioned stereotactic photon radiotherapy of

choroidal melanoma. Radiother Oncol 2013;108:348-353.

Muller K, Nowak PJ, de Pan C, et al. Effectiveness of fractionated stereotactic radiotherapy for uveal melanoma. Int J Radiat Oncol Biol Phys 2005;63:116-122.

Zehetmayer M, Kitz K, Menapace R, et al. Local tumor control and morbidity after one to three fractions of stereotactic external beam irradiation for uveal melanoma.

Radiother Oncol 2000;55:135-144.

The Collaborative Ocular Melanoma Study (COMS) randomized trial of pre-enucleation radiation of large choroidal melanoma III: local complications and observations

following enucleation COMS report no. 11. Am J Ophthalmol 1998;126:362-372.

Ang KK, Peters LJ, Weber RS, et al. Postoperative radiotherapy for cutaneous melanoma of the head and neck region. Int J Radiat Oncol Biol Phys 1994;30:795-798.

Huguenin PU, Kieser S, Glanzmann C, et al. Radiotherapy for metastatic carcinomas of the kidney or melanomas: an analysis using palliative end points. Int J Radiat

Oncol Biol Phys 1998;41:401-405.

Jia Z, Jiang G, Zhu C, et al. A systematic review of yttrium-90 radioembolization for unresectable liver metastases of melanoma. Eur J Radiol 2017;92:111-115.

Gonsalves CF, Eschelman DJ, Adamo RD, et al. A prospective phase II trial of radioembolization for treatment of uveal melanoma hepatic metastasis. Radiology

2019;293:223-231.

PRINCIPLES OF RADIATION THERAPY

REFERENCES

NCCN Guidelines Version 2.2021

Melanoma: Uveal

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

NCCN Guidelines Index

Table of Contents

Discussion

UM-C

1 OF 3

SYSTEMIC THERAPY FOR DISTANT METASTATIC DISEASE

The literature is not directive regarding the specific systemic agent(s) offering superior outcomes, but does provide evidence that uveal melanoma is sensitive to some

of the same systemic therapies used to treat cutaneous melanoma. Although there are no systemic therapies that have reliably improved the overall survival in patients

with metastatic uveal melanoma, individual patients may derive benefit on occasion. Given the lack of positive phase III studies, clinical trials are preferred.

See NCCN Guidelines for Management of Immunotherapy-Related Toxicities.

See Management of Toxicities Associated with Targeted Therapy from the NCCN Guidelines for Melanoma: Cutaneous (ME-K).

The listed systemic therapy options do not cover BRAF or KIT mutated tumors. In general, uveal melanomas rarely have BRAF or KIT mutations.

Preferred Regimens

• When available and clinically appropriate,

enrollment in a clinical trial is recommended.

Other Recommended Regimens

• Consider one or more of the following options:

Immunotherapy

◊ Anti PD-1 monotherapy

– Pembrolizumab

– Nivolumab

◊ Nivolumab/ipilimumab

◊ Ipilimumab

Cytotoxic Regimens

◊ Dacarbazine

◊ Temozolomide

◊ Paclitaxel

◊ Albumin-bound paclitaxel

◊ Carboplatin/paclitaxel

Targeted Therapy

c,d

◊ Trametinib

References

NCCN Guidelines Version 2.2021

Melanoma: Uveal

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

NCCN Guidelines Index

Table of Contents

Discussion

UM-C

2 OF 3

Immunotherapy

Pembrolizumab and Nivolumab

• Kottschade LA, McWilliams RR, Markovic SN, et al. The use of pembrolizumab for the treatment of metastatic uveal melanoma. Melanoma Res

2016;26:300-303.

• Algazi AP, Tsai KK, Shoushtari AN, et al. Clinical outcomes in metastatic uveal melanoma treated with PD-1 and PD-L1 antibodies. Cancer

2016;122:3344-3353.

Nivolumab/ipilimumab

• Piulats JM, Espinosa E, de la Cruz Merino L, et al. Nivolumab Plus Ipilimumab for Treatment-Naive Metastatic Uveal Melanoma: An Open-Label,

Multicenter, Phase II Trial by the Spanish Multidisciplinary Melanoma Group (GEM-1402). J Clin Oncol 2021;39:586-598.

• Pelster MS, Gruschkus SK, Bassett R, et al. Nivolumab and Ipilimumab in Metastatic Uveal Melanoma: Results From a Single-Arm Phase II Study. J

Clin Oncol 2021;39:599-607.

Ipilimumab

• Zimmer L, Vaubel J, Mohr P, et al. Phase II DeCOG-study of ipilimumab in pretreated and treatment-naive patients with metastatic uveal melanoma.

PLoS One 2015;10:e0118564.

• Danielli R, Ridol R, Chiarion-Sileni V, et al. Ipilimumab in pretreated patients with metastatic uveal melanoma: safety and clinical ecacy. Cancer

Immunol Immunother 2012;61:41-48.

• Luke JJ, Callahan MK, Postow MA, et al. Clinical activity of ipilimumab for metastatic uveal melanoma: a retrospective review of the Dana-Farber

Cancer Institute, Massachusetts General Hospital, Memorial Sloan-Kettering Cancer Center, and University Hospital of Lausanne experience. Cancer

2013;119:3687-3695.

SYSTEMIC THERAPY FOR METASTATIC OR UNRESECTABLE DISEASE

REFERENCES

Continued

NCCN Guidelines Version 2.2021

Melanoma: Uveal

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

NCCN Guidelines Index

Table of Contents

Discussion

UM-C

3 OF 3

Cytotoxic Regimens

Dacarbazine

• Serrone L, Zeuli M, Sega FM, et al. Dacarbazine-based chemotherapy for metastatic melanoma: thirty-year experience overview.

J Exp Clin Cancer Res 2000;19:21-34.

Temozolomide

• Bedikian AY, Papadopoulos N, Plager C, et al. Phase II evaluation of temozolomide in metastatic choroidal melanoma. Melanoma Res 2003;13:303-

306.

Paclitaxel

• Wiernik PH and Einzig AI. Taxol in malignant melanoma. J Natl Cancer Inst Monogr 1993;15:185-187.

Albumin-bound paclitaxel

• Hersh EM, O'Day SJ, Ribas A, et al. A phase 2 clinical trial of nab-paclitaxel in previously treated and chemotherapy-naïve patients with metastatic

melanoma. Cancer 2010;116:155-163.

• Kottschade LA, Suman VJ, Amatruda T, et al. A phase II trial of nab-paclitaxel (ABI-007) and carboplatin in patients with unresectable stage iv

melanoma: a north central cancer treatment group study, N057E(1). Cancer 2011;117:1704-1710.

Paclitaxel/carboplatin

• Rao RD, Holtan SG, Ingle JN, et al. Combination of paclitaxel and carboplatin as second-line therapy for patients with metastatic melanoma. Cancer

2006;106:375-382.

• Homsi J, Bedikian AY, Papadopoulos NE, et al. Phase 2 open-label study of weekly docosahexaenoic acid-paclitaxel in patients with metastatic uveal

melanoma. Melanoma Res 2010;20:507-510.

Targeted Therapy

Trametinib

• Falchook GS, Lewis KD, Infante JR, et al. Activity of the oral MEK inhibitor trametinib in patients with advanced melanoma: a phase 1 dose-escalation

trial. Lancet Oncol 2012;13:782-789.

• Shoushtari AN, Kudchadkar RR, Panageas K, et al. A randomized phase 2 study of trametinib with or without GSK2141795 in patients with advanced

uveal melanoma. J Clin Oncol 2016;34:9511-9511.

SYSTEMIC THERAPY FOR METASTATIC OR UNRESECTABLE DISEASE

REFERENCES

Used with permission of the American College of Surgeons, Chicago, Illinois. The original source for this information is the AJCC Cancer Staging Manual, Eighth Edition

(2017) published by Springer International Publishing.

American Joint Committee on Cancer (AJCC)

Denitions of TNM for Choroidal and Ciliary Melanoma (8th ed., 2017)

Table 1. Denitions for T, N, M

Choroidal and Ciliary Body Melanomas

T Primary Tumor

TX Primary tumor cannot be assessed

T0 No evidence of primary tumor

T1 Tumor size category 1

T1a Tumor size category 1 without ciliary body involvement and extraocular extension

T1b Tumor size category 1 with ciliary body involvement

T1c Tumor size category 1 without ciliary body involvement but with extraocular extension ≤5 mm in largest diameter

T1d Tumor size category 1 with ciliary body involvement and extraocular extension ≤5 mm in largest diameter

T2 Tumor size category 2

T2a Tumor size category 2 without ciliary body involvement and extraocular extension

T2b Tumor size category 2 with ciliary body involvement

T2c Tumor size category 2 without ciliary body involvement but with extraocular extension ≤5 mm in largest diameter

T2d Tumor size category 2 with ciliary body involvement and extraocular extension ≤5 mm in largest diameter

T3 Tumor size category 3

T3a Tumor size category 3 without ciliary body involvement and extraocular extension

T3b Tumor size category 3 with ciliary body involvement

T3c Tumor size category 3 without ciliary body involvement but with extraocular extension ≤5 mm in largest diameter

T3d Tumor size category 3 with ciliary body involvement and extraocular extension ≤5 mm in largest diameter

T4 Tumor size category 4

T4a Tumor size category 4 without ciliary body involvement and extraocular extension

T4b Tumor size category 4 with ciliary body involvement

T4c Tumor size category 4 without ciliary body involvement but with extraocular extension ≤5 mm in largest diameter

T4d Tumor size category 4 with ciliary body involvement and extraocular extension ≤5 mm in largest diameter

T4e Any tumor size category with extraocular extension >5 mm in largest diameter

Notes

1. Primary ciliary body and choroidal melanomas are classied according to the four tumor size categories dened in Figure 1. (See ST-3)

2. In clinical practice, the largest tumor basal diameter may be estimated in optic disc diameters (DD; average: 1 DD = 1.5 mm), and tumor thickness may be

estimated in diopters (average: 2.5 diopters = 1 mm). Ultrasonography and fundus photography are used to provide more accurate measurements.

3. When histopathologic measurements are recorded after xation, tumor diameter and thickness may be underestimated because of tissue shrinkage.

Continued

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(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

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Discussion

ST-1

American Joint Committee on Cancer (AJCC)

Denitions of TNM for Choroidal and Ciliary Melanoma (8th ed., 2017)

Table 1. Denitions for T, N, M (continued)

N Regional Lymph Nodes

NX Regional lymph nodes cannot be assessed

N0 No regional lymph node involvement

N1 Regional lymph node metastases or discrete tumor

deposits in the orbit

N1a Metastasis in one or more regional lymph node(s)

N1b No regional lymph nodes are positive, but there are

discrete tumor deposits in the orbit that are not contiguous

to the eye (choroidal and ciliary body).

M Distant Metastasis

No distant metastasis by clinical classication

Distant metastasis

M1a Largest diameter of the largest metastasis ≤3.0 cm

M1b Largest diameter of the largest metastasis 3.1–8.0 cm

M1c Largest diameter of the largest metastasis ≥8.1 cm

G Histologic Grade

Grade cannot be assessed

Spindle cell melanoma (>90% spindle cells)

Mixed cell melanoma (>10% epithelioid cells and <90% spindle cells)

Epithelioid cell melanoma (>90% epithelioid cells)

Note: Because of the lack of universal agreement regarding which proportion

of epithelioid cells classies a tumor as mixed or epithelioid, some ophthalmic

pathologists currently combine grades 2 and 3 (non-spindle, ie, epithelioid cells

detected) and contrast them with grade 1 (spindle, ie, no epithelioid cells detected).

Used with permission of the American College of Surgeons, Chicago, Illinois. The original source for this information is the AJCC Cancer Staging Manual, Eighth Edition

(2017) published by Springer International Publishing.

Table 2. AJCC Prognostic Stage Groups

T N M

Stage I T1a N0 M0

Stage IIA T1b-d N0 M0

T2a N0 M0

Stage IIB T2b N0 M0

T3a N0 M0

Stage IIIA T2c-d N0 M0

T3b-c N0 M0

T4a N0 M0

Stage IIIB T3d N0 M0

T4b-c N0 M0

Stage IIIC T4d-e N0 M0

Stage IV Any T N1 M0

Any T Any N M1a-c

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Melanoma: Uveal

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

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Discussion

ST-2

Figure 1: Classication of Ciliary Body and Choroid Uveal Melanoma Based on Thickness and Diameter

Thickness (mm)

>15.0 4 4 4

12.1–15.0 3 3 4 4

9.1–12.0 3 3 3 3 3 4

6.1–9.0 2 2 2 2 3 3 4

3.1–6.0 1 1 1 2 2 3 4

≤3.0 1 1 1 1 2 2 4

≤3.0 3.1–6.0 6.1–9.0 9.1–12.0 12.1–15.0 15.1–18.0 >18.0

Largest basal diameter (mm)

Used with permission of the American College of Surgeons, Chicago, Illinois. The original source for this information is the AJCC Cancer Staging Manual, Eighth Edition

(2017) published by Springer International Publishing.

NCCN Guidelines Version 2.2021

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NCCN Guidelines Index

Table of Contents

Discussion

ST-3

NCCN Guidelines Version 2.2021

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NCCN Guidelines Index

Table of Contents

Discussion

NCCN Categories of Evidence and Consensus

Category 1 Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.

Category 2A Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate.

Category 2B Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate.

Category 3 Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.

All recommendations are category 2A unless otherwise indicated.

NCCN Categories of Preference

Preferred intervention

Interventions that are based on superior ecacy, safety, and evidence; and, when appropriate,

aordability.

Other recommended

intervention

Other interventions that may be somewhat less ecacious, more toxic, or based on less mature data;

or signicantly less aordable for similar outcomes.

Useful in certain

circumstances

Other interventions that may be used for selected patient populations (dened with recommendation).

All recommendations are considered appropriate.

CAT-1

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Discussion

Table of Contents

Overview ......................................................................................... MS-2

Staging ........................................................................................ MS-2

Molecular Characteristics ............................................................. MS-2

Risk Factors for Uveal Melanoma ................................................. MS-3

Literature Search Criteria and Guidelines Update Methodology ........ MS-5

Diagnosis and Workup .................................................................... MS-5

Characteristics, Detection, and Differential Diagnosis ................... MS-5

Initial Workup of Suspicious Pigmented Uveal Lesion ................... MS-7

Observation for Uncertain Diagnosis in Patients with Low Risk ...... MS-14

Further Workup Prior to Treatment ................................................ MS-15

Treatment of Localized Primary Uveal Melanoma .......................... MS-15

Surgical Options......................................................................... MS-16

Radiation Therapy ...................................................................... MS-17

Other Ablative Techniques ......................................................... MS-22

Treatment for Extraocular/Extrascleral Extension ....................... MS-23

Treatment of Localized Uveal Melanoma .................................... MS-24

Treatment of Primary Tumor in Patients with Metastatic Disease MS-25

Follow-up ...................................................................................... MS-25

Patterns of Local Recurrence ..................................................... MS-25

Patterns of Treatment Complications .......................................... MS-27

Surveillance Methods for Local Recurrence or Complications ..... MS-30

Follow-up for the Treated Eye .................................................... MS-31

Risk in Contralateral (Fellow) Eye............................................... MS-31

Patterns of Metastases .............................................................. MS-32

Risk Factors for Metastasis ....................................................... MS-32

Surveillance Methods for Distant Metastatic Disease ................. MS-34

Risk of Developing Secondary Cancers During Follow-up .......... MS-35

Follow-up for Distant Metastasis ................................................ MS-35

Management of Recurrence .......................................................... MS-36

Workup for Recurrence ............................................................. MS-36

Treatment for Local Recurrence ................................................ MS-37

Treatment for Metastatic Disease .............................................. MS-37

References ................................................................................... MS-52

This discussion corresponds to the NCCN Guidelines for Melanoma: Uveal. Last updated: June 25

, 2021.

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Overview

Uveal melanoma is the most common type of primary intraocular

malignancy in adults, with new cases occurring in 5 to 10 people per

million per year.

1-7

Uveal melanomas can arise anywhere in the uveal

tract, with less than 75% arising in the choroid, and the remainder arising

in the iris or ciliary body.

1,3,6,8,9

The distribution of uveal melanoma by sex, race, and geography differs

from that of cutaneous melanoma.

1,3,10

Most uveal melanomas are

localized at first presentation, and only a small percentage of cases

present with metastases (<3%).

6,10-14

Risk of metastasis varies by stage at

presentation, with 5-year risk of metastasis ranging from 3% to 5% for

stage I to 44% or greater for stage III.

8,13

Large population-based analyses

have reported disease-specific survival (for uveal melanoma) between

70% to 81% at 5 years,

2,5,6,10,15-17

and this rate has remained stable over

time.

Disease-specific survival varies by the extent of disease at

presentation.

12,13,15,18

For those with early-stage uveal melanoma (stage I–

II), 5-year melanoma-specific survival is 85% or better.

13,15,18

For those

with distant metastatic disease, most studies report estimated 5-year

survival of less than 20%,

13,15,19-22

which has not improved over the past

few decades.

These NCCN Guidelines include recommendations for management of

melanomas arising in the choroid or ciliary body. Recommendations for iris

melanomas are not included in these guidelines, because iris melanomas

are rare (3%–5% of uveal melanomas),

3,8,9,24,25

have a low rate of systemic

metastasis (~5% at 5 years compared with 15%–20% for ciliary body or

choroidal melanomas),

8,27-30

have a better prognosis than other types of

uveal melanoma,

25,30

have a different AJCC staging system,

and have a

different molecular signature.

32-36

Treatments for iris melanoma may differ

from other types of uveal melanoma due to these factors, as well as

anatomic considerations, ease of resection,

37-40

and the negative effects of

radiation to the iris.

41-46

Moreover, patients with iris melanomas were

excluded from many of the large randomized trials that inform treatment

recommendations for uveal melanomas.

14,47,48

Staging

The patterns of presentation and prognosis for uveal melanoma are

completely different from cutaneous melanoma, and the AJCC Staging

Manual, 8

Edition, includes separate staging systems for cutaneous,

uveal, and conjunctival melanoma.

The staging system for uveal

melanoma is further subdivided into separate T-staging for iris versus

choroidal or ciliary body melanoma.

Each of these staging systems is

empirically based on survival data from large epidemiologic studies, albeit

with more data independently validating the staging system for melanoma

of the choroid and ciliary body

12,13,18

compared with the iris

conjunctiva.

49,50

Molecular Characteristics

Cutaneous, uveal, and conjunctival melanomas also have different

molecular signatures.

34,51-61

Whereas BRAF, NRAS, KIT, and TERT

promoter mutations are extremely rare in uveal melanoma,

34,51-54,60,62,63

they are more common in conjunctival and cutaneous melanomas.

55-61

Most notably, BRAF mutations occur in 20% to 50% of conjunctival

melanomas, suggesting that conjunctival melanoma may be more similar

to cutaneous melanoma than to uveal melanoma.

55-58,60

Molecular markers

common in uveal melanomas (and may have prognostic significance) are

not often found in conjunctival or cutaneous melanoma. These include

chromosomal abnormalities (particularly chromosomes 3 and 8),

12,64-68

and

mutations in GNAQ or GNA11 (>80% of uveal cases),

34,51,66,69,70

BAP1,

71,72

SF3B1, and EIFAX.

36,73,74

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Risk Factors for Uveal Melanoma

Studies of large populations of patients with and without uveal melanoma

have identified a number of risk factors for the development of uveal

melanoma.

Choroidal Nevi

Large population-based studies have found that choroidal nevi occur in

1.9% to 6.5% of the population, depending on the population studied.

75-77

Choroidal nevi are more common in whites (4.6%–7.9% in the United

States) than in Hispanics or blacks.

Due to differences in prevalence

across races, it is not surprising that the reported rate also depends on

geography. Several large studies have shown that there is no association

between choroidal nevi and cutaneous melanoma.

Choroidal nevi can

transform into choroidal melanoma,

78,79

and one study reported that of

uveal melanomas diagnosed, 8% arose from a previously documented

nevus.

Others have argued that the fraction of uveal melanomas that

arise from nevi may in fact be much higher, as many patients diagnosed

with uveal melanoma have not had an ophthalmologic exam for many

years.

The rate of transformation from nevi to uveal melanoma is an issue of

much debate. Large population studies comparing the prevalence of

choroidal melanoma with the prevalence of choroidal nevi have estimated

the annual rate of malignant transformation of a choroidal nevus to range

from 1/4300 to 1/8845.

76,81,82

Many studies have aimed to more directly

determine the rate at which choroidal nevi transform into uveal melanoma

by evaluating changes in presumed nevi or indeterminate melanocytic

lesions over time.

83-87

Choroidal nevi can be difficult to distinguish from

choroidal melanoma, however, and there is much debate about how to

distinguish choroidal nevi from melanoma, as there is evidence from

multiple studies that many small lesions presumed to be nevi based on

size may actually be melanoma (See Diagnosis and Workup section).

88,89

Because the criteria for diagnosis of choroidal melanoma differed across

studies, and diagnosis was rarely confirmed by histology, there is concern

that in many studies some fraction of the population diagnosed with uveal

melanoma was in fact misdiagnosed. Given the debate about differential

diagnosis, the actual rate of transformation is unclear. Due to uncertainty

regarding uveal melanoma diagnosis, other analyses have looked at the

likelihood of lesion growth in patients with untreated melanocytic choroidal

lesions.

90,83,84,91-97

Growth has been correlated with risk of metastasis,

even though some growing choroidal nevi do not undergo malignant

transformation.

98,99

These studies have found that 13% to 36% of lesions

grew by 5 years.

83,90,94,95

The wide variability in rates across studies is

likely due to differences in the population selected for study and the

retrospective nature of data collection in some of these studies. More

importantly, these studies have also identified factors predictive of growth

(Table 1). Several analyses used tumor thickness greater than 2 mm,

tumor diameter greater than 5 mm, and tumor margin within 3 mm of the

optic disc as cutoffs for these risk factors.

94,96

Some of these

characteristics have also been associated with increased risk of tumor

metastasis: proximity to optic disc, documented growth, and tumor

thickness.

It is important to note that for patients with small lesions presumed to be

nevi or indeterminate, who are observed and treated upon evidence of

transformation (eg, growth, development of orange pigment, subretinal

fluid, other symptoms), the risk of metastasis is low.

91,95

The risk of death

from ocular melanoma in this situation is also low (1/2341 patients per

year),

but these risks increase with increasing baseline tumor size.

Patient characteristics that increase the likelihood of choroidal nevi growth

include Birt-Hogg-Dubé syndrome, myotonic dystrophy, and

immunocompromise. Cases of patients with uveal melanoma and

myotonic dystrophy have been reported,

100,101

and a retrospective study

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found an increased risk of choroidal melanoma in patients with myotonic

dystrophy (relative to the general population).

102

Cases of choroidal

melanoma have been reported in patients with Birt-Hogg-Dubé

syndrome.

103,104

Cases of ocular melanoma have been reported in

immunocompromised patients.

105,106

Ocular/Oculodermal Melanocytosis

The rate of ocular/oculodermal melanocytosis, which causes

hyperpigmentation of the episclera, uvea, and skin, is much higher in

patients with uveal melanoma than in the general population.

107-112

Familial Uveal Melanoma

Although only a small percentage of patients with uveal melanoma have at

least one family member with uveal melanoma,

113,114

this rate is higher

than would be expected by coincidence, given the very low incidence of

uveal melanoma in the population as a whole.

115,116

Having a family

member with uveal melanoma is therefore considered a risk factor for

melanoma. Studies of families with more than one member with uveal

melanoma have shown that there are several family cancer syndromes

associated with increased risk of uveal melanoma.

BAP1 Tumor Predisposition Syndrome

Certain BAP1 germline mutations have been associated with

predisposition for uveal melanoma, malignant mesothelioma, cutaneous

melanoma, and renal cell carcinoma.

72,116-126

Some families with BAP1

tumor predisposition syndrome also tend to have atypical Spitz tumors,

which are benign/precursor melanocytic lesions that have distinctive

clinical and pathologic features.

116,120,123,127-129

In individuals with germline

BAP1 mutations associated with this syndrome, the risk of uveal

melanoma is high (up to ~30%),

123,129,130

uveal melanoma tends to develop

at a younger age,

122,129

primary lesions tend to be larger and involve the

ciliary body,

and the disease has a more aggressive course.

72,131

Some

individuals with this syndrome develop more than one type of primary

cancer,

129,130,132

and there is a high likelihood of BAP1-associated cancers

in first- or second-degree relatives.

116,129

PALB2

Mutations in PALB2 have been associated with increased risk for

developing breast, ovarian, and pancreatic cancer. Pathogenic variants

leading to biallelic inactivation of PALB2 were identified in tumors of two

patients with familial uveal melanoma.

133

This finding from a

retrospective case series might warrant further investigation into PALB2

as a uveal melanoma susceptibility gene.

MBD4

MBD4 deleterious mutations have been identified in uveal melanoma

tumors at increased incidence compared with the general population and

associated with high tumor mutation burden.

134,135

Questions remain

whether MBD4 germline variants or somatic loss predisposes individuals

to uveal melanoma.

136

How MBD4 inactivation might affect

immunotherapy response is also worth further investigation.

134,137

Neurofibromatosis Type 1 (NF-1)

Neurofibromatosis type 1 (NF-1): Based on case reports of uveal

melanomas developing in patients with neurofibromatosis,

138-145

this

condition is thought to be a risk factor for uveal melanoma, although

population statistics supporting this claim are lacking.

146

Other Potential Risk Factors

Other risk factors include atypical cutaneous nevi, common cutaneous

nevi, iris nevi, and cutaneous freckles. These associations are based on

moderate-quality evidence from several studies, including meta-analyses,

a systematic review, a case study of familial uveal and cutaneous

melanoma, and case-controlled studies.

147-151

Patient characteristics

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associated with increased uveal melanoma risk are fair skin color, light

eye color, and propensity to sunburn.

147,152

In conclusion, the NCCN Panel recommends evaluation for evidence of

hereditary syndrome and referral for genetic counseling and testing in

case of: early age of diagnosis (<30 years of age), history of other primary

cancers in the patient, or family or personal history of other cancers known

to be associated with a hereditary syndrome (eg, BAP1 – renal cell

carcinoma, mesothelioma, cutaneous melanoma, cholangiocarcinoma,

meningioma; BRCA, PALB2 – breast, ovarian, and pancreatic cancer).

The Relationship Between Uveal and Cutaneous Melanoma

Clinic-based studies (n < 250) evaluating the likelihood of finding

concurrent cutaneous melanoma in patients with ocular melanoma

suggest a relationship between these two cancers.

151,153-155

Most large

population-based studies reveal no relationship between preexisting

cutaneous melanoma and the subsequent development of uveal

melanoma.

156-160

However, one SEER-based study revealed a potential

relationship between these two cancers.

161

Currently the NCCN Panel

does not consider cutaneous melanoma to be a risk factor for uveal

melanoma, and patients with cutaneous melanoma do not need more

frequent ocular screening than the general population.

For patients who present with uveal melanoma as their first primary

cancer, some population-based studies have shown increased risk of

subsequent cutaneous melanoma,

157-159,162

and others have not found the

risk to be significantly higher than in the general population.

163

One

analysis based on Swedish Cancer Registry data and re-analysis of

archival tissue found that some tumors originally recorded as primary

cutaneous melanomas were in fact uveal melanoma metastasis.

160

After

correcting the classification, the standardized incidence ratio (SIR) for

primary cutaneous melanoma in patients with prior uveal melanoma was

no longer significant.

160

Literature Search Criteria and Guidelines Update

Methodology

For each update to the NCCN Guidelines for Melanoma: Uveal, an

electronic search of the PubMed database was performed to obtain key

literature. The search results were narrowed by selecting studies in adult

patients published in English. Articles were also excluded if they: 1)

involved investigational agents that have not yet received FDA approval;

2) did not pertain to the disease site; 3) were clinical trial protocols; or 4)

were reviews that were not systematic reviews. The search results were

further narrowed by selecting publications reporting clinical data, meta-

analyses and systematic reviews of clinical studies, and treatment

guidelines developed by other organizations. The potential relevance of

the PubMed search results was examined by the oncology scientist and

panel chair, and a list of selected articles was sent to the panel for their

review and discussion at the panel meeting. The panel also reviewed and

discussed published materials referenced in institutional review comments

or provided with submission requests. The Discussion section was

developed based on review of data from peer-reviewed publications as

well as articles from additional sources deemed as relevant to these

guidelines and/or discussed by the panel (eg, e-publications ahead of

print, meeting abstracts). Any recommendations for which high-level

evidence is lacking are based on the panel’s review of lower-level

evidence and expert opinion.

The complete details of the development and update of the NCCN

Guidelines are available at www.NCCN.org.

Diagnosis and Workup

Characteristics, Detection, and Differential Diagnosis

The majority of uveal melanomas are symptomatic at

presentation,

9,78,164,165

but studies have reported 13% to 30% of patients

were asymptomatic at diagnosis (and are discovered by routine eye

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exam).

9,78,165,166

The most common symptom is blurred vision (38%–49%);

other common symptoms include visual field defect/loss, photopsia,

irritation and pain, metamorphopsia, floaters, redness, pressure, and

change in appearance.

9,78,165

Although in patients where a lesion was

detected, current imaging techniques provide very high accuracy of

diagnosis of medium to large uveal melanomas,

167,168

real-world studies

have reported relatively high rates of delay in diagnosis and treatment

(23%–37%) due to failure to detect these lesions in the initial

ophthalmologic exam.

9,78,165,169

Another surprising result was the high rate

at which uveal melanomas were initially missed in symptomatic

patients.

9,78

These studies underscore the importance of full dilation of the

pupil and meticulous examination of the fundus in any patient presenting

with symptoms.

Ciliary body melanoma can be difficult to detect,

as it is often hidden

behind the iris,

170

and symptoms often do not develop until the tumor is

large.

9,41,46,170

Ciliary body melanoma can cause lens tilting or

displacement,

46,170

cataract development,

46,170,171

and elevated intraocular

pressure,

and is often associated with dilated episcleral “sentinel”

vessels,

170

but only rarely has extrascleral extension.

170

Ciliary body

melanomas usually present with a dome shape,

46,170

but occasionally have

a circumferential ring shape.

170,172

Uveal melanoma typically presents as a pigmented lesion. One study of

8033 eyes with uveal melanoma found that the lesion was pigmented in

55%, nonpigmented in 15%, and 30% had a mixture of pigmented and

nonpigmented areas.

173

Some smaller studies report that a higher

percentage of patients have lesions with pigmentation,

166

likely due to

varying clinical diagnostic practices resulting in lower detection of

nonpigmented lesions. Uveal melanoma most often presents as a dome-

shaped tumor (75%), but approximately 20% present with a mushroom

shape due to the rupture of Bruch’s membrane and growth into the sub-

retinal space.

173

A small number of cases present as a diffuse, flat,

plateau-shaped tumor (6%) or have a multinodular tapioca appearance

(<1%).

173

Subretinal fluid is present in the majority of cases (75%).

173

Uveal melanoma tumors are associated with intraocular hemorrhage in

~10% of cases, and extraocular extension is apparent at presentation in

3% of patients.

173

As described above (see section entitled Risk Factors for Uveal

Melanoma), several risk factors have been identified that may increase the

risk of uveal melanoma. Included among these are rare diseases and

family cancer syndromes. When a pigmented lesion on the ciliary body or

choroid is discovered, these factors should be evaluated, as they may

inform the index of suspicion.

Studies of lesions that were thought to be uveal melanoma but later were

assigned an alternate diagnosis showed that the most common simulating

lesion is choroidal nevus.

174-177

These studies have reported a variety of

other conditions mistaken for uveal melanoma, including congenital

hypertrophy of the retinal pigment epithelium (RPE), and choroidal

hemangioma, peripheral exudative hemorrhagic chorioretinopathy,

hemorrhagic detachment of the retina or pigment epithelium, and age-

related macular degeneration.

174-177

There is a considerable overlap in size

between small uveal melanomas and large uveal nevi, and there is

evidence from several studies that many small lesions presumed to be

nevi based on size may actually be melanoma.

88,89

Although likely but not

explored, there is the possibility that some of the treated lesions were nevi

and not melanoma. Therefore, size and appearance based on clinical

exam may not be sufficient for diagnosis.

It is also important to rule out metastasis to the uvea from other cancers—

either known cancers based on patient history or occult primary cancer.

Among patients with metastases to the eye or orbit, the most common

primary cancer diagnosis is breast cancer, followed by lung cancer, which

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together account for over half of the cases.

178-180

The remainder of uveal

metastases arise from a variety of cancers, each cancer type accounting

for less than 5% of the population, including cancers of the kidney,

gastrointestinal (GI) tract, skin, prostate, thyroid, pancreas, and

others.

179,180

Initial Workup of Suspicious Pigmented Uveal Lesion

Upon discovery of a suspicious pigmented lesion in the ciliary body or

choroid, clinical evaluation should be performed to determine whether the

lesion is uveal melanoma, and if so, the extent of disease and other

characteristics that should inform management. Clinical evaluation should

include a complete history and physical, including personal or family

history of prior or current cancers (outside the eye), as this may help

determine whether the lesion is primary uveal cancer or a metastasis from

another primary cancer. A wide variety of imaging and clinical exam

techniques have been tested for their utility in diagnosis and

characterization of uveal melanoma. In most cases, the diagnosis of uveal

melanoma and characterization for treatment planning (or follow-up) can

be achieved based on comprehensive exam of the front and back of the

eye including biomicroscopy and dilated fundus exam (indirect

ophthalmoscopy), along with color fundus photography, and conventional

ocular ultrasound (US).

45,46,80,181

In some cases, additional imaging may be

needed to confirm diagnosis or better characterize the tumor for treatment

planning (or monitoring). Additional imaging options that may be useful

include autofluorescence of the ocular fundus, optical coherence

tomography (OCT), retinal fluorescein angiography of the ocular fundus,

transillumination, and MRI.

Features that are essential to measure and document as part of workup

include visual acuity (VA), location and size of the tumor (ie, diameter,

thickness), distance from the tumor to the disc and to the fovea, ciliary

body involvement, and subretinal fluid and orange pigment, if present. The

reason for recording each of these features and the utility of different

techniques for diagnosis and assessment of these features is described

below.

Features to Record

Visual Acuity

It is important to measure VA during workup, as many uveal melanomas

(as well as simulating lesions) can disturb vision, and changes in VA can

be an indication of progression, response to treatment, or a side effect of

certain treatments. VA or changes in VA can contribute to the differential

diagnosis, as benign nevi rarely cause visual impairment,

76,182

whereas

visual impairment or a decline in VA is associated with malignancy.

9,78,87,96

In patients with uveal melanoma, VA in the affected eye tends to be worse

than in the fellow eye.

A baseline measure of VA is also important to

determine effects of uveal melanoma treatment. Radiation therapy (RT)

can cause a decline in VA, although the effects are highly variable.

183-185

Larger tumor size and tumor location near the optic disc are associated

with greater loss of VA and higher rates of local complications that result in

lower rates of improvement in VA in eyes treated with iodine-125

brachytherapy.

186-188

Size

The size of the tumor is an element that contributes to the differential

diagnosis, particularly when trying to distinguish uveal melanoma from

choroidal nevus. Although size alone does not determine diagnosis, it is

one of the features that informs the diagnosis, as uveal melanomas are

generally larger than choroidal nevi, and size (thickness >2 mm, tumor

diameter >5 mm) is predictive of growth in melanocytic lesions.

94,96

For

lesions thought to be nevi, or small lesions with uncertain diagnosis,

accurate measurements of size are important for monitoring for growth, as

rapid growth is a sign of likely malignancy.

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As described in subsequent sections on treatment options for uveal

melanoma, tumor size (largest basal diameter and thickness) is also

important for selecting and planning treatment. For brachytherapy,

selection of the appropriate size plaque is important to ensure that the

lesion is fully covered, and alternative or additional treatment options need

to be considered for tumors that exceed the size of the largest

commercially available plaque. Selection among alternative treatment

options (eg, particle beam RT, stereotactic radiosurgery [SRS],

enucleation) should also depend on tumor size, and accurate description

of size and shape are needed for planning particle beam RT and SRS.

Accurate measurements of size and shape of the tumor are also needed

for monitoring response or progression after treatment.

As described in subsequent sections, baseline tumor size (ie, largest basal

diameter, thickness) is needed to determine the T stage of the tumor,

which is one of the elements that determines the prognostic risk category

used to inform post-treatment surveillance. (See UM-4 in the algorithm for

other determinants of the prognostic risk category).

Location, Distance from Disc and Fovea, Ciliary Body Involvement

Lesion location is one of many features that can contribute to diagnosis.

Proximity to the optic disc is considered a diagnostic feature of uveal

melanomas, as it is correlated with likelihood of growth in melanocytic

choroidal lesions.

90-92,94

As described in subsequent sections, lesion

location, including distance from disc and fovea, and ciliary body

involvement, can impact imaging results, such as the ability to detect

certain diagnostic features and the ability to accurately discern borders for

measurement of tumor size. In some cases, color fundus photography,

US, and complete clinical exam may not be sufficient for detection and/or

characterization of ciliary body involvement; this is a feature that may

require additional imaging approaches.

181

As described in subsequent

sections, lesion location may also impact the efficacy and safety of specific

treatments, and should be considered when selecting and planning

treatment. Lesion location can help explain visual symptoms, which can be

helpful for determining whether any of the treatment options are likely to

improve visual symptoms. Ciliary body involvement is also one of the

elements that determines the T stage of the tumor and prognostic risk

category used to inform post-treatment follow-up surveillance.

Subretinal Fluid

Subretinal fluid is another feature that supports the diagnosis of uveal

melanoma, as it is rare in benign choroidal nevi,

85,99

and has been shown

to develop during growth of choroidal nevi and transformation to

melanoma.

79,86

The presence of subretinal fluid has been shown to be

predictive of growth in choroidal nevi or small indeterminate melanocytic

lesions.

86,91,92,94,189

One study of a large number of uveal melanomas (n =

8033) reported that subretinal fluid was present in 75% of cases.

173

However, ocular metastases from other types of primary cancer (eg,

breast, lung) can also give rise to subretinal fluid,

179

which is why other

features must also be considered for a differential diagnosis.

Orange Pigment

Orange pigment, also called lipofuscin, can be present in benign choroidal

nevi;

85,99

however, it has been shown to develop during nevi growth and

transformation to uveal melanoma.

79,86

In nevi or indeterminate small

lesions, the presence of orange pigment is predictive of future growth and

increased likelihood of future diagnosis as a uveal melanoma.

83,86,90-96

Therefore, it is important to record the presence of orange pigment during

initial clinical exam.

Imaging Methods

Comprehensive Eye Exam (biomicroscopy)

Initial workup should include a comprehensive eye exam using

biomicroscopy to examine the front and back of the eye, including a

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dilated fundus exam (indirect ophthalmoscopy). Meticulous analysis of the

fundus after full pupil dilation will allow detection of most choroidal

melanomas,

and can be used to record many of the relevant features

needed for diagnosis and treatment planning. Whereas ciliary body

melanomas can be difficult to detect by this method, fundus exam with

good indentation can sometimes help.

Color Fundus Photography

Color fundus photography is useful for documenting the clinical features of

lesions, with the advantage of giving the most identical appearance to

clinical examination.

190

Color fundus photography can be used to evaluate

the borders of the lesion, and thereby record the location and shape;

calculate lesion basal diameter and area; and be used to detect orange

pigment, drusen, and halo.

80,190-192

Areas of orange pigment seen by color

fundus photography have been shown to correlate with those seen by

fundus autofluorescence.

191,192

Obtaining a baseline image is important

because serial fundus photography helps to monitor nevi or indeterminate

lesions for growth, and for those diagnosed with uveal melanoma, helps in

monitoring response to treatment and surveillance for recurrence.

Because serial images are often compared, it is important that the

baseline color photograph includes all the tumor margins.

171

A wide-angle

camera may be needed to capture choroidal lesions that are particularly

large or peripheral.

It is important to note that color fundus photography

alone is not sufficient for a differential diagnosis, and diagnostic accuracy

based on color fundus photography has wide interobserver variation.

193

Ocular Ultrasound

In addition to comprehensive clinical ophthalmologic exam and color

fundus photography, US of the eye (ocular echography) is one of the most

useful tools for diagnosis of choroidal melanomas.

45,194-196

In experienced

hands, US in combination with complete ophthalmologic clinical exam

results in a high level of diagnostic accuracy (>99%) for studies of medium

to large uveal melanomas that confirmed diagnosis based on histologic

evaluation after enucleation.

167,168,197

Melanomas tend to exhibit low

internal reflectivity as well as an intrinsic acoustic quiet zone on US,

196

features that distinguish them from a variety of other intraocular

conditions. US is particularly useful when a mass cannot be visually

inspected due to opacity or pathology of structures in the anterior portion

of the eye such as corneal scars, cataract, or blood in the vitreous.

US can help in the detection of ciliary body melanomas that may be

missed by fundoscopy.

198

US is particularly useful for determining the

thickness of the tumor,

171,194

and has been shown to have a high level of

accuracy compared with tumor height measurements based on

histopathology of enucleated specimens.

199,200

For measurements of tumor

thickness it is important to place the caliper at the internal scleral surface,

hold the probe at right angles to the scleral and tumor surfaces, and

account for overlying retinal detachment.

171

By facilitating measurement of

tumor dimensions, US is useful for detecting lesion growth.

170,195

US can

also be used to detect extraocular extension,

which shows

hyporeflectivity on US.

There are two modes of US to evaluate the eye, A-mode and B-mode.

Uveal melanomas show low reflectivity on both A-scan and B-scan

ultrasonography, although other features differ, and these two modes have

different uses.

A-Scan Ultrasonography

Uveal melanomas typically show low to medium internal reflectivity on A-

mode US,

41,45,170,195,201

which further decreases toward the sclera.

45,80

Other A-scan US hallmarks specific to uveal melanoma are: 1) a regular

internal structure with similar height of the inner tumor spikes or regular

decrease in height (positive angle kappa sign); 2) solid consistency with

no aftermovement of tumor spikes; and 3) echographic sign of

vascularization with a fast, spontaneous, continuous, ﬂickering vertical

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motion of single tumor spikes.

41,201

In contrast, choroidal metastases from

other types of cancer typically show an irregular structure on A-mode

US,

201

hemangiomas show much higher reflectivity,

45,195,201

and nevi and

melanocytomas show higher reflectivity and more irregular structures than

malignant melanoma.

201

Fresh choroidal hemorrhages may have similar

structure and reflectivity as melanomas, but will show aftermovement

following small eye movements.

201

B-Scan Ultrasound

On B-scan US, posterior uveal melanomas appear as hyperchromic mass

with lower reflectivity than the surrounding choroid, thus giving an

acoustically hollow appearance.

41,45,80,170

Posterior uveal melanomas,

particularly the larger ones, show choroidal excavation and orbital

shadowing on B-scan US.

41,45,170,195

These features help confirm clinical

diagnosis, and are distinct from hemangiomas or metastases to the eye,

which typically show high reflectivity.

170,202

However, some other lesions

that may show choroidal excavation include: hemangiomas, long-standing

nevi, and choroidal metastases.

197

B-scan US is used for obtaining tumor

dimensions, extent, and shape,

41,195,202

and is useful for characterizing

larger ciliary body tumors.

Extraocular extension can be observed by B-

scan US as areas of hyporeflectivity compared to normal orbital

tissue.

80,170

Additional Imaging

Depending on the disease characteristics observed by clinical evaluation,

additional testing options may be needed to either confirm diagnosis or

assess the extent of disease to determine first-line treatment options.

Additional imaging options that may be considered in certain situations

include: autofluorescence of the ocular fundus, OCT, retinal fluorescein

angiography of the ocular fundus, and transillumination. In select

situations, MRI is occasionally needed to confirm diagnosis or to plan

treatment. In most cases these imaging methods are not needed, as

equivalent or better information can be obtained through standard US

combined with comprehensive clinical exam.

Autofluorescence of Ocular Fundus

Fundus autofluorescence has been proposed as a method to help in the

diagnosis and characterization of uveal melanomas.

171,191,203,204

Choroidal

melanoma generally shows slight intrinsic hyperautofluorescence and the

brightness increases with tumor pigmentation and disrupted RPE.

205,206

Orange pigment (lipofuscin) is the most highly autofluorescent uveal

melanoma feature.

203,205-210

Drusen can also be detected by

autofluorescence,

209

and have increased, normal, or decreased

autofluorescence.

203,207,210

Fibrous metaplasia also shows elevated

autofluorescence.

206,207,209

Autofluorescence can be used to distinguish

orange pigment from drusen in both pigmented and non-pigmented

tumors.

170

Unlike uveal melanoma and choroidal nevi, melanocytomas show

hypofluorescence.

211

Comparative studies have shown that the

autofluorescence pattern often matches that of orange pigment and

hyperpigmentation seen by color fundus photography.

45,192,207

Based on

comparative studies, it is not clear that fundus autofluorescence increases

the detection rate of orange pigment relative to standard ophthalmologic

exam.

212

Optical Coherence Tomography

OCT is another imaging method proposed for assisting diagnosis of uveal

melanoma

45,171

and treatment planning.

Spectral domain OCT (SD-OCT)

allows the detailed evaluation of the retina and RPE, changes in which are

more common in choroidal melanoma versus choroidal nevi.

45,203

OCT can

help identify overlying retinal detachment or edema, even before clinically

apparent.

203

Results differ across comparative studies regarding whether

OCT is more sensitive than standard ophthalmologic exam plus US for

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detecting subretinal fluid.

212-214

OCT can detect subretinal and intraretinal

fluid, subretinal lipofuscin, retinal epithelium atrophy and degeneration,

shaggy photoreceptors, and structural loss of photoreceptors in the

neurosensory retina.

45,170,203,215,216

These features are more likely in

choroidal melanoma than in choroidal nevi, although some features are

more useful than others for differential diagnosis, especially in small

lesions.

45,214,215,217,218

In OCT, the structure of the lesion differed between choroidal nevi,

melanomas, hemangiomas, and metastases.

216

Optical density ratio based

on OCT can also be used to distinguish choroidal melanomas from

choroidal metastases.

219

Enhanced depth imaging OCT (EDI-OCT) is

particularly useful for detecting small lesions, and distinguishing small nevi

from small choroidal melanoma. It is less useful for thick tumors.

OCT

angiography (OCT-A) can be used to distinguish choroidal nevi from

choroidal melanoma based on margin character (well-delimited vs.

imprecise), reflectivity of choroid capillary vasculature (hyper vs. hypo),

and characteristics of lesion vasculature.

220,221

Both OCT and US have

been evaluated for characterizing iris and ciliary body tumors. US

biomicroscopy provides better overall visualization and better resolution of

the posterior margin, while OCT provides better resolution of the anterior

segment anatomy and margin.

222

Retinal Fluorescein Angiography

Retinal fluorescein angiography can be used to characterize lesion

vasculature, which can aid in diagnosis because choroidal melanomas

may have intrinsic tumor circulation, sometimes called “double circulation,”

in addition to normal choroidal vasculature.

41,45,80,170,195,196,223

Observation

of the tumor vasculature is helpful in distinguishing melanomas from

choroidal nevi, hemorrhagic degeneration, or choroidal melanoma.

45,80,224

After treatment with brachytherapy, fluorescein angiography is also useful

for detection of complications such as radiation retinopathy.

45,80

Transillumination

Transillumination has been tested as a method for detecting and

measuring uveal melanomas that may be difficult to detect or fully

characterize by other techniques. Examples include large ciliary body

melanomas,

41,45,80

or tumors obscured by cataracts.

225

Compared with

tumor dimension measurements based on histology of enucleated eyes,

transillumination tends to overestimate both the thickness and diameter of

tumors, and is prone to shadowing artifacts.

200,226

Therefore, it is only used

if other methods have proven inadequate.

MRI

MRI is generally not needed for diagnosis and workup, but occasionally is

necessary in cases with features that may make other imaging methods

difficult, such as secondary vitreous hemorrhage, extensive retinal

detachment, or cataract.

45,80

MRI may be useful in determining whether

cataract is caused by an underlying ciliary body melanoma, and can help

distinguish uveal melanomas from hemangiomas.

Uveal melanomas

usually have high signal intensity in T1-weighted MRI images and low

signal intensity in T2-weighted images.

41,45,80,170

Although similar signal

pattern can be caused by hemorrhage or necrosis,

45,80

hemangiomas

typically have hyperintense signal on T-weighted images and T2-weighted

images are isointense with the vitreous.

MRI is useful for detecting and

characterizing extraocular extension,

45,80,170,194,227,228

and is also used for

RT planning.

80,170,194,229,230

Biopsy

The use of biopsy as part of workup for uveal melanoma is an issue of

some debate. Potential benefits of biopsy during workup are 1)

cytologic/histologic confirmation of diagnosis; 2) potential for molecular

analysis that may impact eligibility for current or future clinical trials; and 3)

potential for molecular analyses that may provide more accurate

prognostic assessment for risk of metastasis, which may inform future

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follow-up surveillance. Potential harms of biopsy of the primary tumor

include 1) risk of complications from the procedure that damage the eye;

2) the risk of tumor seeding leading to local or distant recurrence; and 3)

the risk of inadequate sampling resulting in misdiagnoses or inaccurate or

inconclusive molecular testing results. As discussed in greater detail

below, the likelihood of each of these potential benefits and potential

harms is debated, as there are many different biopsy methods than can be

used, and the likelihood of benefit versus harm may also vary across

practitioners.

There are a wide variety of biopsy techniques that have been tested and

are sometimes used for choroidal or ciliary body tumors. Some involve a

transscleral (direct) approach, where the tumor is approached from the

outside, the needle first puncturing the sclera over the tumor, then the

tumor itself, leaving the retina intact.

231

Others use a transvitreal (indirect)

approach, with anterior entry through the pars plana opposite the tumor,

going through the vitreous body and retina to reach the tumor.

231

Tumor

location is a major determinant of which approach is likely to be successful

and safe. Table 2 provides a list of techniques (or categories of

techniques) for biopsying choroidal and ciliary body tumors that have been

used to assist with diagnosis and/or prognostication in primary uveal

melanomas. Key features of these biopsy methods are also included in

Table 2: the typical surgical approach (transscleral or

transvitreal/transretinal), tumor location(s) for which the biopsy method

was developed and/or is most often used, and the type of sample

obtained, as some of these methods provide aspirated cells that can be

analyzed by cytopathology, whereas other methods can provide tissue

samples that can be sectioned for histopathology. Table 2 also lists

representative studies that describe these biopsy methods in more detail,

report diagnostic and/or prognostic yield for these biopsy options (percent

of biopsies providing sufficient material for diagnostic or prognostic

analyses), and provide safety data, including intraoperative or

postoperative procedure-related complications and analyses aimed at

determining the risk of tumor seeding (eg, evidence of tumor cell

tracks/contamination in neighboring tissues; rates of local recurrence

during follow-up).

There is some risk of complications with any biopsy procedure. Any of

these procedures can result in the following intraocular

complications/morbidities, which if severe may require secondary

procedures or other interventions for management: hemorrhage (eg,

vitreal, subretinal, choroidal, perilesional), decrease in VA, retinal

detachment (eg, rhegmatogenous, exudative), retinal perforation,

hypotony, and endophthalmitis.

232-243

Longitudinal population-based

studies have shown that biopsy does not impact all-cause mortality or

disease-specific death—for better or worse—in patients with uveal

melanoma.

244-246

Fine-Needle Aspiration Biopsy

Fine-needle aspiration biopsy (FNAB) is the simplest, most inexpensive,

and most commonly used method for biopsy of choroid or ciliary body

tumors presumed to be melanoma.

231,247,248

Details of the technique are

described in several review articles,

231,247,248

as well as multiple primary

reports from many different centers.

88,232,233,235,249-251

FNAB can be done

via a transvitreal or transscleral approach depending on the location of the

tumor. The transvitreal approach is generally easier due to better

intraoperative illumination and visualization options.

231,248

The disadvantage to FNAB is that the amount of material obtained may be

small, and multiple passes may be needed to obtain enough material for

cytologic and molecular genetic analysis.

232,236,251,252

The yield from

FNAB—both for cytologic confirmation of diagnosis and for molecular

analyses for prognostication—varies across studies.

88,232,233,235,236,245,246,249-

258

Some studies suggest that transvitreal (vs. transscleral) approach is

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associated with improved FNAB yield, but some studies found no

difference in yield.

232,233,235,256,258,259

Some studies have suggested that

FNAB yield is higher for larger tumors, and is particularly impacted by the

thickness of the tumor,

233,246,250,256-258

but a recent study showed that high

yields (>87%) can be obtained even in thin tumors (<3.5-mm thick), for

both the transscleral and transvitreal approach.

232

Studies of patients with

uncertain diagnoses based on standard noninvasive techniques have

shown that FNAB can help distinguish between uveal melanoma and

borderline or benign melanocytic nevus, even among small lesions,

88,257

and can clarify whether a lesion is a primary uveal melanoma versus

metastasis from another cancer, another type of primary ocular tumor, a

melanocytoma, or RPE proliferation.

251

For FNAB, the most common complication is vitreal hemorrhage, but its

rate varies widely across studies.

232,233,236,245,250,259

Some studies describe

methods to reduce or prevent this.

254

Most vitreal hemorrhages are

focal/localized and resolve without further intervention,

232,233,245,250,251,259

but

some are diffuse, more extensive, persist and/or impact VA, and require

secondary surgical intervention (eg, vitrectomy) for

management.

232,233,235,236

The risk of hemorrhage requiring secondary

surgical management varies widely, even across recent studies, ranging

from 1% to 15% of patients with FNAB.

232,233,235,236,250

Some studies have

suggested that vitreal hemorrhage is more likely with a transvitreal than

with a transscleral approach.

232,235

FNAB may also impact VA, improving

some cases but reducing VA in other cases.

233

Other complications that

have been reported, but are rare, include rhegmatogenous retinal

detachment and worsening exudative retinal

detachment.

233,235,236,245,246,251,259

Concerns about FNAB causing tumor seeding have been raised based on

findings of melanoma cells left in the needle track,

253,255,260-262

and some

have suggested procedure adjustments for reducing the likelihood of

tumor cell seeding FNAB.

248,253,261

A few case reports found local

recurrences at FNAB entry sites.

263-265

However, multiple follow-up studies

with large patient populations have revealed no local recurrences after

FNAB (and non-surgical treatment),

88,232,235,245,246,250,251,254,255,259

and one

case series found no increased risk of metastasis among untreated

patients who had post-biopsy evidence of melanoma cell dissemination

inside the eye.

260

FNAB is therefore generally thought to be safe and to

have low risk of seeding.

Other Biopsy Techniques

Other biopsy techniques that have been tested in large populations of

patients with uveal melanoma are those that use tools from vitrectomy

systems both to access tumor via a transvitreal/transretinal approach and

to extract tumor tissue using the vitreous cutter and aspiration through the

canula. These procedures do not necessarily include a vitrectomy. There

are a variety of procedures that fall into this category, and are described in

a series of publications based on clinical practices both in the United

States and Europe, including several reviews.

231,237,238,240,248,266,267

These

techniques have been used successfully on anterior, posterior, equatorial,

and peripapillary lesions.

237-240,268

They generally result in larger sample

sizes than FNAB, although like FNAB multiple passes may be

necessary.

237,238,266,267

For this reason it has been suggested that these

methods may be useful in patients with tumors that are too small or

inaccessible for FNAB, or for tumors where FNAB has failed. One study

reported that for choroidal melanomas with thickness of 2.0 mm or less,

sufficient sample for prognostic evaluation was obtained in 100% of

patients.

237

Reported yields from these procedures range from 89% to

99% for diagnosis of choroidal lesions, and 97% to 100% for prognostic

testing on uveal melanomas.

237-240,267,268

Studies have shown that these

biopsy techniques can be used to diagnose tumors that are unclassifiable

based on standard noninvasive diagnostic techniques, and can

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differentiate uveal melanoma from benign nevus, metastases from other

cancers, vasoproliferative tumor, hemorrhage, gliosis, and scleritis.

240,268

These approaches are less broadly used than FNAB, are more expensive,

and require additional expertise.

231,248

Like FNAB, hemorrhage is the most

common complication with these biopsy procedures, is normally localized,

and usually resolves without intervention.

237,239,240

Because these

techniques are more invasive, however, retinal detachment and severe

hemorrhage are more common, and more patients require intervention for

management, either at the time of biopsy or as a later procedure.

234,238-

240,248

Decrease in VA due to these procedures is not uncommon.

238,239

Like FNAB, studies have published evidence that these procedures may

leave tumor cells along the access pathways, but most studies, including

those with large patient samples, have not observed local recurrence

during follow-up.

239,240

There are a few cases reported of local recurrences

at biopsy entry sites.

264,268-270

Incisional biopsy techniques are more

invasive than vitrectomy system-assisted biopsies, and likewise yield more

material, but also are more likely to lead to complications.

241-243

These

methods have been used for cases that are particularly hard to diagnose.

Excisional biopsy, using either transscleral resection or endoresection,

was also explored as an option for both biopsy and primary treatment,

271

but is not included in Table 2 because it is no longer used due to technical

challenges, risk of complications, and concerns about tumor

seeding.

170,272-282

NCCN Biopsy Recommendations

Biopsy may be considered if needed to confirm diagnosis or for prognostic

analysis for risk stratification. Biopsy is usually not necessary for initial

diagnosis of uveal melanoma and selection of first-line treatment, but may

be useful in cases of uncertainty regarding diagnosis, such as for

amelanotic tumors or retinal detachment. Biopsy of the primary tumor may

provide prognostic information that can help inform frequency of follow-up

and may be needed for clinical trial eligibility. If biopsy is performed,

molecular/chromosomal testing for prognostication is preferred over

cytology alone. The risks/benefits of biopsy for prognostic analysis should

be carefully considered and discussed.

Observation for Uncertain Diagnosis in Patients with Low

Risk

Findings from the clinical workup should be used to determine initial

management. Observation may be appropriate for patients with uncertain

diagnosis and/or fewer than three risk factors for lesion growth (Table 1).

Studies have found that for patients with small choroidal lesions presumed

to be nevi or indeterminate, deferring treatment until evidence of growth or

features of malignancy develop (eg, orange pigment, subretinal fluid,

symptoms) is associated with a very low risk of metastasis,

91,95

and even

lower risk of death from uveal melanoma.

For patients who meet the

criteria for observation (rather than immediate treatment), regular follow-up

is recommended to periodically re-evaluate for growth or features of

malignancy. Follow-up tests should include the same tests recommended

for initial workup and diagnosis that would help clarify if there is

progression and determine the natural history of the indeterminate lesion.

Initially (ie, upon first discovery of the lesion), these patients should be re-

evaluated every 2 to 4 months to determine rate of growth (if any) and to

monitor for other changes indicative of malignancy. Close follow-up for 5

years is recommended to firmly establish whether or not there is any

growth or progression; some lesions that initially seem stable may

suddenly begin to grow and transform. The frequency of re-evaluation

should depend on the index of suspicion, patient age, and medical frailty.

For example, the presence of one to two risk factors for growth (Table 1),

or evidence of changes would increase suspicion. If the size and features

of a lesion appear static after 5 years of follow-up, the patient can be

followed annually thereafter. Lesions that demonstrate growth or develop

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additional risk factors for growth (>3 total) should be managed as uveal

melanoma, even if diagnosis is still uncertain.

Further Workup Prior to Treatment

Further workup prior to treatment may be needed in some cases to aid in

treatment selection and planning. For example, for tumors that are large,

close to the optic nerve, or have suspected/confirmed extraocular

extension, MRI should be performed, if not previously done, to determine

whether radiation (particle beam or SRS) is an option, or whether

enucleation is needed, and for radiation planning. MRI should be

performed with and without contrast unless contrast is contraindicated.

MRI is useful for detecting and characterizing extraocular extension and

for RT planning (particle beam or SRS).

45,80,170,194,227-229

Ciliary body

involvement or extraocular extension should be assessed and

documented, as these features may impact the feasibility, safety, and

efficacy of certain treatment options. If not already performed, biopsy of

the primary tumor should be considered for prognostic analysis, as risk

stratification should inform the frequency of follow-up treatment. There is

some evidence to suggest that radiation (all modalities) may alter

molecular genetic features of the tumors, reducing the accuracy of

prognostication based on samples taken after radiation treatment.

283

Baseline imaging to screen for systemic disease is also recommended

prior to treatment. Despite lack of treatment options for patients with

metastatic disease, NCCN favors staging before primary treatment. For

patients who have small, low-risk tumors, but are planning to receive

treatment (ie, those with a definite diagnosis of uveal melanoma, or

uncertain diagnosis but three or more risk factors for growth [Table 1]),

deferring extraocular baseline imaging until after primary treatment can be

considered. The most frequent sites of metastasis are liver, lungs,

skin/soft tissue, and bones.

At minimum, all patients receiving baseline

imaging should have contrast-enhanced MR or US of the liver, with

modality preference determined by expertise at the treating institution.

Additional imaging modalities may include chest/abdominal/pelvic CT with

contrast. However, screening should limit radiation exposure whenever

possible. Unless there is a specific contraindication to the administration of

IV contrast (ie, renal impairment or history of a severe allergy), all cross-

sectional imaging studies should be performed with and without IV

contrast.

If not already performed, biopsy of the primary tumor for prognostic

analysis should be considered prior to treatment.

Treatment of Localized Primary Uveal Melanoma

Most uveal melanomas are localized at first presentation, and only a small

percentage of cases present with metastases (<3%).

6,10-14

Local treatment

for primary uveal melanoma is effective in preventing local recurrence in

greater than 85% of cases,

272,284

yet the rate of metastasis within 20 years

after treatment is approximately 20% to 70% for patients who present with

localized uveal melanoma, depending on tumor stage/size at

diagnosis.

8,13,26,285

Whereas surgical approaches are the mainstay of

treatment for localized cutaneous melanoma, and historically most uveal

melanomas were treated with surgery, the field has moved away from

using surgery in all patients,

2,286

because different modalities, primarily

various forms of RT, have been found to be just as safe and effective for

those with limited disease, and can preserve the affected eye. Some

surgical approaches are still used in patients with extensive local disease,

but most patients with localized primary uveal melanoma are treated with

some form of RT.

287

There are a number of other ablative techniques that

are occasionally used for localized primary melanoma, including laser

therapy, cryotherapy, and photodynamic therapy. Each of these primary

treatment modalities is described in more detail below. Selection among

these techniques is guided by many case-specific factors, including the

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size and location of the tumor, presence of extraocular extension, visual

potential, patient age, and preference.

Surgical Options

Prior to the development of effective RT options, surgery was used to treat

most uveal melanomas.

Local Resection

There are a variety of methods for local resection of uveal melanoma

aimed at conserving the eye and useful vision.

170,280,281

These include

transretinal (endoresection) and transscleral (exoresection) approaches.

170

These methods can be technically challenging,

41,170

with high rates of

immediate postoperative complications such as hemorrhage, retinal

detachment, ocular hypertension, and proliferative vitreoretinopathy, which

may require repeat surgery.

170,277,280-282

Endoresection is the less

technically challenging approach,

280,281

and based on retrospective

analyses is associated with low local failure rate (<6%).

272,288-293

Due to

lack of prospective data on this technique, it is unclear whether it provides

the same protection from recurrence and metastases as treatment options

that have been prospectively studied (ie, brachytherapy, enucleation).

Exoresection is the more technically challenging form of local resection,

particularly with large and posterior tumors, and is usually performed with

hypotensive anesthesia and other measures to control intraoperative

hemorrhage.

277,280,281

Most studies (all retrospective) have reported high

local failure rates (20%–24%) after trans-scleral resection,

272-275

which

tend to be higher than with enucleation or brachytherapy.

276-279

Local resection is not recommended in the NCCN Guidelines for

Melanoma: Uveal as a primary treatment option for choroidal or ciliary

body melanoma. For patients with primary tumors amenable to eye-

conserving approaches, RT-based approaches are preferred. For tumors

too large for brachytherapy, enucleation is preferred over local resection,

as the latter is technically difficult for large tumors.

Enucleation

Enucleation is a technically less challenging procedure than local

resection of uveal melanoma, and historically is the most widely used

treatment for uveal melanoma. Results from the Collaborative Ocular

Melanoma Study (COMS) prospective randomized trial suggest that

enucleation is associated with a very low risk of local recurrence

(~1%),

294,295

notably lower than the rate of local recurrence reported for

retrospective studies in patients treated with primary local resection.

272-

275,288-293

Enucleation procedures have been standardized; they involve

complete removal of the eye and in most cases include insertion of an

orbital implant.

170,281,296,297

Both porous and nonporous implants have been

shown to result in similar outcomes, although there may be a higher

incidence of ptosis with acrylic implants, and a greater need for ocularists’

treatment (eg, topical antibiotics, polishing or refitting of prosthesis) with

hydroxyapatite implants.

298

For enucleation, the complications reported in the COMS trial, during or

less than 24 hours following surgery, include pain, hemorrhage,

nausea/vomiting, cardiovascular or pulmonary problems, urinary retention,

fever, and local surgical problems.

294

Complications 1 to 6 weeks after

surgery included pain requiring longer hospital stay, pain requiring

medication, conjunctival wound dehiscence, infection, decreased facial

sensation, eyelid swelling, inflammation, implant displacement, loss of

hair, ptosis, conjunctival chemosis, ecchymosis, and orbital or conjunctival

hemorrhage.

294

Long-term follow-up has shown that other problems after

enucleation include poor motility of prosthesis, poor alignment of

prosthesis, severe ptosis, and displacement of implant.

294

Enucleation can

also result in phantom eye syndrome, including visual sensations, seeing,

and pain, which can be distressing to some patients.

299

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Pre-enucleation RT is generally not used because results from the COMS

randomized trial in large tumors (height ≥2 mm and diameter ≥16 mm; or

height ≥10 mm and any diameter; or height ≥8, any diameter, if proximal

tumor border <2 mm to optic disc) showed that pre-enucleation RT had no

impact on survival (death from melanoma metastasis, all-cause death)

compared with enucleation alone,

294,300,301

confirming results of prior

retrospective studies.

302

In the COMS trial for large tumors, 5-year tumor-

related mortality was 28% for patients treated with enucleation.

300

In the COMS randomized trial in medium choroidal melanoma tumors

(height 2.5–10 mm, diameter ≤16 mm, and no extrascleral extension ≥2.0

mm thick), outcomes (ie, cumulative mortality, melanoma-specific

mortality) for enucleation were similar to those with iodine-125

brachytherapy.

303,304

For medium tumors, the 5-year disease-specific

survival rate was 11% for patients treated with enucleation (14% and 5%

for patients with tumor diameter >11 mm and ≤11 mm, respectively).

304

One prospective and several retrospective studies also found that survival

was similar after enucleation versus cobalt plaque brachytherapy,

305-309

a mix of brachytherapy plaque types,

310

or versus proton beam RT.

311

Retrospective studies suggest that outcomes (ie, overall survival [OS],

metastasis-free survival, melanoma-related mortality) are similar for

enucleation versus proton beam RT or versus SRS.

312-315

Despite the

negative aspects of enucleation (relative to RT therapy), including worse

effects on certain visual functions (eg, peripheral vision, night driving,

judging distances), greater decrease in role functioning, and larger

reductions in physical and functional well-being, some studies have found

that overall quality of life for patients undergoing enucleation appears to be

similar to that for those treated with RT.

316-321

Based on results of the prospective studies comparing enucleation with

brachytherapy, enucleation is generally only recommended for patients

with tumors that are unsuitable for brachytherapy treatment, such as those

that are too large to be effectively treated by commercially available

plaques, or that have optic nerve involvement. For such tumors,

enucleation is an option, but other types of RT (ie, particle beam,

stereotactic RT [SRT]) are also possibilities. Enucleation is sometimes

reserved for cases that would be difficult to treat using only RT, such as

those with neovascular glaucoma, tumor replacing greater than 50% of the

globe, blindness, painful eyes, or extensive extraocular extension. In

addition to use as a primary treatment, enucleation is also often used as a

secondary therapy for patients who develop local recurrence or

complications after eye-sparing primary treatment. Pathologic evaluation

should follow the uveal melanoma synoptic report recommendations by

the College of American Pathologists (available at:

http://documents.cap.org/protocols/cp-uveal-melanoma-17protocol-

4000.pdf).

322

Radiation Therapy

RT is the most commonly used first-line treatment for uveal melanoma,

several RT approaches have been shown to have similar efficacy as

enucleation for reducing the risk of metastasis and death from disease.

303-

315

Brachytherapy and charged particle RT are the RT modalities

considered appropriate for primary therapy for most cases of uveal

melanoma, whereas photon RT and SRT are less often used as primary

treatment for uveal melanoma. SRS is sometimes used for large primary

tumors, and photon RT is generally only used as an adjuvant to surgery.

Plaque Brachytherapy

Plaque brachytherapy is a commonly used form of definitive RT for the

primary tumor.

286,287,323,324

Brachytherapy is often used (for localized

primary uveal melanoma) based on results from a large prospective

randomized trial (COMS) showing that long-term outcomes were not

significantly different with plaque brachytherapy (n = 657) versus

enucleation (n = 660) for patients with small- to medium-sized choroidal

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melanomas (2.5–10.0 mm in apical height [2.5-8.0 mm if peripapillary] and

≤16 mm in maximum basal diameter, no extrascleral extension ≥2.0 mm

thick).

303,304

In this study the 5-year risk of treatment failure after

brachytherapy was 10.3%.

187

Treatment failure was defined as tumor

expansion (≥15% increase in height or ≥250 µm in any tumor boundary) or

extrascleral extension (>2 mm). Risk factors for treatment failure were

older age, greater tumor thickness, and proximity of the tumor to the foveal

avascular zone. Other more recent studies have reported local failure

rates ranging from 0% to approximately 20% for patients treated with

iodine-125 plaques, and local failure rates were in this range for patients

treated with other types of brachytherapy plaques (ie, ruthenium-106,

palladium-103, cesium-131).

272,325-328

It is important to note that late

treatment failures (up to 12 years) after brachytherapy have been

observed.

327

In the COMS randomized trial in medium choroidal melanoma tumors

(height 2.5–10 mm, diameter ≤16 mm, no extrascleral extension ≥2.0 mm

thick), after a minimum of 5 years of follow-up (range, 5–15 years), there

were no treatment-dependent differences in all-cause mortality or death

with confirmed melanoma metastasis.

304

There was no difference across

arms in the rate of death with histologically confirmed metastasis

(enucleation vs. brachytherapy: 11 vs. 10% at 5 years; 17 vs. 18% at 10

years) or all-cause mortality (19% at 5 years and 35% at 10 years, for

each arm).

304

The only factors correlated with these outcomes were age

and maximum basal diameter, but even after adjustment for these

variables, there were no treatment-dependent differences in all-cause

mortality or mortality with confirmed melanoma metastasis at time of

death.

304

In the same trial, intraoperative/immediate postoperative complications

observed with similar frequency across brachytherapy and enucleation

arms included anesthetic complications, pain requiring medication, other

hemorrhage, cardiovascular or pulmonary problems, urinary problems,

and local surgical problems.

303

Immediate complications seen only in the

brachytherapy arm included intraocular hemorrhage, scleral perforation,

and vortex vein rupture.

303

In the brachytherapy arm, the most common

long-term complications were loss of VA and growth of tumor or other

indications that lead to enucleation.

303

After 3 years of follow-up,

approximately half of the patients (49%) treated with brachytherapy lost six

or more lines of VA (compared with before treatment), and of patients with

VA better than 20/200 before treatment, 43% had VA of 20/200 or

worse.

186

Factors associated with loss of VA included greater baseline

tumor apical height, shorter distance between the tumor and the foveal

avascular zone, presence of tumor-associated retinal detachment, non–

dome-shaped tumor, and patient history of diabetes.

186

During the first 5

years of follow-up, cataracts developed in 68% of eyes treated with

brachytherapy, and 12% had undergone cataract surgery.

329

Cataract

surgery results in VA improving by 2 or more lines in 66%, and stabilizing

VA in 26%.

329

The 5-year cumulative rate of enucleation was

approximately 12%,

187,303

most often due to treatment failure during the

first 3 years after brachytherapy, and to eye pain beyond 3 years after

treatment.

187

When evaluating patients for brachytherapy, it is important to consider the

entry criteria and treatment parameters used in the COMS trial that

compared brachytherapy with enucleation. The COMS trial included only

patients with tumors that were choroidal;

303

those with tumors contiguous

with the optic disc were excluded, as were those with metastases from

melanoma or another cancer (except nonmelanoma skin cancers).

304

Only

16% of patients had tumors less than 2.0 mm from the optic disc.

303

Most

of the tumors included were dome-shaped on B-scan US (77%), and

about half had non-rhegmatogenous retinal detachment (54%–55%); a

few (<1%) had rhegmatogenous retinal detachment.

303

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Prospective studies in patients with small choroidal tumors also found that

iodine-125 brachytherapy resulted in tumor regression in most cases

(98%),

330

less than 3% recurred, and 98% achieved globe conservation.

331

Melanoma-specific mortality at 5 years was 3.9%.

331

Whereas the plaques used in the COMS trial were all iodine-125, one

prospective and several retrospective studies also found that survival was

similar after enucleation versus cobalt plaque,

305-309

or a mix of

brachytherapy plaque types.

310

A meta-analysis of studies testing Ru

plaques in patients with uveal melanoma reported a 5-year melanoma-

related mortality rate of 6% for small and medium tumors (T1/T2), and

26% for large tumors (T3).

332

Palladium-103 brachytherapy plaques also

appear to perform similarly to iodine-125 plaques.

333

Recent analyses, including a few prospective studies, have aimed at

identifying factors associated with loss of VA after brachytherapy, with

varying results. Factors identified in one or more studies include applicator

size, tumor basal diameter, juxtapapillary location, dose (close to foveola,

or retinal), increased tumor height, radiation maculopathy, and radiation

optic neuropathy.

184,334,335

Some studies have reported adjustments to

technique that may reduce the risk of vision decline.

328

One prospective

study of 650 patients with medium-sized choroidal melanoma found that

retinal hemorrhage in the macular and peripapillary zone, optical disc

hemorrhage, microaneurysms, and foveal RPE atrophy were more

prevalent and severe after brachytherapy than before treatment.

336

Macular angiographic leakage tended to worsen after brachytherapy, and

optic neuropathy was present in 27% of patients 5 years after treatment.

336

NCCN Recommendations for Brachytherapy

Plaque brachytherapy is appropriate as an upfront therapy after initial

diagnosis, or after local recurrence following a prior local therapy. Plaque

brachytherapy is appropriate for patients with tumors 19 mm or less in

largest base diameter, and 10 mm or less in thickness, based on the size

of the largest commercially available plaques. The plaque margin on the

tumor border should be 2 mm or greater when feasible (diameter of plaque

≥4 mm larger than largest base diameter of tumor; the plaque should

cover the tumor with a ≥2-mm circumferential margin). The exception is for

tumors near the optic nerve where it may be impossible to achieve

adequate coverage of the margins. The largest commercially available

brachytherapy plaque is 23 mm in diameter; thus, plaque brachytherapy is

recommended only for tumors with largest basal diameter 19 mm or less.

Round or custom plaques are most commonly used. Custom plaques (eg,

notched) are commonly used for tumors in specific locations (eg,

peripapillary). Preliminary data from a prospective study suggest that

slotted plaques provide local control of choroidal melanomas adjacent to

the optic nerve, but with a high risk of radiation optic neuropathy.

337

Plaque

brachytherapy should be performed by an experienced multidisciplinary

team including an ophthalmic oncologist, radiation oncologist, and

brachytherapy physicist.

185

Tumor localization for brachytherapy may be

performed using indirect ophthalmoscopy, transillumination, light pipe

diathermy, and/or US (intraoperative and/or preoperative).

338

MRI or CT

may be used for preoperative planning.

Dosing Recommendations for Brachytherapy

In patients receiving plaque brachytherapy for uveal melanoma, the

radiation dose at the base of the tumor (the surface of the tumor closest to

the plaque) will always be higher than the dose at the apex of the tumor

(the point of the tumor furthest from the plaque). Clinical practice varies

regarding whether the radiation dose prescribed is the dose at the base of

the tumor or the dose at the apex of the tumor.

Using iodine-125 COMS plaques, 85 Gy should be prescribed to the apex

of the tumor at low dose-rate (≥0.6 Gy/h), as this was the dose used in the

COMS study of medium-sized uveal melanomas, showing similar survival

with brachytherapy versus enucleation.

303,304

Dose adjustments may need

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to be made for non-COMS plaques.

339

Other prospective and retrospective

studies using iodine-125 brachytherapy dosing similar to COMS have

reported similarly high rates of local control,

327,328,340-343

and a retrospective

study found that efficacy outcomes were similar to those in patients

treated with SRT.

344

As expected, studies using iodine-125 brachytherapy

doses higher than in COMS (eg, 100 Gy to tumor apex) also reported

recurrence rates that compared favorably with other treatment modalities

(eg, transpupillary thermotherapy [TTT], proton beam RT).

330,345

contrast, both retrospective and randomized prospective studies using

iodine-125 brachytherapy doses of less than or equal to 80 Gy reported

recurrence rates higher than with particle beam RT.

47,346-349

One

prospective and several retrospective studies have reported that a lower

iodine-125 brachytherapy dose was associated with local tumor

recurrence and decreased systemic control,

338,350-352

whereas other

retrospective studies have found no significant correlation between dose

and local recurrence, distant metastasis, or survival.

342,353,354

A meta-

analysis found that recurrence rates tended to decrease with increasing

iodine-125 brachytherapy dose to the tumor apex, but the effect was small

and not statistically significant.

325

Another issue of some debate is the relationship between brachytherapy

dose and complications, changes in vision after treatment, and eye

preservation. One prospective and multiple retrospective analyses have

found correlations between increasing iodine-125 dose and loss of VA,

risk of RT-related complications (eg, cataract, optic neuropathy,

glaucoma), and/or need for secondary enucleation.

334,342,351,353-358

Results

are mixed, however, and retrospective analyses did not always find

significant correlations between dose and these negative

outcomes.

356,359,360

It is important to note that for the few comparative

studies that used relatively high doses of iodine-125 brachytherapy (≥85

Gy to the tumor apex), rates of RT-related complications and vision loss

were still similar to or better than with SRT or particle-beam RT.

344,345

Prospective trials are needed to determine optimal iodine-125 dosing.

Studies using brachytherapy plaques made of other radioisotopes,

primarily ruthenium-106, but also palladium-103, strontium-90, and cobalt-

60, have tested a wide range of doses (60–150 Gy to tumor apex), but

most reported mean/median dose to the apex between 80 and 130

Gy.

184,332,333,345,361-369

Only a few of these studies were prospective.

333,366

Although there is evidence to suggest that results differ between isotopes

(even when apex dose is similar),

345,362

the optimal dose has not been

determined for any of these isotopes. Results are inconsistent across

retrospective studies that attempted to evaluate the impact of dose on

local/distant failure rate,

361,367

or the impact of dose on RT-related

complications and VA loss.

184,365

Results from a few retrospective studies

using ruthenium-106 plaques suggest that while a target dose of 100 Gy to

the tumor apex may result in poorer local control than proton beam RT,

higher doses (mean 137 Gy at apex) may provide similar local control as

SRS.

345,368

Due to lack of data, the NCCN Panel recommendations are

fairly broad, suggesting that when using ruthenium-106, palladium-103,

strontium-90, cobalt-60, and cesium-131 plaques, 60 to 100 Gy may be

prescribed at low dose rate to the tumor apex; alternatively, a minimum

dose may be prescribed to the base of the tumor. The plaque margin on

the tumor border may vary for other (non–iodine-125) radioisotopes.

Particle Beam Radiation Therapy

Particle beam RT includes radiation with protons, carbon ions, or helium

ions, and is a common form of definitive RT for the primary tumor.

323

Prospective studies and a systematic review found that disease-specific

survival in patients with uveal melanoma treated with particle beam RT

was similar or better than for plaque brachytherapy.

47,347,349

Compared with

brachytherapy, particle beam RT was associated with higher rates of local

control and similar or lower rates of enucleation during follow-up.

47,347,349

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Across studies, local recurrence rates with charged particle therapy

ranged from 3% to 10%.

272,370

However, multivariate analysis of a real-

world database found that treatment with protons was associated with

poorer OS compared with brachytherapy treatment.

371

Decrease in VA and loss of vision can occur with particle beam RT.

370,372

Toxicities include vitreous hemorrhage, subretinal exudation in macula,

posterior subcapsular opacity, radiation keratopathy, rubeosis/neovascular

glaucoma, radiation maculopathy, and papillopathy.

370,373

NCCN Recommendations for Particle Beam Radiation Therapy

Particle beam RT should be performed by an experienced multidisciplinary

team including an ophthalmic oncologist, radiation oncologist, and particle

beam physicist.

374

In settings where the appropriate expertise is available,

particle beam therapy (proton, carbon ion, or helium ion) is appropriate as

upfront therapy after initial diagnosis, after margin-positive enucleation, or

for intraocular or orbital recurrence. It is important that the team have

experience treating uveal melanoma with the specific type of particle beam

used (proton, carbon ion, or helium ion). Particle beam RT is an option

regardless of the size of the primary lesion, and is the preferred method of

RT for tumors that are too large or too near the optic nerve to be

effectively treated with brachytherapy. Tumor localization for particle beam

RT may be performed using indirect ophthalmoscopy, transillumination,

and/or US (intraoperative and/or preoperative), MRI, and/or CT.

Dosing Recommendations for Particle Beam Radiation Therapy

Particle beam dosing for intraocular tumors is as follows: using protons,

50–70 cobalt Gray equivalent (CGyE) in 4 to 5 fractions should be

prescribed to encompass the planning target volume (PTV) surrounding

the tumor;

370,374,375

using carbon ions, 60 to 85 CGyE in 5 fractions should

be prescribed to encompass the PTV surrounding the tumor.

373

Fiducial

markers (tantalum clips) are encouraged to permit eye and tumor position

verification for image-guided radiotherapy delivery. Volumetric planning in

three dimensions (with or without CT and/or MRI) is encouraged to

maximize radiation delivery to tumor and minimize radiation delivery to

organs and tissues at risk of injury from radiation.

Stereotactic Radiation

SRT includes both single-fraction and hypofractionated stereotactic

techniques, referred to collectively as SRS in these NCCN Guidelines.

Compared with brachytherapy and particle beam RT, there are fewer

prospective comparative study data on SRS for treatment of primary uveal

melanoma. Available data suggest that SRS may be as effective as other

RT modalities, but may also be associated with a higher risk of

complications. One series that compared SRS with iodine-125

brachytherapy found that rates of tumor recurrence, distant metastasis,

and secondary enucleation were similar across treatments.

344

Risk of

cataract appeared similar across treatments, but SRS appeared to be

associated with higher rates of certain complications, including

neovascular glaucoma, radiation retinopathy, and radiation

papillopathy.

344,376

Another study also reported similar rates of local control

with brachytherapy versus SRS.

368

A retrospective study comparing

ruthenium-106 brachytherapy versus SRS found a nonsignificant trend

toward increased secondary glaucoma after SRS.

364

A retrospective study

comparing SRS versus proton beam RT reported similar rates of local

control and eye retention across treatments, but higher rates of VA decline

with SRS.

377

Studies using SRS as primary treatment for uveal melanomas have

reported local failure rates ranging between 2% to 16%.

183,272,344,368,377-391

Rates of 5-year metastasis-free survival after SRS ranged from 69% to

84%.

344,379,381,392

OS 5 years after SRS has been reported to be 55% to

98%.

380,381,385,392,393

These large ranges likely reflect differences in the

populations studied; thus, in the absence of randomized trial data it is

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difficult to know whether these outcomes are better or worse than those

reported for other treatment modalities.

In studies testing SRS as primary treatment for uveal melanoma, eye

retention rates ranged from 73% to 98%.

377,380,383-387,390,392-395

In addition to

causing a decrease in VA, complications associated with SRS include

cataracts, neovascular glaucoma, radiation retinopathy, radiation

papillopathy, radiation maculopathy, hemorrhage, macular edema, optic

neuropathy, and keratitis sicca (dry eye).

344,376,379,380,382,383,387-389,395-399

Some studies have linked the rate and/or severity of complications to the

radiation dose, tumor location, tumor size, and VA before

treatment.

382,384,387,397,400,401

NCCN Recommendations for Stereotactic Radiation

Due to the lack of randomized prospective data (compared with other RT

techniques described above), SRS is the least often used form of definitive

RT for the treatment of primary or recurrent intraocular tumors. Like

particle beam RT, SRS can be used to treat large choroidal melanomas.

The choice between these two options generally depends on the radiation

oncology facilities available. In rare cases when both particle beam RT

and SRS facilities are available, some NCCN Panel members prefer

particle beam RT because there are more supporting data for this

approach. Tumor localization, fiducial marker use, and planning for SRS

are generally consistent with particle beam RT approaches. Using

fractionated SRS, 45 to 70 Gy in 2 to 5 fractions should be prescribed.

Using single-fraction SRS, 18 to 45 Gy in 1 fraction should be prescribed.

RT Toxicity (Ocular)

In order to avoid secondary enucleation, a variety of methods for

preventing or managing RT-associated complications have been tested in

prospective studies. Toxicity management methods tested include

panretinal photocoagulation for ocular ischemia,

402

transscleral local

resection for exudative retinal detachment,

403

and intravitreal anti-vascular

endothelial growth factor (VEGF) (eg, bevacizumab, ranibizumab,

aflibercept) or intravitreal corticosteroids (eg, triamcinolone,

dexamethasone) for treating optic neuropathy, macular radiation

vasculopathy, or papillopathy or macular edema.

404-411

These intravitreal

therapies have also been tested for prophylaxis.

412-414

The NCCN

Guidelines for Melanoma: Uveal do not currently have recommendations

for management of RT side effects.

Other Ablative Techniques

Laser Therapy

Laser Photocoagulation

Laser photocoagulation has also been used for treatment of primary or

recurrent uveal melanomas, sometimes as monotherapy but more often as

an adjunct to RT or surgery.

45,46,171,277,281,415-430

The sparse data available

suggest that laser photocoagulation is associated with high rates of

recurrence if used as the sole primary therapy,

415,421

but that when used as

a supplement to brachytherapy can increase rate of tumor regression.

426

Transpupillary Thermotherapy

TTT, also called diode laser hyperthermia, is a technique that uses a

modified infrared diode laser to slowly heat up a specified area to

approximately 45 to 60°C. TTT can be used to treat a large spot and has

deep tissue penetration. TTT has been tested in prospective studies as

the sole primary treatment for uveal melanoma tumors, but local

recurrence rates varied widely across studies, with some studies reporting

high rates of recurrence (>50%), even for small tumors.

272,330,431-436

TTT

has also been tested as an adjunct therapy to radiation (brachytherapy,

proton beam RT, SRS or fractionated SRT) to reduce the risk of local

recurrence.

350,366,437-443

One prospective randomized trial found that TTT

administered at 1, 6, and 12 months after proton RT reduced the likelihood

of retinal detachment and lowered the secondary enucleation rate.

438

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retrospective study (n = 133) on matched groups found that addition of

TTT to brachytherapy improved rate of tumor regression, 5-year tumor

recurrence rate, eye-globe preservation, and recurrence-free survival.

444

There was no impact on metastasis-free survival, OS, rate of

complications, or visual outcomes.

444

However, two other studies showed

that adding TTT to brachytherapy did not improve the rate of globe

conservation, and was associated with greater loss of VA.

366,445

The larger

of these studies (n = 449) also showed that rate of local failure, distant

metastasis, and cause-specific death were not improved by TTT.

366

Complications associated with TTT include retinal hemorrhage, vitreous

hemorrhage, retinal vascular occlusions, optic disc atrophy, macular

edema, retinal detachment, retinal traction, exudative serous

neurosensory detachment, vitritis, and postoperative pain.

433,446

Cryotherapy

Use of cryotherapy for treatment of primary or recurrent uveal melanomas,

either alone or in conjunction with other therapies, has been described in

case reports and case series in the literature,

435,447-453

and retrospective

reports and review articles suggest that this method is occasionally being

used in clinical practice.

26,310,454

Treatment for Extraocular/Extrascleral Extension

Extraocular/extrascleral extension has been reported to be present in

approximately 3% of patients at diagnosis of uveal melanoma,

166,173,200,455

is more common among tumors with higher T stage (12% of T4 tumors),

285

and is associated with poor prognosis.

18,26,284,456-458

Extrascleral/extraocular

extension can be detected by preoperative imaging, or found or confirmed

at the time of enucleation.

294,459

Sometimes the evidence of extraocular

extension is microscopically positive or close margins after enucleation,

without clinical, intraoperative, or radiographic evidence of gross residual

disease to the orbit. In other cases, extraocular tumor is visible

intraoperatively or intraoperative findings suggest that there may be gross

disease to the orbit. In the COMS trial of patients with large uveal

melanomas that tested enucleation with versus without pre-enucleation

RT, unexpected extrascleral extension was found in 2% of patients who

underwent enucleation, despite extensive clinical and imaging

workup.

294,301

Orbital Exenteration

Orbital exenteration is surgical removal of the globe and adjacent orbital

contents, for cases with extraocular extension and/or orbital

invasion.

41,185,196,422,425,460

Retrospective studies of large databases suggest

that exenteration is used in less than 1% of patients,

and among patients

undergoing enucleation, 2.5% need orbital exteneration.

461

The value of

orbital exenteration is disputed in the literature, largely based on low-

quality data such as case reports and retrospective studies. Some studies

support orbital exenteration because it provided superior outcomes

compared with other (nonsurgical) approaches,

462

whereas others report

poor outcomes after orbital exenteration, arguing that it may not be

justified.

463,464

Radiation Therapy for Extraocular/Extrascleral Extension

A retrospective study (n = 202) found that in patients treated with

enucleation, postoperative RT improved survival, particularly in young

patients (age <30 years) and those with choroidal tumor height greater

than 3 mm.

461

Another retrospective study (n = 17) reported a local

recurrence rate of 6% in patients with extrascleral extension who were

treated with enucleation followed by adjuvant external beam RT to the

orbit.

465

For patients with limited extraocular extension less than 3 mm

thick, brachytherapy may also be an option, as a retrospective study (n =

17) showed no intraocular or extraocular tumor relapse after a median

follow-up of 63 months (range, 23–164 months).

466

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Melanoma: Uveal

MS-24

Treatment of Localized Uveal Melanoma

Following workup and staging, patients with localized uveal melanoma

should be treated. Treatment options depend on the tumor size (diameter

and thickness) and proximity to the optic nerve.

Tumor Size: Largest Diameter 5–19 mm and Thickness <2.5 mm

For thin tumors (<2.5 mm) with largest diameter ranging from 5 to 19 mm,

the recommended primary treatment options are plaque brachytherapy or

particle beam RT. For highly select patients who are not good candidates

for brachytherapy or particle beam RT, other options to consider include

laser therapy or enucleation.

Tumor Size: Largest Diameter ≤19 mm and Thickness 2.5–10 mm

Brachytherapy and particle beam RT are also options for treating tumors

with largest diameter 19 mm or smaller and thickness 2.5 mm to 10 mm.

If there is concern that adequate response was not achieved from initial

RT, then further treatment should be considered. Recommended options

for further treatment include laser therapy or cryotherapy. In highly select

cases, resection is sometimes considered. Tumors in this size range may

also be treated with enucleation. Although there is a trend toward avoiding

enucleation, it is recommended for patients with neovascular glaucoma,

tumor replacing greater than 50% of globe, or blind, painful eyes.

Enucleation should also be considered in cases of extensive extraocular

extension.

Tumors Not Appropriate for Brachytherapy

Given the limitations in the size and RT penetrance of commercially

available brachytherapy plaques (diameter ≤23 mm), this method is not

appropriate (and not recommended) for tumors that are too large in

diameter (>19 mm; any thickness), too thick (>10 mm; any diameter), or

have optic nerve involvement and thickness (>8 mm; any diameter). RT

options for such tumors include particle beam RT and SRS. The choice

between these two RT modalities usually depends on which modality is

available at the treating institution. In the rare scenario that the institution

has both SRS and particle beam facilities, some practitioners would opt for

particle beam because there are more data supporting its efficacy.

Enucleation is also a recommended option, especially in cases with

extensive extraocular extension, neovascular glaucoma, tumor replacing

greater than 50% of globe, or blind, painful eyes.

Additional Treatment Considerations

An essential feature of high-quality care is that clinical decisions are

informed by a variety of case-specific factors (patient preferences and

characteristics such as age, status of the other eye, disease

characteristics, and medical history), such that for some patients the best

clinical approach may not be one of the listed options. The recommended

treatment options are largely based on data from choroidal melanomas.

For small ciliary body and iris tumors (<3 clock hours), surgical excision

may be considered.

Additional Primary Treatment for Extraocular Extension

For patients with limited extraocular extension, brachytherapy with scleral

patch graft should be considered. For patients treated with enucleation for

their primary tumor, additional treatment may be needed if extraocular

extension is present. For patients with microscopically positive or close

margins after enucleation, but no clinical, intraoperative, or radiographic

evidence of gross residual disease to the orbit, recommended options

include observation (no further treatment), mapping biopsy, and/or

consideration of RT to the orbit (using particle beam or photon beam

therapy). For patients with visible extraocular tumor or suspicion of gross

disease in the orbit at the time of enucleation, biopsy of the extraocular

tissue is recommended, if possible. Additional treatment options to

consider include one or more of the following: intraoperative cryotherapy,

orbital exenteration, and/or RT to orbit using particle beam or photon

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beam RT. For photon or proton beam RT to the orbit (after enucleation), a

dose of 20 to 30 Gy in 5 fractions should be prescribed to the clinical

target volume at risk for recurrence

294,467

using intensity-modulated or

conformal techniques with image guidance.

Treatment of the Primary Tumor in Patients with Metastatic Disease

Palliative local therapy to the primary tumor may be considered in the

setting of metastatic disease. In general, if the metastatic disease is being

treated, the primary tumor should also be treated. Patients who present

with advanced metastatic disease and limited life expectancy may elect to

have no treatment to their primary tumor.

Follow-up

In order to make educated choices about monitoring and follow-up after

treatment of the primary lesion, it is important for patients and treating

clinicians to be aware of what is known about the typical trajectory of the

disease, including the typical characteristics and time frame until

presentation of treatment complications, recurrence, and metastasis.

Monitoring should also be informed by consideration of a patient’s risk for

each of these outcomes.

For patients whose primary uveal melanoma was treated with RT or

surgery, the subsequent disease-free interval is highly variable, ranging

from a few months to many years.

327,347,372,388,440,441,468

Uveal melanoma is

characterized by early micrometastasis (often before treatment) followed

by variable latency period before emergence of overt metastasis.

469

Local

recurrence is rare, occurring in less than 10% of patients after the primary

lesion is treated using one of the modalities recommended in these

guidelines.

47,187,272,294,295,326,327,330,331,333,337,338,347,366,439,441,468,470,471

Development of detectable distant metastatic disease is much more

common than local recurrence, and develops in up to 70% of patients,

depending on the stage and other risk factors at the time of

diagnosis.

8,13,26,285

For example, large retrospective studies (n > 7000)

found that after long-term follow-up the percent of patients who had

developed metastasis was 20% for those with stage I at diagnosis, but

~70% for those with stage III at diagnosis.

13,285

Patterns of Local Recurrence

Due to the rarity of local recurrence, data characterizing local recurrences

are somewhat limited. The likelihood, typical time frame for development,

location, and risk factors for local recurrence may depend on whether the

patient received primary treatment with enucleation or some form of

radiation (ie, brachytherapy, particle beam, SRT).

Local Recurrence After Enucleation

Local recurrence after enucleation for localized primary melanoma is

extremely rare, occurring in only ~1% of patients, and presents as tumor

growth in the orbit.

294,295,471

In the COMS randomized controlled trials (for

medium and large tumors), the few patients who developed local

recurrences after enucleation all had distant metastases before the local

recurrence developed.

294

Retrospective studies reported similar findings,

suggesting that development of distant metastasis is due to

micrometastasis that developed prior to enucleation.

471

The rarity of the

event precludes meaningful evaluation of risk factors for local recurrence

after enucleation.

Local Recurrence After Radiation (Brachytherapy, Particle Beam

RT, or Stereotactic RT)

In prospective trials reporting on patients who received brachytherapy as

primary treatment for localized uveal melanoma, tumor regression was

observed in most cases (97%–98%),

330,367

and occurred over the first 2

years after treatment.

367

Prospective studies have reported local failure

rates ranging from 0% to ~20% for patients with localized primary uveal

melanoma treated with brachytherapy with iodine-125 or other types of

plaques (ruthenium-106, palladium-103, cesium-

(NCCN

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131).

47,187,326,327,330,331,333,337,338,347,366,439,441,468,470

Most of these studies

reported local failure rates less than 10%, and a systematic review that

included more than 3000 patients from 22 studies, including retrospective

studies, found that the weighted mean rate of local failure after

brachytherapy was 9.45%.

272

Prospective studies have reported that local

recurrence after brachytherapy, although rare, occurs over a wide time

range.

47,187,327,366,440,441,468

Whereas some studies report median time to

local recurrence between 2 and 4 years,

327,440,441,468

most also show curves

that never really plateau, due to late recurrences developing throughout

long-term follow-up, as late as 12 years or more after

treatment.

47,187,327,366,440,441,468

A variety of risk factors for local recurrence have been identified. Although

results vary across studies, multiple analyses have found that tumor size

and location are associated with risk of local recurrence after

brachytherapy.

47,187,347,366,441,468

Regarding primary tumor location as a risk

factor, prospective studies have found higher risk of local recurrence

associated with ciliary body involvement, epicenter location in the macula,

proximity to the foveal avascular zone, proximity to the optic nerve, and

extension under the foveola.

47,187,347,441,468

One large prospective study

reported that presence of visual symptoms at the time of uveal melanoma

diagnosis was correlated with higher risk of local recurrence after

brachytherapy.

327

Several studies have shown that local recurrence is at

least mildly associated with a higher risk of melanoma-related death.

187,327

For patients with primary uveal melanoma treated with particle beam RT,

local recurrence rates ranged from 3% to 10% across studies.

272,370

Tumor

regression following particle beam RT can begin within 6 months of

treatment, and tumor shrinkage may continue to occur throughout 5 years

of follow-up.

370,472

As with brachytherapy, local recurrence after particle

beam RT as treatment for primary localized uveal melanoma occurs over

a long time range, as early as 2 months after treatment and as late as 12

years.

372,416,473

Prospective studies have found that most local recurrences

occurred in the first 4 to 5 years, with median time to recurrence of less

than 2 years.

47,372,416,473

Primary tumor size and ciliary body involvement

were shown to be independent risk factors for local recurrence in a

multivariate analysis of results from a large prospective observational

study of patients who received particle beam RT as primary treatment for

uveal melanoma.

473

Local recurrence after particle beam RT has been

shown to be associated with an increased risk of metastasis and

increased risk of death from metastatic uveal melanoma.

372,473

Studies using SRT as primary treatment for uveal melanoma have

reported local failure rates ranging between 2% to 16%.

183,272,344,368,377-390

This large range likely reflects differences in the populations studied.

Following SRT of the primary tumor, prospective studies found that many

uveal melanomas showed a transient increase in tumor height, volume, or

both.

383

Responses to SRT first began to appear 6 months after treatment,

with progressive decreases in tumor height and volume continuing for at

least 3 years.

183,379,384,388,389

Prospective follow-up showed that the fraction

of patients with response or stable disease increased during the first year

after treatment.

183,389

Prospective studies have found that following SRT

there is a small percentage of patients with persistent tumor growth, which

can occur soon after treatment (failure to achieve local control) or after a

period of local control, and some studies reported recurrences many years

after treatment.

381,383,387-390,396

The few prospective studies that have

attempted to identify risk factors for tumor growth after SRT have not

found any correlation between RT dose or tumor diameter before

treatment.

379,388

There are some prospective data that suggest that local

recurrence after SRT may be correlated with poorer survival.

380

For all of the above RT modalities (brachytherapy, proton beam RT, and

SRT), prospective studies have reported that tumor growth after treatment

occurred at the margins of the treated area for some patients, but for other

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patients appeared as tumor growth in all dimensions, including growth

within the treated volume.

347,370,373,383,389,416,468,473

Patterns of Treatment Complications

Complications After Enucleation

For patients treated with enucleation for primary uveal melanoma,

complications between 1 to 6 weeks after surgery included pain requiring

longer hospital stay, pain requiring medication, conjunctival wound

dehiscence, infection, decreased facial sensation, eyelid swelling,

inflammation, implant displacement, hair loss, ptosis, conjunctival

chemosis, ecchymosis, and orbital or conjunctival hemorrhage.

294

Long-

term follow-up showed that other problems include poor motility of

prosthesis, poor alignment of prosthesis, severe ptosis, and displacement

of implant.

294

Enucleation is also associated with loss of certain visual

functions, such as peripheral vision, night driving, and judging

distances.

316,317,319

Complications After Brachytherapy

Effects on Visual Acuity

Prospective studies of patients treated with brachytherapy for uveal

melanoma have shown that VA in the treated eye tends to steadily

decrease during at least the first 5 years of follow-up, both in terms of

severity and the percent of patients with poor vision.

186,331,334,335,347,366,468

Studies with long-term follow-up (>10 years) showed that the percent of

patients with poor VA increases more slowly between 10 and 15 years

after brachytherapy, and one study reported a median time to VA score

(VAS) less than or equal to 50 of 39 months.

334,468

Factors associated with

loss of VA or poor vision outcomes included greater baseline tumor apical

height, shorter distance between the tumor and the foveal avascular zone,

ciliary body involvement, presence of tumor-associated retinal

detachment, non–dome-shaped tumor, and patient history of diabetes.

Results from multiple prospective studies suggest that risk of poor vision

outcomes depends on baseline tumor thickness and

location.

186,331,334,335,347,366,468

Locational elements suggested to be

associated with increased risk of poor vision include juxtapapillary

location, proximity to foveola, optic nerve or optic disc, ciliary involvement,

central tumor location, mid-choroid and macula location, and retinal

invasion. Some prospective studies have suggested additional risk factors

for poor vision outcomes, including baseline VA, patient age, diabetes,

baseline tumor shape, retinal detachment at baseline, and development of

radiation maculopathy or radiation optic neuropathy.

186,335,366,468

Cataracts

Prospective studies have reported that following treatment with

brachytherapy for uveal melanoma, the percent of patients with cataracts

in the treated eye steadily increases over the first 5 years of follow-up.

Cataracts may affect more than two thirds of patients by 5 years, although

a much smaller number of patients underwent cataract surgery.

329,468

the COMS trial, median time to development of cataract was 2.5 years,

and the median time to cataract surgery was 3.5 years.

329

Cataract

surgery resulted in VA improving by two or more lines in 66% of patients,

and stabilizing in 26%.

329

Older age, larger baseline tumor size, and higher

radiation dose may be risk factors for development of cataract after

brachytherapy.

329

Other Serious Complications

Treatment of uveal melanoma with brachytherapy can result in a variety of

radiation-related complications in the treated eye, or can worsen

conditions initially caused by the uveal tumor.

336,441,468

Examples of more

serious complications include radiation retinopathy, optic neuropathy,

papillopathy, maculopathy, neovascular glaucoma, retinal detachment,

and various types of hemorrhages and vascular abnormalities.

331,336,468

Prospective studies have found that the development or worsening of

(NCCN

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complications typically occurs during the first 5 years after treatment,

although the time frame for development may differ slightly between

specific types of complications.

336,468

These complications occasionally

develop more than 5 years after treatment, especially in patients who had

large tumors prior to treatment.

468

Enucleation

Prospective studies of patients treated with brachytherapy for uveal

melanoma have found that up to 40% of patients needed enucleation

during follow-up, either due to treatment failure, loss of VA, or

complications.

47,186,187,303,366,468

The rate of enucleation after brachytherapy

was lower in some studies that included only patients with smaller tumors

at baseline.

187,366

In these studies the cumulative rate of enucleation

increased gradually over a long period of time, at least 15 years after

follow-up.

47,186,187,437,468

The need for enucleation at late time points reflects

that local recurrences can occur many years after

treatment,

47,187,327,366,440,441,468

that VA can persistently decline over many

years,

186,331,334,335,347,366,468

and that some complications have a long time to

onset and/or gradually worsen over many years.

329,336,468

Studies with

long-term follow-up reported that approximately half of the enucleations

were due to local treatment failure, and the other half were due to

complications or poor VA.

47,187,468

Complications that lead to secondary

enucleation included neovascular glaucoma, retinal detachment, vitreous

hemorrhage, and ocular pain.

187,468

Results from the COMS study in

medium-sized tumors suggest that enucleations at early time points were

more often caused by local treatment failure, whereas enucleations at later

time points were more often caused by complications or poor VA.

187

Factors that may be associated with increased risk of enucleation include

the following baseline features (prior to primary treatment): increased

primary tumor thickness, proximity to foveal avascular zone, anterior

location, and epithelioid cell type; poorer VA; and younger age.

187,366,468

Complications After Particle Beam RT or Stereotactic RT

Effects on Visual Acuity

Prospective studies of patients with uveal melanoma have reported

steadily declining VA in the treated eye following proton RT or SRT, both

in terms of the percent of patients with poor VA and in terms of the mean

VA across the whole patient population.

183,347,379-381,383,384,387,388,473

This

decline was observed throughout the duration of follow-up, which was up

to 5 years in these studies. Some of these studies suggest increased risk

of declining VA after proton RT or SRT for patients with low baseline VA,

increased radiation dose to optic nerve, and posterior tumor location.

379,380

Time to loss of VA may be longer for patients treated with lower doses.

388

Other Complications

Following particle beam RT for primary uveal melanoma, toxicities

reported in prospective studies include vitreous hemorrhage, subretinal

exudation in macula, posterior subcapsular opacity, radiation keratopathy,

rubeosis/neovascular glaucoma, retinal detachment, radiation

maculopathy, and papillopathy.

370,373,438

Eyelash loss and low-grade

dermatitis are common short-term toxicities that develop soon after

treatment.

347,474,475

Whereas development of retinal detachment or

neovascular glaucoma rarely occurs beyond 2 to 4 years after

treatment,

373,438

development of RT maculopathy and RT papillopathy may

occur beyond 5 years of follow-up.

473

Results from prospective studies

suggest that risk of RT maculopathy may depend on the distance between

the tumor and the macula, whereas RT papillopathy and neovascular

glaucoma may be related to proximity to the optic disc.

373,473

Increased

tumor size and larger irradiated volumes of critical normal eye structures

may also be associated with increased risk of neovascular glaucoma.

373

Prospective studies have reported a wide variety of complications

associated with SRT treatment of primary uveal melanoma. Alopecia and

eyelash loss typically develop within 1 year of treatment, and have been

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reported to occur in less than 10% of patients, although much higher rates

were observed in patients with large primary tumors.

183,384,387,399

Doses

high enough to cause alopecia can also cause dermatitis, another early,

transient, mild toxicity associated with SRT.

387,399

Fatigue, pain, and dry

eye may also occur after SRT.

183,379,380,387

Fatigue and pain typically occur

soon after treatment, and then abate.

183

Dry eye also typically occurs soon

after treatment (median time to onset 6 months), but can occur much later

(range 3–60 months), and can be severe and/or persistent.

183,379,387

Baseline tumor size (base diameter and height) and higher dose to the

lacrimal gland may increase risk of dry eye.

379,387

Uveitis has been

reported to develop between 6 to 52 months after SRT, occurring in less

than 15% of patients, although larger tumor volume may increase the risk

of uveitis.

379,384,387,399

Diseases of the lacrimal drainage system tend to

have late onset, occurring between 1 to 4 years after treatment, and

usually occur in less than 10% of patients.

387,399

Mild iritis has been

reported after SRT for tumors with ciliary body involvement.

383

Conjunctival problems (such as hyperemia, irritation, tears, and chemosis)

are typically mild, mostly occur within 6 months of treatment, and usually

resolve.

183

Corneal epithelial defect and corneal ulcer have been reported in up to

30% and up to 10% of patients, respectively, and can develop between 6

months and 5 years after SRT treatment for uveal melanoma.

384,387,389,399

These corneal complications can be serious, and some studies suggest

that risk of corneal damage may increase with increasing dose and

increasing tumor diameter.

382,384,399

SRT can cause or worsen exudative retinal detachment, but some cases

of retinal detachment prior to treatment were unchanged or resolved after

treatment.

183,379,383,384,387

One study reported resolution of over half of the

cases with retinal detachment at baseline, with a median time to resolution

of 15.7 months.

387

Increased patient age and tumor size may be

associated with increased risk of retinal detachment.

379,384

Various types of

hemorrhage, including vitreous hemorrhage, subretinal bleeding, retinal

hemorrhage, cutaneous bleeding, and subconjunctival hemorrhage, have

been reported following SRT.

183,379,380,384

Most of these bleeding events are

mild and resolve.

380,384

Vitreous hemorrhage has been reported in 10% or

less of patients, can be more severe, and may develop between 3 to 48

months of follow-up, with a median time to development of 15

months.

379,380,384

SRT can also cause or worsen cataracts, which can be severe and may

require surgery.

183,379,380,382-384,387,389,399

Cataract development after

treatment occurs over a wide time range (3–100 months), with one study

reporting a mean time to development of 19.6 months, and another

reporting a median time to development of 12 months.

183,379,387,389,399

Prospective studies suggest that risk factors for cataract development

after SRT may include advanced age, ciliary body involvement, larger

tumor size, larger PTV, larger RT dose, and larger dose to the lens and

ciliary body.

379,382,384,399

Secondary glaucoma, including neovascular glaucoma, has been

observed in multiple prospective studies of patients treated with

SRT.

183,379,380,382,384,387,389,396,399

Neovascular glaucoma may be mild or

severe, and may effect more than 25% of patients.

379,380,384,387,399

Neovascular glaucoma typically has late onset, developing between 5

months and 10 years after treatment, with one study reporting median time

to development of 30 months.

379,380,387,389,396,399

Results from prospective

studies agree that greater tumor height (at baseline) is a risk factor for

neovascular glaucoma, but differ regarding whether greater RT dose is

associated with greater risk.

379,382,384,387,399

Retinopathy has been reported to occur in up to two thirds of patients

treated with SRT, and may be mild or severe.

183,379,380,383,384,387,389,399

Retinopathy typically has delayed onset, and has been reported to

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develop between 5 to 110 months, with one prospective study reporting a

mean time to development of 15 months, and another reporting a median

time to development of 24 months.

183,379,380,383,387,389

Development of optic

neuropathy after SRT has been observed in multiple prospective studies,

may occur in up to 40% of patients, and can be

severe.

183,379,380,382,384,387,389,399

Optic neuropathy typically has delayed

onset, and has been reported to develop between 4 months and 9 years

after treatment, with a mean time to development of 21

months.

183,380,384,387,389,399

Prospective studies have suggested a variety of

risk factors for optic neuropathy, including larger tumor size, tumor stance

to the optic disc, higher total RT dose, higher dose to the optic nerve, the

ratio of gross tumor volume (GTV) to PTV, or the distance from PTV to the

optic nerve.

379,384,387,399

SRT can also cause optic disc edema, which is

often severe, develops between 1 to 2 years after treatment, and has a

median time to development of 18 months.

379

Enucleation

Prospective studies have found that secondary enucleation was

sometimes needed due to local recurrence or complications in patients

with primary uveal melanoma treated with proton RT or

SRT.

47,373,379,380,384,387,388,396

Among cases of enucleation due to

complications, neovascular glaucoma was the most common cause;

others included angle closure glaucoma, tumor necrosis syndrome,

corneal ulcer, retinal detachment, and pain, sometimes due to elevated

intraocular pressure.

47,373,380,384,387,388,396

These secondary enucleations

occurred over a wide time range, from 2 months to greater than 10 years

after treatment.

47,373,384,389,438,476

Although most enucleations occurred

within 5 years of treatment, the risk of enucleation between 5 to 10 years

after treatment is non-negligible.

47,388,389,396,438,476

Larger tumor size,

proximity to the optic disc, high intraocular pressure, or retinal detachment

before treatment may increase the risk of secondary enucleation after

proton RT.

476

Surveillance Methods for Local Recurrence or Complications

To monitor for local recurrence and possible complications after treatment

of the primary tumor in patients with uveal melanoma, prospective studies

have followed patients with regular clinical and ophthalmologic exams.

For patients treated with enucleation in the COMS trial, there were follow-

up exams at 1 to 2 weeks after surgery to assess healing status, and at 6

months, 12 months, and annually thereafter, in which the eye socket and

eyelids were examined for possible recurrence or complications, and the

fit of prosthesis checked.

301,303,477

For patients treated with RT (brachytherapy, particle beam RT, or SRT) in

prospective studies, follow-up exams typically included complete

ophthalmologic exam of the treated eye, with indirect ophthalmoscopy, slit-

lamp exam, tonometry, color fundus photography, A-scan and B-scan US,

and measurement of VA and visual

field.

47,183,186,187,327,330,331,333,335,347,366,367,370,380,383,384,387-

389,396,437,439,440,468,472,473,477-479

Many prospective studies also included

fluorescein angiography in follow-up exams, either at regular intervals or

as needed.

47,187,330,333,335,336,347,366,384,388,389,439,478

A few prospective studies

used gonioscopy,

187,388

OCT,

335,366,437

or MRI.

383,396

For most prospective

studies following patients with primary uveal melanoma treated with RT,

data taken at regular intervals included VA, intraocular pressure, tumor

dimensions and shape, development of new extrascleral growth, orbital or

ciliary body mass, and retinal invasion, pathologic changes, changes in

tumor appearance, and patient symptoms (ie, ocular pain, vision

problems).

183,186,187,303,331,333,335,367,370,373,380,384,387-389,440,472,479

Some studies

monitored for changes in tumor reflectivity or tumor vascularity as signs of

regrowth/recurrence.

366,367,396,472

The frequency of follow-up exams after RT (brachytherapy, particle beam

RT, or SRT) varied across studies. For patients who were treated with

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brachytherapy in the COMS study, follow-up included an exam within 6

weeks of surgery, at 6 months after treatment, then every 6 months for 5

years, and every 12 months thereafter.

303

Patients with suspected tumor

growth had more frequent follow-up exams. Whereas some prospective

studies in patients treated with brachytherapy had follow-up protocols

similar to COMS,

327,331,367

others used more frequent follow-up, with more

than 2 exams per year during the first year or first few years after

treatment, and exams every 6 to 12 months during later

years.

47,330,333,334,347,439-441,468,479

Prospective studies following patients after

particle beam RT or SRT for primary uveal melanoma sometimes had

frequent follow-up during the first 6 months after treatment (eg, 3–5 exams

in the first 6 months),

183,375,379,380,383,384

and most had follow-up exams at

least every 3 to 4 months during the first year or two.

47,183,347,373,379,384,387-389

A few studies switched to the 6-month follow-up interval starting early (<1

year) from treatment.

370,375,380,396,472,478

Long-term follow-up intervals

ranged between 4 to 12 months.

47,183,347,370,373,375,379,380,383,384,387,388,396

Because some patients treated with RT may have an increase in tumor

size before regression, studies have defined local recurrence in terms of

specific thresholds for growth. For example, the COMS trial defined local

treatment failure (after brachytherapy) as one or more of the following:

increase in height of ≥15% by echography or a ≥250-um expansion of any

tumor boundary by photographs or clinical examination followed by an

additional ≥15% increase in elevation or a further ≥250-um expansion of

any tumor boundary observed and conﬁrmed on subsequent examination;

extrascleral extension based on clinical or echographic ﬁndings; or

development of orbital mass, ciliary body mass, or retinal invasion.

187

Similarly, prospective studies following patients after SRT have used

definitions of tumor recurrence that include tumor growth rate above a

specific threshold that is confirmed over two exam intervals, usually based

on US measurements.

183,373,387,388,396

Follow-up for the Treated Eye

At NCCN Member Institutions, standard follow-up in the affected eye

includes imaging with color fundus photography and ultrasonography

every 3 to 6 months for 3 to 5 years, then every 6 to 12 months thereafter,

if stable. The frequency of follow-up should depend on the size and

location (eg, juxtapapillary location, ciliary body involvement) of the tumor

at presentation, as these factors impact the risk for recurrence.

Risk in Contralateral (Fellow) Eye

In patients who have received treatment for primary unilateral uveal

melanoma, disease can develop in the contralateral eye, but the incidence

is very low. In the COMS trials of patients with medium or large primary

uveal melanoma tumors, prospective monitoring showed that less than 1%

of patients developed disease in the contralateral eye during follow-up

after primary treatment.

295,480,481

Moreover, for the majority of patients who

did not develop disease in the contralateral eye, results from regular

ophthalmologic exams showed that good VA was retained in their fellow

eye throughout the 10 years of follow-up, regardless of the modality used

to treat the primary lesion (brachytherapy, enucleation, or RT followed by

enucleation).

482

Analysis of 8165 patients with ocular melanoma in the

SEER database found bilateral involvement in 0.1% of patients.

One

retrospective study of 52 cases of bilateral uveal melanoma suggests

prognosis in these cases is similar to that of unilateral cases.

483

Additional

cases of uveal melanoma metastasizing to the contralateral eye are

described in case studies.

484-492

NCCN Recommendations for Follow-up for the Contralateral Eye

All patients should receive follow-up for the affected eye. In patients with

uveal melanoma, the contralateral eye is not at increased risk of uveal

melanoma,

10,295,480,481

and can be followed with routine ophthalmologic

care.

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NCCN Guidelines Version 2.2021

Melanoma: Uveal

MS-32

Patterns of Metastases

Most uveal melanomas are localized at first presentation, and only a small

percentage of cases (<3%) have detectable metastatic disease at the time

of diagnosis.

6,10-14,166,493

Development of distant metastatic disease is much

more common, occurring in ~20% to 70% of patients within 20 years after

treatment for primary uveal melanoma, depending on stage/size and

genetic characteristics of the tumor at diagnosis.

8,13,26,48,67,285

Prospective

studies with long-term follow-up (≥5 years) after treatment of primary uveal

melanoma have shown that the cumulative rate of development of distant

metastatic disease steadily increases over many years of follow-

up.

47,331,347,366,372,379,381,387,388,440,441,468,473,480,481

For example, in the COMS

studies in which patients with medium tumors were treated with

brachytherapy or enucleation, and patients with large tumors were treated

with enucleation with or without RT prior to surgery, the Kaplan-Meier

estimates of 2-, 5-, and 10-year metastasis rates were 10%, 25%, and

34%.

481

Although incidence rates declined after the 2-year examination,

and most cases of distant metastatic disease developed within 90 months

of treatment, new cases of distant metastatic disease were detected at

every 6-month interval over the 12-year follow-up period.

480

Although the

proportion of patients who developed distant metastasis differed

depending on the primary tumor size prior to treatment, the cumulative

incidence curves (proportion of patients with metastasis) for both medium

and large tumors did not appear to be plateauing even after 10 years of

follow-up.

480,481

Similar findings have been reported for other prospective

studies monitoring for development of distant metastatic disease after

primary treatment with brachytherapy,

331,366,440,441,468

particle beam

RT,

47,347,372

or SRT.

384,387,388

These studies found that the proportion of

patients with metastasis increased between all consecutive time points

(eg, Kaplan-Meier estimates at 1, 2, 3, 5, 7, 8, 10, and 15

years).

47,331,372,384,387,388,440,441,468

In these studies the development of

metastatic disease occurred as early as 4 months and as late as 14 years

after treatment of primary uveal melanoma,

347,372,381,468

developing

continuously throughout the follow-up period such that cumulative

incidence curves and disease-free survival curves did not appear to be

plateauing even after 6 to 20 years of follow-up.

47,366,388,440,468

Although

difficult to calculate due to ongoing development of distant metastatic

disease, several studies reported mean and median times to first distant

metastasis (for those who developed distant metastasis), which ranged

from 39 to 45 months, and from 35 to 37 months, respectively.

347,372,388,468

Sites of Metastasis

Uveal melanoma most often metastasizes to the liver.

19,21,22,166,295,480,481,494-

501

Of those with distant metastasis, greater than 90% have liver

metastases.

295,480,481

For patients with only one metastasis at the time that

distant metastasis is first detected, most have liver metastasis.

19,21,22,295,497

Other common sites of metastasis, listed in order of decreasing

prevalence, are lung, bone, skin/soft tissue, and lymph

nodes.

11,21,166,295,373,379,480,481

In large prospective studies following patients

after treatment for primary uveal melanoma, metastasis to the lung was

observed in 20% to 30% of patients who developed distant metastasis, to

the bone in 16% to 18%, to skin/soft tissue in 11% to 12%, and to lymph

nodes in 10% to 11%.

295,480

Retrospective studies show similar trends.

21,501

A few studies reported brain metastases in 4% to 5% of patients who

developed distant metastases.

21,295,480

Most patients who develop

metastasis ultimately have multiple sites involved.

295,480

Risk Factors for Metastasis

Numerous studies have evaluated factors prognostic for development of

distant metastasis or for shorter time to development of distant metastasis.

Although the AJCC staging system is based on survival data from large

epidemiologic studies,

12,13,18

characteristics used for AJCC staging have

also been shown to be prognostic for development of distant metastasis.

In the AJCC staging system for melanomas arising in the choroid or ciliary

body, T stage is based on the largest basal diameter and thickness of the

(NCCN

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NCCN Guidelines Version 2.2021

Melanoma: Uveal

MS-33

primary tumor, as well as the presence or absence of ciliary body

involvement and presence and size of extraocular extension.

Multiple

prospective studies and several large retrospective studies (N > 1000)

have shown by multivariable analysis that primary tumor diameter and/or

thickness is associated with risk of metastasis after primary

treatment.

91,324,347,372,456,468,502

Several retrospective studies on large patient

populations have found that risk of metastasis is correlated with AJCC T

stage and with AJCC staging.

8,13,284,501,503-507

Primary uveal melanomas can contain spindle cells, which have ovoid

nuclei and tend to grow in a compact fashion, and epithelial cells, which

are larger, more irregularly contoured, pleomorphic, and contain abundant

cytoplasm, larger nuclei, and nucleoli.

The cell types present in the

primary lesion have been linked to risk of metastasis. One prospective and

several retrospective analyses have found that the histologic cell type(s) in

the primary tumor can be prognostic for metastasis, in that patients whose

primary tumor contains epithelioid cells (either entirely or mixed with

spindle cells) are more likely to develop metastases than those who have

only spindle cell type.

67,257,501,502,506,508-510

The presence of spindle versus

epithelioid cells in the primary tumor had been used as a prognostic factor

to inform frequency of follow-up after primary treatment, but this prognostic

feature is now considered less important than other tumor features and

molecular markers. Lack of concordance among pathologists makes

implementation of risk stratification by histopathology difficult.

In addition to AJCC T stage and tumor histology, multiple tumor molecular

markers have been shown to be associated with increased risk and/or

shorter time to development of distant metastases. Chromosomal changes

were among the first molecular markers to be found to be associated with

risk of distant metastasis in patients with uveal melanoma.

508

Multiple

studies have found that monosomy 3 and gain of chromosome 8q,

especially when numerous copies are found, in the primary uveal

melanoma is associated with increased risk of metastasis.

24,36,48,67,324,509-525

Risk of metastasis is even higher when both of these abnormalities are

present.

24,67,513,516,518,522

Some studies have identified additional

chromosomal abnormalities associated with increased risk of metastasis,

such as loss of 8p,

24,513,515,516,518

loss of 1p,

518

loss of 16q,

513

and loss of

6q.

Gain of 6q may be protective against metastasis,

518

at least in the

context of monosomy 3 and gain of 8q.

A method of using gene expression profiling (GEP) has been developed

as a prognostic tool for uveal melanoma.

526-528

These methods have been

used to sort tumors into two classes, showing that class 2 was associated

with higher risk of metastasis than class 1.

48,252,502,503,512,521,529-535

Multivariate analyses have found that class 2 is associated with a 5-fold to

20-fold higher risk of metastasis than class 1.

48,502,531,534,535

Mutation and expression of certain specific genes have also been

associated with risk of metastasis in patients with uveal melanoma.

Multiple studies have found that BAP1 mutation/deletion (observed in

approximately half of uveal melanomas) and loss of BAP expression in the

primary tumor is associated with increased risk of

metastasis.

36,72,504,506,521,523,532,536,537

One study showed that risk of

metastasis is highest with BAP1 somatic mutation, although also

somewhat elevated in patients with BAP1 germline mutation (compared

with wild-type).

519

Other studies found that BAP1 mutation was associated

with early metastasis (after treatment of primary uveal melanoma).

538,539

Mutation in EIF1AX, found in up to 20% of uveal melanomas,

36,510,532,540

has been associated with lower risk of distant metastasis in patients with

uveal melanoma.

506,538,539

Some studies have found that SF3B1 mutation,

which is present in approximately 20% of uveal melanomas, was

associated with lower risk of metastasis,

36,73

while others found that

patients with this mutation developed late metastases.

506,538,539

PRAME

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NCCN Guidelines Version 2.2021

Melanoma: Uveal

MS-34

expression, present in about a third of uveal melanomas,

503,541

has also

been associated with increased risk of metastasis.

503,533

Surveillance Methods for Distant Metastatic Disease

There are very little data to inform the frequency and modality of follow-up

screening for development of metastatic disease. Prospective studies

following patients after treatment for localized primary melanoma have

typically monitored for development of distant metastasis using regular

follow-up visits including complete cancer-oriented physical exams and

one or more of the following: chest x-ray, liver US, and serum liver function

tests (LFTs).

47,301,327,330,347,366,367,380,384,388,478,480

Liver US and LFTs were

often included as part of routine follow-up because the liver is the most

likely site of distant metastasis.

19,21,22,166,295,480,481,497

Most of these

prospective studies followed patients with physical exams, imaging, and

blood tests every 6 months for at least the first 5

years.

47,327,330,347,366,367,380,384,388,478,480

In real-world clinical practice, there

are regional differences in the preferred methods and frequency of follow-

up screening for metastatic disease in patients with uveal melanoma.

542

For most of the prospective studies that monitored for development of

distant metastatic disease after treatment of primary uveal melanoma, the

total number of patients who developed distant metastases was too small

to produce meaningful results regarding the sensitivity and specificity of

different surveillance modalities. The COMS trials for patients with medium

and large tumors were the largest of these prospective studies, and

included cancer-oriented physical exams, chest x-ray, and LFTs as part of

routine follow-up.

480

Elevated LFTs (aspartate aminotransferase [AST] >2x

the upper limit of normal [ULN]; alanine transaminase [ALT] >2x ULN;

alkaline phosphatase [APH] >1.5 xULN, bilirubin [BIL] ≥2.0 mg/100 mL)

were confirmed by repeat LFT testing, and further diagnostic testing, such

as biopsy and CT/MRI/US of the liver were used to confirm or rule out

distant recurrence.

480,481

These trials measured LFTs at 6, 12, and 18

months after treatment, and then annually thereafter.

477

Using this

approach, the likelihood of an abnormal LFT was low (<1%).

480

Based on

all patients with reported metastasis, the sensitivity, specificity, positive

predictive value, and negative predictive value associated with at least one

abnormal LFT before first diagnosis of metastasis at any site was 14.7%,

92.3%, 45.7%, and 71.0%, respectively. Of the LFTs, APH had the highest

diagnostic attributes. Other diagnostic tests appeared to have higher

sensitivity and specificity because they were often triggered by abnormal

LFTs. The results suggest that use of LFT results followed by other

diagnostic tests has high specificity and predictive values, but low

sensitivity.

480

Whereas 739 patients had distant metastases detected

during follow-up, 13 did not have their metastasis discovered until time of

death.

481

The utility of LFTs for early detection of liver metastases is an

issue of ongoing debate, with sensitivity, specificity, and positive and

negative predictive values varying across specific LFT test types and

differing between studies.

496,497,499,543-547

Whereas some analyses have

concluded that LFTs are among the most useful methods for

screening,

496,543-545,548,549

others argue that the specificity and sensitivity of

these tests is too low to warrant routine use.

499,500,547

The optimal strategy for imaging surveillance is also an issue of debate,

because for each of the methods commonly used (ie, chest x-ray, CT, US,

MRI, PET/CT) results vary, and for all of these options there is at least one

study that reported poor performance on at least one metric.

496-500,544,546,550-

560

Due to the low probability of metastasis at any specific time point, the

yield of all these tests is low, and there is concern regarding cumulative

radiation exposure due to the long-term follow-up needed.

561

Therefore,

imaging is usually focused on the liver, as it is the most likely site of distant

metastasis, and liver US and MRI are favored over CT or PET/CT. Some

studies have found MRI to be moderately better than CT or PET/CT for

detection of liver metastases from uveal melanoma,

550,554,555

and

(NCCN

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NCCN Guidelines Version 2.2021

Melanoma: Uveal

MS-35

prospective studies in high-risk patients showed promising results for

using liver MRI for early detection of liver metastases.

500,556

The value of surveillance imaging and tests is debated because it is

unclear whether early detection of distant metastases improves outcomes,

especially given that most treatments for distant metastatic disease are

relatively ineffective. Some retrospective studies found that survival was

better for patients whose distant metastases were asymptomatic at the

time of detection,

495,562

whereas other studies observed no such

correlation,

21,563

or reported that the difference was transient.

564

Risk of Developing Secondary Cancers During Follow-up

Due to the long-term surveillance needed for detection of distant

metastatic disease in patients with uveal melanoma, it is not uncommon

for screens to identify other primary cancers.

11,159,160,162,559,565-568

The two

COMS randomized trials in patients with medium to large primary uveal

melanomas showed that the proportion of patients with secondary cancers

increased steadily over the entire duration of follow-up (median 10 years,

range 5–16 years).

566

Various types of secondary malignancies were

observed.

159,566

Uveal melanoma may increase the risk of developing other

cancers,

160

especially in patients with familial uveal melanoma or other

familial cancers.

113,114

Follow-up for Distant Metastasis

Given the lack of high-quality data to inform the frequency or modality of

follow-up screening for distant metastatic disease, the NCCN

recommendations are based on clinical practice at NCCN Member

Institutions. Patients with no evidence of disease (NED) after treatment for

uveal melanoma should be followed for signs of metastatic disease. The

most frequent sites of metastasis are liver, lungs, skin/soft tissue, and

bones. Recommended follow-up for distant metastatic disease includes

imaging to evaluate signs or symptoms of distant metastasis, and may

include regular surveillance imaging. LFTs may be considered as a

component of follow-up visits, although some studies showed poor

sensitivity for early detection of liver metastases.

Recognizing that there are limited options for systemic recurrence and that

regular imaging may cause patient anxiety, patients should discuss with

their treating physician the potential benefits and risks of surveillance

imaging, and some patients may elect to forgo surveillance imaging.

Providers may also want to discuss mental health resources with patients.

See the NCCN Guidelines for Survivorship (www.NCCN.org

). Participation

in a clinical trial is strongly encouraged.

For patients who elect to have surveillance imaging to screen for distant

metastatic disease, options include contrast-enhanced MR or US of the

liver, with modality preference determined by expertise at the treating

institution. Additional imaging modalities may include

chest/abdominal/pelvic CT with contrast, or dual-energy subtraction chest

x-ray. However, screening should limit radiation exposure whenever

possible. Scans should be performed with IV contrast unless

contraindicated. Recommendations for imaging modality are based on

clinical practice at NCCN Member Institutions, as there are very few data

to inform selection of modality.

For those choosing to have regular surveillance (imaging with or without

blood tests), the recommended frequency is based on the risk of distant

metastasis. The NCCN Guidelines recommend risk stratifying patients into

low, medium, and high risk of distant metastasis based on the highest risk

factor present. For patients with high risk of distant metastasis who opt to

have surveillance imaging, the recommended frequency is every 3 to 6

months for 5 years, then every 6 to 12 months for years 6 through 10, then

as clinically indicated. For patients with medium risk of distant metastasis

who opt to have surveillance imaging, the recommended frequency is

every 6 to 12 months for 10 years, then as clinically indicated. For patients

(NCCN

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NCCN Guidelines Version 2.2021

Melanoma: Uveal

MS-36

with low risk of metastasis who opt to have surveillance imaging, consider

imaging every 12 months. Adjusting follow-up frequency based on risk of

metastasis is based on clinical practice at NCCN Member Institutions, and

this approach has not been prospectively tested to determine whether it

results in better yield from imaging or better outcomes. There are very little

data to inform the recommended frequency of imaging follow-up.

Risk factors for metastasis include a variety of genetic markers as well as

tumor size at presentation. The NCCN Guidelines list specific risk factors

to be used for risk stratification to determine the frequency of surveillance

imaging during follow-up. The NCCN Guidelines recommend using AJCC

T stage for risk stratifying according to primary tumor size. T1 is

considered low risk, T2 and T3 medium risk, and T4 high risk. For patients

who had a biopsy of their primary tumor, both cell histology and certain

molecular features have been shown to be prognostic for risk of distant

spread, and should be used for risk stratification. GEP as described by

Onken et al

is recommended to determine whether the tumor is Class 1A

(low risk), Class 1B (medium risk), or Class 2 (high risk) to inform

frequency of follow-up. The following chromosomal abnormalities are also

considered risk factors that should inform frequency of follow-up: disomy 3

(low risk), gain of chromosome 6p (low risk), monosomy 3 (high risk), and

gain of chromosome 8q (high risk). Mutations in several genes have also

been shown to be prognostic for distant metastasis, and should be used

for risk stratification: EIF1AX (low risk), SF3B1 (medium risk), and BAP1

(high risk). PRAME expression is also an indicator of high risk to be used

to inform frequency of follow-up. If biopsy not performed, then follow

medium- or high-risk pathways, depending on whether any high-risk

features are present.

Management of Recurrence

Workup for Recurrence

If a recurrence is detected, workup should include history and physical to

identify any signs or symptoms associated with recurrence or metastasis.

Biopsy may also be appropriate. Whereas intraocular recurrence can often

be diagnosed and managed without a biopsy, additional prognostic FNA

biopsy may be valuable to determine whether the tumor has developed

any high-risk features that warrant more frequent surveillance. Extraocular

recurrence or metastasis should be confirmed histologically whenever

possible or if clinically indicated. Appropriate biopsy techniques in this

setting may include FNA or core biopsy. For patients with metastasis who

are considering treatment with targeted therapy, tissue should be obtained

for genetic analysis (screening for mutations that may be potential targets

for treatment or to determine eligibility for a clinical trial) from either biopsy

of the metastasis (preferred) or archival material. Broader genomic

profiling may be considered if the results could inform future treatment

decisions or eligibility for clinical trials.

Patients with local recurrence should have ocular orbital imaging (if not

recently previously done) to evaluate the extent of local recurrence.

Patients who develop distant metastatic disease after treatment of primary

uveal melanoma should have ocular orbital imaging as part of workup to

check for local recurrence, since asymptomatic local recurrences may be

present at the time distant metastasis is discovered. Workup for patients

with recurrence should include broader imaging to investigate specific

signs or symptoms, and/or for baseline staging. Because the most

frequent sites of metastasis are liver, lungs, skin/soft tissue, and bones,

imaging options for baseline staging in patients with recurrence or

metastasis include contrast-enhanced MR or US of the liver, with modality

preference determined by expertise at the treating institution. Additional

imaging may include chest/abdominal/pelvic CT with contrast and/or

whole-body FDG PET/CT. Brain MRI with IV contrast may be performed if

(NCCN

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Melanoma: Uveal

MS-37

neurologic symptoms are present, but routine CNS imaging is not

recommended. All scans should be performed with IV contrast unless

contraindicated. As described below, for patients with distant metastasis, a

thorough evaluation of the size and location of all metastases can help in

assessment of prognosis and evaluation of treatment options.

For patients with distant metastases, consider measuring LFTs, including

LDH, as part of workup. However, their role in risk stratification of

metastatic uveal melanoma is unknown. As described below, elevation of

LFTs has been associated with poorer OS in patients with metastatic

uveal melanoma.

19,20,22,497,569-574

Treatment for Local Recurrence

Given the rarity of local recurrence after treatment of primary uveal

melanoma, data on treatment of local recurrences are scant, and it is

unclear which approaches result in the best outcomes. Most studies had

fewer than 10 patients with local recurrence, and many studies either

managed all local recurrences with enucleation or did not report on

retreatment approaches. In the few studies that reported outcomes after

treatment of local recurrence (n ≥ 10),

348,388,416,423,443,575-579

reasonably high

rates of local control were achieved with the following globe-conserving

modalities: laser photocoagulation,

348,416

TTT,

443,578

proton-beam

RT,

416,423,576-578

and plaque brachytherapy RT.

388,443,578,579

Similar to the

primary treatment setting, some patients treated with globe-conserving

therapy for local recurrence subsequently underwent enucleation due to

(suspected or confirmed) tumor regrowth or complications such as pain

and neovascular glaucoma.

348,416,423,575,576,578,579

There is very little

evidence to inform selection of treatment for recurrence. Results from one

retrospective study of 73 patients with local recurrence suggest that

treating recurrence with proton-beam RT (n = 31) versus enucleation (n =

42) may result in similar metastasis-free survival and OS.

577

Another

retrospective analysis of 51 patients with local recurrence found that local

control after treatment of recurrence was more likely in those with longer

times between primary treatment and development of recurrence, and risk

of metastasis was higher in patients whose local recurrence was

characterized by vertical/diffuse growth versus horizontal/marginal

growth.

348

NCCN Recommendations for Treatment of Local Recurrence

The recommended treatment options for local recurrence depend on the

extent of disease. For intraocular recurrence (limited to the eye, without

orbital involvement), the recommended options include radiation, either by

plaque brachytherapy or particle beam, enucleation, or laser ablation. For

small recurrences in patients who cannot undergo RT or surgery, trans

TTT is recommended. TTT is usually reserved for small recurrences,

particularly when recurrence is likely due to incomplete plaque coverage

during primary brachytherapy; it is generally not appropriate for

recurrences occurring within the RT field or recurrences that may be too

thick (>3 mm) for laser treatment to reach the base. It is important to have

an in-depth discussion with patients about their treatment options for local

recurrence. If there is extraocular involvement, surgical resection is

needed, but can be coupled with RT to the orbit (particle beam or photon

beam) and/or cryotherapy to the orbital tumor. If there is orbital

involvement and the patient has had prior enucleation, options include

surgical resection or cryotherapy to the orbital tumor, and/or RT to the

orbit (particle beam or photon beam). Recommendations for administration

of different RT modalities are in the section entitled Radiation Therapy

(above).

Treatment for Metastatic Disease

Survival after detection of distant metastatic disease varies widely across

studies, with median OS ranging from 3 to 30 months.

569,580

Survival

outcomes vary widely even between studies testing the same or similar

treatments,

569,580,581

and even when only considering studies with large

(NCCN

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Melanoma: Uveal

MS-38

patient sample sizes (n > 100; median OS 3–20 months).

21-23,481,495,570,580

Part of the variation could be due to differences in patient selection, as

there are many factors that have been shown to be associated with

survival. Some meta-analyses suggest that survival after metastasis is

shorter for studies of unselected patients compared with studies of

selected patients, but those with selected patients were also more likely to

be testing an active treatment and those of unselected patients were more

likely to include cases managed with best supportive care or palliative

approaches.

569

Several studies have found that a small percentage of

patients with uveal melanoma metastasis experience long-term survival

(≥5 years) after development of distant metastatic disease.

19,21,481

Several

long-term studies have shown a bimodal distribution suggesting a

population with short-term survival (median OS <1 year) and a separate

population with long-term survival (median OS >2 years).

19,21

Studies have reported a wide range of factors associated with OS after

detection of metastasis, and results vary across studies. Patient

characteristics reported by multiple studies, including multivariable

analyses, to be associated with poorer OS after metastasis include older

age, male sex, and poorer performance status, although there are

opposing data for each of these factors.

19-22,481,497,501,563,569-572,574

Multiple

studies have also found that poor OS after metastasis is associated with

symptoms at the time of metastasis (compared with asymptomatic

metastasis detected by surveillance), shorter disease-free interval before

metastasis, higher number of anatomic sites involved, involvement of liver,

and greater disease volume (based on various metrics, such as percent of

liver involvement, volume of liver metastases, total number of metastases,

number of liver metastases, size of largest metastasis or largest liver

metastasis, M-stage).

19-22,497,501,546,562-564,569-574,582-585

In addition, elevated

liver enzymes at the time of diagnosis of metastasis, particularly LDH and

APH, have been associated with shorter OS.

19,20,22,497,569-574

Whereas in recent years the options for treating metastatic cutaneous

melanoma have dramatically improved, treatment of distant metastases

from uveal melanoma still presents a major clinical challenge. Several

retrospective studies suggest that treatment for distant metastases (from

uveal melanoma) improves survival, although it is unclear whether these

results are influenced by selection bias.

21,23,501,574,584

Other studies did not

find that treatment improved survival,

481,572

reporting that patients treated

with supportive care only had median OS ranging from 1.7 to 4.9 months,

although those opting for supportive care are more likely to have risk

factors for poor survival.

23,501,584

For treatment of distant metastasis from

uveal melanoma, a wide variety of approaches have been tested,

including surgery, RT, ablative approaches, vaccines, various systemic

therapies (chemotherapies, immunotherapies, targeted therapies, and

various combinations), and localized

chemotherapy/immunotherapy.

22,569,580,581,585-587

Systematic reviews, meta-

analyses, and retrospective studies that included patients treated with a

variety of therapies suggest that the best outcomes are seen in patients

who received liver-directed treatments, particularly those treated with

surgery, especially if complete resection was

achieved.

19,22,500,562,563,569,571,574,580,582,585,588,589

It is unclear whether these

effects are due to other factors, such as the lower volume of metastatic

disease, which would make a patient eligible for surgery and/or liver-

directed treatments, and more likely to have complete resection. One

phase III randomized trial (EORTC 10821) found no difference in OS in

171 patients with liver metastasis from uveal melanoma treated with IV

fotemustine versus hepatic arterial infusion (HAI) with fotemustine, despite

the HAI approach showing higher response rates and progression-free

survival (PFS).

590

A few studies suggest that better survival was seen in

those who had a response to therapy for metastatic disease,

21,569

but

some did not find an association.

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

NCCN Guidelines Version 2.2021

Melanoma: Uveal

MS-39

Resection of Metastases

As mentioned above, multiple prospective and retrospective studies and

meta-analyses have found that among patients with metastatic uveal

melanoma, those who can be treated with surgery have the best

outcomes, especially if complete resection is achieved.

21,562,563,569,580-

582,585,589,591-595

Multiple studies have reported median OS greater than 20

months after resection of uveal melanoma

metastases.

21,562,563,581,585,589,591,592,594-599

For liver metastases, rates of

complete resection ranged from 27% to 88%.

21,563,582,585,591,592,595,597

Multiple studies reported on combination therapy with resection and

hepatic arterial infusion, radiofrequency ablation (RFA), transarterial

chemoembolization (TACE), or adjuvant systemic

therapy.

562,563,581,585,591,596,600-602

Liver-Directed Therapy

Due to the tendency of uveal melanoma to metastasize to the liver, a wide

range of liver-directed therapies have been tested in patients with liver

metastases from uveal melanoma. These include regional isolation

perfusion of the liver, various methods of embolization (eg, chemotherapy,

radiation, immunotherapy), ablative procedures (eg, RFA), and

resection.

22,569,580,581,589,603-605

Whereas there are a large number of

prospective pilot, phase I, and phase II studies that reported outcomes for

liver-directed approaches, it is unclear which liver-directed approaches are

the best because of the lack of randomized comparative studies in

patients with liver metastases from uveal melanoma.

Regional Isolation Perfusion

Several techniques have been developed for localized delivery of

pharmaceutical therapy to the liver for treatment of hepatic metastases.

The idea behind these techniques is that higher doses can be

administered locally than would be feasible systemically due to toxicity.

Methods include isolated hepatic infusion (IHP), percutaneous hepatic

perfusion (PHP), HAI, and embolization techniques, which are described

in the next section.

Liver metastases derive most of their blood supply from the hepatic artery,

whereas the blood source for benign hepatocytes is primarily the portal

vein.

606

IHP and HAI both deliver therapy via the hepatic artery to

maximize drug delivery to liver metastases while limiting exposure to

healthy parenchyma.

607

For IHP, higher temperatures are often used to

further increase the effective concentration of therapeutic agent while

limiting systemic exposure.

607

Whereas IHP is done during surgery, has

risk of morbidity, and usually can only be done once, HAI and PHP are

less invasive techniques, with lower risk of morbidity, and have the

potential to be performed multiple times to increase depth of

response.

581,589,605,607

IHP is an open surgical procedure involving vascular isolation of the liver,

allowing high doses of heated chemotherapy to be directly delivered to the

organ through an arterial catheter.

581,589,603,605,607

Alkylating agents are

generally preferred because they can be effective even with short

exposure time, and the dose-response curve is steep.

589

Several small

prospective studies (n < 40)

608-612

and a few retrospective studies (n = 19

to 68)

613-616

have tested hyperthermic IHP in patients with liver metastasis

from uveal melanoma. The agent most commonly used in these studies

was melphalan, with or without tumor necrosis factor alpha (TNF-alpha) or

cisplatin.

608-612

Good response rates to IHP have been reported in some of

these prospective studies (overall response rate [ORR], 50%–68%),

608-611

and retrospective studies (ORR, 67%–83%).

613-615

However, the IHP

procedure is often lengthy (>8 hours),

581,589,603,608,609

involves significant

blood loss (median 2–3.5 L),

581,608,609

involves long hospital stays (7–10

days),

589,603,608,609,615,616

can result in significant complications/morbidities

(eg, portal vein thrombosis, transient grade 3/4 hepatic toxicity),

589,603,608-

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NCCN Guidelines Version 2.2021

Melanoma: Uveal

MS-40

610,613-616

and mortalities from the procedure were also

observed.

603,608,613,616

For these reasons IHP is not widely used.

HAI is a technique using catheters in the hepatic artery to deliver

chemotherapy directly to the liver.

589

The number of times HAI can be

repeated depends on the type of catheter used.

589

Efficacy of HAI for liver

metastases from uveal melanoma has been reported in several small

prospective studies (n = 8–31)

617-621

and several retrospective studies (n =

10–100).

622-626

Most of these studies used fotemustine,

618,619,622,623,625

but

other agents tested include carboplatin;

617,625

nab-paclitaxel;

620

decitabine;

621

a combination of cisplatin, vinblastine and dacarbazine;

624

and melphalan.

626

Response rates to HAI were lower and more variable

(than for IHP) in both prospective (ORR, 0%–44%)

617-621

and retrospective

studies (16%–36%).

622,625

One phase III randomized trial (EORTC 10821)

in patients with liver metastasis from uveal melanoma found no difference

in OS for IV fotemustine versus HAI fotemustine (median OS, 13.8 vs.

14.6 months), despite the HAI approach showing higher response rates

(2.4 vs. 10.5%) and PFS (median 3.5 vs. 4.5 months; HR, 0.62; 95% CI,

0.45–0.84, P = .002).

590

Complication rates varied widely across studies,

but in general appear to be lower than those reported in studies testing

IHP, and are manageable.

590,617-619,622,623,625,626

Grade 3/4 adverse events

(AEs) were mostly hematologic (eg, anemia, leukopenia,

thrombocytopenia, neutropenia).

590,617,621-623

Grade 3–4 catheter-related

complications occurred in a minority of patients (≤12%), as did liver toxicity

(<10%).

590,622

Deaths from toxicity were reported in one study,

590

but not in

others.

PHP is a simpler, less invasive alternative to IHP that can be

repeated.

589,605

It uses a double-balloon catheter inserted into the inferior

vena cava to isolate hepatic venous blood that is then filtered

extracorporeally.

589,605

Several prospective studies tested PHP in patients

with liver metastases from uveal melanoma, but efficacy results are

lacking.

627-629

Retrospective studies suggest good response rates (>40%),

especially if multiple rounds are used.

630-632

In all these studies melphalan

was the agent used.

627-632

PHP appears to be somewhat better tolerated

than IHP, with no treatment-related fatalities, but many patients still

experienced hematologic grade 3–4 events, some had non-hematologic

grade 3–4 AEs (eg, bleeds, thromboembolism), and some had extended

hospital stays (4–5 days) or had to be readmitted.

629-631

Hepatic Embolization

Hepatic arterial embolization is a method for delivering to the liver

chemotherapy, immunotherapy, or radioactive agents, while increasing

dwell time and providing selective ischemia.

589,603

Hepatic Chemoembolization

There are no standard protocols for hepatic chemoembolization, also

called hepatic TACE or hepatic arterial chemoembolization (HACE). In

general, two approaches have been used for treatment of uveal melanoma

metastases to the liver. One involves HAI with the active agent, followed

by addition of either a transient or permanent embolic agent.

589,603

The

active agent is usually mixed with ethiodized oil (to increase dwell time),

and embolization agents include absorbable gelatin sponge or polyvinyl

alcohol particles.

589,603

The other approach uses drug-eluting beads

produced from a polyvinyl alcohol hydrogel that has been modiﬁed with

sulfonate groups for the controlled loading and delivery of chemotherapy

agents.

603

These beads serve for localized drug delivery and as an

embolic agent to render tumors ischemic.

603

Multiple retrospective

633-640

as well as a few prospective studies

641-644

have

evaluated chemoembolization for treatment of hepatic metastasis in

patients with uveal melanoma. Using traditional methods (active agent

infusion + addition of embolic agent), response rates varied widely, but

could be as high as 57%.

633,634,636,637,639-645

Chemotherapies used included

(NCCN

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NCCN Guidelines Version 2.2021

Melanoma: Uveal

MS-41

BCNU, mitomycin C, fotemustine, cisplatin, carboplatin, doxorubicin, and

1,3-bis (2-chloroethyl)-1-nitrosourea; embolic agents used included gelatin

sponge, polyvinyl sponge, resorbable microspheres, and polyvinyl alcohol

particles.

633,635,636,638-645

Only a few studies reported outcomes for patients with liver metastases

from uveal melanoma that were treated with trans-arterial chemotherapy-

eluting beads.

646-648

One phase II study reported 100% ORR in the 10

patients treated with irinotecan-loaded polyvinyl alcohol microspheres.

646

In contrast, a retrospective study of irinotecan-loaded beads in 28 patients

with uveal melanoma liver metastases reported much lower response

rates.

648

A retrospective study including 58 patients treated with TACE

using irinotecan-charged microbeads reported an ORR of 27.5% (all

partial responses).

649

Another prospective noncontrolled study testing

beads loaded with doxorubicin in patients with unresectable liver

metastases from ocular melanomas only reported toxicity and quality of

life.

647

Comparisons of hepatic chemoembolization with other treatments for

uveal melanoma liver metastasis are limited. One retrospective study

compared cisplatin-based chemoembolization (TACE) versus HAI and

versus systemic therapy, and found that chemoembolization was

associated with the best response rate, although OS did not differ between

the groups.

634

However, those who responded to TACE had better OS

than those who did not respond and better than those treated with HAI or

systemic therapy.

634

For patients with uveal melanoma liver metastases

treated with chemoembolization, several studies found that OS was better

in responders versus non-responders,

634,637,638,640,641,643

whereas others did

not find a significant association.

642,649

Chemoembolization is well tolerated in patients with liver metastases from

uveal melanoma, with few or no treatment-related deaths.

636,642,644,645,647-650

AEs reported in more than one study include abdominal pain, fever,

nausea, vomiting, liver dysfunction, and

thryombocytopenia.

633,636,639,640,644,646,648,649

Some studies recommend

supportive treatment with antibiotic and antiemetic prophylaxis, IV

hydration, and major analgesic before and after the procedure.

644,646

Hepatic Immunoembolization

Hepatic immunoembolization involves infusion of an immunologic

stimulant into the hepatic artery, followed by addition of an embolizing

agent.

603

The rationale is that the ischemia will start the destruction of the

tumor, releasing antigens so that local simulation of the immune system

may result in systemic immune response to prevent tumor growth.

603

Several studies in patients with liver metastases from uveal melanoma

have tested immunoembolization using granulocyte-macrophage colony-

stimulating factor (GM-CSF) ethiodized oil plus a gelatin sponge.

651,652

GM-CSF is a glycoprotein secreted by immune cells such as activated T

cells that increases myeloid cell production, stimulates macrophages,

increases cytotoxicity of monocytes toward tumor cell lines, and promotes

maturation of dendritic cells.

603

A phase I trial with 34 uveal melanoma

patients and unresectable liver metastases occupying less than 50% of

total liver volume reported an ORR in the liver of 32%, and response

correlated with better OS.

651

A phase II randomized trial with 52 patients

with uveal melanoma and hepatic metastases only (also <50% liver

volume) reported an ORR of 21.2% for the 25 patients treated with

immunoembolization versus 16.7% for the 27 who received bland

embolization (GM-CSF replaced with saline).

652

In this study hepatic

response was not correlated with OS, but was associated with better PFS.

AEs associated with immunoembolization in these studies included

abdominal pain, fever, nausea, and transient increases in hepatic

enzymes.

651,652

One patient had acute respiratory failure but recovered;

there were no treatment-related deaths.

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

NCCN Guidelines Version 2.2021

Melanoma: Uveal

MS-42

Hepatic Radioembolization

Hepatic radioembolization, also called hepatic transarterial

radioembolization (TARE) or selective internal RT (SIRT), is a procedure

in which glass or resin yttrium-90 microspheres are introduced to the

hepatic artery, both as a mechanism for radiation delivery and for

embolization.

603

The microspheres must be of sufficient size to have

embolic effect.

603

Response rates from retrospective studies varied widely

(6%–100%), but disease control rate was consistently greater than

50%.

653-658

A phase II study reported ORR of 39% in the 23 patients who

received radioembolization as first-line treatment for liver metastasis, and

ORR of 33% in the 24 patients who received radioembolization after

progression on immunoembolization, with disease control rate of 87% and

58%, respectively.

659

Across studies, radioembolization was well tolerated,

with most toxicities being grade 1–2 and self-limiting, and no treatment-

related deaths.

653-657

AEs included abdominal pain/discomfort, nausea and

vomiting, LFT elevation (sometimes due to progression), transient

lymphopenia, and gastric ulcer.

654-657,659

Ablative Procedures for Liver Metastases

Although ablative procedures such as cryotherapy and thermal ablation

have been used with some success for liver metastases from other kinds

of cancer, there are very little reported clinical data on the efficacy of these

techniques for liver metastases from uveal melanoma. The supposed

advantage of ablative techniques is that compared to surgery these

techniques are tissue-sparing, less invasive, cost-saving, and have lower

rates of complications, while still being potentially curative.

660

Ablation may

be feasible for tumors that are difficult to resect (due to location), although

for some tumors ablative options may be limited due to tumor visibility and

correct interpretation of tumor extent and stage.

660

The most commonly

used methods of thermal ablation for liver tumors include RFA and

microwave ablation (MWA).

660-662

Both methods use heat induction and

destroy tissue through thermally induced coagulative necrosis. The

difference is that RFA uses alternating electric current at frequencies from

375 to 500 kHz, and MWA uses an electromagnetic field at frequencies

greater than 900 kHz.

660,662,663

RFA uses an electrode to deliver alternating

current that heats tissue to 50 to 100°C near the electrode, causing almost

instant coagulation necrosis.

660,662,663

For RFA, ablation volume is limited

by tissue boiling and charring that then insulate the effect through

increased impedance, and limited by the heat-sink effect caused by blood

flow dispersing the thermal energy.

661-663

The resulting ablation area may

have unpredictable size and shape, and multiple sessions or multiple

electrodes may be needed to fully ablate the target area.

661,663

MWA uses

an antenna probe to generate an electromagnetic field that rapidly heats

surrounding tissue to greater than 150°C, causing necrosis.

660-663

The

heat-sink effect is more limited than in RFA, and the resulting ablation

zone is larger and more homogeneous than with RFA.

660-664

However, the

ability to rapidly ablate a larger area can result in larger areas of healthy

tissue damage.

663,665

Based on data from other (non-uveal) types of liver

tumors, safety of MFA and RFA appears similar.

662,663,665-667

Both methods

rarely lead to major complications (<3%), such as hemorrhage, infection,

organ injury, liver failure, pneumothorax, pleural effusions, ascites, fever,

and portal vein thrombosis.

662,663,667

Due to the need for grounding pads to

complete the circuit, RFA can also cause skin burns.

663

Cryoablation uses rapid gas expansion at a probe tip to quickly cool

surrounding tissues to as low as -140°C.

660,661,668

This creates an ice ball

that dehydrates tissues, and causes irreversible cell damage and cell

death.

660,661,668,669

Vascular injury also causes cell death by ischemic

hypoxia.

668,669

Repeated freeze-thaw cycles are often used to maximize

tissue cell death throughout the target area.

660,661,668,670

Cryotherapy can

be performed percutaneously, laparoscopically, or during open surgery.

670

The result of the procedure is a zone of central necrosis surrounded by

tissue in which cells are not fully damaged.

670

Damage to the

microvasculature can cause edema, inflammation, and thrombosis.

670

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NCCN Guidelines Version 2.2021

Melanoma: Uveal

MS-43

Complications may include pain, infection (eg, wound infection,

pneumonia), hemorrhage, biliary injury, thrombocytopenia, pleural

effusion, renal impairment, and in older literature, occasionally a fatal

complication called “cryoshock.”

661,668,670,671

Whereas some studies found

that cryoablation was more likely to cause complications compared with

RFA, other analyses suggest that complication rates are similar to RFA,

especially in more recent studies.

660,661,668,669,671-673

There are very few studies reporting outcomes for patients with liver

metastases from uveal melanoma treated with ablative therapy.

596,601,674-677

Methods tested include RFA

596,601,675,677

and laser-induced interstitial

thermotherapy (LITT).

674

The efficacy and safety of ablative techniques is

difficult to ascertain, because most of these studies contained fewer than

20 patients with uveal melanoma,

601,674-677

included both patients with

uveal melanoma and other types of melanoma (and did not report results

separately),

675,676

or combined the ablative therapy with other therapies (ie,

surgery, TACE, systemic therapy).

596,601,674,677

Nonetheless, it is notable

that several retrospective studies reported that relatively long median OS

was greater than 20 months in cohorts of uveal melanoma patients with

liver metastases treated with LITT (±TACE),

674

RFA,

675

or percutaneous

thermal ablation (± systemic therapy).

676

In a retrospective study of uveal

melanoma patients with liver metastases treated with surgery alone (n =

57) or a combined approach in which some metastases were resected and

others treated with RFA (n = 13), those treated with the combination

approach had similar disease-free survival as those treated with surgery

alone (median 7 vs. 10 months) and OS (median 28 vs. 27 months).

596

Moreover, there were no recurrences at the 22 sites treated with RFA after

a median follow-up of 63 months (range 7–83 months).

596

These results

suggest that RFA may be as effective as surgery, and could be used in

lieu of surgery for metastases that are difficult to resect.

External Beam Radiation for Uveal Melanoma Metastases

Published data on external beam RT for uveal melanoma metastases are

extremely scant with no study reporting outcomes or palliative effects.

Systemic Therapy for Distant Metastatic Disease

Many systemic therapies have been tested in prospective trials as

treatment for metastatic uveal melanoma, including chemotherapies

590,678-

688

targeted therapies,

685-687,689-699

and immunotherapies.

700-713

Many

systemic therapy combinations have also been tested in prospective trials,

including chemotherapy combinations,

681,714-723

biochemotherapy

(chemotherapy + immunotherapy),

724-727

and a variety of other systemic

therapy combinations.

684,728-732

For treatment of metastatic uveal

melanoma, systemic therapies have largely been tested in small phase II

studies, and most have shown little activity (response rate <10%),

587,589,733-

735

especially compared with the efficacy of checkpoint immunotherapies

and BRAF/MEK inhibitor combinations in metastatic cutaneous

melanoma.

736-744

The few larger randomized phase II/III trials comparing

systemic therapies for metastatic uveal melanoma have failed to identify

any systemic therapies that are consistently more effective than

chemotherapy,

681,684-687,693,695,728

although there are some recent promising

results from noncomparative studies that warrant further investigation. As

noted above, meta-analyses suggest that for metastatic uveal melanoma,

systemic therapy appears to result in worse outcomes than localized

treatment (surgery or liver-directed therapies), although differing patient

selection criteria across studies may be a confounding factor in these

analyses.

22,580,581,589

One randomized trial showed that (IV) systemic

chemotherapy results in lower response rate and shorter PFS than HAI

chemotherapy in patients with liver metastases, although OS was similar

across arms.

590

For patients who are not appropriate for localized therapy,

selection of systemic therapy is very challenging, necessitating further

study into better options.

(NCCN

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NCCN Guidelines Version 2.2021

Melanoma: Uveal

MS-44

Cytotoxic Regimens

A wide variety of chemotherapies have been tested in prospective trials

(ie, pilot, phase I, phase II) in patients with metastatic uveal melanoma,

and outcomes have been reported for the following single-agent

chemotherapies: dacarbazine,

684-687

paclitaxel,

680

DHA-paclitaxel,

679

temozolomide,

678,685,687

fotemustine,

590

bendamustine,

682,683

treosulfan,

681

liposomal vincristine,

683

arsenic trioxide,

688

and lenalidomide.

745

Most

studies evaluated patients for response to treatment, but responses to

these therapies were rarely observed.

590,678-688,745

In these prospective

trials the few responses observed were in patients treated with

fotemustine (2/83),

590

liposomal vincristine (1/4),

683

dacarbazine (3/36),

686

and DHA-paclitaxel (1/22).

679

For the studies that measured PFS and OS

with these single-agent chemotherapy regimens, median PFS was always

less than 4 months,

590,678,679,681,684-687

and median OS was nearly always

greater than 10 months.

590,678,679,685-687

EORTC 10821, a phase III

randomized trial, reported median OS of 13.8 months for patients treated

with IV fotemustine, but this longer OS is likely due to the trial including

only patients with liver metastases (no extrahepatic metastases).

590

remains unclear whether any single-agent chemotherapy improves

survival relative to best supportive care.

Combination chemotherapies that have been tested in prospective trials

for metastatic uveal melanoma include gemcitabine/treosulfan,

681,714-718

dacarbazine/treosulfan,

720

cisplatin/gemcitabine/treosulfan,

719,746

cisplatin/dacarbazine/vinblastine,

721

docetaxel/carboplatin,

722

and

tirapazamine/cisplatin.

723

All of these were tested in pilot, phase I, or

phase II studies, most of which reported response rates of less than 5%.

Due to an early pilot study that reported a response rate of nearly 29% for

patients with metastatic uveal melanoma (n = 14),

718

gemcitabine/treosulfan was tested in multiple studies, but in the five

subsequent studies the response rate was much lower, ranging from 0%

to 4.2%.

681,714-717

Four of these studies (including the pilot) reported PFS

and OS data, with median PFS ranging from 2.5 to 6.7 months, and

median OS ranging from 7.5 to 14.2 months.

681,714,715,717,718

Results from

one phase II study suggested that higher treosulfan doses (≥3500 mg/m

)

provided better outcomes with this combination. Nonetheless the response

rate at these higher doses was only 5.2%.

714

A randomized phase II study

found that gemcitabine/treosulfan combination, using the higher treosulfan

dose, did provide better PFS and a trend for better response compared

with treosulfan alone, but the overall response was still relatively low

(4.2% in the combination arm), and the PFS relatively short (mean 3

months in the combination arm).

681

Addition of cisplatin to

gemcitabine/treosulfan did not improve results—there were no responses

in both of the studies that tested this triplet.

719,746

There were also no

responses seen in the phase II trials that tested dacarbazine/treosulfan,

720

docetaxel/carboplatin,

722

and tirapazamine/cisplatin.

723

The one phase II

study testing cisplatin/dacarbazine/vinblastine reported a surprisingly high

ORR of 20%, with median PFS of 5.5 months and median OS of 13.0

months.

721

This result needs to be repeated, and may be a product of

patient selection.

Meta-analyses combining results across studies that tested chemotherapy

in patients with metastatic uveal melanoma report ORRs ~4%,

587

median

PFS of 2.6 months,

and median OS ranging from 9 to 11 months.

22,580

Targeted Therapy

Targeted therapies that have been tested in prospective studies as single-

agent therapy for patients with metastatic uveal melanoma include the

tyrosine kinase inhibitors (TKIs) imatinib

689,690,747

and sunitinib,

686,692

the

mitogen-activated protein kinase (MEK) inhibitors trametinib

693,694

and

selumetinib,

685

the multi-kinase inhibitor sorafenib,

691

the receptor TKI

cabozantinib,

687,695

the VEGF inhibitor aflibercept,

698

the HSP90 inhibitor

ganetespib,

696

and the topoisomerase inhibitor 9-nitro-camptothecin.

699

Targeted therapy combinations that have been tested in prospective trials

(NCCN

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NCCN Guidelines Version 2.2021

Melanoma: Uveal

MS-45

include trametinib plus uprosertib, an inhibitor of protein kinase B (AKT);

693

binimetinib (MEK inhibitor) plus sotrastaurin (PKC inhibitor);

735

and

everolimus (mTOR inhibitor) plus pasireotide (IG1FR inhibitor).

697

Prospective studies in patients with metastatic uveal melanoma have also

tested combinations of chemotherapy plus targeted therapy, including

carboplatin/paclitaxel/sorafenib,

731

fotemustine/sorafenib,

748

dacarbazine/selumetinib,

684

temozolomide/bevacizumab,

732

and

carboplatin/paclitaxel/bevacizumab ± everolimus.

728

These prospective

studies were pilot studies, phase I trials, and phase II trials, and in most of

them the overall response was less than 10%.

685,689-691,693-699,747

Although uveal melanomas often express KIT, they rarely harbor the c-KIT

mutations associated with response to imatinib in other cancers.

59,689,747,749

It is thus perhaps not surprising that response rates to imatinib were low in

patients with metastatic uveal melanoma.

689,690,747

Two studies reported no

responses,

689,690

and 8% response was observed in a third study that

selected patients with high KIT expression.

747

These responses were seen

in patients who did not have activating mutations of c-KIT in exons 11, 13,

or 17.

747

Given the unimpressive median PFS (2.8 months) and OS (6.9

months) for the 25 patients in this study, imatinib is not considered a good

option for patients with metastatic uveal melanoma.

747

Results were similar

for the other TKI, sunitinib. A pilot study in 20 patients with metastatic

uveal melanoma expressing KIT reported an ORR of 5% for patients

treated with sunitinib,

692

but a subsequent larger phase II randomized

study reported no responses in the 38 patients treated with sunitinib (vs.

ORR of 8% with dacarbazine), and PFS and OS with sunitinib were no

better than the comparator dacarbazine.

686

Although BRAF mutations are rare in uveal melanoma,

34,51,53,54,60,62,63

most

uveal melanomas carry mutations in GNAQ or GNA11 that result in

constitutive activation of the RAS/RAF/MEK/ERK

pathway.

34,35,51,64,66,69,70,750

Prospective studies of MEK inhibitors have

yielded mixed results in patients with metastatic uveal melanoma.

685,693,694

A large phase II randomized trial in 101 patients with metastatic uveal

melanoma reported responses in 14% of the 50 patients treated with

selumetinib, and no responses in the 51 patients in the comparator arm

(chemotherapy with temozolomide or dacarbazine).

685

Selumetinib

modestly improved PFS compared with chemotherapy (median 3.7 vs. 1.6

months; P < .001), although the effect on OS was not significant (median

11.8 vs. 9.1 months; P = .09).

685

However, in a phase III randomized trial

in 129 patients with metastatic uveal melanoma that compared selumetinib

plus dacarbazine versus placebo plus dacarbazine, selumetinib did not

improve response (3% vs. 0%) or PFS (median 2.8 vs. 1.8 months).

684

Results from other MEK inhibitors were not impressive. No responses to

trametinib were observed in the 16 patients with metastatic uveal

melanoma in a phase I trial, and the median PFS was unremarkable (1.8

months).

694

In a subsequent phase II study, 1 of 18 (5.6%) patients with

metastatic uveal melanoma responded to single-agent trametinib, and

PFS was slightly better (median 3.6 months).

693

Addition of uprosertib, an

AKT inhibitor, yielded very similar results (ORR 4.8%, PFS median 3.6

months).

693

A phase Ib/II trial of combination binimetinib (MEK inhibitor)

and sotrastaurin (PKC inhibitor) yielded no responses in patients with

metastatic uveal melanoma.

735

Across studies it appeared that GNAQ and

GNA11 mutation status did not impact response rate or outcomes in

patients treated with MEK inhibitors.

684,685,694

Taken together, these data

show that some patients with uveal melanoma may respond to the MEK

inhibitor selumetinib, and there are limited data suggesting that trametinib

may also be marginally effective. Although the data are strongest for

selumetinib, it was not FDA approved for use in humans at the time of the

most recent Guidelines update, so it could not be included as a

recommended option. Trametinib is included as a recommended option

based on the positive data for selumetinib and the general lack of systemic

therapy options for patients with uveal melanoma. Further study of

trametinib for uveal melanoma is needed. Low-grade AEs are common in

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patients treated with MEK inhibitors, with the most common being rash or

dermatitis acneiform, diarrhea, nausea, fatigue, hypertension, peripheral

edema, elevated AST/ALT, creatinine kinase elevation, and blurred vision

or other visual changes.

684,685,693,694,751

Grade 3–4 events were observed in

20% to 40% of patients, and dose reductions were often needed to

manage toxicities.

684,685,693,694,751

The multikinase inhibitor sorafenib did not result in any responses in the

32 patients with metastatic uveal melanoma in a phase II trial.

691

A phase

II trial combining sorafenib with carboplatin/paclitaxel also showed no

responses in 24 patients with metastatic uveal melanoma.

731

Of the other single-agent targeted therapies tested in prospective trials in

patients with metastatic uveal melanoma (aflibercept,

698

cabozantinib,

687,695

ganetespib,

696

and 9-nitro-camptothecin

699

), responses

were reported only for the HSP90 inhibitor ganetespib, with one response

in the 17 patients tested in the phase II study (ORR of 5.9%).

696

Across

these studies median PFS was less than 6 months for all these

agents.

687,695-699

The combination of everolimus and pasireotide resulted in no responses in

the 13 patients in a phase II trial with metastatic uveal melanoma.

693

Combining bevacizumab with chemotherapy resulted in response rates

between 0% and 6%, with median PFS less than 6 months, and adding

everolimus did not help.

728,732

Combining bevacizumab and interferon

(IFN) alpha yielded similar results.

729

Taken together, most meta-analyses

concluded that targeted therapy did not improve outcomes relative to

conventional chemotherapy.

22,580,587,735

Immunotherapy

Given that immunotherapies have dramatically improved treatment

landscapes for other difficult-to-treat cancers, there is some hope that the

same will be true for uveal melanoma, and a wide variety of

immunotherapies have been tested for treatment of metastatic disease,

including checkpoint immunotherapies, IFN, interleukin-2 (IL-2), vaccines,

and tumor-infiltrating lymphocytes (TILs).

Biochemotherapy

Interferon alpha-2b (IFN alpha-2b) and IL-2 were among the first

immunotherapies tested in prospective trials in metastatic uveal

melanoma, mostly in combination with chemotherapy as part of

biochemotherapy regimens. Two prospective trials of

bleomycin/vincristine/lomustine/dacarbazine (BOLD) chemotherapy in

combination with IFN-alpha-2b yielded different results, with one reporting

no response in 24 patients with uveal melanoma metastasis,

724

and

another reporting four responses among 23 patients (ORR 20%).

727

A third

prospective trial tested BOLD in combination with human leukocyte IFN-

alpha, and reported three responses in the 20 evaluable patients with

metastatic uveal melanoma (ORR 15%).

725

A fourth prospective trial tested

BOLD + INF alpha-2b + IL-2, and reported two responses among 25

patients with metastatic ocular melanoma (ORR 8%), including one

complete response.

726

Results from these studies suggest that

biochemotherapy may provide slightly better response rates than

conventional chemotherapy for patients with metastatic uveal melanoma,

but it is not clear that these regimens improve PFS or OS.

580,587

Checkpoint Immunotherapy

Checkpoint immunotherapies tested in prospective studies for metastatic

uveal melanoma include anti-CTLA-4 agents ipilimumab and

tremelimumab,

704,705,712

anti-PD-1 agents nivolumab and

pembrolizumab,

707-710

and ipilimumab/nivolumab combination

therapy.

711,713

In prospective trials,

704,705,712

expanded access programs (EAPs),

752-757

and

a named patient program,

758

anti-CTLA-4 agents resulted in response

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rates ranging between 0% to 6.5%, median PFS between 2 to 4 months,

and median OS of less than 13 months. Meta-analyses have concluded

that anti-CTLA-4 systemic therapy results in outcomes that are similar or

worse than conventional systemic chemotherapy.

580,587,734

Results for other immune checkpoint inhibitor regimens in patients with

metastatic uveal melanoma look somewhat more promising. Although one

prospective study reported no responses in 17 patients treated with anti-

PD-1 systemic therapy,

708

three other prospective trials and one EAP

reported ORRs between 6% to 38%, with eight responses among a total of

81 patients treated (8%).

707,709,710,759

Median PFS ranged from 2.3 to 11

months.

707-709,759

Two ongoing phase II trials (NCT02626962 and

NCT01585194) testing ipilimumab/nivolumab in patients with metastatic

uveal melanoma have reported ORRs of 15.8% and 17.0%, median PFS

of 5.0 and 6.1 months, and median OS of 19.4 months in one study and

not reached in the other due to insufficient follow-up.

711,713

Comparative

studies are needed to determine whether combination anti-CTLA-4/anti-

PD-1 consistently improves outcomes in patients with metastatic uveal

melanoma.

Other Immunotherapy

Other immunotherapies for which there are efficacy data from prospective

studies in metastatic uveal melanoma include tebentafusp (formerly

IMCgp100),

700,760

dendritic cell vaccination,

702

and adoptive transfer of

TILs.

701

Of these, responses were only seen with TILs adoptive transfer,

with responses in 7 of 20 evaluable patients (ORR 35%).

701

These results

need further investigation.

NCCN Recommendations for Treatment of Distant Metastatic

Disease

Given that there are no treatments for metastatic uveal melanoma that

have clearly and consistently been shown to improve outcomes, it is

important to consider all clinical trial options carefully, and when available

and clinically appropriate, enrollment in a clinical trial is recommended.

For those who are not appropriate for treatment in the context of a clinical

trial, the recommended options are largely based on clinical practice at

NCCN Member Institutions. It is important to be aware that even among

therapies often used at NCCN Member Institutions, efficacy is limited, and

it is not clear which approaches are most effective. Therefore, the

guidelines indicate that a combination of approaches may be needed, and

it is important to consider each patient’s prognosis and treatment goals to

determine whether palliative care is the most appropriate option.

Selection of treatment should depend on the location and extent of

disease. For patients with metastasis to the liver, regionally hepatic-

directed therapies should be considered. Options include: hepatic isolation

perfusion, embolization (ie, chemoembolization, radioembolization,

immunoembolization), and ablation procedures (ie, thermal ablation,

cryotherapy). For patients with extrahepatic disease or hepatic disease

that is not amenable to liver-directed therapy, systemic therapy can be

considered, although there are no systemic therapies that have reliably

improved OS in patients with metastatic uveal melanoma. See below for

recommended systemic therapy options.

For both hepatic and extrahepatic metastases, patients with limited or

symptomatic disease should consider resection and/or RT by photon

beam or SRS. Recommendations for treating uveal melanoma metastases

with RT can be found in the section (above) describing Radiation Therapy

recommended for uveal melanoma, and in the Principles of Radiation for

Metastatic Disease in the NCCN Guidelines for Melanoma: Cutaneous

(available at www.NCCN.org

). Photon beam radiotherapy can be used for

treatment of distant metastases at risk for causing symptoms or for

palliation of symptomatic distant metastases. Dosing for distant

metastases: Doses of 8 to 30 Gy in 1 to 10 fractions should be prescribed

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to the appropriate target volume

761

using appropriate 3-D or intensity-

modulated RT (IMRT) techniques with or without image guidance.

NCCN Recommendations for Systemic Therapy for Metastatic Disease

Given the lack of positive phase III studies, when available and clinically

appropriate, enrollment in a clinical trial is recommended as the preferred

option for systemic therapy. The literature is not directive regarding the

specific systemic agent(s) offering superior outcomes, but does provide

evidence that uveal melanoma is sensitive to some of the same systemic

therapies used to treat cutaneous melanoma. In general, uveal

melanomas have lower response rates than cutaneous melanoma and no

systemic therapies have reliably improved the OS of metastatic uveal

melanoma patients. However, individual patients may derive benefit on

occasion.

Options to consider (other recommended regimens) include select

checkpoint immunotherapies, cytotoxic regimens, and targeted therapy.

Recommended checkpoint immunotherapy options for uveal melanoma

include anti-PD-1 monotherapy with pembrolizumab or nivolumab,

ipilimumab (monotherapy), and combination therapy with nivolumab and

ipilimumab. Treatment-related AEs occur in a high percentage of patients

treated with anti-CTLA-4 or anti-PD-1 agents, and grade 3–4 related AEs

occur in as many as 20% of patients receiving single-agent therapy and in

~50% receiving ipilimumab monotherapy or nivolumab/ipilimumab

combination therapy. Careful selection of patients and AE monitoring and

management are therefore critical to the safe administration of these

agents. See the NCCN Guidelines for Management of Immunotherapy-

Related Toxicities (available at www.NCCN.org

). Recommended cytotoxic

regimens include dacarbazine, paclitaxel, albumin-bound paclitaxel, or

carboplatin/paclitaxel. The only recommended targeted therapy is

trametinib. For patients being treated with trametinib, see Management of

Toxicities Associated with Targeted Therapy in the NCCN Guidelines for

Melanoma: Cutaneous (available at www.NCCN.org).

NCCN Recommendations for Follow-up and Subsequent Therapy

Following treatment for metastatic disease, patients should receive

imaging to assess response or progression. The recommended cross-

sectional imaging modalities are the same as those recommended for

workup. At minimum, all patients should have contrast-enhanced MR or

US of the liver, with modality preference determined by expertise at the

treating institution. Additional imaging may include chest/abdominal/pelvic

CT with contrast and/or whole-body FDG PET/CT; however, screening

should limit radiation exposure whenever possible. Brain MRI with IV

contrast may be performed if neurologic symptoms are present, but

routine CNS imaging is not recommended. Scans should be performed

with IV contrast unless contraindicated. Those with NED after treatment

for metastases may be eligible for clinical trials testing adjuvant therapies.

If they opt to forgo adjuvant treatment, then the recommended follow-up

surveillance is similar to the follow-up for patients with NED after treatment

of localized disease. See recommendations in the Follow-up section. If

post-treatment imaging shows residual or progressive disease, the NCCN

Panel recommends trying other options for treatment of distant metastatic

disease.

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Table 1. Risk Factors for Growth in Small Intraocular Melanocytic Lesions

Risk Factor

Studies Demonstrating Correlation with Tumor Growth

Detection Method(s)

Symptoms Augsburger, 1989

; Butler, 1994

; Shields, 1995

;

Shields, 2000

; Singh, 2006

; Shields, 2009

; Lane, 2010

History and physical

Lesion thickness

(>2 mm)

Augsburger, 1989

; Butler, 1994

; Shields, 1995

;

COMS 1997

; Shields, 2000

; Singh, 2006

; Lane, 2010

;

Shields, 2009

; Dalvin, 2019

Ultrasound

Lesion diameter

(>5 mm)

COMS 1997

; Dalvin, 2019

Comprehensive eye exam, color fundus photography,

ultrasound

Subretinal fluid Shields, 1995

; Shields, 2000

; Shields, 2009

Color fundus photography, comprehensive eye exam

Ancillary option: OCT

Orange pigment

(lipofuscin)

Augsburger, 1989

; Butler, 1994

; Shields, 1995

;

COMS 1997

; Shields, 2000

; Singh, 2006

;

Shields, 2009

; Dalvin, 2019

Color fundus photography, comprehensive eye exam

Ancillary options: ocular fundus autofluorescence, OCT

Proximity to optic disc

(tumor margin <3 mm)

Augsburger, 1989

; Shields, 1995

; Shields, 2000

;

Shields, 2009

Comprehensive eye exam, color fundus photography

Ultrasound hollowness

Shields, 2009

; Dalvin, 2019

Ultrasound (A- and B-scan)

Absence of halo

Shields, 2009

Comprehensive eye exam, color fundus photography

OCT, optical coherence tomography

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Table 2. Biopsy Options for Choroidal or Ciliary Body Tumors

a,231,248

Biopsy Type

Surgical

Approach

Tumor

Location

Sample Analysis

Studies Describing Technique, Reporting Yield or Safety

(number of patients biopsied)

Fine-needle

aspiration biopsy

(FNAB)

Transscleral Anterior Cytopathology Glasgow, 1988

261

(n=6)

Eide, 1999

251

(n=50)

Shields, 2007

259

(n=73)

Shields, 2007

258

(n=24; ≤3 mm thick)

McCannel, 2012

246

(n=170)

Chang, 2014

256

(n=38)

Grixti, 2014

234

(n=291)

Sellam, 2016

235

(n=185)

Singh, 2016

233

(n=71)

Kim, 2018

232

(n=11)

Matet, 2019

249

(n=24)

Transvitreal Posterior Cytopathology Glasgow, 1988

261

(n=15)

Eide, 1999

251

(n=14)

Cohen, 2001

250

(n=83)

Augsburger, 2002

(n=34; diameter

≤10 mm; thickness, ≥1.5 mm but ≤3 mm)

Shields, 2007

259

(n=67)

Shields, 2007

258

(n=32; ≤3 mm thick)

Correa, 2014

252

(n=159)

Chang, 2014

256

(n=38)

Augsburger, 2015

236

(n=80)

Singh, 2016

233

(n=64)

Sellam, 2016

235

(n=32)

Kim 2017

255

(n=10)

Kim, 2018

232

(n=33)

Reddy 2017

254

(n=57)

Singh, 2017

253

(n=20)

Vitrectomy system

(vitreous-cutter)-

assisted biopsy

Transvitreal/

transretinal

Posterior or

equatorial

Cytopathology or

Histopathology

(depends on

exact technique

used)

Jensen, 1997

240

(n=92)

Bechrakis, 2002

268

(n=23)

Sen, 2006

267

(n=14)

Bagger, 2013

239

(n=123)

Grixti, 2014

234

(n=448)

Bagger, 2015

266

(n=39)

Nagiel 2017

237

(n=17; ≤2.0 mm thick)

Grewal, 2017

238

(n=18)

Incisional biopsy

with Essen forceps

Transvitreal Anterior Histopathology Akgul, 2011

242

(n=20)

Incisional biopsy

(standard forceps)

Transvitreal Posterior Histopathology Kvanta, 2005

243

(n=10)

Seregard, 2013

241

(n=46)

Although review articles on techniques for biopsying intraocular lesions include excisional biopsy,

231,248

and historical literature includes reports of transscleral

resection or endoresection being used for uveal melanoma biopsy, these methods are not included in this table because they are no longer commonly used for uveal

melanoma due to technical challenges, risk of complications, and concerns about tumor seeding.

170,272-282

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Surgical Approach: Table lists typical surgical approach used for each biopsy method. In procedures using a transscleral (direct) approach, where the tumor is

approached from the outside, with the needle first puncturing the sclera over the tumor, then the tumor itself, leaving the retina intact.

231

Procedures using a

transvitreal (indirect) approach involve anterior entry through the pars plana opposite the tumor, going through the vitreous body and retina to reach the tumor.

231

Tumor Location: Although each biopsy method may be used successfully in a range of locations, the feasibility and success rate for each method varies based on

tumor location. The table lists the tumor location(s) for which the biopsy method was developed and/or is most often used.

Sample Analysis: Some methods provide cellular aspirate that can be used for cytopathology; others provide tissue samples that can be sectioned for histopathology.

The table reflects the type of sample usually obtained by each of the biopsy methods listed. Both types of samples can be used for molecular analyses for

prognostication.

For each biopsy method, the table lists representative studies including at least 10 cases that reported at least one of the following: detailed description of biopsy

technique used, analysis of yield (percent of biopsies providing sufficient material for diagnostic or prognostic analyses), analysis of safety (rates of intraoperative or

postoperative procedure-related complication), or analysis to assess risk of seeding (histologic analyses to detect tracts of tumor cells or follow-up for local

recurrence). Note that inclusion criteria varied across studies listed in the table. Whereas some studies included only patients with suspected or confirmed uveal

melanoma, others included patients with other intraocular conditions.

In these studies, biopsy procedure removal of vitreous body (vitrectomy) to reduce the risk of vitreous hemorrhage from transvitreal FNAB.

Vitrectomy system (vitreous-cutter)-assisted biopsy: Includes a variety of methods that use vitrectomy tools both to access tumor via a transvitreal/transretinal

approach and to extract tumor tissue using the vitreous cutter and aspiration through the canula. These procedures do not necessarily include a vitrectomy.

Incisional biopsy techniques described in the literature sometimes included use of a vitreous cutter, vitrectomy, and other procedures to access the biopsy site,

wherein the tumor tissue was incised with a diamond knife and removed with forceps.

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NCCN Guidelines Version 2.2021

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MS-98

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NCCN Guidelines Version 2.2021

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NCCN Guidelines Version 2.2021

Melanoma: Uveal

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NCCN Guidelines Version 2.2021

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NCCN Guidelines Version 2.2021

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NCCN Guidelines Version 2.2021

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