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Uveal Melanoma Guidelines January 2015
Uveal Melanoma National Guidelines
January 2015
Authors:
Nathan P, Cohen V, Coupland S, Curtis K, Damato B, Evans J, Fenwick S, Kirkpatrick L, Li O, Marshall E,
McGuirk K, Ottensmeier C, Pearce N, Salvi S, Stedman B, Szlosarek P, Turnbull N
This project is the independent work of the Uveal Melanoma Guideline Development Group
and is funded by Melanoma Focus (http://melanomafocus.com/)
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Uveal Melanoma Guidelines January 2015
Uveal Melanoma
1.
2.
Executive Summary ......................................................................................................................... 6
1.1
Care Pathway .......................................................................................................................... 6
1.2
Recommendations ................................................................................................................ 10
1.2.1
Patient Choice and Shared decision-making ................................................................ 10
1.2.2
Service Configuration .................................................................................................... 10
1.2.3
General Guidance.......................................................................................................... 10
1.2.4
Primary management ................................................................................................... 11
1.2.5
Prognostication ............................................................................................................. 14
1.2.6
Surveillance ................................................................................................................... 15
1.2.7
Metastatic disease ........................................................................................................ 16
Background ................................................................................................................................... 18
2.1
Introduction .......................................................................................................................... 18
2.2
Strengths and limitations of the evidence ............................................................................ 19
2.3
Risks versus benefits ............................................................................................................. 19
2.4
Scope and purpose................................................................................................................ 19
2.4.1
Aim of the guideline ...................................................................................................... 19
2.4.2
Clinical areas covered by the guideline......................................................................... 20
2.4.3
Target population and target audience ........................................................................ 20
2.5
3.
4.
Acknowledgements............................................................................................................... 20
Methodology................................................................................................................................. 20
3.1
Levels of Evidence ................................................................................................................. 21
3.2
Grade of recommendations .................................................................................................. 22
Management of the primary tumour ........................................................................................... 22
4.1
Introduction .......................................................................................................................... 22
4.2
Methods ................................................................................................................................ 23
4.2.1
Questions addressed..................................................................................................... 23
4.2.2
Inclusion and Exclusion criteria for selecting evidence ................................................ 24
4.2.3
Appraisal and Extraction ............................................................................................... 24
4.3
Evidence Summary ................................................................................................................ 24
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Uveal Melanoma Guidelines January 2015
4.3.1
Question 1. What are appropriate pre-operative investigations for the primary
tumour? 24
4.3.2
Question 2. Should patients be staged before primary treatment? ............................ 26
4.3.3
Question 3. What is the optimal primary treatment? .................................................. 28
4.4
5.
4.4.1
Pre-operative investigations ......................................................................................... 40
4.4.2
Staging before primary treatment ................................................................................ 41
4.4.3
Primary Treatment ........................................................................................................ 41
4.5
Recommendations ................................................................................................................ 42
4.6
Linking evidence to recommendations ................................................................................. 42
Prognostication ............................................................................................................................. 44
5.1
Introduction .......................................................................................................................... 44
5.2
Methods ................................................................................................................................ 44
5.2.1
Questions addressed..................................................................................................... 44
5.2.2
Inclusion and exclusion criteria for selecting evidence ................................................ 45
5.2.3
Appraisal and extraction ............................................................................................... 45
5.3
Review of Evidence ............................................................................................................... 45
5.3.1
Is there a preferred prognostic tool? ............................................................................ 45
5.3.2
What is the role of prognostic biopsy? ......................................................................... 48
5.4
6.
Evidence Statements............................................................................................................. 40
Evidence Statements............................................................................................................. 49
5.4.1
Prognostic factors/tool ................................................................................................. 49
5.4.2
Prognostic biopsy .......................................................................................................... 49
5.5
Recommendations ................................................................................................................ 49
5.6
Linking Evidence to Recommendations ................................................................................ 49
Surveillance of patients at risk of recurrence ............................................................................... 50
6.1
Introduction .......................................................................................................................... 50
6.2
Methods ................................................................................................................................ 51
6.2.1
Questions addressed..................................................................................................... 51
6.2.2
Inclusion and exclusion criteria for selecting evidence ............................................... 52
6.2.3
Appraisal and extractions ............................................................................................. 52
6.3
Evidence summary ................................................................................................................ 52
6.3.1
Question 1: Should all patients be offered surveillance? ............................................. 52
6.3.2
Question 2: Should there be a risk-adapted strategy for surveillance? If so, what is a
high-risk and or low-risk uveal melanoma? .................................................................................. 53
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Uveal Melanoma Guidelines January 2015
7.
6.3.3
liver?
Question 3: What is the optimal imaging modality for surveillance, overall and of the
54
6.3.4
Question 4: What is the optimal surveillance interval? ................................................ 55
6.3.5
Question 5: What is the duration of surveillance? ....................................................... 55
6.4
Evidence Statements............................................................................................................. 56
6.5
Recommendations ................................................................................................................ 56
6.6
Linking evidence to recommendations ................................................................................. 56
Metastatic Disease ........................................................................................................................ 57
7.1.1
7.2
Introduction .................................................................................................................. 57
Methods ................................................................................................................................ 61
7.2.1
Questions addressed..................................................................................................... 61
7.2.2
Inclusion and exclusion criteria for selecting evidence ................................................ 62
7.2.3
Appraisal and extraction ............................................................................................... 63
7.3
Evidence summary ................................................................................................................ 63
7.3.1
Question 1. What is the optimal method of staging? .................................................. 63
7.3.2
Question 2. Is there a preferred prognostic method for a patient with metastatic
disease 64
7.3.3
Question 3. What is the optimal management of systematic metastases? ................. 65
7.3.4
liver
Question 4. What is the optimal treatment for oligometastatic disease outside the
66
7.3.5
Question 5. What is the optimal management of liver only metastases?.................... 67
7.3.6
Question 6. Is regional liver therapy more effective than systemic therapy................ 68
7.3.7
Question 7. What is the role of surveillance following liver metastases treatment? .. 68
7.4
Evidence Statements............................................................................................................. 69
7.4.1
Staging ........................................................................................................................... 69
7.4.2
Preferred prognostic method ....................................................................................... 69
7.4.3
Management of systemic disease ................................................................................. 69
7.4.4
Management of oligometastatic-extrahepatic metastatic disease .............................. 70
7.4.5
Management of liver disease ........................................................................................ 70
7.4.6
Systemic versus targeted liver treatment ..................................................................... 70
7.4.7
Surveillance following liver treatment .......................................................................... 70
7.5
Recommendations ................................................................................................................ 70
7.6
Linking evidence to recommendations ................................................................................. 70
7.6.1
Staging ........................................................................................................................... 70
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Uveal Melanoma Guidelines January 2015
8.
7.6.2
Preferred prognostic method ....................................................................................... 71
7.6.3
Management ................................................................................................................. 71
7.6.4
Surveillance following liver treatment .......................................................................... 72
Using and implementing the guideline ......................................................................................... 72
8.1
Potential organisational and financial barriers in applying its recommendation................. 72
8.2
Audit criteria ......................................................................................................................... 74
9.
10.
Review and updates ...................................................................................................................... 76
Research recommendations ..................................................................................................... 76
References ............................................................................................................................................ 76
Appendices.......................................................................................................................................... 102
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Uveal Melanoma Guidelines January 2015
1. Executive Summary
1.1. Care Pathway
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Uveal Melanoma Guidelines January 2015
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Uveal Melanoma Guidelines January 2015
BOX 1 TREATMENT OPTIONS
Treatment
RADIOTHERAPY
Brachytherapy
Ruthenium 106
Iodine 125
Proton Beam
radiotherapy
Used for
Outcomes
Complications
Comments
Small/Medium /Large
uveal melanoma <20mm
in basal diameter
Medium to Large uveal
melanoma which can
not be treated with
brachytherapy or
resection
Good local
tumour control
Dose and position of plaque can be
adjusted to limit the loss of vision
Stereotactic
radiosurgery
Juxta papillary uveal
melanoma ; patients
unsuitable for
ruthenium plaque or
unfit for surgery
Good local
tumour control
Loss of vision
Tumour
recurrence
Loss of vision
Loss of the eye
from neovascular
glaucoma
Tumour
recurrence
Loss of vision
Radiation related
complications.
Tumour
recurrence
Local recurrence and of
adjuvant therapy of
uveal melanoma
Improves local
tumour control
Loss of vision
Extraocular
tumour
recurrence
Small melanoma
Uncertain
Tumour
recurrence
Very occasionally used by some centres
for small melanoma nasal to the optic
disc. When considering preservation of
vision , for example in a one eyed
patient; as it avoids radiotherapy
complications. However, it is no longer
recommended routinely as a sole
primary treatment
Avoids radiotherapy complications
New treatment option not widely used
for uveal melanoma. This is an
experimental treatment.
Medium to large
melanoma with a
narrow basal diameter
Variable
Endoresection +/radiotherapy
Medium-sized uvela
melanoma.
Toxic tumour syndrome
post PBR
Variable
Retinal
detachment
Loss of vision
Loss of the eye
Tumour
recurrence
Risk of orbital
dissemination of
tumour
Transient
intraocular
haemorrhage;
Rarely tumour
seeding
Enucleation
Large uveal melanoma
Melanoma associated
with neovascular
glaucoma +/- extensive
retinal detachment
Large extra-ocular
extension after uveal
melanoma
100% local
tumour control
if completely
excised
Socket related
complications.
Orbital
recurrence
Cosmetic results are reasonably good
with an orbital implant and artificial eye
100% local
tumour control
if completely
excised
Orbital recurrence
Rarely performed in the UK.
PHOTOTHERAPY
Transpupillary
thermotherapy
Photodynamic
therapy
SURGERY
Exoresection +/plaque
Exenteteration
Good local
tumour control
Not available in all ocular oncology units
Not available in all ocular oncology units
Only performed in limited centres.
Always performed with brachytherapy
to reduce the risk of recurrence.
Only performed in limited centres in the
UK
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Uveal Melanoma Guidelines January 2015
BOX 2 PROGNOSTICATION
BOX 3 SURVEILLANCE
The following features should be recorded:
 Age
 Gender
 Tumour location
 Tumour height
 Tumour Largest basal diameter
 Ciliary body involvement
 Extraocular melanoma growth
The following features should be recorded if tissue is
available:
 Cell type (modified Callender system)
 Mitotic count (number/40 high power fields in H&E
stained sections)
 Presence of extravascular matrix patterns
(particularly closed connective tissue loops;
enhanced with Periodic acid Schiff staining).
Prognostication and surveillance should be led by a
A minimum dataset for uveal melanoma from the Royal
College of Pathology should be recorded.
of screening. An individual plan should be developed.
Any molecular testing should be carried out within an
accredited laboratory with appropriate quality assurance in
place to provide the standards of the diagnostic test.
Patients judged at high-risk (see Section 6.3.2) of
The prognostic testing should take place within a tertiary
referral centre.
Tests for novel serological biomarkers should only used within
clinical trials or research programmes.
COMMISSIONING OF CARE
The suspected diagnosis of uveal melanoma by the
referring clinician should follow the same pathways as any
other suspected cancer. The ocular oncology centre should
be notified within 48 hours of presentation and the patient
should be seen by the specialist within two weeks.
Surgeons who see a patient with a recurrence who was
treated elsewhere should inform the treating centre.
Patients should be informed about and recruited into
clinical trials wherever possible.
Supra-regional specialist multi-disciplinary teams (MDT),
using a network model, should be established that allow a
coordinated approach for the care and follow-up of all
patients with metastatic uveal melanoma. For advanced
disease a specialist oncology MDT should consist of a
medical or clinical oncologist, an interventional radiologist,
a histopathologist, a liver surgeon and a clinical nurse
specialist, all with experience in treating of uveal melanoma
and with direct links to ocular surgical oncology centres.
The MDT should make recommendations on an individual
patient’s tumour staging and management, and have
available all treatments and trials locally or by referral.
specialist multidisciplinary team that incorporates
expertise from ophthalmology, radiology, oncology,
cancer nursing and hepatic services.
Prognostication and risk prediction should be based on
the best available evidence, taking into account clinical,
morphological and genetic cancer features.
All patients, irrespective of risk, should have a holistic
assessment to discuss the risk, benefits and consequences
of entry into a surveillance programme. The discussion
should consider risk of false positives, the emotional
impact of screening as well as the frequency and duration
developing metastases should have 6-monthly life-long
surveillance incorporating a clinical review, nurse
specialist support and liver-specific imaging by a nonionising modality.
Liver function tests alone are an inadequate tool for
surveillance.
PATIENT INFORMATION AND SHARED
DECISION MAKING
All specialist ocular oncology multidisciplinary teams (MDTs)
should collaborate to produce an information leaflet on the
options available nationally.
All available procedural and treatment options both locally
and nationally should be discussed with the patient.
The risks and benefits of any procedures and treatments
being considered should be fully discussed with the patient,
including their impact on quality of life.
A national register, based on a standardised minimum data
set, should be established where details of every patient
with a diagnosis of uveal melanoma are entered, with
follow-up data collected at least annually.
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Uveal Melanoma Guidelines January 2015
1.2. Recommendations
Note: All of the recommendations are listed in this section and are not duplicated in the clinical chapter.
Within each clinical chapter there are hyperlinks to the relevant recommendations and a hyperlink to return to
the chapter.
The grading of the recommendations is detailed in the methodology section.
1.2.1. Patient Choice and Shared decision-making
1.
All specialist surgical ocular oncology multidisciplinary teams (MDTs) should collaborate to produce
an information leaflet on the options available nationally. [GPP]
2.
All available procedural and treatment options, local, national and international should be
discussed with the patient. [GPP]
3.
The risks and benefits of any procedures and treatments being considered should be fully discussed
with the patient, including their impact on quality of life. [GPP]
1.2.2. Service Configuration
4.
Supra-regional specialist multi-disciplinary teams (MDT), using a network model, should be
established that promote a coordinated approach for the care and follow-up of all patients with
uveal melanoma. For advanced disease, a specialist oncology MDT should consist of a medical or
clinical oncologist, an interventional radiologist, a diagnostic radiologist a histopathologist, a liver
surgeon and a clinical nurse specialist, all with experience in treating uveal melanoma and with
direct links to ocular surgical oncology centres. The MDT should make recommendations on an
individual patient’s tumour staging and management, and have available all treatments and trials
locally or by referral. [GPP]
5.
Any molecular testing should be carried out within an accredited molecular pathology laboratory
with appropriate quality assurance in place to provide the required standards and experienced
interpretation of the diagnostic test, in compliance with national requirements. [GPP]
6.
A national register, based on a standardised minimum data set, should be established where details
of every patient with a diagnosis of uveal melanoma are entered, with follow-up data collected at
least annually. [GPP]
1.2.3. General Guidance
7.
All local recurrences of the primary uveal melanoma should be reported to the surgical ocular
oncology centre where treatment for the primary tumour took place. [GPP]
8.
All Optometrists and Ophthalmologists should receive training in the recognition of uveal
melanoma, in order to allow earlier detection and timely referral of patients with uveal melanoma.
[GPP]
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Uveal Melanoma Guidelines January 2015
9.
Each surgical ocular oncology centre should audit their results and share them nationally. [GPP]
10. The suspected diagnosis of uveal melanoma by the referring clinician should follow the same
pathways as for any other suspected cancer. The ocular oncology centre should be notified within
48 hours of presentation and the patient seen by the specialist within two weeks. Grade C
11. Suspicious lesions or lesions diagnosed as uveal melanoma should be referred to a consultant
surgical ocular oncologist in one of the surgical oncology centres for ocular malignancies. Grade D
12. Specimens should be reported by an ophthalmic pathologist within a specialist centre. [GPP]
13. All patients with a new diagnosis of uveal melanoma should be offered referral to a medical or
clinical oncologist with a specialist interest in the disease. [GPP]
14. Patients should be informed about and recruited into clinical trials wherever possible. [GPP]
15. Patients should be offered the opportunity to participate in uveal melanoma specific research. With
patient consent, samples should be taken surplus to diagnostic requirements and stored in an
ethically-approved quality biobank for research purposes. [GPP]
1.2.4. Primary management
Pre-operative investigations
16. Make a diagnosis of uveal melanoma using ophthalmoscopy, fundus photography and conventional
ocular ultrasound. Grade A
17. Ciliary body melanoma should be imaged with Ultrasound Biomicroscopy (UBM) or anterior
segment Optical Coherence Tomography (OCT). Grade D
18. If the clinical diagnosis is uncertain following the above-mentioned techniques then diagnostic
biopsy should be considered and balanced against potential risks of the procedure [GPP]
19. Fine needle aspiration biopsy can be performed either with a direct transcleral approach or using a
transvitreal approach. Grade D
Staging before primary treatment
20. A decision on staging should be made based on the individual circumstances of the patient, but
staging should not delay the primary management of the tumour. [GPP]
21. Staging should be considered in the following circumstances:

The patient is at particularly high risk because of the clinical features of their presentation.

The patient is particularly anxious and requires reassurance [GPP]
Treatment of the primary tumour
22. Patients should be informed that there is no proven survival advantage between any of the offered
modalities. Grade A
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Uveal Melanoma Guidelines January 2015
23. Treat patients using table below
Page 12 of 112
Uveal Melanoma Guidelines January 2015
Treatment
RADIOTHERAPY
Brachytherapy
Ruthenium 106
Iodine 125
Used for
Outcomes
Complications
Comments
Grade of
recommendati
ons
Grade A
Small/Medium /Large
uveal melanoma*
<20mm in basal
diameter
Good local
tumour
control
Loss of vision
Tumour
recurrence
Dose and position of
plaque can be adjusted
to limit the loss of
vision
Proton Beam
radiotherapy
Medium to Large
uveal melanoma
which cannot be
treated with
brachytherapy or
resection
Good local
tumour
control
Loss of vision
Loss of the eye
from
neovascular
glaucoma
Tumour
recurrence
Not available in all
ocular oncology units
Grade C
Stereotactic
radiosurgery
Juxta-papillary uveal
melanoma ; patients
unsuitable for
ruthenium plaque or
unfit for surgery
Good local
tumour
control
Loss of vision
Radiation
related
complications
Tumour
recurrence
Not available in all
ocular oncology units
Grade C
Local recurrence and
of adjuvant therapy
of uveal melanoma
Improves
local tumour
control
Loss of vision
Extraocular
tumour
recurrence
Grade C
Small melanoma
Uncertain
Tumour
recurrence
Very occasionally used
by some centres for
small melanoma nasal
to the optic disc. When
considering
preservation of vision,
for example in a one
eyed patient; as it
avoids radiotherapy
complications.
However, it is no
longer recommended
routinely as a sole
primary treatment.
Avoids radiotherapy
complications
New treatment option
not widely used for
uveal melanoma. This
is an experimental
treatment.
PHOTOTHERAPY
Transpupillary
thermotherapy
Photodynamic
therapy
Grade D
SURGERY
Page 13 of 112
Uveal Melanoma Guidelines January 2015
Exoresection +/plaque
Medium to large
melanoma with a
narrow basal
diameter
Variable
Endoresection +/radiotherapy
Medium-sized uveal
melanoma.
Toxic tumour
syndrome post PBR
Variable
Enucleation
Large uveal
melanoma
Melanoma associated
with NVG +/extensive retinal
detachment
Large extra-ocular
extension after uveal
melanoma
100% local
tumour
control if
completely
excised
Exenteteration
100% local
tumour
control if
completely
excised
* = as defined by (Diener-West, Hawkins et al. 1992)
Retinal
detachment
Loss of vision
Loss of the eye
Tumour
recurrence
Risk of orbital
dissemination of
tumour
Transient
intraocular
haemorrhage;
Rarely tumour
seeding
Rarely performed in
the UK.
Only performed in
limited centres.
Always performed with
brachytherapy to
reduce the risk of
recurrence
Grade C
Only performed in
limited centres in the
UK
Grade D
Socket related
complications
Orbital
recurrence
Cosmetic results are
reasonably good with
an orbital implant and
artificial eye
Grade A
Orbital
recurrence
Rarely performed in
the UK.
Grade D
Follow-up after primary treatment
24. Patients treated with plaque brachytherapy, proton beam radiotherapy or stereotactic
radiotherapy should be monitored for tumour regression intensively over the first two years
following treatment. Long-term follow up intervals depend of the response of the tumour to
brachytherapy and the radiotherapy complications experienced. [GPP]
Return to chapter by clicking HERE
1.2.5. Prognostication
Prognostic factors/tool
25. Prognostic factors of uveal melanoma are multi-factorial and include clinical, morphological and
genetic features. The following features should be recorded:

Age

Gender

Tumour location

Tumour height

Tumour Largest basal diameter

Ciliary body involvement

Extraocular melanoma growth (macroscopic)
The following features should be recorded if tissue is available:
Page 14 of 112
Uveal Melanoma Guidelines January 2015

Cell type (modified Callender system)

Mitotic count (number/40 high power fields in H&E stained sections)

Presence of extravascular matrix patterns (particularly closed connective tissue loops; enhanced
with Periodic acid Schiff staining). Grade A

Presence of extraocular melanoma growth (size, presence or absence of encapsulation). [GRADE A]
Prognostic biopsy
26. There should be a fully informed discussion with all patients, explaining the role of biopsy including
the benefits and risks. The discussion should include:

Risk of having the biopsy

Limitations of the investigation

Benefits for future treatments (including possible recruitment to trials)

Impact on quality of life

Recruitment to trials

Follow-up [GPP]
27. The minimum dataset for uveal melanoma from the Royal College of Pathology should be recorded.
http://www.rcpath.org/publications-media/publications/datasets/uveal-melanoma.htm Grade D
28. Tests for novel serological biomarkers should only be used within clinical trials or research
programmes. [GPP]
29. Consider collecting molecular genetic and/or cytogenetic data for research and prognostication
purposes where tumour material is available and where patient consent has been obtained as part
of an ethically approved research programme. [GPP}
30. Use of the current (i.e. 7th) Edition of the TNM staging system for prognostication is highly
recommended. Grade A
31. Use of multifactorial prognostication models incorporating clinical, histological,
immunohistochemical and genetic tumour features - should be considered. Grade D
Return to chapter by clicking HERE
1.2.6. Surveillance
32. Prognostication and surveillance should be led by a specialist multidisciplinary team that
incorporates expertise from ophthalmology, radiology, oncology, cancer nursing and hepatic
services. [GPP]
33. Prognostication and risk prediction should be based on the best available evidence, taking into
account clinical, morphological and genetic cancer features. [GPP]
34. All patients, irrespective of risk, should have a holistic assessment to discuss the risk, benefits and
consequences of entry into a surveillance programme. The discussion should consider risk of false
Page 15 of 112
Uveal Melanoma Guidelines January 2015
positives, the emotional impact of screening as well as the frequency and duration of screening. An
individual plan should be developed. [GPP]
35. Patients judged at high-risk (see Section 6.3.2) of developing metastases should have 6-monthly
life-long surveillance incorporating a clinical review, nurse specialist support and liver-specific
imaging by a non-ionising modality. [GPP]
36. Liver function tests alone are an inadequate tool for surveillance. Grade C
Return to chapter by clicking HERE
1.2.7. Metastatic disease
Staging
37. Patients should have whole body staging (chest, abdomen and pelvis) with CT scan or PET CT.
Grade D
38. Brain imaging should not be carried out in the absence of symptoms. [GPP]
39. Patients who have symptomatic bony pain should have a bone scan to assess the presence of bony
disease. [GPP]
40. Contract enhanced MRI with diffusion weight imaging should be used to stage liver disease when
assessing operability. Grade D
41. Contrast-enhanced CT scan should be used to stage extrahepatic disease. Grade D
Prognostic method
42. This minimum data set should be collected for all patients with systemic disease (Stage IV) for
future validation:

Metastatic Tumour Burden (site, diameter and number),

LDH

ALP

GGT

Bilirubin

Presence or absence of ascites

Gender

Age

Performance status,

DFS following definitive primary therapy. [GPP]
43. A tissue sample should be taken to confirm the diagnosis of metastatic uveal melanoma unless
contraindicated. [GPP]
44. Curative (R0) resection is the most important positive prognostic factor following liver resection.
[GPP]
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Uveal Melanoma Guidelines January 2015
Management of systemic and oligometastatic -extrahepatic disease
45. Patients should be considered for clinical trials wherever possible and be informed of available trial
options at other centres.[GPP]
46. Patients with good performance status (PS 0-2) who decline trials or for whom no suitable clinical
trials are available should be offered systemic treatments and managed in specialist centres with
appropriate oncology expertise in uveal melanoma. [GPP]
47. Specialist centres should be involved in treatment decisions and review, but a patient may prefer to
receive supportive care and systemic treatment locally. [GPP]
48. Patients with liver predominant disease should be considered for regional therapy. Grade D
49. Loco-regional treatment for the management of oligometastatic disease (i.e. when metastases are
limited to a single or limited number of organs) should be considered. This may include surgery,
stereotactic treatment or other forms of ablation. [GPP]
50. Ipilimumab can be offered in the UK following NICE approval of this drug for use in melanoma
generically.
Management of liver metastases
51. For patients with technically resectable disease, assessment for curative intent hepatic resection
should be offered. Grade D
52. Pre-operative diagnostic laparoscopy should be performed in patients with radiologically resectable
liver metastases, as many of these patients will have a miliary pattern of disease. Grade D
53. Regional or systemic treatments may be considered in patients with liver dominant disease where
resection is not suitable. [GPP]
Surveillance following liver treatment
54. Patients treated with curative intent should be followed with regular (3-4 monthly) hepatic MRI
and CT of chest, abdomen and pelvis. [GPP]
55. Patient outcomes for this selected group should be collected centrally and prospectively. [GPP]
Return to chapter by clicking HERE
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Uveal Melanoma Guidelines January 2015
2. Background
2.1. Introduction
Uveal melanoma has an incidence of approximately 2-8 per million per year in Caucasians (Virgili, Gatta et al.
2007) these tumours are even less common in races with brown eyes. More than 90% involve the choroid, the
remainder being confined to iris and ciliary body. Both sexes are affected in equal numbers. (McLaughlin, Wu
et al. 2005, Damato and Damato 2012) The age at presentation peaks at approximately 60 years, except for iris
melanomas, which usually present at a younger age. (Damato and Damato 2012) (Shields, Shields et al. 2001)
Risk factors for uveal melanoma include light-coloured irides (Saornil 2004), congenital ocular melanocytosis
(Singh, De Potter et al. 1998), melanocytoma (Reidy, Apple et al. 1985) and neurofibromatosis (Singh, De Potter
et al. 1998). The role of sunlight is uncertain (Singh, Rennie et al. 2004). Familial cases are very rare but some
patients may have familial atypical mole and melanoma syndrome; these cases require monitoring by a
dermatologist as they are also at risk of cutaneous melanoma (Smith, Padnick-Silver et al. 2007). Rare families
carry germline mutations of the BAP1 gene on chromosome 3, which predisposes them to develop uveal
melanoma, mesothelioma and other cancers (Cheung, Talarchek et al. 2013).
Staging for uveal melanoma follows the American Joint Committee on Cancer (AJCC) Tumor-Node-Metastasis
(TNM) staging system for eye cancer (Finger and The 7th Edition AJCC-UICC Ophthalmic Oncology Task Force
2009, Kujala et al. 2013). Outcomes for patients with uveal melanoma vary widely, but for patients with early
tumours they are excellent. In a cohort of 8033 patients, the 10-year metastatic rate for a 1-mm-thick uveal
melanoma was 5%, for a 2-mm-thick uveal melanoma it was 10%, and that for a 6-mm-thick uveal melanoma it
was 30% (Shields, Furuta et al. 2009). When grouping 7621 uveal melanomas into small (0-3mm thick, 29.8%),
medium (3.1-8 mm thick, 49%) or large (>8 mm thick, 20.9%) tumours, the 10-year rates of detecting metastases
were 11.5%, 25.5% and 49.2% respectively (Shields, Furuta et al. 2009).
An online tool, the Liverpool Uveal Melanoma Prognosticator Online (LUMPO), has been developed and is freely
available. It generates an all-cause mortality curve according to age, sex, AJCC TNM size category (based on basal
tumour diameter and tumour height), ciliary body involvement, melanoma cytomorphology, closed loops,
mitotic count, chromosome 3 loss, and presence of extraocular spread (www. ocularmelanomaonline.com)
(Damato, Eleuteri et al. 2011).
Cytogenetic and molecular genetic features of the uveal cells have been demonstrated to have strong
prognostication value in uveal melanoma. The most striking abnormality in uveal melanoma is the complete or
partial loss of chromosome 3. Other common genetic abnormalities of uveal melanoma include loss on the short
arm (p) of chromosome 1, and gains on 6p and 8q (see review, (Coupland, Lake et al. 2013). The abovementioned chromosomal alterations in primary UM are clinically relevant because of their correlation with the
risk of metastatic death. Chromosome 3 loss is associated with a reduction of the 5-year survival probability
from approximately 100% to about 50%. Similarly, chromosome 8 gains and loss of chromosome 1 significantly
correlate with reduced survival. (Sisley, Parsons et al. 2000, Patel, Edmondson et al. 2001)Conversely, gains in
chromosome 6p correlate with a good prognosis, suggesting this aberration may have a functionally protective
effect.
The natural history of uveal melanoma is characterised by the frequent development of metastases and patients
develop metastatic disease at any time from the initial diagnosis of the primary to several decades later (Kujala,
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Uveal Melanoma Guidelines January 2015
Makitie et al. 2003, Diener-West, Reynolds et al. 2005, Marshall, Romaniuk et al. 2013). The risk of metastatic
relapse for an individual varies greatly dependent on primary tumour characteristics and genetic alterations.
Outcomes are poor once metastatic disease occurs. The median survival from the time of the development of
distant metastatic disease is 2 to 12 months and 1-year survival 10-15%. This range reflects a number of
prognostic factors including the burden of metastatic disease and the effect of metastatic screening programmes
(Augsburger, Correa et al. 2009).
The liver is the most common site for uveal melanoma metastases, with 50% of patients having liver-only
disease, and 90% of those with metastases elsewhere (bowel, bone, lung and lymph nodes) also having liver
metastases (Lorigan, Wallace et al. 1991, Willson, Albert et al. 2001). Liver disease is usually multifocal, often in
a miliary distribution, but some patients may develop isolated metastases, enabling surgical removal. Liver
involvement is the cause of death in most patients with metastatic uveal melanoma (Willson, Albert et al. 2001).
Most patients die from parenchymal liver failure, but obstructive jaundice may result from liver metastases
compressing the common hepatic or intrahepatic ducts or, less commonly, from porta hepatis nodal disease
compressing the extrahepatic duct.
2.2. Strengths and limitations of the evidence
Due to the rarity of uveal melanoma and associated poor prognosis, there is limited clinical evidence guiding the
optimal treatment of metastatic disease. Most reports in the literature are of small case series of ten or fewer
patients. Larger non-randomised studies were scrutinised carefully for a survival bias as mortality is so high.
With regard to treatment of primary tumours, each UK centre tends to have specific areas of interest and no
centre offers all potential treatment options. Whilst the centres compare their results in regular meetings, there
are no randomised comparative trials (RCT) from the UK. The COMS study (Collaborative Ocular Melanoma Study
(http://www.jhu.edu/wctb/coms/) in the US has provided a valuable source of data; however, overall, the
limitations of the evidence base in the literature are considerable. The COMS study is discussed in more detail
in section 4.
2.3. Risks versus benefits
In weighing up the risks and benefits of any intervention, the Guideline Development Group (GDG) has
concentrated on an analysis of clinical benefit and, where appropriate, toxicity. It has not performed any costeffectiveness analyses as this falls outside the remit of these guidelines.
2.4. Scope and purpose
2.4.1. Aim of the guideline
The aim of these guidelines is to optimise patient care by providing recommendations based on the best
available scientific evidence. These guidelines should assist the planning of patient care and provide an
indication of the likely clinical outcomes, as well as facilitating patient counselling and informed decision-making.
Where adequate evidence is lacking, the GDG has, where possible, arrived at an expert consensus. The Group
recognises, however, that each patient is an individual.
These guidelines should therefore neither be
prescriptive nor dictate clinical care; however, where care significantly differs from the guidelines, it should be
justifiable. Our review also identifies gaps in current evidence, thereby defining scope for further research and
audit.
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The GDG has reviewed the evidence, where available, for the key areas of uncertainty in the field, which include:

The use and effectiveness of new technologies such as cytogenetics/genetic analysis for
prognostication.

The appropriate pathway for the surveillance of patients following treatment for primary uveal
melanoma.

The use and effectiveness of new technologies in the treatment of hepatic recurrence.

The use of systemic treatments.
2.4.2. Clinical areas covered by the guideline
This guideline addresses the diagnosis and management of primary uveal melanoma, including iris and ciliary
body melanoma in adults (>16 years). It does not address conjunctival melanoma, which has a pathogenesis
and behaviour more in common with mucosal and cutaneous melanomas.
The guideline addresses four main clinical topics:

Management of the primary tumour

Prognostication

Surveillance of patients at risk of recurrence

Metastatic disease
2.4.3. Target population and target audience
The guideline is relevant to people with a confirmed or suspected diagnosis of uveal melanoma, as well as their
family and carers.
The guideline will be helpful to all health professionals who provide care for people with uveal melanoma. This
includes ophthalmologists, optometrists, liver surgeons, radiologists, pathologists, specialist cancer nurses and
oncologists.
2.5. Acknowledgements
The GDG is grateful to Melanoma Focus for its support in funding the development of this guideline and for
hosting the consultation and the final product on its web page http://melanomafocus.com/activities-2/umguidelines-resources/. We would like to thank those people who helped with the searches and review of the
evidence. These include: the Royal College of Physicians Library Services, who carried out the searches; Ruth
Poulter, Clinical Trial Coordinator at University of Liverpool, who obtained papers; and Dr Rachel O’Mahony,
who reviewed and extracted the evidence where the members of the GDG was unable to do so due to time
constraints. The GDG members also express their gratitude to all those colleagues worldwide who gave their
constructive comments on the draft. See Appendix E for the names of those who provided comments.
3. Methodology
The guideline was convened under the UK Melanoma Study Group, a precursor of Melanoma Focus, now a
national charity with a professional core membership undertaking research and education in the field of
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Uveal Melanoma Guidelines January 2015
melanoma and skin cancers. The guideline and supporting documentation are available on the Melanoma Focus
website http://melanomafocus.com/activities-2/um-guidelines-resources/). The development of the guideline
was led by Dr Paul Nathan, who is a trustee of Melanoma Focus and a medical oncologist with an interest and
expertise in the treatment metastatic melanoma. Other officers and trustees of Melanoma Focus played no part
in the development of the guideline and did not comment on the guideline prior to the public consultation.
The number of health professionals who provide care to patients with uveal melanoma in the UK is relatively
small and the aim was to reflect the views of a significant proportion of these within the GDG. There are three
ocular oncology referral centres in England that deliver primary treatment (surgery) for patients with uveal
melanoma (Liverpool, London and Sheffield) while a handful of other centres have a specialist interest in the
treatment of uveal melanoma metastatic disease. GDG members were selected to represent these centres as
well as the professions involved in delivering care. In addition to the thirteen health professionals, including a
trainee, there were originally three patient representatives (one of whom resigned for personal reasons) and a
project manager on the GDG. The guideline was started in February of 2012, with the first Guideline
Development Group meeting held in April 2012; in all, seven GDG meetings were held over a period of two years.
GDG members completed a Declaration of Interest form prior to the first meeting, which was subsequently
updated. All interests were declared at the first meeting and it was agreed that members who had a commercial
interest in a drug or technology under discussion could remain in the room and answer questions from GDG
members but could not participate in the discussion or the formulation of recommendations.
As the clinical area and the associated body of literature is small, it was decided to do one all-encompassing
initial literature search and then to sift references for each question within the database. The original search
was carried out by the Royal College of Physicians on 27 March 2012, with the search repeated to identify new
evidence on 21 June 2013 and again 16 April 2014. Questions were drafted based on input from GDG members.
Subgroups of content experts on the GDG worked on each topic, agreeing the criteria for including papers, then
appraising and extracting references using a ‘Scottish Intercollegiate Guidelines Network’ (SIGN) checklist as a
guide. However as most of the evidence consisted of small case series, for some questions additional criteria
were applied to appraise quality, in particular whether the case series included patients from more than one
centre. The sub-groups were supported and advised by a guideline methodologist. The subgroups presented
the evidence review and extraction tables to the full GDG at the group’s meetings. The full GDG discussed the
evidence and formulated evidence statements and recommendations.
A great deal of work was done
electronically and following update search revisions all GDG members were sent several drafts of chapters for
comment.
The evidence was appraised and extracted into tables; see Appendix A, which includes many references that
were reviewed but not included in the final document.
A detailed description of the methodology is available in the document entitled Uveal Melanoma Guideline
Development Methodology at http://melanomafocus.com/activities-2/um-guidelines-resources/
3.1. Levels of Evidence
The grading of the evidence is based on the Scottish Intercollegiate Guidelines Network (SIGN) grading system
1999-2012 http://www.sign.ac.uk/guidelines/fulltext/50/annexoldb.html
1++
High quality meta-analyses, systematic reviews of RCTs, or RCTs with a very low risk of bias
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Uveal Melanoma Guidelines January 2015
1+
12++
2+
23
4
Well-conducted meta-analyses, systematic reviews, or RCTs with a low risk of bias
Meta-analyses, systematic reviews, or RCTs with a high risk of bias
High quality systematic reviews of case control or cohort or studies. High quality case control or cohort
studies with a very low risk of confounding or bias and a high probability that the relationship is causal
Well-conducted case control or cohort studies with a low risk of confounding or bias and a moderate
probability that the relationship is causal
Case control or cohort studies with a high risk of confounding or bias and a significant risk that the
relationship is not causal
Non-analytic studies, e.g. case reports, case series
Expert opinion
3.2. Grade of recommendations
The grading of recommendations is also based on SIGN 199-2012:
A
At least one meta-analysis, systematic review, or RCT rated as 1++, and directly applicable to the target
population; or A body of evidence consisting principally of studies rated as 1+, directly applicable to the
target population, and demonstrating overall consistency of results
B
A body of evidence including studies rated as 2++, directly applicable to the target population, and
demonstrating overall consistency of results; or Extrapolated evidence from studies rated as 1++ or 1+
C
A body of evidence including studies rated as 2+, directly applicable to the target population and
demonstrating overall consistency of results; or Extrapolated evidence from studies rated as 2++
D
Evidence level 3 or 4; or Extrapolated evidence from studies rated as 2+
GPP
Recommended best practice based on the clinical experience of the guideline development group
4. Management of the primary tumour
4.1. Introduction
Most uveal melanoma patients present with symptoms, including blurred vision, visual field loss, distorted
vision, photopsia (i.e. flashing lights), visible tumour in iris or episclera, red eye and pain. In the UK approximately
30%-40% of patients are asymptomatic, their tumour being detected on routine ophthalmic examination by an
optometrist or ophthalmologist (Damato 2001). Delay in referral leads to an increased likelihood that the
patient will require an enucleation (removal of the eye) and as the result of more advanced disease stage at
presentation (including disseminated melanoma) (Damato 2012).
Without timely treatment, uveal melanomas tend to make the eye blind, painful and unsightly as a result of
retinal detachment, neovascular glaucoma (NVG) and uveitis. Despite successful ocular treatment, up to 50% of
all patients with large ciliary body melanoma develop metastatic disease, which almost always involves the liver
and which is usually fatal within a year of the onset of symptoms. With successful treatment of the primary, the
outlook is excellent for many patients with uveal melanoma. In a cohort of 8033 patients, the 10-year metastatic
rate for a 1-mm-thick uveal melanoma was 5%, while for a 2-mm-thick uveal melanoma it was 10%, and for a 6mm-thick uveal melanoma it was 30% (Shields, Furuta et al. 2009). When grouping 7621 uveal melanomas into
small (0-3mm thick, 29.8%), medium (3.1-8 mm thick, 49%) or large (>8 mm thick, 20.9%) tumours, the 10-year
rates of detecting metastases were 11.5%, 25.5% and 49.2% respectively (Shields, Furuta et al. 2009). In the
COMS study, the five-year survival figures for medium-sized choroidal melanoma were 91% in a group of patients
randomized to radiotherapy and 89% in the group randomized to enucleation (Diener-West, Earle et al. 2001).
At 12 years the survival figures were 79% in the radiotherapy group and 83% in the enucleation group. (COMS
report no 28) (based on histopathologically confirmed melanoma metastasis alone). (Hawkins 2006)
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Uveal Melanoma Guidelines January 2015
The objectives of ocular treatment are to attempt to prevent metastatic disease and if possible to conserve the
eye with as much useful vision as possible. Enucleation has therefore been replaced, whenever possible, by
various forms of external radiotherapy, phototherapy and local resection, which are administered either
individually or in combination. Many factors influence the choice of ocular treatment, including: tumour size and
location, visual acuity in the affected eye and the fellow eye, and the patient’s general health as well as the
patient’s visual needs, wishes and concerns.
4.2. Methods
4.2.1. Questions addressed
The following questions were addressed.
Question
Population
Intervention
Comparator
Outcome
Q 1. What are
appropriate preoperative
investigations for the
primary tumour?
Patients with
possible
primary uveal
melanoma
With each
other/ With
observation
only
Selection of appropriate
treatment modality (see
Q 3)
Q 2. Should patients
be staged before
primary treatment?
 Which patients
should be staged
before primary
treatment, and
how and when?
 What is the
benefit of staging
before primary
treatment?
 In what
circumstances
does
investigation
inform primary
management?
Q 3. What is the
optimal primary
treatment?
Patients with
primary uveal
melanoma
Biopsy
B-ultrasound
sonography (USS),
ultrasound
biomicroscopy,
Photography
Fluorescein angiogram
Optical Coherence
Tomography (OCT),
fundus
autofluorescence
Any staging
investigation
No staging
Change of treatment of
primary tumour
Including:
• Enucleation
• Proton beam therapy
• Plaque therapy
• Endo-resection
• Trans-scleral
resection
• Stereotactic
radiotherapy
• Thermotherapy
With each other
or with usual
care
Primary:
1. Survival/ Distal
recurrence
2. Preserving eye
3. Preserving vision
Patients with
primary uveal
melanoma
Secondary:
1. Quality of life
2. Visual Acuity
3. Local recurrence
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Uveal Melanoma Guidelines January 2015
4. Side-effects
/complications
4.2.2. Inclusion and Exclusion criteria for selecting evidence
Inclusion Criteria for all sections were: All study types in humans were considered but case-series had to be N>5.
Older treatment forms, such as Xenon Arc photocoagulation that are no longer in use, were excluded.
4.2.3. Appraisal and Extraction
All references were sifted first by one individual. The primary reasons for excluding papers were that the papers
did not address the question, or the techniques are now obsolete due to more recent advances, where
techniques have changed, or that papers had been superseded by more contemporary results.
The four different reviewers (members of the GDG) appraised and reviewed the included papers, and the quality
of the studies was assessed using the modified SIGN checklists. Most of the studies were case-series and,
because SIGN does not have a quality checklist for this study type, additional criteria were used to assign an
overall quality rating to these studies.
Information from each of the studies was extracted and presented to the GDG for discussion with an update of
the evidence presented after an update search in June 2013. For full details of each of the included studies, see
the evidence tables in Appendix B.
4.3. Evidence Summary
4.3.1. Question 1. What are appropriate pre-operative investigations for the
primary tumour?
4.3.1.1. Choroidal melanoma
In most cases the diagnosis of choroidal melanoma is based on ophthalmoscopy, fundus photography and
conventional ocular ultrasound. An early report on the diagnostic accuracy of ophthalmoscopy, fundus
photography and conventional ocular ultrasound showed that the combination of these tests gave a diagnostic
accuracy of 99.52% (Albert and Marcus 1990).
Conventional A and B scan ocular ultrasound is key to making the diagnosis (Wang, Yang et al. 2003),(Romani,
Baldeschi et al. 1998). In the COMS trial, 99.7% (1559 of 1563) of medium sized and large ocular tumours were
diagnosed to be melanoma using ocular ultrasound alongside other features, a diagnosis that was later
confirmed by pathology (Collaborative Ocular Melanoma Study, Boldt et al. 2008). Diagnostic accuracy of
ultrasound is likely to be lower in small uveal melanomas. Uveal melanoma demonstrates ultrasonographic
hollowness, choroidal excavation and has a typical dome or ‘collar-stud’ configuration on B scan
ultrasonography. Ultrasonographic hollowness or low internal reflectivity is also a suspicious sign in atypical
choroidal naevi and helps to predict which naevi may progress to frank malignancy (Shields, Furuta et al. 2009).
Evidence would suggest that ocular ultrasound sonography (USS) is better than computer tomography (CT) or
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magnetic resonance imaging (MRI) at detecting extrascleral/orbital extension (Scott, Murray et al. 1998,
Collaborative Ocular Melanoma Study, Boldt et al. 2008). Some have considered ocular positron emission
tomography (PET/CT) as a diagnostic investigation because cutaneous melanoma demonstrates high metabolic
activity and this can be demonstrated using Fludeoxyglucose positron emission tomography (FDG-PET)/CT
(Finger, Kurli et al. 2004, Reddy, Kurli et al. 2005). However, uveal melanoma shows variable metabolic activity
and, therefore, it is unlikely that an ocular PET/CT will be able to usefully distinguish between naevi and
melanoma (Finger, Kurli et al. 2004, Reddy, Kurli et al. 2005). The reason for poor FDG uptake in uveal melanoma
remains unknown (Strobel, Bode et al. 2009).
Other tests scan be used to distinguish a choroidal naevus from a choroidal melanoma, tests that are especially
useful when considering small melanoma or amelanotic melanoma. Autofluorescence is a property of lipofuscin
(the orange pigment seen on top of melanoma which appears brown on the surface of an amelanotic
melanoma). Quantification of autofluorescence images can distinguish a choroidal melanoma from a naevus
with a sensitivity 89% and specificity of 93% (Albertus, Schachar et al. 2013). A study conducted by Ausberger
in 1989 first described the presence of orange pigment clumps as a risk factor for predicting growth of
melanocytic choroidal lesions (Shields, Shields et al. 1995)(Augsburger, Schroeder et al. 1989) Other risk factors
(tumour thickness>2mm; the clinical presence of subretinal fluid; visual symptoms; and proximity to the optic
disc <3mm) can all be determined with ophthalmoscopy and conventional ocular ultrasound. The significance
of subretinal fluid on Optical Coherence Tomography (OCT) is yet to be determined, but OCT may be used to
monitor suspicious choroidal lesions. As enhanced depth imaging with OCT improves, it is likely that a better
understanding of the choroidal appearance of melanoma will be achieved, and this in turn is likely to assist in
the differential diagnosis of choroidal tumours.
4.3.1.2. Ciliary body and iris melanoma
The evidence for investigation with more recently developed diagnostic tools is based on comparative case
series. Bianciotto et al (Bianciotto, Shields et al. 2011) evaluated 200 iris and ciliary body tumours (47 were
melanomas): they reported that Anterior Segment Optical Coherence Tomography (AS-OCT) was useful for iris
melanoma but was not superior to Ultrasound Biomicroscopy (UBM) when considering ciliary body tumours.
AS-OCT suffers from optically-related image shadowing with large, pigmented lesions (Razzaq, Emmanouilidisvan der Spek et al. 2011). Large iris pigment epithelium cysts and ciliary body lesions cannot be adequately
imaged with AS-OCT. Recent evidence suggests that small anterior iris melanoma can be adequately imaged
with AS-OCT (Hau et al in print). UBM with a 50MHz probe is considered to be the best tool to image the ciliary
body (Gunduz, Hosal et al. 2007). Further, Conway et al compared UBM with conventional A/B scan ultrasound
in 132 iris/ciliary body masses (55 were melanoma). They reported only 29% correspondence between the
anatomical structures invaded by melanoma as identified by B-scan versus disease extent defined by UBM with
UBM being superior (Conway, Chew et al. 2005). The disadvantages of UBM include patient discomfort due to
the eye contact with a water bath, and the increased time taken to perform this test. However, more recent
UBM machines are now fitted with probes that do not always require a waterbath.
4.3.1.3. Intraocular Biopsy for Diagnosis
If the diagnosis is still uncertain following the above investigations, then biopsy has a role in distinguishing small
melanomas from naevi and amelanotic melanomas from metastases. Various methods have been described,
using tools such as fine-needle aspiration, vitreous cutter and Essen Forceps, (Augsburger, Correa et al. 2002,
Sen, Groenewald et al. 2006, Bornfeld 2007, Shields, Ganguly et al. 2007, Konstantinidis, Roberts et al. 2013).
Biopsy is associated with a number of risks, which include: failure, especially with small tumours (Cohen,
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Dinakaran et al. 2001, Augsburger, Correa et al. 2002); rhegmatogenous retinal detachment; and rarely
endophthalmitis (Kvanta, Seregard et al. 2005). Seeding to extraocular tissues can also occur but this is
exceptionally rare (Char, Kemlitz et al. 2006, Schefler and Abramson 2009, Caminal, Ribes et al. 2012).
Fine needle aspiration biopsy can be performed with a direct transcleral approach or using a transvitreal
approach. Cohen et al reported a cohort of 83 patients who underwent 25-gauge fine needle aspiration biopsy
for indeterminate choroidal lesions. Overall a diagnosis could be achieved in 88% but the small indeterminate
lesions did not always yield sufficient cells to make a diagnosis especially if less than 2mm in thickness (<2mm
40% diagnostic 2-4mm 90% diagnostic) (Cohen, Dinakaran et al. 2001). (Konstantinidis, Roberts et al. 2013)In
another cohort study of 34 patients in the ‘naevus versus melanoma category’ (1.5-3mm in thickness), who
underwent a 25-gauge fine needle aspiration biopsy, the diagnostic yield was 65% (Augsburger, Correa et al.
2002). Transcleral conventional biopsy is best suited for anteriorly positioned tumours. Infrequent potential
complications of biopsy include tumour seeding within the eye or orbit, infection and intraocular haemorrhage,
although the latter is usually only transient (Kvanta, Seregard et al. 2005). Biopsy can be difficult to perform and
the resulting specimen difficult to interpret. Therefore, these surgical procedures should only be undertaken in
a specialist surgical ocular oncology centre by those with expertise and with the aid of a specialist ocular
pathologist. (Cohen, Dinakaran et al. 2001, Augsburger, Correa et al. 2002, Konstantinidis, Roberts et al. 2013).
4.3.2. Question 2. Should patients be staged before primary treatment?
4.3.2.1. Incidence of metastases at staging
In the majority of patients with uveal melanoma, metastatic disease is not detectable at diagnosis. It is a rare
finding at diagnosis being reported in less than 1% (70 out of 7,541) of patients screened for the COMS trial.
(Diener-West, Reynolds et al. 2004). However, this study has limitations as only liver function tests (LFTs) and
chest X-Rays (CXR) were used to stage patients. Using FDG-PET/CT, Finger et al. staged 52 patients with the
diagnosis of primary uveal melanoma, and metastases were only found in 2 patients (3.8%) (Finger, Kurli et al.
2004). More recently, Feinstein et al used abdominal CT to stage 91 patients with uveal melanoma, and
metastases were found in 3 patients (3.3%) (Feinstein, Marr et al. 2010). In a study by Freton et al, 333 patients
with uveal melanoma were screened with PET/CT and 7 patients (2.1%) were found to have metastatic
melanoma. (Freton, Chin et al. 2012)
There is evidence to suggest that the risk of detecting metastatic disease at diagnosis can be stratified according
to the size of the uveal melanoma. The incidence of liver metastases at diagnosis in 911 British patients from
2007-2011 was only 0.6% in the small-to-medium uveal melanoma group compared to 7.7% in those patients
scheduled for enucleation [Papastefanou et al 2012, conference presentation]. These patients were all staged
with an abdominal ultrasound and LFTs: if an abnormality was detected, they had further imaging with either
PET/CT, CT or MRI of the abdomen. None of the patients with metastatic disease had a normal abdominal
ultrasound, although 40% of patients with CT-confirmed metastatic disease had normal LFTs. This is in
concordance with a large body of literature questioning the value of LFTs in uveal melanoma staging and
surveillance (see below and Chapter 6).
4.3.2.2. Staging investigations
If staging is performed, there is still debate regarding the optimum staging investigation to select and to date no
prospective trials have compared different staging systems. Unlike cutaneous melanoma, the liver is almost
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Uveal Melanoma Guidelines January 2015
always the first site where metastases are seen (Finger, Kurli et al. 2005). Therefore, imaging should be targeted
towards the liver.
Liver Function tests
Liver function tests are widely performed in staging of uveal melanoma. However, all authors accept the low
sensitivity of this blood test. In the COMS trial, an abnormal LFT was reported if it was at least twice the upper
limit of normal. This prompted liver imaging or a biopsy to confirm metastatic disease. The sensitivity and
specificity of at least one abnormal liver enzyme in predicting metastatic disease were 15% and 92% respectively
(Diener-West, Reynolds et al. 2004). Alkaline phosphase was suggested to be the enzyme with the highest
diagnostic accuracy; however the combination of abnormal alkaline phosphase (ALP) and Gammaglutamyltransferase (GGT) raised the likelihood of detecting metastatic disease (Hicks, Foss et al. 1998). These
same authors however reported that LFTs had a positive predictive power of <50%, and therefore found them
of little value.
Kaiserman et al recorded serial LFTs in 30 uveal melanoma patients who subsequently developed metastases
and compared this group with 80 uveal melanoma patients without metastatic disease (Kaiserman, Amer et al.
2004). They found that liver enzymes rose 6 months prior to the detection of metastatic disease but 50% still
remained within normal limits. These authors recommended staging/screening with combined liver imaging and
sequential LFTs.
Abdominal Ultrasound
Eskelin et al recommended abdominal ultrasound combined with LFTs with a semi-annual screening detecting
>95% of metastasis while they are still asymptomatic. They reported that abdominal USS revealed unequivocal
hepatic metastases in 36 of 46 patients (78%) with metastatic disease, of whom 12 (33%) had normal LFTs.
Ultrasound was suggestive of metastases in 5 additional patients (11%), all of whom were confirmed to have
hepatic metastases by fine-needle aspiration biopsy, CT, or both. Liver USS was negative (false negative) in only
2 patients (4%), both of whom had liver metastases and at least 1 abnormal LFT. Ultrasound is the preferred
imaging modality in many centres due to its lower cost and ease of accessibility (Eskelin, Pyrhonen et al. 1999).
If an abnormality is detected in the liver on USS, further qualification is performed with either CT or MRI. Hicks
et al found the specificity of 100% and positive predictive power of greater than 50% of abdominal ultrasound
in detecting metastatic disease. (Hicks, Foss et al. 1998).
Abdominal CT scan
Feinstein and associates reviewed the records of 91 patients who underwent CT scanning within 1 month of
uveal melanoma diagnosis. CT scan detected a large variety of benign hepatic lesions such as cysts and fatty
liver: 90% of hepatic lesions could be classified. The sensitivity, specificity, Positive Predictive Value (PPV) and
Negative Predictive Value (NPV) of a CT scan in detecting metastatic disease were 100%, 91%, 27%, and 100%
respectively. The low PPV was attributable to a variety of benign hepatic lesions detected with CT. Patients with
multiple lesions on abdominal CT scanning were significantly more likely to have metastatic disease (Feinstein,
Marr et al. 2010).
Abdominal MRI with or without contrast
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There has been no published assessment of the value of an MRI of the liver for staging of patients presenting
with a primary uveal melanoma. In the follow up of patients with a ‘high risk’ of metastatic disease, MRI has
proved to be an accurate method for staging (Marshall, Romaniuk et al. 2013).
Fludeoxyglucose (FDG)-PET/CT
The value of FDG-PET in detecting metastatic disease in uveal melanoma remains uncertain. In a study of 27
patients 6/13 patients with liver metastases from UM were PET avid, whilst 7/13 were not (Strobel, Bode et al.
2009). In an earlier study 2/52 patients presenting with primary choroidal melanoma had FDG avid metastases
at diagnosis (Finger, Kurli et al. 2005). False positives were seen in 3/52 (3.8%) patients when further evaluated
by histopathology and/or additional imaging; 7 patients (13.4%) had PET detected inflammatory or benign
lesions elsewhere. No comparison was made in this study with other imaging techniques, specifically high
resolution CT, MRI or USS. Further studies comparing PET/CT to other imaging modalities would be useful to
evaluate the detection rate and specificity of FDG-PET in the staging of uveal melanoma.
Chest radiography
The sensitivity and specificity of chest radiography (CXR) in a series of 235 choroidal melanoma patients
undergoing preoperative testing were reported to be 1.8% and 100% respectively (Hicks et al). In the COMS,
restricting the analysis to chest x-rays (CXR) obtained within the 90-day period before diagnosis of metastasis,
sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were 35%, 98%, 65%,
and 93%.
The COMS and other studies have recommended pre- operative CXR to rule out a primary lung tumour, but no
routine follow-up CXR. (Hicks et al, 1998) However, since the PPV of the test prior to local treatment is even
lower than when used for follow-up, the usefulness of this test at diagnosis or follow-up is questionable.
4.3.2.3. Does detection of metastatic disease at diagnosis influence management of the eye?
No evidence was found to address this question.
4.3.3. Question 3. What is the optimal primary treatment?
4.3.3.1. Enucleation
Prior to the advent of radiotherapy, the traditional treatment of choroidal melanoma was enucleation of the
affected eye as soon as the diagnosis was established with reasonable clinical certainty. The number of patients
needing enucleation has diminished with the availability of alternative globe-sparing treatment options. In spite
of this, enucleation is required in up to one-third of patients due to the tumour being too large for treatment by
other means, the potential complications of treatment being too great, or patient choice. Enucleation entails
the complete removal of the eyeball, thus avoiding any disturbance of the intraocular tumour. In the event that
there is extraocular spread, complete tumour excision should be attempted where possible. If this is not
achievable during surgery, adjuvant orbital radiotherapy is required.
Up to 50% of uveal melanoma patients develop metastatic disease because the tumour has disseminated at an
early stage before detection and treatment of the ocular tumour (Kujala, Makitie et al. 2003). Zimmerman et al
(Zimmerman, Mclean et al. 1978) previously suggested that enucleation surgery was associated with
acceleration of metastatic death. This hypothesis was not supported by the COMS report 24 (Hawkins 2004),
which indicated that pre-enucleation radiotherapy did not show an advantage. Gambrelle et al (Gambrelle,
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Grange et al. 2007) found the 5-year melanoma-specific survival rate was around 32% after primary enucleation
(Isager, Ehlers et al. 2004).
After enucleation, there is an obviously reduced visual field to the side of the artificial eye along with loss of
depth perception. Many of the skills of depth perception are relearned with time and most patients continue
with their same jobs and activities without difficulty. Steeves et al (Steeves, Gonzalez et al. 2008) suggest that
one-eyed individuals maintain perfectly normal lives and are not limited by their lack of binocularity. Quality of
life studies have shown that following enucleation, patients have lower levels of anxiety compared to patients
treated with radiotherapy (Melia, Moy et al. 2006).
4.3.3.2. Brachytherapy
In most centres, brachytherapy is the first choice of treatment. The procedure involves suturing of a radioactive
plaque to the episclera (usually under general anaesthesia or deep sedation) and a second operation, following
a specific period of time during which the prescribed dose is delivered, to remove the plaque. Treatment is
completed once the plaque is removed. It may take up to 6 months before regression can be recorded. In
Europe, ruthenium-106 is the most popular isotope whereas in the USA iodine-125 is generally preferred.
Currently ruthenium-106 is the only radioisotope prescribed for the treatment of uveal melanoma in the UK,
and therefore these guidelines will consider, first, the published evidence for ruthenium-106 plaque
brachytherapy.
Ruthenium
Ruthenium plaque brachytherapy can be used to treat small to medium sized melanoma, with excellent 5-year
local control rates of 95.6%, 93.6% and 98% being reported (Verschueren, Creutzberg et al. 2010, Marconi, de
Castro et al. 2013). However, no 10-year local control rates were reported in these studies. A meta-analysis of
1066 patients with uveal melanoma treated by ruthenium plaque brachytherapy recorded the 5-year mortality
for small/medium T1/T2 tumours (small tumours: height 1-3 mm, diameter more than 5mm; medium tumours:
height 2.5-10.0mm and diameter <=16 mm; T1, T2 and T3 reflect particular subcategories of the 6th edition of
AJCC TNM Staging system used at the time) as 6%, and for large T3 tumours (height >=10 mm or diameter >=16
mm) as 26% (Seregard 1999). For the population as a whole, the 5- and 10-year mortalities were 14% and 22%
respectively (Seregard 1999). This reflects the tumour selection criteria for ruthenium plaque brachytherapy, as
many ocular oncologists do not select this treatment for larger tumours. Ruthenium plaque brachytherapy is
used for thick posterior uveal melanomas only in some centres where alternative modalities such as I-125 or
teletherapy such as proton beam or stereotactic radiosurgery are not available to treat thick tumours In one
small, non-randomised study, thick posterior uveal melanomas (thickness>/=8mm)
were treated with
enucleation or ruthenium plaque brachytherapy (Kaiserman, Kaiserman et al. 2009). Despite a low 71% control
rate in the ruthenium plaque group and the thicker tumours being in the enucleation group (p<0.001),
melanoma-related mortality rates were the same in both groups (at 5 years 20.5% and 28.1% p=0.6 and at 10
years 46.2% and 44.0% p=0.9). The authors concluded that ruthenium plaque brachytherapy is a safe alternative
treatment that does not compromise survival (Kaiserman, Kaiserman et al. 2009). Local tumour control is
compromised when ruthenium plaque brachytherapy is applied to thicker tumours, with control rates of 71%,
82% and 86% in three studies (Bergman, Nilsson et al. 2005, Kaiserman, Kaiserman et al. 2009, Ritchie, Gregory
et al. 2012). Lack of response to ruthenium plaque brachytherapy was associated with uveal melanomas >5mm
in height (Papageorgiou, Cohen et al. 2011). The selection criteria for ruthenium plaque brachytherapy vary
between European centres but there is general consensus that ruthenium plaque brachytherapy should be
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restricted to uveal melanoma below 7-8mm in height (Bergman, Nilsson et al. 2005, Isager, Ehlers et al. 2006,
Ritchie, Gregory et al. 2012). Other risk factors for local recurrence/poor tumour control are large basal
diameter, anterior location, young patient age and foveal location (Isager, Ehlers et al. 2006, Papageorgiou,
Cohen et al. 2011). Transpupillary thermotherapy TTT can be combined with primary ruthenium plaque therapy
to improve tumour control and globe preservation rates (see section on TTT) (Yarovoy, Magaramov et al. 2012).
Visual complications from ruthenium plaque brachytherapy are less severe than those recorded from the
collateral damage of iodine plaque brachytherapy or proton beam radiotherapy (PBR). Patients are warned
about the risk of postoperative diplopia but the risk is very low. The incidence of ocular motility disorders
following ruthenium plaque brachytherapy in a cohort of uveal melanoma cases treated in London was rare at
1.7% over 8 years (Dawson, Sagoo et al. 2007). The incidence of radiation cataract is low at 16% (Marconi, de
Castro et al. 2013). The incidence of NVG is only 3% and related to the TNM stage (6th edition of TNM staging of
AJCC) of the tumour, i.e., it increased after treatment of larger tumours (Summanen, Immonen et al. 1996,
Marconi, de Castro et al. 2013). In the long term, radiation damage to the optic disc and macular can destroy
central vision. Predictive factors for visual deterioration from radiation maculopathy include: a) proximity of the
posterior tumour border to the fovea; b) poor presenting visual acuity; and c) age <40 years (Summanen,
Immonen et al. 1996, Rouberol, Roy et al. 2004, Bergman, Nilsson et al. 2005). Predictive factors for loss of light
perception were proximity to the optic disc and increasing size of the tumour (Summanen, Immonen et al. 1995).
Visual deterioration, cataract and vitreous haemorrhage is associated with increasing tumour height, as these
tumours require a higher dose of radiation to achieve tumour control (Summanen, Immonen et al. 1995,
Summanen, Immonen et al. 1996). The plaque can be positioned eccentrically with its posterior edge aligned
with the posterior tumour margin to reduce the radiation dose to the optic disc and fovea (Russo, Laguardia et
al. 2012) Tumour control was not compromised using this technique even at 4 years follow up. However, in
general, good visual results are seen following ruthenium plaque brachytherapy, especially for anterior tumours.
Damato and his group (Damato, Kacperek et al. 2005) reported visual conservation of 20/40 or better in 55% at
9 years; loss of vision correlated with: posterior tumour extension (p < 0.001), temporal tumour location (p =
0.001), increased tumour height (p = 0.01), and older age (p < 0.01).
After plaque brachytherapy for uveal melanoma, ophthalmological follow up entails regular ocular examinations
and investigations for radiotherapy complications, which typically manifest 2-5 years after primary treatment.
Tumour regression is recorded with serial ocular ultrasound and dilated fundus examination with visits to the
respective Ocular Oncology service, especially in the first and second year after completing primary treatment.
Tumour regression rates are variable (Shields, Shields et al. 1998). Kivela and associates were unable to correlate
time to 25% or 50% reduction in tumour size following ruthenium plaque brachytherapy with time to metastatic
disease (Rashid and Kivela 2012). Therefore, it appears that tumour response to brachytherapy cannot be relied
upon with certainty as a prognostic indicator.
Iodine-125
I-125 episcleral plaque therapy is an effective, low morbidity treatment for medium and small sized but rapidly
growing choroidal melanomas (Vullaganti, DeVilliers et al. 2011) (Badiyan, Rao et al. 2012) It circumvents an
intraocular procedure and provides a margin of safety in the treatment of clinically undetectable disease). . It is
a safe and effective alternative to enucleation with regard to survival and local tumour control (Badiyan, Rao et
al. 2012) and provides a fair chance of preserving the eye with acceptable cosmesis and a reasonable chance of
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conserving useful vision for 1 to 2 years in these patients with large choroidal melanomas. (Puusaari, Heikkonen
et al. 2003, Krohn, Monge et al. 2008).
The use of brachytherapy to treat choroidal melanoma is heavily influenced by evidence from COMS. There were
three main trial arms:
1. The COMS "Small" study: No RCT exists for small uveal melanoma, the publications from this group for small
uveal melanoma were from observations only. 204 patients with small choroidal melanomas (height 1-3 mm,
diameter more than 5mm) were prospectively observed. This study showed that with prospective follow-up,
overall survival was comparable to the general population (COMS report No 4 and 5) (Hawkins and Melia 1997,
Melia, Diener et al. 1997).
2. The COMS "Medium" randomized trial: 1317 patients with medium tumours (height 2.5-10.0mm and
diameter <=16 mm) were randomized to either treatment with I-125 plaque brachytherapy (85 Gy) or
enucleation. The overall survival and risk of death from metastatic disease were comparable between the two
groups, thus establishing plaque brachytherapy as a reasonable primary treatment for choroidal melanomas. At
5, 10 and 12 years, the mortality rates for patients treated with brachytherapy were 10%, 18% and 21% and for
patients treated with enucleation, they were 11%, 17% and 17% respectively (COMS report 16,17,18, 28)
(Diener-West, Earle et al. 2001, Hawkins, Vine et al. 2001, Hawkins 2001, Melia, Abramson et al. 2001, Hawkins
2006).
3. The COMS “Large” randomized trial: 1003 patients with large tumours (height >=10 mm or diameter >=16
mm) were randomized to pre-enucleation external beam radiation therapy (EBRT) 20/5 or enucleation only
without EBRT. This study showed that pre-enucleation radiotherapy does not provide any additional benefit
(COMS report 9, 10, 11, 15, 24) (Schachat 1998, Willson, Albert et al. 2001, Hawkins 2004).
Treatment dose and parameters:
The American Brachytherapy Society recommends a minimum tumour I-125 dose of 85 Gy at a dose rate of 0.601.05 Gy/h. It has been shown that treatment of choroidal melanomas less than 5mm in apical height with I-125
brachytherapy to the true apical height is equally effective when compared to treatment with 85Gy to 5.0mm
(as performed in the COMS trial) and has a lower incidence of radiation-related complications (Vullaganti,
DeVilliers et al. 2011, Murray, Markoe et al. 2013).
Local control:
I-125 brachytherapy is effective in tumour control in 92-97%, allowing preservation of the eye and useful visual
function for the majority of patients. (Jensen, Petersen et al. 2005, Garcia-Alvarez, Saornil et al. 2012). It allows
for safe and effective therapy in patients with ocular melanoma of various sizes depending on location
(Fontanesi, Meyer et al. 1993).
Anterior location: The use of 125I plaque brachytherapy to treat melanomas situated anterior to the equator
allows good local and systemic control with a low rate of macular and optic disc complications. The most
frequent complication is cataract formation. (Lumbroso, Charif et al. 2004). Shields et al. have shown that better
visual outcomes are seen after plaque radiotherapy for choroidal melanoma in younger patients with small
tumours at sites remote from the optic disc and foveola (Shields, Shields et al. 2000).
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Juxtapapillary location: Sagoo et al demonstrated that juxtapapillary choroidal melanoma can be treated with
brachytherapy with 80% tumour control at 10 years and adjuvant TTT did not add to the success rate (Sagoo,
Shields et al. 2011). Slotted or notched plaques can be used for tumours within 1.5 mm, touching or surrounding
the optic disc. Krema et al showed that both I-125 brachytherapy and stereotactic radiotherapy demonstrate
comparable efficacy in the management of juxtapapillary choroidal melanoma. Stereotactic radiotherapy (see
section 4.6.3) showed statistically significantly higher radiation-induced ocular morbidities at 4 years postradiotherapy but I-125 had higher recurrence rate (11% compared to 7%) (Krema, Heydarian et al. 2013),
(Krema, Heydarian et al. 2013).
Melanomas with extraocular extension: Small and medium-sized ciliary body and choroidal melanoma with
clinically visible extraocular extension less than 3 mm in thickness can, in selected cases, be treated successfully
with plaque radiotherapy (Gunduz, Shields et al. 2000).
Melanomas with thickness between 5-7 mm: The management of choroidal melanoma with a thickness of 5-7
mm is controversial. Iodine seems to provide higher local tumour control, while ruthenium induces less radiation
complications. I-125 may represent a better option in this subgroup of tumours, especially for preventing
metastatic disease (Tagliaferri, Smaniotto et al. 2012).
Treatment failure:
There is a low risk of local treatment failure or secondary enucleation after definitive I-125 brachytherapy for
choroidal melanoma. Jampol et al have shown the risk factors for local recurrence include older age at time of
treatment, greater apical height, and proximity to the foveal avascular zone (Jampol, Moy et al. 2002). Char et
al have also shown that late recurrence is possible five or more years later in patients treated with radioactive
plaque (Char, Kroll et al. 2002) Risk factors for enucleation following I-125 plaque radiotherapy in these studies
included: male gender; greater apical height of the tumour; longer basal dimension; poorer visual acuity in the
tumour-containing eye at baseline; collar-button tumour shape; presence of retinal detachment over the
tumour; lower radiation dose to the tumour apex; and higher dose to the sclera. In patients with large posterior
uveal melanomas (> or =8-mm thick) the rate of enucleation was 24% at 5 years and 34% at 10 years (Shields,
Naseripour et al. 2002).
Visual loss after I-125 brachytherapy:
The COMS report number 16 showed that the visual acuity during the first 3 years after I-125 plaque
radiotherapy for choroidal melanoma declined on average at a rate of approximately two lines per year (Melia,
Abramson et al. 2001): 49% of patients had substantial loss of visual acuity at 3 years. High risk characteristics
for visual loss were: tumour height >5.0 mm; distance between tumour and foveal avascular zone <2.0 mm;
diabetes; non–dome-shaped tumour; and presence of tumour-associated retinal detachment. In patients with
large posterior uveal melanomas (> or =8-mm thick), Shields et al. have shown the most important risk factors
for poor visual acuity include retinal invasion by melanoma, increasing patient age, use of I- 125 isotope, and <2
mm distance to the optic disc (Shields, Shields et al. 2000).
A study from New Zealand showed that a high percentage of patients retaining mobility vision following I-125
brachytherapy (>6/12 in 35% patients and >6/60 in 51% patients) (Stack, Elder et al. 2005).
Radiation retinopathy, neuropathy and cataract:
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Radiation retinopathy and cataract formation are common toxicities 3 years following I-125 plaque
brachytherapy for medium-sized choroidal melanomas (COMS criteria)(Badiyan, Rao et al. 2013). Three-year
rates of radiation retinopathy, radiation papillopathy, and exudative retinal detachment were 45%, 14%, and
10%, respectively. The 3-year rates of cystoid macular oedema, vitreous haemorrhage, and enucleation due to
radiation toxicity were 17%, 12%, and 4% respectively. The risks of anterior segment complications were much
higher in patients treated for large melanomas (COMS criteria). In these patients the 5-year rates of cataract
formation, neovascularization of the iris and NVG were 69%, 62% and 60%, respectively (Puusaari, Heikkonen et
al. 2004).
Development of complications was related to the tumour location and dose to non-tumour structures. A dose
of more than 90 Gy to the macula gave a 63% chance of developing maculopathy (P < 0.01). A tumour larger
than 4 mm significantly increased the risk of developing radiation maculopathy. Development of radiation
cataract was also dose-related; >25 Gy to the lens gave a 44% risk of cataract development (P < 0.001). For
tumours less than 4 mm from the disc margin there was a 50% risk of optic neuropathy (Stack, Elder et al. 2005).
Bianciotto et al showed that proliferative radiation retinopathy developed in 7% of eyes by 10 years after I-125
plaque radiotherapy for uveal melanoma. The main factors for development of proliferative radiation
retinopathy included young age, pre-existent diabetes mellitus and shorter tumour distance to the optic disc
(Bianciotto, Shields et al. 2010). The use of bevacizumab has reduced the need for enucleation due to I-125
radiation toxicity (Badiyan, Rao et al. 2013). Treatment modalities for radiation retinopathy include intravitreal
injections of triamcinolone and bevacizumab, laser photocoagulation, hyperbaric oxygen treatment,
photodynamic therapy and oral pentoxyphylline.
Metastasis risk:
The risk of metastasis was found to be 10% at 5 years and 27% at 10 years in a study of patients treated with I125 (1163) In patients treated for large posterior melanomas (> or =8-mm thick), the tumour-related metastases
rate was 30% at 5 years and 55% at 10 years (Shields, Naseripour et al. 2002).
Other factors influencing choice of brachytherapy:
The COMS report number 3 looked at quality of life after I-125 brachytherapy or enucleation for choroidal
melanoma. Patients treated with brachytherapy reported significantly better visual function than patients
treated with enucleation with respect to driving and peripheral vision for up to 2 years following treatment. This
difference diminished by 3 to 5 years post-treatment, paralleling the decline in visual acuity in brachytherapytreated eyes. Patients treated with brachytherapy were more likely to have symptoms of anxiety during followup than patients treated with enucleation. Given that no significant differences in survival between enucleation
and brachytherapy have been found, the differences demonstrated here for driving and anxiety will allow the
individual patient and physician to make informed choices regarding treatment based on personal preferences
(Melia, Moy et al. 2006).
Compared to ruthenium plaque treatment, the cost price of iodine treatment is much higher owing to the
requirement for frequent replacement of the iodine grains due to a short half-life of 60 days in comparison with
the 374 day half-life of ruthenium (Ru-106). The deeper penetration of the γ rays of I-125 (compared to β-rays
of Ru-106) allows treatment of larger and thicker tumours (up to 10mm height by I-126 compared to up to 57mm height by Ru-106), but at the cost of causing more radiation damage to healthy surrounding tissues, hence
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optic neuropathy, maculopathy, and visual loss. Successful use of other isotopes, such as palladium, has been
demonstrated by Finger et al, and others (Shields, Cater et al. 2002, Finger, Chin et al. 2009).
4.3.3.3. Stereotactic radiosurgery
Stereotactic radiosurgery (SRS) usually consists of a single-session delivery of ionizing radiation to a
stereotactically localized volume of tissue. Certain centres use fractionated SRS for uveal melanoma (Muller,
Naus et al. 2012).
The patient receives standard retrobulbar anaesthesia to prevent globe movement during SRS. Based on the
MRI, the target volume for each patient’s tumour is identified stereotactically and the radiation parameters are
calculated. A stereotactic frame is attached to the skull for the treatment and the entire treatment is completed
in a matter of hours. Advantages of this procedure are that it is minimally invasive (needing only local
anaesthesia); it is particularly useful in patients unfit for general anaesthesia as it does not involve any surgery;
and is performed as an outpatient.
SRS is particularly useful in juxtapapillary choroidal melanomas (Zorlu, Selek et al. 2009, Al-Wassia, Dal Pra et al.
2011) and those tumours not suitable for ruthenium plaque therapy. Dunavoelgyi et al (Dunavoelgyi, Dieckmann
et al. 2011) have demonstrated an excellent local tumour control rate of 95.9% after 5 years and 92.6% after 10
years in patients with uveal melanoma treated with SRS.
In the UK, SRS has been used for the treatment of ocular melanomas since the 1990s at the Sheffield Ocular
Oncology Centre. In 1996, Rennie et al. published their initial experience in the use of SRS (Rennie, Forster et al.
1996). The initial use of a high isodose at 70Gy was found to be effective but associated with a high incidence of
radiation related adverse reactions. Reducing the isodose from 70 Gy to 35 Gy led to a dramatic decrease in
complications, vision loss and salvage enucleation, whilst not compromising patient survival. Cohen et al (Cohen,
Carter et al. 2003) have shown that the metastasis-free survival after SRS was comparable to that after
enucleation in patients treated at Sheffield (74% in the stereotactic treatment group versus 51% in the
enucleation treatment group at 5-years, with no significant difference after multi-variant analysis). A
retrospective analysis comparing the outcomes of patients from Sheffield treated with SRS versus proton beam
is currently under way.
In centrally-located choroidal melanomas, Dunavoelgyi et al demonstrated that hypo-fractionated SRS showed
a low to moderate rate of adverse long-term side effects comparable to those after PBR. Future fractionation
regimens should seek to further reduce adverse side effects rate while maintaining excellent local tumour
control. Suesskind et al (Suesskind, Scheiderbauer et al. 2013) found that SRS combined with tumour resection
might be associated with increased tumour control and fewer radiation complications than SRS alone as
monotherapy. However, the protocol was stopped after 3 unexplainable deaths following tumour resection
surgery.
Modorati et al (Modorati, Miserocchi et al. 2009), in a 12-year study from Italy have demonstrated a survival
rate with SRS of 81.9% at 5 years. The median tumour thickness reduction after treatment was 1.96 mm (-32.1%).
The most frequent treatment-related complications were: exudative retinopathy (33.3%), NVG (18.7%),
radiogenic retinopathy (13.5%) and vitreous haemorrhages (10.4%). A reduction of visual acuity was observed
but the eye was retained in 90% patients, and the authors concluded SRS should be considered as an alternative
to enucleation surgery. Chabert et al (Chabert, Velikay-Parel et al. 2004) demonstrated no difference in quality
of life scores between plaque brachytherapy and SRS for the treatment of uveal melanoma.
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4.3.3.4. Proton beam radiotherapy
PBR offers a more targeted delivery of radiation compared to conventional external beam radiotherapy. This
precision is achieved by the highly collimated beams with their destructive ionising radiation peaking at the
depth where the charged particles stop travelling (the Bragg peak), hence it targets the discrete area with limited
damage to surrounding tissues. The treatment dose prescribed is fractionated, typically four sessions are
required and treatment is completed in one week. Treatment planning (simulation) is an important aspect of
proton beam radiotherapy that must be performed several weeks ahead. Tantalum markers are sutured to the
eye and intraoperative measurements are taken so that the tumour position and shape can be recorded. An
ocular X-ray reveals the location of the tantalum markers. Detailed ultrasound measurements of tumour height
are required for accurate modification of the proton beam. PBR is custom-designed for each individual patient
with uveal melanoma.
Protons achieve high rates of local tumour control in patients considered unsuitable for other forms of
conservative treatment. Multiple studies are consistent in demonstrating this high rate of local control of PBR:
between 87% and 96% at 5 years (Damato, Kacperek et al. 2005, Dendale, Lumbroso-Le Rouic et al. 2006, Aziz,
Taylor et al. 2009, Caujolle, Mammar et al. 2010), and between 92.1%-96.8%% at 10 years (Mosci, Polizzi et al.
2001, Damato, Kacperek et al. 2005, Caujolle, Mammar et al. 2010). There is only one publication to date
comparing local tumour control following PBR, ruthenium and iodine plaque brachytherapy. Wilson et al
reported that patients treated with ruthenium plaque brachytherapy had significantly greater risk of local
tumour recurrence than did those patients treated with either 125-Iodine plaque brachytherapy (P = 0.0133;
confidence interval [CI], 1.26-7.02; risk ratio, 2.97) or proton beam radiotherapy (P = 0.0097; CI, 1.30-6.66; risk
ratio, 2.94) (Wilson and Hungerford 1999). There was no significant difference in tumour control between PBR
and 125- Iodine plaque brachytherapy. Risk factors for failure of local tumour control following PBR were
identified as a reduction of the safety margin, large tumours infiltrating the ciliary body, the presence of an
eyelid within the irradiation field, inadequate delimitation of the tumour border by tantalum clips, and male
gender (Egger, Schalenbourg et al. 2001).
Metastasis-free survival after PBR was 88.3% at 5 years and 76.4% at 10 years (Caujolle, Mammar et al. 2010),
(Damato, Kacperek et al. 2005). Similarly, Dendale et al (Dendale, Lumbroso-Le Rouic et al. 2006) showed 5year overall survival and metastasis-free survival rates were 79% and 80.6% respectively. When considering
patients with large choroidal melanoma, there was no significant difference between enucleation or PBR for
cumulative all-cause mortality, melanoma-related mortality and metastasis-free survival (log-rank test, p = 0.56,
p = 0.99 and p = 0.25, respectively) (Mosci, Lanza et al. 2012).
Another survival study on the relative rates of metastatic death, cancer death, and all-cause mortality between
enucleation and PBR revealed a statistically significant survival benefit in the PBR group in the first two years of
treatment. However, by the sixth year the survival benefit was not maintained. Results suggest that treatment
choice has little overall influence on survival in patients with uveal melanoma (Seddon, Gragoudas et al. 1990).
4.3.3.5. Complications of Proton Beam Radiotherapy (PBR)
One early main complication after PBR is intraocular inflammation. Lumbroso et al (Lumbroso, Desjardins et al.
2001) found 28% of patients developed ocular inflammation. Inflammation following PBR is not unusual, but is
usually limited to mild anterior uveitis, which rapidly resolves with topical steroids and cycloplegics. It is
correlated with larger initial tumours (tumour height and irradiation of a large volume of the eye) and may be
related to an exudative retinal detachment and tumour necrosis, both of which in turn are thought to lead to an
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associated release of cytokines and neovascular glaucoma (NVG) (termed, ‘toxic tumour syndrome’). The good
local control results are tempered somewhat by the appreciable ocular morbidity, which may necessitate
removal of the eye (secondary enucleation) usually as a result of NVG. Secondary enucleation rates following
PBR correlate strongly with tumour size (Foss, Whelehan et al. 1997, Damato, Kacperek et al. 2005). The overall
eye retention rate in 2648 uveal melanoma patients (tumour diameter 4mm-27.5 mm and tumour height 0.915.6 mm) treated with proton beam radiotherapy was 88.9% at 5 years, 86.2% at 10 years and 83.7% at 15 years
(Egger, Zografos et al. 2003). After optimization of the technique, retention rates at 5 years increased from
97.1% to 100% for small tumours, from 86.7% to 99.7% for medium, and from 71.1% to 89.5% for large tumours
(Egger, Zografos et al. 2003). Similar rates from Scotland were reported for ciliary body and choroidal
melanomas, where proton beam treatment is mainly used in the treatment of medium and large uveal
melanomas. Of the 147 patients identified, 22.4% required enucleation (Macdonald, Cauchi et al. 2011). Mean
time to enucleation was 23.8 months and the main reasons were suspected recurrence (48%) and NVG (42%).
The actuarial 5-year eye retention rate was 71.3% (Macdonald, Cauchi et al. 2011). In a larger study of 1406
patients with uveal melanoma treated by proton beam radiotherapy, the 5-year enucleation rate for
complications was 7.7%, the main indication being NVG. Independent prognostic factors for enucleation for
complications of PBR were tumour thickness (p < 0.0001) and lens volume receiving at least 30 Cobalt Gray
Equivalent (CGE)(p = 0.0002) (Dendale, Lumbroso-Le Rouic et al. 2006). Foss et al demonstrated that the
presence of retinal detachment and large tumour dimensions, i.e., those tumours too large to be treated by
ruthenium plaque, are important risk factors in predicting NVG (Foss, Whelehan et al. 1997). If both are present
the risk of NVG at 4 years is 88%, if one is present the risk is 37% and, if neither are present, there was no risk of
developing NVG.
An alternate to enucleation in the event of ‘toxic tumour syndrome’ development following PBR secondary
include local resection and endoresection (Cassoux, Cayette et al. 2013); (Konstantinidis, Groenewald et al.
2014); (McCannel 2013). These procedures have been introduced recently by a few ocular oncology centres with
good effect.
Prognosis for vision is less positive: 18.5% of patients had vision less than 3/60 pre-treatment, compared to 74%
post-irradiation (p < 0.0001) (Aziz, Taylor et al. 2009). Preservation of acuity is influenced by the stage of the
tumour. Results from Genoa show that visual acuity better than 2/10 was 30% in T1 and T2 tumours, and 21%
in T3 tumours (Mosci, Polizzi et al. 2001). An early report on 538 patients treated with high energy proton beam
showed one-third of patients with adequately scored visual acuity pre- and post-treatment had stable, if not
improved vision, and half the patients retained useful vision post-treatment, despite two-thirds having posterior
pole tumours (Courdi, Caujolle et al. 1999, Mosci, Polizzi et al. 2001). In Liverpool, of 349 patients with choroidal
melanoma treated with PBR, 79.1% had post-treatment vision of counting fingers or better, 61.1% had vision of
20/200 or better and 44.8% achieved 20/40 or better. Visual loss can be unpredictable due to toxic tumour
syndrome (Damato, Kacperek et al. 2005). Progressive visual field deficits have also been reported following
PBR for parapapillary choroidal melanoma, and not unexpectedly, the scotoma usually correlates with the area
of the retina exposed to irradiation (Park, Walsh et al. 1996).
A systematic review and meta-analysis of PBR concluded that a strong recommendation favouring PBR above
enucleation or plaque brachytherapy could not be made from the currently published evidence (Wang, Nabhan
et al. 2013). The overall quality of the evidence was low (Wang, Nabhan et al. 2013). Other important factors
need to be considered for comparative effectiveness decisions. Patients’ opinions and preferences should
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heavily influence the decision, including their feelings about enucleation, their willingness to try a therapy
without extensive prospective outcome data (PBR), their willingness to travel to tertiary care centres, and in
some cases their financial and other resources. In Europe, the availability of PBR is currently limited to a few
tertiary care centres.
4.3.3.6. Transpupillary thermotherapy
Transpupillary thermotherapy (TTT) is another method of treating uveal melanoma. The heat from a laser
induces ischaemia, free radical damage and tumour necrosis. The treatment is delivered in the clinic using a
modified infrared diode
laser at 810 nm with an adjustable beam width of 1.2 mm, 2.0 mm and 3.0 mm. The
infrared delivery system is adapted to a slit-lamp biomicroscope and delivered through a contact lens. The end
point of treatment is a colour change in the tumour, and this is best seen at the first treatment of a pigmented
uveal melanoma. Intravenous indocyanine green can be given just before TTT to increase the laser energy uptake
by amelanotic uveal melanoma (Sagoo, Shields et al. 2011).Intravenous indocyanine green administration
before TTT does not alter the tumour regression pattern (De Potter and Jamart 2003). Several treatment
sessions are required to achieve total tumour destruction (Kociecki, Pecold et al. 2002).
TTT has been used as primary treatment for small uveal melanoma with some success. Shields et al reported
4% recurrence at 1 year, 12% at
2 years, and 22% at 3 years (Shields, Shields et al. 2002). Of serious concern is
that there have been accounts of extraocular extension following primary TTT (Shields, Shields et al. 2002). It is
vital therefore that tumours are carefully selected for this primary treatment. The following maximum cut off
values for selecting tumours for primary TTT have been recommended: tumour height not greater than 3.0 mm,
basal diameter not greater than 10 mm and maximum systolic velocity of the tumour on Doppler ultrasound not
greater than 11.7 cm/s (Yarovoy, Magaramov et al. 2010). Other risk factors for local recurrence include
amelanotic pigmentation, presence of subretinal fluid, tumours abutting or overhanging the optic disc, tumour
requiring more than 3 sessions of TTT and incomplete regression following primary TTT (Shields, Shields et al.
2002, Parrozzani, Boccassini et al. 2009, Yarovoy, Magaramov et al. 2010).
Transpupillary thermotherapy can cause damaging effects to the retina, leading to visual loss shortly
after
treatment. Shields et al. reported visual outcomes in their first 100 cases (Sagoo, Shields et al. 2011).The visual
acuity was worse in 42 eyes (42%). The main reason for poor vision was treatment of a subfoveal tumour with
induction of a visual scotoma in the treated area (Kociecki, Pecold et al. 2002). Retinal traction was seen in 10%
of cases. It was most frequently associated with treatment of uveal melanoma distal and temporal to the optic
disc (Shields et al 2011). Other visual threatening complications include macular pucker 11%, macular oedema
4%, vitreous haemorrhage 3%, vein occlusion 8%, exudative retinal detachment and NVG in 3% (Kociecki, Pecold
et al. 2002, Parrozzani, Boccassini et al. 2009).
The concern about poor local control rates and extraocular recurrence with primary TTT led researchers to
suspect that the depth of penetration of the diode laser was insufficient to treat the majority of uveal
melanomas. Deeper tumour necrosis at the base of the uveal melanoma was more likely to be achieved with
simultaneous plaque radiotherapy (Kociecki, Pecold et al. 2002). Hence in centres where TTT is used, it is used
in conjunction with plaque brachytherapy, known as ’sandwich‘ therapy to improve local tumour control
(Gragoudas, Li et al. 2002); (Shields, Cater et al. 2002). 5-year recurrence rates as low as 3% have been achieved
using ’sandwich‘ therapy (Gragoudas, Li et al. 2002), (Shields, Cater et al. 2002). This combination treatment
appears to provide better 5-year local tumour control (96% versus 83% p=<0.034), a better globe preservation
(98% versus 87% p=<0.024) and recurrence free survival rate (89% versus 67% p=<0.017) than ruthenium plaque
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brachytherapy alone in medium sized tumours (COMs criteria) (Yarovoy, Magaramov et al. 2012). There was no
difference in overall patient survival/metastatic rate (Yarovoy, Magaramov et al. 2012). TTT is widely used to
manage radiotherapy complications such as ‘toxic tumour syndrome’ (see above under 4.3.3.5) and local tumour
recurrence (Yarovoy, Magaramov et al. 2012). When early plaque brachytherapy-related vision loss is accounted
for, the addition of TTT did not result in significantly worse visual acuity (Drury, Chidgey et al. 2012). However
at 1 and 4 years follow up, the visual outcome was worse in patients who had received ’sandwich‘ therapy
compared to those who had received plaque brachytherapy alone (Drury, Chidgey et al. 2012). Adjuvant TTT
did not improve the local tumour control of juxtapapillary uveal melanoma treated by Iodine-125 plaque
brachytherapy (Sagoo, Shields et al. 2011).
TTT has also been used in conjunction with PBR: in a randomized study of 151 patients, PBR was combined with
TTT for the treatment of large uveal melanomas (Desjardins, Lumbroso-Le Rouic et al. 2006). Patients who
received adjuvant TTT had a significantly lower risk of secondary enucleation (p=0.02) and had a more marked
reduction in tumour thickness (p=0.06). No statistically significant difference was observed between the 2
groups in terms of cataracts, maculopathy, papillopathy and glaucoma.
4.3.3.7. Exoresection
Exoresection (also termed ‘local resection’ or ‘choroidectomy’) involves removal of the tumour ‘en bloc’ through
a large sclera opening. Previously, full-thickness sclera excision was advocated but this has been replaced by
methods using a lamellar sclera flap to close the eye. Exoresection of choroidal melanomas is a difficult
procedure, demanding considerable surgical experience. Furthermore, it requires significant systemic
hypotension to control haemorrhage. For these reasons, this operation is performed by only a very few surgeons
around the world. Exoresection of small, ciliary body tumours (cyclectomy) is less difficult and is therefore
undertaken more widely. Exoresection of iris melanomas (iridectomy) is in turn easier than either of the above
procedures, but is increasingly being replaced by radiotherapy (e.g. PBR and ruthenium plaques; see below).
The largest exoresection series reported to date was published by Damato et al over 20 years ago (Damato, Paul
et al. 1993). In 163 completed resections, the tumours had a mean diameter of 13.3 mm and a mean thickness
of 7.4 mm, with 38 tumours extending to within 1 disc diameter (DD) of the optic disc, fovea or both. Cox
multivariate analysis showed that the most significant preoperative factors for predicting retention of good
vision (6/12 or better) were nasal tumour location (p = 0.002) and distance of more than 1 DD between the
tumour and the optic disc or fovea (p = 0.010). The most significant predictive risk factor for severe visual loss
(hand movements or worse) was posterior tumour extension to within 1 DD of the optic disc and/or fovea (p =
0.009). One year post-operatively, all 28 patients with medial tumours not extending to within 1 DD of the optic
disc or fovea retained the eye with 57% having vision of 6/12 or better and 93% having vision of counting fingers
or better. In 68 patients with lateral tumours, 90% retained the eye at 1 year with preservation of vision of
counting fingers or better in 82% of 56 eyes without posterior tumours extension and in 50% of 12 eyes with
posterior tumour extension (Damato et al 1993). There were 24 patients (14%) with residual tumour in this
cohort. Forward stepwise logistic regression analysis indicated that posterior extension to within 1 DD of the
optic disc or fovea was the sole best indicator of the risk of residual disease (p < 0.001). After excluding these
cases, 286 patients were studied for the development of delayed local recurrence, which occurred in 57 cases.
Forward stepwise multivariate analysis showed statistically significant predictors for recurrent tumour to be
epithelioid cellularity (p = 0.002), posterior tumour extension to < 1 disc diameter of disc of fovea (p = 0.002),
large tumour diameter > or = 16 mm (p = 0.019) and lack of adjunctive plaque radiotherapy (p = 0.018) (Damato,
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Paul et al. 1996). Rhegmatogenous retinal detachment occurred in 28 (18%) eyes and was significantly more
common in patients with thick tumours (Cox univariate analysis, P = 0.001) and in males (Cox univariate analysis,
P = 0.013), with posterior tumour extension being of borderline significance (Cox univariate analysis, P = 0.069).
Surgical treatment of the retinal detachment was performed in 25 patients. Anatomic success was achieved in
21 (84%) of these 25 patients, with 7 patients retaining counting fingers vision, and 3 seeing 6/60 or better. Ten
eyes treated for retinal detachment were enucleated because of recurrent tumour (four eyes), retinal
detachment (three eyes), wound dehiscence (one eye), phthisis (one eye), and poor visual acuity (one eye).
Eleven eyes known to have a retinal tear underwent prophylactic vitreoretinal surgery at the end of the local
resection, with only one (9%) of these subsequently developing retinal detachment (Damato, Groenewald et al.
2002).
Technical improvements have occurred more recently (Damato 2012, Damato 2012). Techniques have been
developed for conserving the integrity of the ciliary epithelium over the pars plana and for ‘top-slicing’ tumour
adherent to retina, dramatically reducing rates of retinal detachment (Damato 2012, Damato 2012). Rates of
local tumour control have improved greatly, as a result of adjunctive brachytherapy with a 25 mm ruthenium
plaque in all cases (Damato 1997). Such routine adjunctive brachytherapy has reduced the need for wide surgical
margins. These measures have significantly improved ocular outcomes, particularly conservation of vision
(Damato 1997). Outcomes of local resection of uveal melanoma depend greatly on the experience of the
surgeon and on the anaesthetist’s ability to provide profound hypotensive anaesthesia.
Even with earlier resection techniques, various authors have shown that with large uveal melanomas, the results
of local resection are superior to those achieved with radiotherapy (Shields, Cater et al. 2002, Shields, Naseripour
et al. 2002, Puusaari, Damato et al. 2007, Bechrakis, Petousis et al. 2010).
4.3.3.8. Endoresection
With endoresection, the choroidal melanoma is removed piecemeal, using a vitreous cutter. This is done either
through a retinotomy over the tumour or after raising a retinal flap. The technique is evolving, with advances
such as bimanual surgery and the use of heavy liquids. Endolaser treatment is applied to destroy any residual
tumour and to achieve retinopexy. The eye is filled with silicone, which is removed after twelve weeks.
Adjunctive radiotherapy can be applied, either in all patients or if histology and genetic studies indicate that the
tumour is aggressive. Some centres perform endoresection only after neo-adjuvant radiotherapy, because of
concerns about iatrogenic tumour seeding (Bechrakis and Foerster 2006, Schilling, Bornfeld et al. 2006).
In a series of 52 endoresections by Damato, the tumours had a mean largest basal diameter of 8.2 mm and a
mean tumour thickness of 3.9 mm (Damato, Groenewald et al. 1998). Forty tumours extended to within 2 disc
diameters of the optic disc, with 17 involving the disc. Follow-up ranged from 40 days to 7 years (median 20
months). At the last visit, 90% of eyes were retained, with vision of 6/6-6/12 (two), 6/18-6/36 (three), 6/60 to
counting fingers (18), hand movements (nine), and light perception (four). The main complications were retinal
detachment in 16 and cataract in 25 patients. Secondary endoresection (n=11) was performed after plaque
radiotherapy (four), photocoagulation (four), trans-scleral local resection (two), and PBR (one), with retention
of the eye in nine cases. By the close of the study, no patients developed definite local tumour recurrence but
one died of metastatic disease 41 months postoperatively. The Liverpool Ocular Oncology Centre experience in
local resection of an additional 71 patients is reported in a recent publication (Konstantinidis, Groenewald et al.
2014).
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The only other major series is that reported by Garcia et al in 2008 (Garcia-Arumi, Zapata et al. 2008). In a series
of 38 patients, the authors reported outcomes after a follow-up time ranging from 23 to 129 months (mean
70.63 months). Preoperative visual acuity ranged from ’hand-movements‘ to 20/20 (mean, 20/60). In primary
cases, mean tumour thickness was 10.1 mm and mean base diameter 9.9 mm. At the latest visit, 92.1% patients
still retained the eye. Final visual acuity ranged from ’no light perception‘to 20/30 (mean 20/300). Two patients
experienced local recurrence before 3 years of follow-up. Metastatic disease was found in two patients at 5
years of follow-up. Kaplan-Meier survival analysis for all causes was 88.2% at 5 years. Specific survival was 90.9%
at 5 years.
4.3.3.9. Treatment of Iris Melanoma
These tumours have the best survival outcomes, if the ciliary body is not involved the 10-year survival data is
close to 100%. Nevertheless, treatment is still recommended as an enlarging iris tumour will produce ocular
complications.
Resection of small iris tumours is a very successful treatment option especially if there is no ciliary body
involvement. Iris sector defects can result in visual side effects such as photophobia, glare and halo formation
around lights, which make night driving difficult. Pupilloplasty (i.e. reconstruction of the iris) can be performed
to minimise this problem. PBR has been used but in this subgroup of patients the eye retention rates are worse
than for ciliary body or choroidal melanoma. In a recent review of 15 cases, eye retention following PBR was
80% (Rundle, Singh et al. 2007). 53% of patients with iris melanomas following proton beam treatment had
glaucoma, although this was a pre-existing condition in 33% of the original group of 15 patients (Rundle, Singh
et al. 2007). Damato et al reported complication rates from a larger series of 88 patients with iris melanomas.
Glaucoma was present before treatment in 13 patients and developed after treatment in another 3, and in
several patients it was difficult to control (Damato, Kacperek et al. 2005). Post-irradiation cataract is a common
although treatable complication following PBR of iris melanoma. Lumbroso et al found 45% of these patients
developed cataract within 24 months of treatment (Lumbroso-Le Rouic, Delacroix et al. 2006). In another series
of 78 iris melanomas treated by PBR, 51% developed cataract (8873). Both Damato et al (Damato, Kacperek et
al. 2005) and Rundle et al (Rundle, Singh et al. 2007) found 20% of patients developed cataract following proton
beam irradiation for iris melanomas, and the latter group also reported 27% of patients developed dry eye.
Ruthenium plaque brachytherapy resulted in 100% tumour control in a series of 15 pure iris melanomas from
London with a long median follow-up of 96 months (Tsimpida, Hungerford et al. 2011). The eye retention rate
was also 100%, as no cases of NVG were reported. Like PBR cataract was reported in 60% and dry eyes were
seen in 20% of patients. Slightly higher rates of cataract formation have been recorded following Iodine plaque
brachytherapy.
4.4.
Evidence Statements
4.4.1. Pre-operative investigations
Uveal melanoma is a rare cancer and the combination of a multi-disciplinary skill set together with specialist
expertise is required. Level 4 - Government advice
Delay in referral results in more advanced disease at presentation and an increased likelihood that the patient
will require an enucleation. Level 3
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The diagnosis of uveal melanoma made using ophthalmoscopy, fundus photography and conventional ocular
ultrasound has an accuracy of 99% in medium sized to large melanomas. Level 1Conventional A and B scan ocular ultrasound is key to making the diagnosis. Level 3
Ocular Oncology Centres tend to have more experienced ocular ultrasonographers and better ultrasound
equipment. Level 4
The evidence for investigation with more recently developed diagnostic tools, based on comparative case series,
demonstrate that anterior segment OCT is useful for iris melanoma but is not superior to UBM when considering
ciliary body tumours. Level 3
UBM with a 50MHz probe is the best tool to image the ciliary body. Level 3
If the diagnosis is still uncertain then biopsy has a role. Level 3
Small indeterminate lesions may not yield sufficient cells to make a diagnosis especially if less than 2mm in
thickness. Level 2+
4.4.2. Staging before primary treatment
Tumour size at diagnosis is associated with incidence of metastasis and therefore can be used to aid
stratification. Level 2+
Knowledge of the presence of metastatic disease only affects management of the primary tumour when
considering enucleation of a painless asymptomatic eye. In this situation, it may be appropriate after careful
counselling of the patient to postpone primary treatment or to not perform the operation, to avoid needless
mutilation. Level 4
LFTs are highly specific but not sensitive in detecting metastatic disease. Level 2+
When evaluating biochemical markers of liver function combined GGT and ALP were the most helpful in
predicting patients with metastatic disease. Level 3
A rising trend in liver enzyme levels over time is more important than the absolute value, which may be within
the normal range. Level 2Abdominal ultrasound, abdominal CT and PET/CT have been used to stage uveal melanoma patients at the time
of diagnosis of the primary tumour. Level 2
Although there is evidence that MRI is the best imaging modality for assessing the volume and distribution of
liver metastatic disease once it has occurred (Level 2), no reports were found that evaluated the use of MRI to
stage uveal melanoma patients at diagnosis of the primary tumour.
4.4.3. Primary Treatment
Choice of primary treatment has not been demonstrated to have a significant impact upon patient survival in
uveal melanoma. Level 1
There was no significant difference for cumulative all-cause mortality, melanoma-related mortality and
metastasis-free survival (log-rank test, p = 0.56, p = 0.99 and p = 0.25, respectively) in patients with large
choroidal melanoma after primary treatment with enucleation compared to PBR. Level 2+
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Five-year local control rates of over 95% have been reported for Ruthenium plaque brachytherapy. Level 2Risk factors for local recurrence/poor tumour control include large basal diameter, anterior location, young
patient age and foveal location. Level 3
Visual complications of ruthenium plaque brachytherapy are less severe than those recorded from the collateral
damage of iodine plaque brachytherapy or PBR. Level 3
Visual deterioration, cataract and vitreous haemorrhage is associated with increasing tumour height following
brachytherapy, as these tumours require a higher dose of radiation to achieve tumour control. Level 3
Tumour response to brachytherapy may not be a reliable prognostic indicator. Level 3
There is a risk of later extraocular extension following primary TTT, particularly in larger tumours. Level 3
TTT used in conjunction with plaque brachytherapy, known as “sandwich” therapy, provides better 5-year local
tumour control (96% versus 83% p=<0.034), a better globe preservation (98% versus 87% p=<0.024) and
recurrence free survival rate (89% versus 67% p=<0.017) than ruthenium plaque brachytherapy alone in medium
sized tumours (COMS criteria) but there was no difference in overall patient survival/metastatic rate. Level 2+
At 1- and 4-years follow-up the visual outcome was worse in patients who had received ’sandwich‘ therapy
compared to those who had received plaque brachytherapy alone. Level 2+
In patients with tumour diameter ranging from 4 to 27.5 mm, and tumour height from 0.9 to 15.6 mm receiving
PBR, the overall eye retention rate post-treatment at 5 years was 88.9%, 86.2% at 10 years and 83.7% at 15
years. Level 3
Eye retention rates following PBR are lower for iris melanoma with a higher incidence of post-irradiation cataract
and NVG. Level 2
4.5. Recommendations
Refer to recommendations related to this chapter which in Section 1.2 by clicking HERE
4.6.
Linking evidence to recommendations
In formulating these recommendations, the GDG appraised the data where available. Where data were lacking,
the GDG considered how best to combine what data were available with data and experience from similar
situations in other oncological areas, as well as their own experience of managing the disease. The GDG did not
formally assess the cost of any of the recommendations as the focus of these guidelines is on the identification
of those clinical management changes that could be: a) clinically justified; and b) lead to improved health
outcomes. However, the GDG was generally aware that recommendations need to be practical if they are able
to result in a change of practice. An example was discussions regarding imaging technology to stage patients
presenting with ‘high risk’ primary uveal melanomas. Whilst we agreed that contrast-enhanced MRI is the
optimal modality for assessing the burden of metastatic liver disease, many centres perform an initial hepatic
assessment using USS performed by highly experienced operators and only progress to other modalities when
USS-detected abnormalities are seen. Whilst the GDG agreed that USS provides less accurate information
regarding disease burden than MRI, using it as an initial screening tool may be entirely reasonable if it has a low
false negative rate. USS also has major advantages regarding speed of assessment and cost, and without
evidence that patients were at a disservice by having an MRI scan only following an abnormal ultrasound, the
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GDG was unable to recommend MRI staging for all ‘high risk’ patients. This is an area that would benefit from
further investigation.
The GDG believes that our recommendations regarding patient access to information about options available at
each of the surgical centres, the development of a national uveal melanoma database, education of health care
professionals who are likely to detect primary uveal melanoma, and timely referral to medical oncology will
combine to significantly improve the quality of patient care.
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5. Prognostication
5.1. Introduction
Uveal melanoma can arise in the iris, ciliary body and the choroid, with the latter being the most common site.
Despite successful treatment of the primary tumours in most cases, approx. 40%-50% of patients will develop
disseminated disease, predominantly in the liver, but also in the lungs, bone and elsewhere. Early surgical
removal of metastases has improved patient survival in some cases (Frenkel, Nir et al. 2009, Mariani, Piperno et
al. 2009); however, in general, the prognosis of UM patients with metastatic disease is currently poor because
of the lack of effective systemic agents.
Several parameters have been identified in the literature, which have prognostic significance with varying
degrees of strength that predict metastasis and therefore survival in uveal melanoma patients. These can be
grouped into: a) clinical-; b) histomorphological-; c) immunohistochemical-; d) genetic; and e) serologicalfeatures (see references below). Some of these have been reviewed in depth by the AJCC TNM staging
committee and have been included into this staging system for prognostication purposes (Finger and The 7th
Edition AJCC-UICC Ophthalmic Oncology Task Force 2009, Kivela and Kujala 2013). Others have undergone
extensive analysis using large data sets, either as part of a one-centre or multicentre analysis either as single
parameters or in combination. Finally, other prognostic parameters noted in the literature have undergone less
robust evaluation and their true significance remains unclear. The purpose of the following Chapter is to review
the proposed prognostic parameters, determine whether there is a preferred prognostic tool and to suggest the
role for prognostic biopsy.
5.2. Methods
5.2.1. Questions addressed
The questions that the developer(s) aimed to address were:
Question
Population
Intervention
Comparator
Outcome
Is there a
preferred
prognostic tool?
• Patients with
diagnosed primary
uveal
melanoma
with and without
clinical evidence of
metastatic disease
Clinical variables
Histomorphological
features
Immunohistochemical
features
Genetic data
Serological markers
Each other
Survival
(hazard
ratio for prognostic
factors)
What is the role
of the prognostic
biopsy?
Patients with uveal
melanoma with and
without
clinical
evidence
of
metastatic disease
Intraocular biopsy
With no biopsy
Patient
surveys
and satisfaction
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5.2.2. Inclusion and exclusion criteria for selecting evidence
All papers regarding prognostic parameters predicting survival outcome described for primary uveal melanoma
were included. Preclinical and animal studies, in vitro cytogenetic markers and cell line studies, single centre
unvalidated series and single case reports were excluded.
5.2.3. Appraisal and extraction
Information from each of the investigation was extracted and presented to the Guideline Development Group
for discussion on July 10 2013, with an update of the evidence presented after the update search. Tables 1-4
show the papers that were reviewed. For full details of each of the included studies, see the evidence tables in
Appendix A.
All references were sifted initially by one individual, and grouped according to whether the prognostic
parameter(s) described was/were of the following types: a) clinical; b) histomorphological; c)
immunohistochemical; d) genetic; or e) serological. Where several or combinations of prognostic parameters
described, these were also evaluated. The primary reasons for excluding papers were that they did not address
the question. The reviewer appraised and reviewed the included papers, and the quality of the studies was
assessed using the SIGN checklists as a guide.
5.3. Review of Evidence
5.3.1. Is there a preferred prognostic tool?
When evaluating the literature with respect to this question, it became apparent that the definition of the word
’tool‘ had to be addressed. Ultimately, it was decided that the word ’tool‘ had several meanings but principally
referred to a ’method‘ or ’methods‘, including clinical, histomorphological, immunohistochemical, genetic,
serological and ‘combined’ methods, which had been applied to determine the prognosis of uveal melanoma
patients.
Clinical factors that have been consistently demonstrated in the literature to have strong statistical significance
when predicting the risk of metastasis (and therefore have a role in prognostication) include:
1.
Patient age (Seddon, Albert et al. 1983);.(Folberg, Rummelt et al. 1993, Hawkins 2006, Damato,
Duke et al. 2007, Virgili, Gatta et al. 2008, Shields, Furuta et al. 2009, Shields, Kaliki et al. 2013).
2.
Patient gender (Folberg, Rummelt et al. 1993, Virgili, Gatta et al. 2008, Damato and Coupland
2012).
3.
Tumour height (Diener-West, Hawkins et al. 1992, Shields, Furuta et al. 2009 , Shields, Kaliki et
al. 2013).
4.
Tumour basal diameter (Seddon, Albert et al. 1983 , Folberg, Rummelt et al. 1993, Hawkins
2006, Damato and Coupland 2009, Shields, Furuta et al. 2009, Kivela and Kujala 2013, Shields,
Kaliki et al. 2013).
5.
Tumour location – i.e. ciliary body involvement (Seddon, Albert et al. 1983, Damato and
Coupland 2009, Shields, Furuta et al. 2009, Kujala et al. 2013 , Kivela and Kujala 2013).
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6.
Presence and extent of extraocular melanoma growth (Seddon, Albert et al. 1983, Group 1998,
Coupland, Campbell et al. 2008, Kivela and Kujala 2013, Shields, Kaliki et al. 2013).
Most of these parameters have been included in the 7th Edition of the AJCC TNM staging system (Kivela
and Kujala 2013). http://www.springer.com/medicine/surgery/book/978-0-387-88440-0
Histomorphological factors shown in numerous papers to be prognostic significance comprise:
1.
Tumour cell type (McLean, Foster et al. 1982, McLean, Foster et al. 1983, Damato, Duke et al.
2007)
2.
Mitotic count (on haematoxylin staining only) (Folberg, Rummelt et al. 1993, Collaborative
Ocular Melanoma Study 2003 , Damato, Duke et al. 2007, Coupland and Damato 2009, Damato,
Dopierala et al. 2010).
3.
Mean diameter of ten largest nucleoli (McLean, Keefe et al. 1997, Al-Jamal and Kivela 2006,
Al-Jamal, Toivonen et al. 2010).
4.
Presence of extravascular matrix patterns, particularly ‘closed loops’ (Folberg, Rummelt et al.
1993, Rummelt, Folberg et al. 1995, McLean, Keefe et al. 1997, Damato, Duke et al. 2007).
5.
Microvascular density (Foss, Alexander et al. 1996, Schaling and Pauwels 1996, Lane, Egan et
al. 1997, Makitie, Summanen et al. 1999, Chen, Maniotis et al. 2002).
6.
Presence and size of extraocular melanoma growth (Seddon, Albert et al. 1983, Group 1998,
Coupland, Campbell et al. 2008, Kujala, Damato et al. 2013, Shields, Kaliki et al. 2013).
Immunohistochemical parameters described to be of prognostic significance in uveal melanoma include:
1.
Tumour cell proliferation markers (Ki-67, PCNA/PC-10, Ser10/PHH3) (Mooy, Luyten et al.
1995, Seregard, Spangberg et al. 1998, Al-Jamal and Kivela 2006, Onken, Worley et al. 2010,
Angi, Damato et al. 2011).
2.
Density of tumour-infiltrating macrophages (Folberg, Rummelt et al. 1993, Whelchel, Farah
et al. 1993, de Waard-Siebinga, Hilders et al. 1996, Makitie, Summanen et al. 2001, Toivonen,
Makitie et al. 2004, Mougiakakos, Johansson et al. 2010).
3.
Density of tumour-infiltrating lymphocytes (de la Cruz, Specht et al. 1990, Durie, Campbell et
al. 1990, Tobal, Deuble et al. 1993, de Waard-Siebinga, Hilders et al. 1996, 1998, Maat, Kilic
et al. 2008, Bronkhorst, Vu et al. 2012, Herwig, Bergstrom et al. 2013).
Cytogenetic and molecular genetic features of the tumour cells have been demonstrated to have strong
prognostication value in uveal melanoma. The most striking abnormality in uveal melanoma is the complete or
partial loss of chromosome 3. Other common genetic abnormalities of uveal melanoma include loss on 1p, 6q,
8, and 9p as well as gain on 1q, 6p, and 8q (see review, (Coupland, Lake et al. 2013). The above-mentioned
chromosomal alterations in primary uveal melanoma are clinically relevant because of their correlation with the
risk of metastatic death. Chromosome 3 loss is associated with a reduction of the 5-year survival probability
from approximately 100% to about 50% (Prescher, Bornfeld et al. 1992, Prescher, Bornfeld et al. 1994, Damato,
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Duke et al. 2007, Onken, Worley et al. 2007, Shields, Ganguly et al. 2007, Young, Burgess et al. 2007, Young, Rao
et al. 2007, Damato and Coupland 2009, Damato, Dopierala et al. 2010, Onken, Worley et al. 2012, Singh,
Aronow et al. 2012, Thomas, Putter et al. 2012, Vaarwater, van den Bosch et al. 2012). Similarly, chromosome
8 gains and loss of chromosome 1 significantly correlate with reduced survival (Sisley, Rennie et al. 1990,
Damato, Duke et al. 2007, Damato, Dopierala et al. 2010). Both chromosome 3 loss and polysomy 8q are also
associated with other poor prognostic factors, including increasing tumour basal diameter, ciliary body
involvement, presence of epithelioid cells, high mitotic count, and closed connective tissue loops (Scholes,
Damato et al. 2003, Damato, Duke et al. 2007, Damato, Dopierala et al. 2010). Conversely, gains in chromosome
6p may correlate with a good prognosis, suggesting this aberration has a functionally protective effect (White,
Chambers et al. 1998, Damato, Duke et al. 2007, Damato, Dopierala et al. 2010).
Different methods (i.e. techniques or ’tools‘) can be applied to assess the genetic alterations of uveal
melanomas. The most commonly used tests are fluorescent in situ hybridization (FISH), multiplex ligation
dependent probe amplification (MLPA), microsatellite analysis (MSA), single nucleotide polymorphisms (SNP)
array (aSNP) and a PCR-based 12-gene assay based on gene expression profiling (GEP) (see Review by (Coupland,
Lake et al. 2013)). The latter technique divides uveal melanoma into two ‘classes’ on the basis of an mRNA
expression signature: class 1 and class 2 (Onken, Worley et al. 2010, Onken, Worley et al. 2012). Essentially,
‘Class 1’ uveal melanoma often show 6p and 8q gain. ‘Class 2’ uveal melanoma tend to show more aneuploidy
with 1p loss, 3 loss, 8p loss, and 8q gain. Class 2 UM are also strongly associated with inactivating mutations of
‘BRCA1-associated protein-1 (BAP1), located at 3p21 (see below) (Harbour, Onken et al. 2010). The GEP-based
test has been patented (DecisionDx-UM; www.castlebiosciences.com/test_UM.html). To date, there has been
a paucity of studies that directly compare prognostic techniques in uveal melanoma (Singh, Aronow et al. 2012).
Only limited comparative analyses have been performed (Onken, Worley et al. 2007, Young, Burgess et al. 2007),
(Young, Rao et al. 2007, Petrausch, Martus et al. 2008, Onken, Worley et al. 2012, Singh, Aronow et al. 2012,
Vaarwater, van den Bosch et al. 2012, Coupland, Damato et al. 2013, Coupland, Lake et al. 2013), each with their
respective flaws, and therefore no statement regarding superiority of a particular technique over another can
be made.
Some serological markers have been proposed to be associated with poorer prognosis and ‘high-risk’ uveal
melanoma: these include MIA-1 (Schaller, Bosserhoff et al. 2002, Reiniger, Schaller et al. 2005, Barak, Frenkel et
al. 2007, Missotten, Korse et al. 2007); S-100B (Missotten, Beijnen et al. 2003, Barak, Frenkel et al. 2007,
Missotten, Korse et al. 2007), osteopontin (Kadkol, Lin et al. 2006) ,(Barak, Frenkel et al. 2007); TPS (Barak,
Frenkel et al. 2007); GDF-15 (Suesskind, Ulmer et al. 2011); B2-microglobulin (Triozzi, Achberger et al. 2012);
and circulating cell free DNA (Metz, Scheulen et al. 2013). Most of these serological biomarkers are being
investigated as a research tool but to date are not being used to influence clinical management.
Combined prognostic models have been designed and validated by some ocular oncology centres (Taktak, Fisher
et al. 2004, Kaiserman, Rosner et al. 2005, Damato, Eleuteri et al. 2008, Damato, Eleuteri et al. 2011). The
prognostic models take into account a number of the stronger prognostic parameters in uveal melanoma, which
have been incorporated into statistical systems (e.g. conditional hazard estimating neural network; artificial
neural networks; and accelerated failure time) using test and validation sets, for individualised prediction of
prognosis. It has been demonstrated that these models increase the accuracy of prognosis prediction rather
than using one single prognostic parameter. In some centres, the prognostication model is being used for
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patient counselling and to determine screening frequency and the ultimate modality for screening (e.g. MRI
versus ultrasound) applied (Marshall, Romaniuk et al. 2013).
5.3.2. What is the role of prognostic biopsy?
The proposed roles of prognostic biopsy are:
1.
The identification of a high-risk group allows for: a) determination of liver scan frequencies and studies
comparing screening methodologies; b) early surgical intervention of metastatic disease; and c) development of
systemic adjuvant therapies using either two-stage or multistage phase II studies (Whitehead, Tishkovskaya et
al. 2012).
Whilst genetic testing may alter management of patients at ocular oncology centres (Damato, Eleuteri et al.
2011), to date there is only one documented prospective single-arm study in the literature, whereby those
asymptomatic uveal melanoma patients with a predicted 5-year mortality of greater than 50% underwent 6monthly screening using MRI (Marshall, Romaniuk et al. 2013). This resulted in metastases being detected
before symptoms in 83 (92%) of 90 patients developing systemic disease, with 49% of these having less than five
hepatic lesions all measuring less than 2 cm in diameter. Of these 90 patients, 12 (14%) underwent hepatic
resection, all surviving for at least a year afterwards. Whether this results in prolongation of life after taking
lead-time bias into account, requires further follow-up and investigation.
2.
Aid patient counselling – Patient demand is increasing for prognostication biopsies in uveal melanoma.
Some studies (Beran, McCannel et al. 2009, Cook, Damato et al. 2009) have demonstrated that one of the main
benefits perceived by patients is that they would have greater control knowing the genetic ‘type’ of their tumour,
and that screening for metastatic disease and early treatment might enhance chances of survival. Further,
psychological status did not vary significantly as a function of cytogenetic test result. Prognostic information was
important to patients with choroidal melanoma, even in the absence of prophylactic measures that might
improve prognosis (Beran, McCannel et al. 2009).
5.3.2.1. Tumour biopsy complications
Opinions vary about the scope of ocular tumour biopsy and the balance between the benefits of performing the
biopsy and the theoretical risk of affecting tumour growth and/or the small risk of seeding. To date, there is no
evidence in the literature suggesting that performing a biopsy of a uveal melanoma (and indeed any malignancy)
affects the subsequent behaviour of the tumour – e.g. stimulating a high-grade transformation of an initially
low-grade melanoma. On the other hand, episcleral seeding of uveal melanoma following biopsy has been
reported, albeit it is rare (Raja et al. 2011, Caminal et al. 2006, Glasgow, B.J et al. 1988). In such cases, these
have been treated by excision of any nodules with adjunctive cryotherapy.
Other complications of intraocular biopsy, such as transient or persistent vitreous or subretinal haemorrhage,
retinal detachment, infectious endophthalmitis and rhegmatogenous retinal detachment (Shields, Ganguly et al.
2007) (Eide N et al. 2009, Grixti A et al. 2014). With the exception of transient vitreous haemorrhage after transvitreal biopsy, all of these complications are rare in the hands of an experienced surgeon, and are treated in the
usual fashion (Grixti et al. 2014).
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5.3.2.2. Tumour Heterogeneity
The use of fine needle biopsy in uveal melanoma prognostication relies on the assumption that the sampled
tissue is representative of the entire tumour. Concern has been raised regarding tumour biopsy, as sampling
error can potentially be introduced as a result of tumour heterogeneity. FISH analysis performed on paraffin
sections has revealed some heterogeneity of monosomy 3 in uveal melanoma (Sandinha, Farquharson et al.
2006, Maat, Jordanova et al. 2007, Mensink, Vaarwater et al. 2009, Schoenfield, Pettay et al. 2009). This was
also examined using MLPA using formalin-fixed enucleated globes; however, in the latter study it was found in
most uveal melanomas that despite some variation in results of the individual loci examined in differing sites,
the interpretation of the overall chromosome 3 status was consistent across the tumour (Dopierala, Damato et
al. 2010). Indeed preliminary data demonstrate a very high concordance rate between MLPA and MSA results
of intraocular biopsies of uveal melanomas that were subsequently enucleated and re-examined using these
techniques (Coupland et al. 2014). Some rare cases are exceptions to the rule (Callejo et al 2011). To date,
there are no reports examining uveal melanomas using other techniques, including gene expression profiling.
In general, it is highly recommended that interpretation of the cytogenetic or molecular results take into
consideration the clinical data and history as well as the histomorphological features of the specimen
examined. Disomy 3 or Class I results are to be interpreted with caution if the sample has not been examined
for cellular content or cell type.
5.4. Evidence Statements
5.4.1. Prognostic factors/tool

Prognostic factors of uveal melanoma are multi-factorial and include clinical, morphological,
immunohistochemical and genetic features. Level 1++

There are a number of different cytogenetic and molecular techniques for evaluating genetic changes
in uveal melanoma but there is insufficient comparative data. No evidence was found that
demonstrated one technique was superior to another. Level 1+

A number of novel serological biomarkers are being investigated but not informed clinical management.
Level 2-
5.4.2. Prognostic biopsy

Biopsy provides powerful prognostic information but there is as yet inadequate evidence to
demonstrate that changing management as a result of this information affects survival. Level 4
5.5. Recommendations
Refer to recommendations related to this chapter, which are in Section 1.2 by clicking HERE
5.6. Linking Evidence to Recommendations
The GDG had a lengthy discussion regarding the risks and benefits of a prognostic biopsy. Some of the clinicians
regarded the biopsy as collecting information for research purposes only, with no therapeutic benefit; others
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were of the opinion that a biopsy assists in identifying patients at ‘high risk’ of metastasis and who could benefit
from more intensive follow-up with the aim of potentially detecting metastases earlier. There was additional
prolonged discussion on how to define a ‘high risk’ uveal melanoma patient (with respect to the development
of metastasis) given the variety of genetic testing methods and their varying degrees of accuracy. Further, the
GDG discussed what the definition of a ‘high risk’ uveal melanoma patient would be without the genetic data.
Currently two of the three ocular oncology referral centres in the UK do not routinely perform prognostic biopsy
as it does not alter patient management in those two particular centres. There is some concern about the
accuracy of the results and about the risks of the procedure. These include the risk of tumour seeding,
intraocular haemorrhage as well as the possibility of a non-diagnostic result. This is in contrast to the third centre
(Liverpool) where routine prognostication has been part of patient management since 1996, and where
considerable expertise has been accumulated.
The discussion focused on patient preferences. The patient representatives were in favour of patients being
informed about and being offered an intraocular biopsy, as this gave them more information on which to base
decisions including future treatment options. They argued that if the biopsy is not performed, this information
would not be available at a later date, particularly if the uveal melanoma was treated by radiotherapy in the
absence of tissue sampling. Without accurate genotyping of their tumours through a biopsy, patients may not
be eligible to be recruited into clinical trials. This was regarded by the patient representatives as a major
handicap. There was a discussion about whether all patients wanted to know the results of the intraocular
biopsies. Experience at the Liverpool Ocular Oncology Centre (and elsewhere) would suggest that most patients
do; however, this information is only incorporated into the pathology reports, if the patient has consented for
the prognostic testing to be done. It was agreed that there should be an informative and neutral discussion
between the patient and surgical ocular oncologist about the risks of intraocular biopsy prior to treatment of
the primary tumour, and these were to be considered against the potential benefits.
6. Surveillance of patients at risk of recurrence
6.1. Introduction
Uveal melanoma is a rare cancer, with a propensity for liver metastasis. Management of localised disease with
either surgery or radiotherapy achieves a high rate of local control; however, about 50% of patients relapse with
predominantly liver metastases. The risk of metastatic disease can be predicted relatively accurately through
the use of clinicopathological features and molecular genetics (see above). Prognosis in the metastatic setting
remains poor, with a median survival of less than 6 months for patients who receive no active treatment; and 6
to 24 months for treated patients. Surgical management of liver metastases offers the only real likelihood of
long-term disease control at present for some patients with isolated metastatic tumours (Frenkel, Nir et al. 2009,
Mariani, Piperno-Neumann et al. 2009), particularly as there are currently no proven systemic therapies that
change outcome in patients with disseminated uveal melanoma. This has led to the introduction of surveillance
programmes for patients with a high-risk of developing disease, with the aim of identifying metastases early,
allowing for resection or clinical trial entry. It has been previously shown that surveillance allows early detection
of metastases prior to the development of symptoms, and that this facilitates trial entry and surgery in a limited
proportion of patients. Although a survival benefit to screening has not been proven, many centres (nationally
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and internationally) now perform periodic screening of patients with high-risk uveal melanoma, and screening
is now considered to be good clinical practice. However the optimal screening method (e.g. CT scanning, MRI,
US), timing, patient selection and overall advantage of surveillance remain under debate. More sensitive
imaging modalities such as PET/CT and contrast-enhanced MRI have been proposed and are increasingly used
internationally. This has been on the assumption that such technologies improve the detection and expedite
detection of metastases and improve resection and hence survival. However this benefit remains to be
demonstrated, and there are clear financial and clinical implications.
Aim – purpose is to identify patients who have relapsed. – i.e. who have developed
metastatic disease.
The GDG agreed that the aim is to detect small volume, pre-clinical disease rather than first identifying large
volume, clinically detectable, metastatic disease.
Aim – to detect metastatic disease as early as possible.
The GDG agreed that there is a need to assess whether early detection makes a difference. There is evidence in
Section 7 that small volume treatment has better outcome. Early treatment potentially may influence benefit
and number of lines of treatment.
6.2. Methods
6.2.1. Questions addressed
1.
2.
3.
4.
5.
Should all patients be offered surveillance?
Should there be a risk-adapted strategy for surveillance?
What is the optimal imaging modality for surveillance?
What is the interval?
What is the duration of surveillance?
Question
Population
Test/Intervention
Comparator
Outcome
Should all patients
be offered
surveillance?
Patients who have
been treated for a
primary uveal
melanoma
With each other
Metastasis
Survival
Should there be a
risk-adapted
strategy for
surveillance?
Patients who have
been treated for a
primary uveal
melanoma, and
who have a ‘high
risk’ of developing
metastatic disease,
according to
clinical,
histomorphological
LFT
USS
MRI (liver, contrast
enhanced)
Laparoscopy
CT Scan
LFT
USS
MRI (liver, contrast
enhanced)
Laparoscopy
CT Scan
Comparing
different risk
levels to each
other
Sensitivity and
specificity of
metastasis
detection
Survival
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What is the optimal
imaging modality for
surveillance?
What is the interval?
and genetic
features.
Patients who have
been treated for a
primary uveal
melanoma
USS
MRI (liver, contrast
enhanced)
CT Scan
Compared to each
other
Sensitivity and
specificity of
metastasis
detection
Survival
What is the duration
of surveillance?
Patients who have
been treated for a
primary uveal
melanoma
USS
MRI (liver, contrast
enhanced)
CT Scan
5 years versus 10
years versus lifelong
Compared to each
other
Sensitivity and
specificity of
metastasis
detection
Survival
6.2.2. Inclusion and exclusion criteria for selecting evidence
Included were Case control studies, Case series >3 patients and Review articles combined with case reports.
Only studies with adult patients were included. Preclinical and animal studies were excluded, as were case
reports (1-3 cases) and review articles without any original case information.
6.2.3. Appraisal and extractions
All references were sifted first by one individual. Two reviewers appraised and reviewed the included papers,
and the quality of the studies was assessed using the modified SIGN checklists as a guide.
Most of the studies were case reports (close to 30%) with only about 10% representing descriptive case series.
Information from each of the studies was extracted and presented to the Guideline Development Group for
discussion on March 14 2014 with an update of the evidence presented after the update search. For full details
of each of the included studies, see the evidence tables in Appendix A.
No studies were found that addressed the duration of surveillance review question.
6.3. Evidence summary
6.3.1. Question 1: Should all patients be offered surveillance?
A recent and very detailed review of studies that investigated periodic surveillance from 1980 to 2009 by
Augsburger et al. (Augsburger, Correa et al. 2011) failed to find evidence of a survival benefit associated with
regular surveillance. Therefore it could be argued that it is futile offering uveal melanoma patients’ surveillance
examinations to detect metastatic disease. However, the majority of the studies reported in this review (n = 31
in total) were small, retrospective, and from single institutions. In addition, a wide and very variable range of
screening methods and strategies were described, further complicating the comparison. Notably, none of the
articles was a report of a randomized or nonrandomized comparative clinical trial of total post-treatment
survival in subgroups assigned to regular periodic surveillance for metastasis versus no surveillance testing
(Augsburger, Correa et al. 2011).
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On the other hand, several studies having clearly demonstrated that periodic liver imaging allows the
identification of liver metastases prior to the development of symptoms (Eskelin, Pyrhonen et al. 1999, Maeda,
Tateishi et al. 2007, Kim, Lane et al. 2010, Marshall, Romaniuk et al. 2013). For example, in the study by Marshall
et al. 92% of patients who developed metastases, were asymptomatic at the time of diagnosis using 6-monthly
non-contrast MRI surveillance (Marshall, Romaniuk et al. 2013). Furthermore, liver surveillance allowed
detection of liver metastases in the majority of patients prior to changes in serum biochemistry.
Liver metastasectomy is currently only possible in approximately 10% of cases using historical screening
programmes (Sato 2010, Marshall, Romaniuk et al. 2013) and reflecting the burden of disease at diagnosis of
metastases. However, the resection rate may be increased with strategic planning of screening, using more
sensitive tools.
6.3.2. Question 2: Should there be a risk-adapted strategy for surveillance? If so,
what is a high-risk and or low-risk uveal melanoma?
As mentioned above in the “Prognostication” section (section 5), the risk of metastatic relapse in uveal
melanoma is determined by multiple factors, including clinicopathological features such as tumour size and
location (Shields, Furuta et al. 2009) and molecular genetic abnormalities, most notably the loss of chromosome
3 (Prescher, Bornfeld et al. 1996, Damato, Eleuteri et al. 2011). In addition, the risk of metastatic disease may
be assessed using multigene expression assays (Onken, Worley et al. 2010). This has enabled the development
of sophisticated prognostic tools, which allow the identification of patients with a high risk of developing
metastases, (Onken, Worley et al. 2010) for whom surveillance is most likely to be beneficial. For example, the
Liverpool Uveal Melanoma Prognosticator Online (LUMPO) is used on a routine basis to stratify uveal melanoma
patients into low- and high-risk groups, and is used in patient counselling, management and screening (www.
ocularmelanomaonline.com) (Damato, Eleuteri et al. 2011).
Targeted screening, in the highest risk patients with the greatest needs, also offers a practical setting where
clinical trials may be most helpful in elucidating the role of follow-up. In the study by Marshall et al (Marshall,
Romaniuk et al. 2013) for example, only patients with monosomy 3 were enrolled, thus limiting surveillance to
patients with a high risk of recurrence, which is reflected in the development of metastases in 48% of patients,
after a median follow-up period of approximately 29 months. Conversely, patients for whom relapse is very
unlikely may be reassured and discharged early. However, the level of risk that is employed as a cut-off is clearly
subject to debate. The risk-versus-benefit ratio of screening in ‘low metastatic risk’ disease poses additional
challenges and must be carefully weighed against potential harm from false positive findings, potential radiation
exposure, psychological morbidity and the economic impact.
The definition of ‘high risk’ uveal melanoma poses difficulties since not all centres apply the molecular genetic
testing, or only in very few selected cases, e.g. enucleation samples. Consequently, a definition of ‘high risk’
cannot in the UK be based only on molecular genetic abnormalities, but must include clinical and
histomorphological features of the tumours, when assessable. A ‘high risk group’ may therefore entail inclusion
of uveal melanomas with:
a. Large tumour size (based on a TNM tumour size and stage cut off - e.g. T3 tumour with a stage IIIA,
corresponding to a 5-year mortality rate of 34%) (Finger and The 7th Edition AJCC-UICC Ophthalmic Oncology
Task Force 2009, Kivela and Kujala 2013)
b. with or without (+/-) Ciliary body involvement
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c. +/- Epithelioid cells
d. +/- Closed connective tissue loops (also termed extravascular matrix loops)
e. +/- High mitotic count (>5 per 40 HPF)
f. +/- Monosomy 3
g. +/- Polysomy 8
h. +/- GEP Class 2
i. +/- A risk of death of 30% at 5 years or higher (i.e. TNM 7th edition Stage III (either A, B or C) (Kujala et al.
2013).
Discussion is required to agree on this definition before any prospective study addressing the usefulness of
surveillance in uveal melanoma subgroups can be commenced. Further, the endpoints of this study would have
to be carefully considered: e.g. time to detection of metastases, time to resection, survival outcomes.
6.3.3. Question 3: What is the optimal imaging modality for surveillance, overall
and of the liver?
Many different imaging modalities are in use or have been suggested including, but not limited to, liver imaging
with USS, CT or MRI (with or without contrast enhancement) or body imaging with CT or PET-CT. The choice of
imaging modality currently reflects local practice access, and also whether or not to exclusively image the liver
or include extrahepatic sites.
The principal hypothesis behind screening in the surveillance of uveal melanoma patients is the detection of
resectable liver metastases, based on the assumption that a significant proportion of patients have liver-only
metastases at first relapse. Consequently, this has led to the use of liver imaging as the primary modality used
for screening. In an imaging study of 110 uveal melanoma patients at different time points following diagnosis
of the primary tumour, 55% had liver-only metastases, and the liver was involved in 92% overall (Lorigan,
Wallace et al. 1991). Several other studies have similarly reported high rates of liver involvement (Einhorn,
Burgess et al. 1974, Gragoudas, Egan et al. 1991). However, in a series evaluating distribution of metastases at
death, the liver was involved in 93%, with 87% of cases showing multiple sites of metastases (Willson, Albert et
al. 2001). Other autopsy series showed liver-only metastases in between 22%-30% of patients with other sites
being affected in up to 90% of patients. (Patel, Didolkar et al. 1978, Borthwick, Thombs et al. 2011). The incidence
of brain metastases is low at 1%.
Therefore, in advanced metastatic disease liver-only uveal melanoma metastases are less common; extrahepatic
metastases at first relapse in the presence of liver metastases can occur (Lorigan, Wallace et al. 1991), but the
frequency is unclear. Recent case series utilising PET-CT have illustrated that UM metastases can be widely
disseminated and include unusual sites such as cardiac, muscle, and thyroid etc. (Klingenstein, Haug et al. 2010)
and (Kurli, Reddy et al. 2005). Extrahepatic relapse in the absence of liver metastases appears uncommon.
Prolonged survival has been described following solitary extrahepatic metastatectomy (Aoyama, Mastrangelo
et al. 2000). The low frequency of isolated extrahepatic relapse would not appear to justify routine imaging
beyond the liver: this would require long-term CT follow-up, which is potentially associated with harmful
radiation effects.
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Liver imaging: Although there has been very limited formal evaluation of imaging in uveal melanoma, a metaanalysis in gastrointestinal cancer reported the highest weighted sensitivity in the detection and assessment of
liver metastases with either MRI or PET-CT (Niekel, Bipat et al. 2010). Two uveal melanoma-specific studies
suggest that MRI may be superior to PET-CT in detecting small hepatic metastases (lesions <10 mm in diameter)
(Servois, Mariani et al. 2010, Orcurto, Denys et al. 2012). However, MRI still remains an imperfect preoperative
modality, given the pattern of miliary liver metastases that can be seen in uveal melanoma. Contrast-enhanced
MRI can further increase high spatial resolution and sensitivity and is the preferred liver-imaging technique for
potentially operable malignant liver disease. The role in routine surveillance is less clear and potentially offset
by high costs, long procedure time and a recognised but low incidence of potentially adverse reactions. A direct
comparison between MRI with and without contrast has not been published in uveal melanoma. Investigation
into the utility of PET-MRI in this setting is also required. This is a relatively new technology that is not in general
use at present. However, PET-MRI has potential advantages, most notably a lower dose of ionising radiation in
comparison to PET-CT.
The choice of modality clearly has implications on the cost-effectiveness of any surveillance programme. The
current estimated costs to the NHS are £85-£125, £380, £370, £450 and £900 for liver USS, contrast CT, noncontrast MRI, contrast MRI and PET-CT, respectively. (Estimated costs in 2014). In the absence of costeffectiveness data, the choice of modality has been based upon a relatively subjective assessment of efficacy in
relation to cost and the scope of the surveillance programme (all patients versus a targeted high-risk population).
6.3.4. Question 4: What is the optimal surveillance interval?
There is very little evidence on which to base decisions regarding either frequency or duration of follow-up.
In a study by Eskelin et al. (Eskelin, Pyrhonen et al. 1999) surveillance was performed annually using liver USS
and 59% of metastases were detected at an asymptomatic stage. The authors hypothesised that 6-monthly
imaging would increase the percentage of asymptomatic detection to 95%. In the study by Marshall et al. (in
which surveillance was performed every 6 months), 92% of patients were detected before the development of
symptoms (Marshall, Romaniuk et al. 2013).
Nonetheless, the general consensus in the field is that 6-monthly imaging is preferable. Advice must take into
account the individual’s risk weighted against the cost and resource implications of shorter scanning intervals as
well as the possible psychological impact on patient and family from more frequent (e.g. 3monthly) testing.
6.3.5. Question 5: What is the duration of surveillance?
Uveal melanoma may continue to relapse for many decades following primary diagnosis, with 20%-33% of
deaths attributed to metastatic recurrence even at 15-42 years (Coupland, Sidiki et al. 1996, Kujala, Makitie et
al. 2003). The Liverpool dataset suggests an almost linear continuation of recurrence over time and beyond 10
years without a visible plateau in risk of recurrence. (Damato and Damato 2012) The role of lifelong screening is
unknown, but it is pertinent to note that surgical resection series report that the outcome appears most
favourable in later relapsing patients, perhaps arguing for prolonged follow-up in some instances. Lifelong
screening in all patients would appear unjustified and expensive, and supports the concept of targeted screening
of higher risk subgroups. Marshall et al. reported that 65% of high-risk patients had relapsed at 5 years on noncontrast liver MRI surveillance, and thus focusing surveillance on this period would appear sensible (Marshall,
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Romaniuk et al. 2013). However, a further period of screening, may also prove to be of value in the detection
of resectable disease.
6.4. Evidence Statements

To date, an effect of screening on survival of uveal melanoma patients has not been demonstrated.
Level 2-

If a substantial and clinically meaningful survival benefit were truly associated with periodic
surveillance testing for uveal melanoma metastases, such benefit would be demonstrated most
convincingly by means of a prospective comparative clinical trial in which subgroups of patients with
uveal melanoma (after treatment of their primary intraocular tumour) were subjected to either regular
periodic surveillance testing by some consistent regimen or no surveillance testing at all and then
followed until death from any cause. It seems unlikely that this could be tested practically. Level 4

Despite the lack of evidence there is general consensus that surveillance testing is not worthless, and
indeed is performed in virtually all centres in a periodic manner using differing methods for differing
lengths of periods. Level 4

Surveillance clearly identifies many patients with metastasis at a substantially less advanced disease
burden than would occur if only postsymptomatic testing were employed. Level 2

Targeted surveillance is likely to bring more benefit. A consensus definition of ‘high-risk’ uveal
melanoma is required, incorporating clinical, histomorphological and genetic features of the tumours.
Level 4

Most surveillance testing for metastatic uveal melanoma concentrates on the liver, with the effect that
highly-sensitive modalities for liver imaging are chosen. Level 2

The role of extrahepatic imaging in surveillance is unclear, particularly as the frequency of extrahepatic
metastatic relapse remains unknown. Level 2

Hepatic surveillance of uveal melanoma has resulted in an increased detection rate of metastases in
the liver, resulting in increased locoregional treatment in some centres and trial recruitment. Level 2

Surveillance is intuitively advantageous, allowing locoregional management of liver-only metastases,
and facilitating early systemic treatment and particularly trial enrolment before the disease burden
causes deteriorations in general health and performance status. Level 4

Additionally, surveillance facilitates patient follow-up, provides a link with oncology services and allows
a more holistic approach to cancer patients that includes early access to cancer nurse specialists and
smooth transition to services such as palliative care at an appropriate stage. Level 2

No evidence was found with respect to the duration of surveillance.
6.5. Recommendations
Refer to recommendations related to this chapter which in Section 1.2 by clicking HERE
6.6. Linking evidence to recommendations
The GDG discussed the reasoning and strategy for surveillance of uveal melanomas at length.
With respect to the question “Should all patients should be offered surveillance”, there was consensus amongst
the GDG that whilst the evidence in the literature would suggest that this practice is futile, all three ocular
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oncology centres and their associated general oncologists supported the concept of conducting surveillance,
with an emphasis on liver screening, particularly as there are other potential benefits for routine imaging studies.
This was supported by studies demonstrating that periodic liver imaging allows the identification of liver
metastases prior to the development of symptoms and/or change in blood values.
Regarding the question “Should there be a risk-adapted strategy for surveillance?”, there was no consensus in
the GDG, due to the inability to agree on a definition of ‘high metastatic risk’, reflecting the varying approaches
between the centres to prognostication. Whilst some centres would employ MRI with or without contrast in
‘high-risk’ uveal melanoma, others indicated that they would remain with the initial hepatic assessment using
USS and only progress to other modalities when USS-detected abnormalities are seen. It was suggested that due
to the insufficient evidence comparing and contrast screening modalities in uveal melanoma patients, a
prospective trial for uveal melanoma surveillance is required before any change of local practice would be
undertaken.
Consensus was achieved amongst the GDG for lifelong 6-monthly liver screening in all uveal melanoma patients
for, despite the lack of evidence in the literature supporting this practice. This is another area that would benefit
from further investigation.
The patient representatives were in favour of the uveal melanoma patients being informed of the strengths and
weaknesses of differing screening methodologies, and being involved in the decision-making process of what
screening method was chosen in their particular case.
7. Metastatic Disease
7.1.1. Introduction
As discussed above, the natural history of uveal melanoma is characterised by the frequent development of
metastases. Close to 50% of patients develop metastatic disease at any time from the initial diagnosis of the
primary to several decades later (Kujala, Makitie et al. 2003, Diener-West, Reynolds et al. 2005). The risk of
metastatic relapse for an individual can vary greatly dependent upon a number of primary tumour
characteristics, including genetic alterations (see section 5 above). Outcomes are poor once metastatic disease
occurs, and the median survival from the time of development of distant metastatic disease is 2 to 12 months
and 1-year survival 10%-15%. This range reflects a number of prognostic factors, including the burden of
metastatic disease and the effect of metastatic screening programmes (Augsburger, Correa et al. 2009).
Metastatic disease almost always involves the liver and is rarely detectable using imaging techniques, at the
time of primary tumour management (<5%). The pattern of disease is distinct from that of cutaneous melanoma.
The liver may be the only metastatic site in a significant percentage of patients although lung, bone and skin
metastases are also well described (Willson, Albert et al. 2001). Brain metastases are extremely uncommon.
Patients with metastatic uveal melanoma are typically managed by oncologists and palliative care teams as part
of skin melanoma services and guided by skin melanoma guidelines in the absence of standards for staging
investigations, metastatic biopsy and treatment.
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A broad spectrum of therapies have been reported and reflect the presenting pattern of metastatic disease.
Treatment may include best supportive care, systemic therapies (chemotherapy, biological therapies) or liverdirected therapies (chemotherapy, radiotherapy or surgery). Systemic chemotherapy results in an objective
response rate that ranges from 5% to 15% and without any strong evidence that conventional chemotherapy
prolongs survival. Access to clinical trials is limited and patients with metastatic uveal melanoma are often
specifically excluded from clinical trials in skin melanoma.
In the absence of a proven standard of care or clinical trial in the UK, many patients with metastatic uveal
melanoma currently receive best supportive care or dacarbazine chemotherapy for 4-6 cycles. Unlike skin
melanoma, mutations in the BRAF gene are exceptionally rare and thus for these patients BRAF-directed
therapies unhelpful. The anti-CTLA4 agent, Ipilimumab has National Institute for Health and Care Excellence
(NICE) approval for previously treated advanced (unresectable or metastatic) melanoma based upon clinical
trials
in
skin
melanoma.
http://publications.nice.org.uk/ipilimumab-for-previously-treated-advanced-
unresectable-or-metastatic-melanoma-ta268
The vast majority of patients with metastatic uveal melanoma have liver involvement and often as the first site
of metastatic relapse. Some patients appear to relapse with liver only disease and may represent a distinct
subgroup who may benefit from regional approaches to therapy. This chapter focuses on the management of
all patients who present with distant metastatic recurrence irrespective of the site and aims to give guidance
on:
Q1. What is the optimal method of staging?
Q2. What is the most robust prognostication (known prognostic factors for survival)?
Q3. What is the optimal management of systemic metastases?
Q4. What is the optimal management of oligometastatic disease outside the liver?
Q 5.What is the optimal management of liver only metastases?
Q 6. Is regional liver therapy more effective than systemic therapy?
Q7. What is the role of surveillance following metastatic treatment?
Staging
Staging is performed once the patient has been found to have clinical, biochemical or radiological evidence of
metastatic disease. Some centres use a surveillance program, which varies depending on the predicted risk of
developing metastases following the primary treatment (Marshall, Romaniuk et al. 2013). The aim of staging is
to identify all sites of metastatic disease in order to determine the most appropriate treatment plan for an
individual patient. For instance, if a patient has multiple lung metastases and lymph node disease within the
abdomen, there is unlikely to be any survival benefit in performing a liver resection for liver metastases.
Cross sectional imaging with CT or MRI are the most commonly used imaging modalities for staging metastatic
disease. MRI of the liver is more sensitive than CT in lesion detection (Niekel, Bipat et al. 2010) and the use of
liver specific MRI contrast agents can increase the number of visualised liver metastases. More recently MRI
diffusion-weighted imaging (DWI) has been shown to increase the detection rate of colorectal liver metastases
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(Koh, Collins et al. 2012) and (Kim, Yu et al. 2012). CT has better spatial resolution than MRI, and is more sensitive
for detection of extrahepatic disease. Uveal melanoma metastases greater than 1 cm are usually seen on PETCT, but small liver metastases are frequently missed (Orcurto, Denys et al. 2012). Despite significant
improvements in cross sectional imaging, miliary and sub-capsular liver metastases, and serosal small bowel
metastases are still commonly missed (Servois, Mariani et al. 2010). This supports the need for pre-operative
staging laparoscopy.
Prognostication
Prognostic factors are critically important in the selection of patients for therapy and in guiding decision making
for both patients and professionals. A number of retrospective studies have used multivariate analysis including
a validated multivariate analysis in over 200 patients that allows grouping of patients into three distinct groups
with differing prognosis.(Eskelin, Pyrhonen et al. 2003, Rietschel, Panageas et al. 2005).
Management
Systemic chemotherapy has been the standard treatment for most patients with liver metastases, with or
without extrahepatic disease. Treatment protocols have often arisen from experience in cutaneous melanoma
despite a lack of uveal melanoma-specific clinical trial evidence. Indeed, previous evidence base is almost
entirely based upon retrospective case series and a small number of uncontrolled phase II clinical trials that are
compounded by case selection. In the absence of an evidence-based standard of care, dacarbazine or
temozolamide has emerged as the standard control arm in a number of recently completed and ongoing
randomised clinical trials (Carvajal 2013, Sacco, Nathan et al. 2013). Progress in basic science and cancer biology
has highlighted an increasing number of potential novel therapeutic targets in uveal melanoma. This has created
a momentum in new clinical trials that are evaluating a wide range of targeted treatments and immunotherapy.
Furthermore, and importantly, the evaluation of new therapies has been underpinned by robust clinical trial
design with clear eligibility and prospective data collection in both national multicentre and international
collaboration.
The delivery of systemic therapies in liver-only metastatic disease has been based on the assumption that liver
resection is unlikely to offer a curative resection, as there are often more metastases within the remnant liver
and occult extra-hepatic micrometastatic disease. In addition the post-operative recovery period could be a
significant proportion of the patient’s remaining life. As morbidity and mortality from liver surgery has reduced,
and more complex resection techniques have evolved, surgery may have a greater role to play in the future.
Wedge resections and other adjunctive therapies can be used to treat small metastases in the remnant liver,
either at the time of primary liver resection or at a later time.
Regional liver therapies have been extensively reported in the setting of liver-only disease; however, most of
the reports are similarly flawed by the low quality of retrospective case series and uncontrolled single arm
clinical trials. There is no doubt that interventional radiology has developed rapidly over the last two decades
and offers potential therapeutic options for selected patients with liver-only metastatic uveal melanoma.
Targeted treatment can be delivered to liver metastases using two different approaches: 1) Percutaneous
thermal needle-based techniques include radiofrequency, laser, microwave and cryo-ablation which are all
capable of treating liver metastases up to 3 cm in diameter with curative intent (Lencioni, Della Pina et al. 2005,
Hamada, Yamakado et al. 2012). Recently non-thermal ablation, using irreversible electroporation, has entered
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clinical practice. This technique involves passing a high voltage current between two or more needles placed
around the metastasis, producing pores within the cell membrane, leading to cell death. 2) Trans-arterial
treatments take advantage of the dual blood supply to the liver. The portal vein provides up to 80% of blood to
the normal liver while most liver metastases, especially highly vascular tumours such as melanoma, recruit a
blood supply from the hepatic artery branches. Delivering treatments through the hepatic artery will therefore
treat liver metastases while sparing normal liver. Historically intra-arterial chemotherapy infusions have been
used after surgical placement of a catheter within the hepatic artery (Cantore, Fiorentini et al. 1994). Clearly the
benefit over systemic chemotherapy relies on the liver chemotherapy retention during the ‘first passage’ of the
injected agent through the liver. A significant portion of the chemotherapy, however, will pass through the liver
and reach the venous circulation.
Conventional chemoembolisation involves injecting a combination of chemotherapy and an embolic agent
through a temporary catheter placed in the hepatic artery, thus slowing transit of the chemotherapy through
the liver and blocking the blood/oxygen supply to the tumour. More recently, drug-eluting beads (Martin, Joshi
et al. 2011) and radiolabelled beads (Van Hazel, Blackwell et al. 2004) have become available to use within the
liver to treat primary and secondary liver cancers. The bead becomes trapped within the tumour
microvasculature where the chemotherapy agent or β radiation, respectively, is maintained in close proximity
to the tumour.
Immunoembolisation replaces the chemotherapy component with an immune modulating agent such as
granulocyte macrophage colony-stimulating factor. In addition to the ischaemic effect of the embolisation, there
is stimulation of antigen presenting cells leading to a possible increased systemic immunity to cancer cells
(Yamamoto, Chervoneva et al. 2009).
Another arterial delivered treatment termed ‘isolated hepatic perfusion’ involves saturating the liver with high
doses of chemotherapy by occluding the venous outflow from the liver for approximately 30 minutes. The drugfilled venous effluent is removed from the body and passes through an extra-corporeal filter to remove the
chemotherapy before the blood is returned to the patient (Zager and Nutting 2012).
Despite more aggressive liver surgery and new interventional techniques, it is the diffuse infiltrative nature of
ocular melanoma liver metastases that continues to provide the greatest challenge in disease control. The rare
nature of this uveal melanoma means that most publications consist of small case series, often mixed with
cutaneous melanoma liver metastases, or metastases from other primary tumours. Comparisons are often made
with historical data sets.
Surveillance
Following any metastatic therapy imaging is performed more frequently, initially to assess treatment response
and then to look for early recurrence. The modality (CT, MRI, PET) of choice will be largely guided by the pattern
of metastases and need for comparison with pre-treatment assessment. The potential benefit of follow-up
imaging is dependent on the availability of subsequent therapeutic options and patient wishes. Early,
presymptomatic detection of relapse or progression may offer the possibility of subsequent treatment or clinical
trial entry but currently there is a lack of evidence base and decisions are most appropriately made on an
individual basis. Patients who have undergone a potential curative liver resection represent a highly selected
subgroup with respect to ongoing surveillance. By virtue of the fact these patients have already developed liver
metastases they are in a particularly high-risk group, and so imaging frequency should increase compared to the
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surveillance group who have yet to develop metastases. It is not clear how long after liver treatment a patient
should return to a surveillance program. As with pre-operative staging, imaging can be performed with MRI or
CT, supplemented by PET-CT. Following ablation treatments the ablated area should be larger than the
underlying metastasis, and should have sharply defined margins with the adjacent liver. There will be a rim of
hyperaemic normal liver adjacent to the periphery of the ablation site within the first week or so, and it is
important that this is not misinterpreted for residual tumour. Post ablation liver imaging at around four weeks
is generally regarded as an appropriate interval to assess treated metastases.
Following intra-arterial treatments imaging assessment is more difficult as the distinction between necrotic
tumour and viable tumour is not always clear. The classic Response Evaluation Criteria In Solid Tumors (RECIST)
method of assessing tumour response almost always underestimates the effectiveness of treatment, as the size
of the treated metastasis may not change. As ablation techniques aim to destroy a rind of normal liver at least
5mm beyond the margin of the metastasis, the RECIST assessment would regard this as progression of disease.
The modified RECIST criteria (Lencioni and Llovet 2010), recently introduced to accommodate newer treatment
techniques, incorporate the reduction of tumour enhancement, following intravenous contrast administration,
as an indicator of response.
7.2. Methods
7.2.1. Questions addressed
The following questions were addressed
Question
Q. 1
What is the
optimal method of
staging?
Population
Patients with
uveal melanoma
with suspected
metastatic
disease
Q2. What is the
most robust
prognostication
(known prognostic
factors for
survival)?
Patients with
uveal melanoma
with metastatic
disease
Q3. What is the
optimal
management of
systemic
metastases?
Patients with
uveal
melanoma with
systemic +/-liver
metastatic
disease
Intervention
LFT
USS
CT chest abdo pelvis
MRI (whole body, liver,
contrast enhanced)
FDG PET CT
Bone scan
Laparoscopy
Clinicopathological
variables;
Performance status
CRP
Platelet/lymphocyte ratio
Other
Treatment variables:
Regional therapy
Systemic therapy
Surgery
Ablation
Regional therapy eg. liver
isolation perfusion, TACE,
other
Systemic therapy
Combination of the above
Best supportive care
Comparator
Outcome
With each other
Assess the extent
of disease
Each other
Survival (hazard
ratio for
prognostic factors)
With each other
Primary - Overall
survival
Progression free
survival
Disease free
survival
Response rate
Toxicity
Quality of life
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Second line
treatment
Q4. What is the
optimal
management of
oligometastatic
disease outside
the liver?
Patients with
uveal
melanoma with
oligometastatic
disease outside
the liver
Surgery
RFA
Radiotherapy
With each other
Q5.What is the
optimal
management of
liver only
metastases?
Patients with
uveal
melanoma with
liver only
metastatic
disease
Surgery
Ablation
Regional therapy eg. liver
isolation perfusion, TACE,
other
Systemic therapy
Combination of the above
Best supportive care
With each other
Q6. Is regional
liver therapy more
effective than
systemic therapy?
Patients with
uveal
melanoma with
liver +/- systemic
metastatic
disease
Surgery
Ablation
Regional therapy eg. liver
isolation perfusion, TACE,
other
Systemic therapy
Combination of the above
With each other
Q7. What is the
role of
surveillance
following
metastatic
treatment?
Patients with
uveal melanoma
following
resection or
regional
treatment
USS
CT
MRI
Each other
Response
toxicity,
QOL,
PFS,
Overall survival
Quality of life
Second line
treatment
response rate, PFS,
OS
Primary - Overall
survival
Progression free
survival
Disease free
survival
Response rate
Toxicity
Quality of life
Second line
treatment
Primary - Overall
survival
Progression free
survival
Disease free
survival
Response rate
Toxicity
Quality of life
Second line
treatment
Survival
Ability to identify
disease recurrence
or new metastatic
disease
7.2.2. Inclusion and exclusion criteria for selecting evidence
Included were all human, adult only, Phase I/II/III studies. All study types were included except for case reports.
Studies relating to prognostic factors in advanced disease and imaging for advanced disease were included.
Studies relating to in vitro cytogenetic markers and cell line studies were excluded.
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7.2.3. Appraisal and extraction
Information from each of the studies was extracted and presented to the GDG for discussion, with an update of
the evidence presented after the update search. For full details of each of the included studies, see the evidence
tables in Appendix B.
All references were sifted first by a GDG member with expertise in the topic. The primary reasons for excluding
papers were that they did not address the question.
The reviewers appraised and reviewed the included papers, and the quality of the studies was assessed using
the SIGN checklists as a guide. Most of the studies were case series and because SIGN does not have a quality
checklist for this study type, the guideline developers used additional criteria to assign an overall quality rating
to these studies. The quality rating was as follows: those with a larger number of subjects and where subjects
were recruited from more than one centre, were considered as being of better quality.
7.3. Evidence summary
7.3.1. Question 1. What is the optimal method of staging?
Systemic: There are no randomised controlled trials evaluating staging investigations in metastatic uveal
melanoma. Most reports consist of small patient numbers from institutional series only and often based upon
retrospective review.
The prevalence and location of metastases from uveal melanoma was reported in 110 patients at the MD
Anderson Cancer Centre (Lorigan, Wallace et al. 1991). In 55% of patients, the liver was the only organ affected.
Extrahepatic metastases included lung, bone, skin and lymph nodes were noted but were rare in the absence of
liver involvement (8%). Brain and adrenal metastases were seen in <5% of cases.
Patel et al (Patel, Winston et al. 2011) reported on the CT characteristics in biopsy-proven liver metastases from
uveal melanoma. Seventy-six patients were identified over an 11-year review period. Radiographic evidence of
extrahepatic metastases was evident in 53% of cases that represented advanced malignancy with high liver
tumour burden. In this cohort, overall survival correlated with tumour volume, hepatomegaly and ascites.
Liver: Several small case series (Servois, Mariani et al. 2010, Orcurto, Denys et al. 2012) report that PET-CT is
not able to detect metastases less than 12mm. MRI is able to detect the majority of liver metastases even as
small as 5mm. Contrast-enhanced MRI was compared with PET CT in the preoperative stage of known liver
metastases in 15 uveal melanoma patients (Servois, Mariani et al. 2010). All patients proceeded to laparotomy.
MRI was superior to PET CT for staging liver metastases. MRI was also more sensitive for detecting small liver
metastases in a second small study (Orcurto, Denys et al. 2012).
While the available evidence for optimal staging of uveal melanoma liver metastases is small, the findings are
consistent with the much larger experience with colorectal liver metastases where MRI with liver specific
contrast is the most sensitive imaging modality for pre-operative staging. This concordance fits with what we
already know about the sensitivity of PET CT. Similarly the false positive rate of PET CT for extrahepatic disease
is as much a problem in ocular melanoma staging (Finger, Kurli et al. 2005) as it is with more common tumour
groups such as colorectal cancer.
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On balance, uveal melanoma liver metastases are best staged with liver specific contrast-enhanced MRI (Servois,
Mariani et al. 2010, Orcurto, Denys et al. 2012) and extrahepatic disease with PET CT (Kurli, Reddy et al. 2005).
As sub centimetre extrahepatic metastases can be missed on PET CT and some metastases can be PET-negative
(Strobel, Bode et al. 2009), a contrast enhanced CT scan, either in addition or as part of PET CT, may increase
the identification of small extrahepatic metastases.
One study (Strobel, Bode et al. 2009) showed that 50% of liver metastases were FDG PET negative. It also showed
that if the liver metastases were PET negative, then so were the extrahepatic metastases. This would suggest
that patients with PET-negative liver metastases need whole body CT for complete staging.
No studies were identified concerning the role of biopsy and histological confirmation in suspected metastatic
uveal melanoma.
7.3.2. Question 2. Is there a preferred prognostic method for a patient with
metastatic disease
Many of the published therapeutic studies incorporate prognostic factor evaluation using univariate and/or
multivariate analysis. This most often represented institutional case series. Factors identified included tumour
burden (maximum diameter of largest tumour, percentage of liver involvement, tumour volume, hepatomegaly,
ascites), performance status, LFTs (e.g. ALP, LDH), gender, pattern of metastases and surgical resection outcome
(R0 resection).
Several institutional series report on variates of survival and potential prognostic indices. (Eskelin, Pyrhonen et
al. 2003) defined a potential prognostic model in 91 consecutive patients combining performance status, tumour
diameter and ALP. A validated multivariate analysis reported by Eskelin 2007 may represent the most robust
prognostication currently available. (Eskelin, Piperno-Neumann et al. 2007)
Retrospective review of 119 patients managed over a 10-year period at Memorial Sloan Kettering Cancer Centre
identified five variates of survival: age < 60 years, long disease-free interval from initial diagnosis to metastatic
disease, treatment with surgery or intrahepatic therapy, lung/soft tissue as the only site of disease and female
gender (Rietschel, Panageas et al. 2005).
None of the putative prognostic factors have been formally evaluated or validated in prospective randomised
controlled trials.
Four papers (Kodjikian, Grange et al. 2005, Shields, Ganguly et al. 2007, Frenkel, Nir et al. 2009, Patel, Winston
et al. 2011)(Eskelin, Pyrhonen et al. 2003) looking at prognostic factors in patients with metastatic liver disease,
all found a correlation between liver metastatic burden and survival. Each paper measured the disease burden
in different ways: greater than 10 metastases in one paper (Kodjikian, Grange et al. 2005), and a volume greater
than 100cm3 of the largest metastasis in another (Patel, Winston et al. 2011) and found that both of these
measures were poor prognostic indicators for survival. In addition to these, two other studies (Kodjikian, Grange
et al. 2005, Patel, Winston et al. 2011) showed that involvement of the ciliary body at the time of primary
diagnosis and the presence of ascites and hepatomegaly were independent negative prognostic factors. It was
not stated whether the ascites was malignant or related to liver failure.
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7.3.2.1. Following surgery
A clear resection margin has a significant impact on survival. The overall median survival in one study (Mariani,
Piperno-Neumann et al. 2009) was 14 months following liver resection, but in the R0 group median survival was
68 months. Similarly, the median survival in another study (Frenkel, Nir et al. 2009) rose from 16.6 months to
65.6 months, when comparing R1/R2 with R0 resections, respectively.
Interestingly, the presence of extrahepatic disease was not found to correlate with a worse survival in one of
the studies (Patel, Winston et al. 2011).
7.3.2.2. Following non-surgical liver treatment
Three studies (Gupta, Bedikian et al. 2010, Huppert, Fierlbeck et al. 2010, Heusner, Antoch et al. 2011)) found
that tumour burden (>9 metastases, >75 % liver replacement and >25% liver replacement respectively) was a
poor prognostic factor in patients who underwent transarterial chemoembolization (TACE) (Gupta, Bedikian et
al. 2010, Huppert, Fierlbeck et al. 2010) and isolated hepatic perfusion (IHP) (Heusner, Antoch et al. 2011). The
baseline LDH level was also a negative prognostic factor in one of the TACE studies (Gupta, Bedikian et al. 2010).
The angiographic appearances of the liver metastases seen at the time of TACE have been shown to correlate
with both the primary tumour location and with survival (Dayani, Gould et al. 2009). Compared to a nodular
pattern of contrast distribution at angiography, an infiltrative pattern tends to be seen with primary tumours
involving the ciliary body or those with extra-scleral spread (p=0.01). The nodular appearance is also significantly
associated with improved survival following TACE (12.7 months) compared to the infiltrative pattern (3.7
months).
7.3.3. Question 3. What is the optimal management of systematic metastases?
7.3.3.1. Systemic Therapy
The evidence base reviewed consists of a heterogeneous collection of reports including single arm prospective
clinical trials, retrospective single institution case series and subset analysis in unselected metastatic melanoma
trials. Two of the larger uveal-specific trials included 48 patients (Becker, Terheyden et al. 2002, Schmittel,
Schmidt-Hieber et al. 2006). The majority of studies evaluated conventional chemotherapy with a smaller
number of reports including biological therapies, including immunotherapy.
Schmittel et al reported a progression-free benefit in the first and only published randomised phase II trial
evaluating treosulfan versus gemcitabine and treosulfan in 48 patients (Schmittel, Schmidt-Hieber et al. 2006).
No overall survival data were presented.
The objective response rate to systemic therapy was very low with stable disease most often reported. Despite
this low response rate, single case responders were not uncommon irrespective of the therapy under evaluation.
Progression-free and overall survival was not consistently reported with a range of PFS (1.5-3months) and OS
(6-12months) reflecting heterogeneity of cases. The largest published case series of 201 uveal melanoma
patients represents retrospective data from a single institutional experience and reported 1% response rate to
systemic chemotherapy (Bedikian, Legha et al. 1995). Only 1 published randomised phase III trials evaluating
systemic therapy against regional therapies or surgery was identified (Leyvraz, Piperno-Neumann et al. 2014).
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7.3.3.2. Emerging therapies
Two randomised clinical trials in patients with metastatic uveal melanoma confined to the liver have been
completed although only one has been published following peer review. A randomised trial comparing
percutaneous hepatic perfusion (PHP) of melphalan compared to best active care (BAC) (including systemic
therapy) reported at the annual meeting of the American Society for Clinical Oncology (ASCO), patients in the
PHP arm had a median PFS of 6.1 months compared with just 1.6 months with BAC (P≤0.001) (Pingpank, Hughes
et al. 2010). Improvement in PFS did not appear to extend to overall survival (OS), which at 12 months was 26%
with BAC and 29% with PHP although OS was confounded by crossover between the study arms. Median survival
was 9.9 months versus 11.4 months respectively.
The EORTC 18021 trial is the largest prospective clinical trial completed to date in metastatic uveal melanoma
and compared intrahepatic chemotherapy versus intravenous treatment (Leyvraz, Piperno-Neumann et al.
2014). Between February 2005 and February 2011, 171 patients were randomized (Hepatic intra-arterial (HIA):
86, Intravenous (IV): 85). Due to poor accrual, an interim analysis was performed after 134 deaths in order to
test futility (power=79%). Intra-arterial chemotherapy led to a higher overall response rate (ORR) (12% versus
2%) and longer PFS (HR=0.62; 6-month rate 41% versus 27%; 1-year rate: 19% versus 8%) compared to IV
administration but did not translate into an improvement in OS (median ~ 13.5 months).
Data from the SUAVE trial, a randomised study comparing sunitinib with dacarbazine in 74 patients, showed no
significant difference in PFS or OS. Results were presented at ASCO 2013 (Sacco, Nathan et al. 2013).
7.3.3.3. Biological Therapies
Uveal melanoma is a unique clinical and molecular subtype of melanoma that has no known effective therapy
in the metastatic setting. The increasing understanding of the underlying biology of uveal melanoma has led to
the identification of a number of novel and promising therapeutic strategies that warrant investigation.
Currently, an increasing number of novel agents are under evaluation in well-designed prospective and uvealspecific phase II clinical trials. A randomised phase II study in 98 patients compared selumetinib versus
temozolamide has reported improved response rate and doubling of PFS (15.9 versus 7 weeks) (Carvajal 2013).
A number of case series have now reported on the activity of ipilimumab in patients with metastatic uveal
melanoma. Luke et al (Luke, Callahan et al. 2013) reported 2 out of 34 patients having a radiological response
with a median overall survival of 9.6 months. Maio et al (Maio, Danielli et al. 2013) also reported a 5% response
rate in 84 patients with a median overall survival of 6 months, and Kelderman et al (Kelderman, van der Kooij et
al. 2013) 1 patient out of 22 having a radiological response and a median overall survival of 5.2 months.
7.3.4. Question 4. What is the optimal treatment for oligometastatic disease
outside the liver
In a single retrospective series of 12 patients with oligometastatic disease, two patients with lung metastases
and one patient with a brain metastasis underwent metastatectomy. The remaining 9 patients had either liver
only or liver plus extra-hepatic metastases.(Aoyama, Mastrangelo et al. 2000). Median recurrence-free and
overall 5-year survival was 15.6% and 53.3%, respectively for the whole series. A single case report of a solitary
pulmonary metastatectomy was also identified (Komatsu, Sowa et al. 2013). The surgical cases were
characterised by a long interval from initial diagnosis (median 8 years) and incidental detection in asymptomatic
patients.
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7.3.5. Question 5. What is the optimal management of liver only metastases?
Intra-arterial treatments (chemotherapy infusion, chemoembolization, immunoembolisation).
There is one randomised controlled trial evaluating optimal management with intra-arterial treatments. Studies
are mostly small case series (Egerer, Lehnert et al. 2001), (Farolfi, Ridolfi et al. 2011), some comparing response
rates with escalating doses of chemotherapy (Agarwala, Panikkar et al. 2004), others using different sorts of
chemotherapy (Gupta, Bedikian et al. 2010) or combination chemotherapy (Melichar, Voboril et al. 2009). All
case series made comparison with historical data sets. These studies provide preliminary support for the concept
that regional therapy produces a higher response rate than systemic chemotherapy. The largest multi-centre
case series (Peters, Voelter et al. 2006) of 101 patients receiving repeated intra-arterial fotemustine
administrations, showed a median survival of 15 months and 2-year survival of 29%. In a small study (Fiorentini,
Aliberti et al. 2009) assessing a series of 10 patients, irinotecan drug-eluting beads showed a response rate in up
to 80 % of patients, with a similar number experiencing an improvement in quality of life. Response rates were
measured using modified RECIST. The results of another study (Yamamoto, Chervoneva et al. 2009) suggest that
immunoembolisation may increase PFS of extrahepatic sites but the numbers are small.
The single published randomised controlled trial (Leyvraz, Piperno-Neumann et al. 2014) compared intra-arterial
fotemustine with IV fotemustine in first line treatment of ocular melanoma liver metastases. Whilst there was
no overall survival difference there was an increased response rate and liver PFS in the intra-arterial arm.
7.3.5.1. Radioembolisation (selective internal radiation therapy)
No randomised controlled trials have been conducted for this relatively new technique. Two papers reported on
radioembolisation, one a single-centre case series (Gonsalves, Eschelman et al. 2011), the other a multi-centre
retrospective case series (Kennedy, Nutting et al. 2009). Both studies showed a response or stabilisation of
disease in 63-100% of patients. This included heavily pre-treated patients (chemoembolization,
immunoembolisation) in the larger study (32 patients) (Kennedy, Nutting et al. 2009, Gonsalves, Eschelman et
al. 2011). The overall median survival was 10 months (PFS of hepatic metastases 4.7 months). A smaller pretreatment liver tumour volume (<25%) improved survival (10.5 months) compared to patients who had >25%
liver replacement (3.9 months). When compared to historical data sets, extrahepatic disease progression was a
more prominent feature in this series of patients, presumably due to slowing of disease progression in the liver.
The smaller study (Kennedy, Nutting et al. 2009) showed a high response rate (1 complete response, 6 partial
responses, 1 stable disease, 1 progressive disease) at 3 months, with 80% survival at 1 year.
7.3.5.2. Percutaneous Isolated Hepatic Perfusion
There have been several technical papers reporting the development of isolated hepatic perfusion (IHP) to treat
a variety of secondary liver tumours including uveal melanoma liver metastases (Alexander, Libutti et al. 2003,
van Etten, de Wilt et al. 2009, Alexander 2012, Lindner, Rizell et al. 2012, Zager and Nutting 2012). Registry data
from Sweden (Olofsson, Cahlin et al. 2014), which included 34 patients with uveal melanoma liver metastases
who were treated with IHP, showed a median overall survival of 27 months, a 14 month improvement over
historical patients not treated with IHP.
A randomised controlled cross-over trial (Alexander 2012) of 93 patients with ocular or cutaneous melanoma
liver metastases comparing IHP with BAC demonstrated a median hepatic progression free-survival of 8.0
months with IHP melphalan versus 1.6 months with BAC. Up to 6 treatments were given every 4-8 weeks. The
cross over design of the study meant that 57% of the BAC patients were also treated with IHP, which made
survival benefit difficult to evaluate.
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7.3.5.3. Surgery
Seven case series (Hsueh, Essner et al. 2004, Pawlik, Zorzi et al. 2006, Herman, Machado et al. 2007, Frenkel, Nir
et al. 2009, Mariani, Piperno-Neumann et al. 2009, Caralt, Marti et al. 2011), mostly retrospective single centre
studies, showed that in a highly selective patient group there is a survival benefit with surgery. The selection
criteria include the absence of extra-hepatic disease after evaluation with CT/MRI and FDG-PET scans; diseasefree interval longer than 24 months after the resection of the primary melanoma; presumed completely
resectable lesions; low tumour burden; absence of clinical co-morbidities. One study (Pawlik, Zorzi et al. 2006),
in 16 patients, showed that patients eligible for liver surgery based on performance status, no extrahepatic
disease, and a favourable liver disease distribution had a significantly longer PFS and median overall survival (9
months and 29 months respectively). Many of the studies, however, included patients who received adjuvant
chemotherapy.
Another study (Mariani, Piperno-Neumann et al. 2009) demonstrated that at >24 months from the primary
resection, an R0 resection, < 5 metastases and absence of miliary disease were consistently found to be good
prognostic factors. Some studies identified more extensive liver disease or unexpected extrahepatic disease in
up to 44% at the time of surgery (Herman, Machado et al. 2007). Accurate staging is therefore vitally important
to try to exclude these inoperable cases. In a large single centre surgical series 255 patients (Mariani, PipernoNeumann et al. 2009), the R2 resection rate was 62%, which probably accounted for the post resection overall
median survival being only 14 months. In the same study, the median survival of the R0 resections rose to 27
months. There is currently no evidence of survival benefit to support hepatic de-bulking surgery. This could be
reconsidered should an effective hepatic regional or systemic therapy be shown to be of greater benefit in
patients with small volume disease, in which case surgical de-bulking may prove to be an adjunct to these
therapies. This would need to be investigated as part of a well-designed clinical trial.
7.3.6. Question 6. Is regional liver therapy more effective than systemic therapy
The question of optimal therapy for liver-only disease remains unanswered but of great relevance to both
patients and clinicians. Whilst many studies combined systemic therapy with liver surgery or targeted liver
intervention there were only a few papers that directly compared systemic treatment with liver treatment for
patients with liver only metastatic disease. Two small randomised trials (Pingpank, Hughes et al. 2010, Leyvraz,
Piperno-Neumann et al. 2014) have been completed and have been described above. Neither study was able to
identify a survival advantage despite improved response rate and PFS. Furthermore, no data on quality of life is
available from these studies.
7.3.7. Question 7. What is the role of surveillance following liver metastases
treatment?
Despite improved overall survival following liver metastatectomy, the majority of patients will relapse a second
time; thus patients who undergo R0 resection remain at high risk of further hepatic and extrahepatic relapse.
No published studies were found addressing the question of continued surveillance in this highly selected
population.
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7.4. Evidence Statements
7.4.1.
Staging

Contrast enhanced MRI is superior to PET in staging liver disease. Level 2+

AJCC/UICC TNM 7th edition includes simple staging by dividing M1 in M1a-M1c. Level 3

Intrahepatic metastases less than 12 mm are often not detected on PET CT. Level 3

Extrahepatic metastases less than 10 mm are often not detected on PET CT. Level 3

Liver metastases can be PET-negative in up to 50% of patients. Level 3

When liver metastases are PET-negative then so are the extrahepatic metastases. Level 3

Small subcapsular or miliary liver metastases may not be detected on MRI. Level 3

PET/CT can identify extra hepatic disease. Level 3

No evidence was found that the FDG component of PET was useful in adding increased sensitivity for
staging. Level 3

There is insufficient evidence that any imaging technique is superior to any other in identifying extrahepatic disease. Level 3
7.4.2. Preferred prognostic method

Metastatic Tumour Burden (volume, diameter and number), LDH, ALP, gender, age, performance
status, DFS have been shown to be prognostic factors. Level 3

The validated Eskelin model may represent the most robust prognostication but the reported factors
that have not been sufficiently investigated. Level 2

The absence of liver disease (soft tissue metastasis) appears favourable to outcome. Level 3

Post-treatment survival (surgical and non-surgical) is worse in patients with a greater liver tumour
burden. Level 3

Liver disease presenting <24 months after primary diagnosis has a worse prognosis. Level 3
Following treatment

The presence of ascites at the time of surgery is associated with a worse prognosis. Level 3

R0 resection achieves a significantly better prognosis than R1 or R2 resections. Level 3

Post treatment survival (surgical and non-surgical) is worse in patients with a greater liver tumour
burden. Level 3

Ciliary body involvement is associated with a worse post resection prognosis. Level 3

High pre-operative LDH levels are associated with a worse post resection prognosis. Level 3

Defined tumours have a better prognosis than miliary tumours. Level 3
7.4.3. Management of systemic disease

Response rates to chemotherapy are very low. Level 3

No high quality evidence was found showing improved survival or quality of life following systemic
therapies.

A small subset of patients may have prolonged stable disease irrespective of the therapy delivered.
Level 3
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
There is no evidence that one chemotherapy regimen is superior to another in terms of outcome or
quality of life. Level 3

MEK inhibitors are an area requiring further evaluation. Level 1+

Occasional patients appear to have benefit from treatment with ipilimumab. Level 3
7.4.4. Management of oligometastatic-extrahepatic metastatic disease

Highly selected patients presenting with oligometastatic disease having had a significant disease-free
interval may benefit from resection of metastasis. Level 3
7.4.5. Management of liver disease

No evidence was identified for ablative techniques.

In selected patients, curative liver resection is associated with longer survival in case series. Level 3

There is no evidence of survival benefit to support hepatic de-bulking surgery. . Level 3

All the regional non-surgical techniques can reduce measurable tumour burden, but there is
inadequate evidence to demonstrate an overall improvement in survival. Level 1-

The data does not enable a differentiation that one intervention is superior to another in terms of
outcomes. Level 3
7.4.6. Systemic versus targeted liver treatment

There is no evidence that liver targeted treatment produces a better overall survival than systemic
therapies.
7.4.7. Surveillance following liver treatment

No evidence was found.
7.5. Recommendations
Refer to recommendations related to this chapter, which are in Section 1.2 by clicking HERE
7.6. Linking evidence to recommendations
7.6.1. Staging
There was insufficient evidence to compare and contrast staging modalities in advanced uveal melanoma
patients. In the absence of evidence, the view of the GDG was that the pattern of relapse in uveal melanoma
metastatic disease should include imaging of the chest, abdomen and pelvis. Because of the low incidence of
CNS metastases, the GDG were of the opinion that that routine brain imaging in the absence of symptoms was
not justified. As bone metastases occur in a minority of patients the GDG thought that routine imaging with
bone scan was not required in the absence of progressive symptoms.
There was evidence that PET CT can detect uveal melanoma metastases but as there was no strong evidence
that this influences management or adds additional information above and beyond CT, the GDG did not
recommend this. Whilst PET CT can detect metastases at all sites within the body it has a relatively high false
negative rate due to either lesion size (<12 mm) or lack of FDG-avidity. Contrast-enhanced CT, which is also more
widely available than PET CT, should be able to detect metastases below 10 mm in diameter at all sites imaged.
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Liver surgery should only be considered when there is no evidence of extrahepatic disease, so accurate staging
with imaging and pre-operative laparoscopy is vitally important. MRI for liver staging in other cancer groups is
generally accepted to be the most accurate imaging modality. From the low volume of evidence available for
the detection of uveal melanoma liver metastases, the GDG were of the opinion that contrast-enhanced MRI
with the addition of DWI offers the best available non-user dependent imaging modality at present.
Overall the GDG felt that the combination of contrast enhanced MR liver and contrast-enhanced CT of the chest,
abdomen and pelvis is the best and most easily available, at present, to stage a patient thought to have
metastatic uveal melanoma.
7.6.2. Preferred prognostic method
No evidence was found to define a single validated prognostic tool for advanced uveal melanoma. A number of
putative factors have been described but require validation in future prospective trials. In the absence of
evidence, the view of the GDG was that prospective collection of these factors is recommended. Outside clinical
trials, specialist centres should collaborate with the aim of developing a common central database that
incorporates primary tumour details, staging information, treatment and outcomes, in order to collect data for
future research to improve care.
Prognosis is likely to be related to a combination of factors: tumour biology, host immune response, disease
volume, achievement of clear resection margins. Recognised poor prognostic indicators in patients with ocular
melanoma liver metastases– e.g. tumour volume, ascites, early (<24 months) liver involvement following
primary diagnosis and ciliary body involvement - are all apparent at the time of surgical assessment. They should
be viewed as contraindications to liver surgery.
Liver resection, in carefully selected patients, gives the best chance of prolonged survival. R0 resection, however,
is only determined following pathological review of the resected liver specimen. In the reviewed surgical studies,
R0 resection was highly significant and the main determinant for prolonged survival.
7.6.3. Management
There was no evidence that current therapies impact on survival or quality of life for most patients with
advanced uveal melanoma. Because of the current absence of evidence, the GDG were of the opinion that
emphasis should be placed on developing and conducting well-designed clinical trials as a priority for all patients,
particularly as there are a number of emerging novel therapies that hold promise but that require further
validation before these can be considered as standards. Outside the clinical trial setting, conventional
chemotherapy delivered according to local protocol or best supportive care remain valid options for selected
patients following a full discussion with the patient of their own potential to benefit.
As in all studies, there was evidence that a small subset of patients may achieve protracted stable disease
irrespective of the therapy; in the view of the GDG conventional chemotherapy should be reserved for patients
with good performance status (PS 0-2) who may benefit. Good performance status patients should be managed
in specialist centres with appropriate oncology expertise in uveal melanoma and that collaborate with
hepatobiliary and interventional radiology services.
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Liver surgery offers the best chance for long-term survival, but patient selection is vitally important to avoid R2
resections. Pre-operative laparoscopy may detect additional disease and should be performed in all patients.
There is no evidence at present that de-bulking liver resection offers any survival benefit.
Whilst there is a trend towards improved survival with non-surgical treatments, the evidence is poor quality and
low in volume. If the patient understands the palliative intent of the selected treatment, and is fully informed
about the potential side effects, then liver targeted treatments could be considered. The available options have
varying degrees of invasiveness, side effects, cost and need for repeated treatments. The choice of treatments
offered varies between and across countries. Published studies are mostly based on case series with their
inherent biases. Despite the fact that two small RCTs have failed to show a survival benefit for regional therapies
over systemic therapy, in the absence of firmer evidence the GDG regarded regional therapy is a viable option
to be considered for patients with liver predominant disease.
The GDG thought that, as a minimum, all patients treated with surgical or liver targeted interventions should be
entered on a registry with an accompanying minimum data set. Ideally every patient should become part of a
well-constructed clinical trial. All patients should be discussed at a specialist multidisciplinary team meeting and
treatment should take place at recognised centres.
7.6.4. Surveillance following liver treatment
No evidence was identified to demonstrate whether a surveillance programme is useful following treatment for
uveal melanoma metastases. It would seem reasonable to perform cross-sectional imaging soon after a surgical
or non-surgical liver procedure (4-6 weeks) to assess treatment response. Thereafter, appropriate posttreatment imaging should be performed to identify disease recurrence at an early stage, which may be suitable
for further intervention. It is recommended that the same imaging modality is used each time to aid the
assessment of treatment response; contrast-enhanced MRI with DWI is thought to be the optimal choice.
8. Using and implementing the guideline
8.1. Potential organisational and financial barriers in applying its
recommendation
The GDG recognises that the lack of evidence base is a significant challenge in defining standards in the context
of a rare cancer. The GDG strongly supports the concept of greater specialisation to facilitate research and
prospective audit and collaboration. Against this background, few barriers to implementation are anticipated
amongst those who specialise in this condition. Where patients choose to receive local care, it is possible that
individual trusts may view some aspects of follow up (eg surveillance) as an added resource pressure. The GDG
considers this a potential barrier to implementation but are aware of the emerging consensus concerning followup imaging in high risk cutaneous melanoma, the very low incidence of uveal melanoma and the opportunity to
support an element of centralised follow up in specialist centres.
The delivery of highly specialist regional therapies merits specific comment. The GDG does not consider the
potential of curative liver surgery to be a barrier given existing resources and standards of care within NHS
specialist hepatobiliary surgical teams. This is not the case with respect to the availability of regional
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interventional therapies, which are considered options within the guideline. At present there is no nationally
agreed funding stream within the NHS specialist commissioning for this aspect of care resulting in a lack of equity
of access or agreed standards. The GDG recognise the critical importance of collaboration amongst specialist
centres to facilitate research and evidence base in this area.
The NHS England Commissioning through Evaluation programme provides one platform to commission novel
therapies and the GDG encourage all specialist uveal melanoma centres to engage and develop opportunities
within this framework.
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8.2. Audit criteria
Guidance
Audit standard
All patients with a diagnosis of melanoma enrolled on a national
uveal melanoma register, based on a standardised minimum
data set, with follow-up data collected at least annually
All patients referred for an initial diagnosis within two weeks
All patients with a diagnosis or a suspected diagnosis of ocular
melanoma are referred to one of the three specialist centres
Documentation of a fully informed discussion with all patients,
explaining the role of biopsy including the benefits and risks
including:
 Risk of having the biopsy
 Limitations of the investigation
 Benefits for future treatments (including possible
recruitment to trials)
 Impact on quality of life
 Recruitment to trials
The following features are recorded:
 Age
 Gender
 Tumour location
 Tumour height
 Tumour Largest basal diameter
 Ciliary body involvement
 Extraocular melanoma growth (macroscopic)
The following features should be recorded if tissue is available:


reference
Exceptions
Comments
Patient consent withheld
None
Documented patient refusal
None
None
Cell type (modified Callender system)
Mitotic count (number/40 high power fields in H&E
stained sections)
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
Presence of extravascular matrix patterns (particularly
closed connective tissue loops).
 Presence of extraocular melanoma growth (size,
presence of encapsulation or not).
Any local recurrences of the primary uveal melanoma are
reported to a surgical ocular oncology centre.
All patients with technically resectable liver disease offered
assessment for curative intent hepatic resection.
This minimum data set collected for all patients with systemic
disease (Stage IV):
 Metastatic Tumour Burden (site, volume, diameter and
number)
 LDH
 ALP
 GGT
 Bilirubin
 Presence or absence of ascites
 Gender
 Age
 Performance status,
 DFS following definitive primary therapy
Documented patient refusal
All patients with systemic disease with or without liver
involvement having whole staging (chest, abdomen and pelvis)
with CT scan or PET CT
Patients with systemic disease should be considered for clinical
trials and informed of available trial options at other centres.
No appropriate trial
available, but consideration
documented
Document type of trial entered (surgical,
cytotoxic agent, targeted therapy, immune
therapy, other biological)
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9. Review and updates
The guideline was published on 13 January 2015 and a full copy of the guideline and appendices is available on
http://melanomafocus.com/activities-2/um-guidelines-resources/ . Melanoma Focus will take administrative
and the chairman, or someone designated by the chairman, will take clinical responsibility for maintaining the
guideline. GDG members will be asked to notify the chairman at any time, if new evidence makes any aspect of
the Guideline unsafe. Annually, the chairman or designate will write to the GDG members and the consultees,
who comprise many of the leaders in the field, asking if there has been any new evidence which would change
the recommendations. At three year intervals, there will be a full search of the literature from the date of the
last search to identify any new evidence which would change a recommendation. This will be reviewed by the
chairman, or designate, and experts from the each of the four GDG sub-groups (Primary treatment,
Prognostication, Surveillance and Metastatic disease). For any section of the Guideline which needs updating,
the members of that subgroup will meet to review the evidence and agree changes. The re-drafted sections of
the Guideline will be sent to the full GDG for agreement before publication. Only if there are several sections
that need updating will the full GDG meet. Updates of the guideline should follow the methodology detailed in
in Uveal Melanoma Guideline Development Methodology (Link), which also contains further details of the update
methods.
10. Research recommendations

Linking the primary tumour genetics to metastatic genetics

Establishment of a register to study the disease

The sensitivity and specificity of liver ultrasound compared to MRI for screening for metastatic disease
as part of primary treatment

Role of a prognostic biopsy - does it identify the right group of patients to follow up the more
intensively? There is a need to identify the risk at each stage, and then quantify the benefit.
Research/trials into systemic treatment options for metastatic disease
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Verschueren, K. M., C. L. Creutzberg, N. E. Schalij-Delfos, M. Ketelaars, F. L. Klijsen, B. I. Haeseker, S.
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Virgili, G., G. Gatta, L. Ciccolallo, R. Capocaccia, A. Biggeri, E. Crocetti, J. M. Lutz, E. Paci and E. W.
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Appendices
A – Extraction tables of Evidence (separate document)
B - Glossary and Acronyms
Anti-angiogenic
Ascites
Brachytherapy
Choroid
Choroidectomy
Ciliary body
Computed Tomography (CT)
CyberKnife
Cyclectomy
Debulking
Embolisation
Inhibiting the formation and differentiation of blood vessels.
Accumulation of fluid in the spaces between tissues and organs in
the abdomen
Targeted radiotherapy when the radiation is placed in or near to
the tumour.
A vascular membrane between the retina and the sclera of the
eye containing large branched pigment cells.
Removal of choroidal melanomas.
A ring of made up mainly of muscle on the inner surface of the
front wall of the eye. Consists of the ciliary body and ciliary
processes, and is responsible for providing the fluid that nourishes
the the lens and cornea of the eye.
A method to use X-rays to give a high resolution pictures of the
inside of the body.
A particular brand of equipment to deliver stereotactic
radiosurgery (SRS).
Removal of small, ciliary body tumours.
Removal of most or all of the tumour, thus reducing the size.
Introduction of pellets into the circulatory system in order to
occlude blood vessels supplying the tumour.
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Endoresection
Enucleation
Exoresection
Extrahepatic
Exudative retinopathy
Fractionate
Fractionated stereotactic radiation
treatments/therapy
Fundus of the eye
GammaKnife
Hepatomegaly
Hypofractionated radiotherapy
treatment
Intraocular
Intraocular haemorrhage
Iridectomy
Iris
Ischaemia
Laproscopy
Magentic Resonance Imaging (MRI)
Miliary spread of melanoma
Monosomy 3
Neovascular glaucoma
Oedema
Ophthalmoscopy
Parenchyma
Pars plana
Pars plana vitrectomy
Percutaneous
The surgical removal of part of an organ or tumour from within.
Removal of the eye.
Removal of the tumour ‘en bloc’ through a large sclera opening.
Outside of the liver (commonly used for metastasis outside of the
liver).
Damage to the retina caused by serum, fibrin (involved in blood
clotting), and white blood cells leaked from blood vessels into the
retina. Fibrin is an insoluble protein in response to bleeding and is
the major component in a blood clot.
Splitting of a whole into different parts.
Treatments of moderately high doses of radiation usually given
over three to eight sessions (fractions).
The interior surface of the eye, opposite the lens. It includes the
retina, optic disc, macula and fovea, and posterior pole.
A particular brand of equipment to deliver stereotactic
radiosurgery (SRS).
Enlargement of the liver.
Radiation treatment split into large doses per timepoint (fraction)
but giving less treatment doses (fractions) than with standard
fractionation. A particular way to improve efficacy of radiation
treatment.
Located within the eye.
Bleeding within the eye.
Removal of the iris or parts of the iris to treat iris melanoma.
A thin, circular structure in the eye, responsible for controlling the
diameter and size of the pupil and thus the amount of light
reaching the retina.
A reduction of blood supply resulting from the blocking of an
artery.
Looking inside of the abdomen using a laparoscope.
A non-invasive diagnostic technique that produces computerized
images of internal body tissues. It uses magnetic signals rather than
X rays.
A large number of small nodules of melanoma that resemble grains
of small seeds (of millet).
Loss of part of or of the whole of one of the two chromosomes
three in cancer cells. Monosomy 3 is present in some uveal
melanomas and then is linked with development of metastases and
an increased risk of dying from uveal melanoma.
The abnormal production of new blood vessels causing increased
pressure in the eye.
Swelling caused by fluid accumulating particularly in the abdomen.
A visual examination with an instrument to look inside of the eye.
The instrument is called an ophtalmoscope. Usually an uveal
melanoma can be seen by ophthalmoscopy.
The functional part of an organ such as the liver.
Translates as ‘flat part’ – the outer ring of the ciliary body.
Surgical removal of vitreous body from the eye, with introduction
of the instruments via the pars plana of the ciliary body.
Translates literally as ‘through the skin’. Used to describe a medical
procedure where inner organs are accessed by needle-puncture of
the skin, rather than by using an "open" approach where inner
organs or tissue are exposed (typically with the use of a scalpel).
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Percutaneous ablative techniques
Plaque therapy
Porta hepatis
Proton beam therapy
R0 resection
R1 resection
R2 resection
Radiogenic retinopathy
Resectable
Retina
Retinopexy
Retinotomy
Sclera
Stereotactic
Stereotactic Radiosurgery
Stereotactic resection
Surgical Ocular Oncology Centre
Thermotherapy
Transcatheter arterial
chemoembolization / Transarterial
Chemoembolization (TACE)
Tumour seeding
Removal or destruction of metastases using a percutaneous
approach. This is usually the case for microwave and
radiofrequency ablation or cryothearapy.
A form of radiation therapy where a radioactive patch (plaque) is
placed on or near the tumour from the outside of the eye for a
period of time.
Also called the transverse fissure of the liver. It is a short fissure
that extends across the under surface of the left portion of the
right lobe of the liver. It contains a number of important structures
of the liver (hepatic portal vein, hepatic artery proper, Common
hepatic duct).
A type of radiation treatment. Beams of particles, called protons,
are aimed at the cancer bearing part of the eye.
Surgery at which a primary tumour or metastasis this is removed
completely. No tumor is found at the edges (margins) of the
removed tissue when examining the tissue under the microscope.
Surgery at which a primary tumour or metastasis this is removed as
far as the eye can see. Under the microscope the tumour reaches
the edges (margins) of the removed tissue.
After surgery visible residual tumour following is left behind.
Long term damage of the retina caused as a side effect of radiation
treatment.
When surgical removal of the tumour is possible.
The light-sensitive layer of tissue, lining the inner surface of the
eye.
A procedure to seal the retina to the surface beneath to stop it
detaching.
A surgical incision through the retina.
The tough white outer layer of the eyeball.
A technique for precisely directing the tip of a delicate instrument
(as a needle) or multiple beams of radiation in three dimensions at
a tumour or other lesion.
A one-session of high dose radiation using stereotactic methods.
Like all radiotherapy is works by reducing or destroying the ability
to the tumour to grow. There are three types
 Particle beam (proton)
 Cobalt-60 based (photon) e.g. Gamma Knife
 Linear accelerator based (linac) e.g Cyber Knife
It can be used to treat parts of the body that can remain or be hel
absolutely still during the treatment.
The removal of the tumour using microsurgery with the aid of the
stereotactic techniques.
One of three treatment centres in the UK that have nationally
recognised expertise for the treatment of eye cancer including
uveal melanoma. They are centrally funded through government.
The use of heat to treat a tumour.
Injection of small particles coated with chemotherapeutic
drugs directly into an artery supplying a tumour. This restricts the
tumour's arterial blood supply and delivers chemotherapy directly
to the target tissue.
Spreading of cancer cells from the place the cancer started
(primary) to another part to other parts of the body. This can be
close to the primary (for example, in the eye) or distant (for
example, the liver).
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Uveal Melanoma Guidelines January 2015
Uvea
Vitreous body
Vitreous haemorrhage
The middle layer of the eye including the iris and ciliary body as
well as the choroid.
The clear jelly-like structure that fills the posterior part of the
eyeball.
Bleeding into the vitreous body.
ALP
BAC
BCNU
CT
CGE
DFS
DTIC
DWI
ELND
FNAB
fSRT
Alkaline phospatase
Best Available Care
Carmustine (bis-chloroethylnitrosourea)
Computed Tomography
Cobalt Gray Equivalent
Disease free survival
Trade name for Dacarbazine
Density weighted imaging
Elective Lymph Node Dissection
Fine Needle Aspiration Biopsy
Fractionated Stereotactic Radiation Therapy
IE or CE
IFN or INF
IHP
IL-2
IND
Intron-A
LDH
LFT
MFS
MRI
NED
NVG
OCT
OS
PBR
PET
RCT
RECIST
RFA
SIRT
SLN
SNB or SLNB
SRS
TACE
TNF
TNM
UBM
US
WLE
Immunoembolization/Chemoembolization
Interferon Alfa-2b
Isolated Hepatic Perfusion
Interleukin-2
Investigational New Drug
Interferon Alfa-2b
Lactate Dehydrogenase
Liver Function Test
Metastatic Free Survival
Magnetic Resonance Imaging
No Evidence of Disease
Neovascular Glaucoma
Optical Coherence Tomography
Overall Survival
Proton Beam Radiotherapy
Positron Emission Tomography
Randomised control trials
Response Evaluation Criteria in Solid Tumours
Radiofrequency Ablation
Selective Internal Radiation Therapy
Sentinel Lymph Node
Sentinel Node Biopsy/Sentinel Lymph Node Biopsy
Stereotactic Radiosurgery
Transcatheter Arterial Chemoembolization/ Transarterial Chemoembolization
Tumour Necrosis Factor
Tumor Node Metastasis staging system
Ultrasound Biomicroscopy
Ultrasound
Wide Local Excision
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Uveal Melanoma Guidelines January 2015
C - Lists of Guideline Development Group members
Dr
Paul
Nathan
Miss
Victoria
Cohen
Prof
Sarah
Coupland
Ms
Kathryn
Curtis
Prof
Bertil
Damato
Dr
Jonathan
Evans
Mr
Stephen
Fenwick
Dr
Ji-Peng Olivia
Li
Dr
Lesley
Kirkpatrick
Dr
Ernie
Marshall
Mr
Kieran
McGuirk
Mr
Bruce
Oliver
Prof
Christian
Ottensmeier
Mr
Neil
Pearce
Moved to USA and did
not attend meetings
after May 2013, but
contributed to the
guideline
electronically.
Consultant Medical Oncologist
Mount Vernon Cancer Centre
Northwood, Middlesex
Consultant Ocular Oncologist
Lead Clinician
Ocular Oncology Service
St
Bartholomew's
and
Moorfields Eye Hospital
London
George Holt Chair of Pathology
and
Deputy Head of Department
Molecular and Clinical Cancer
Medicine
Honorary
Consultant
in
Pathology
University of Liverpool
Patient Representative
OcuMel UK*
Hon.
Professor
of
Ophthalmology
Royal
Liverpool
University
Hospital’
Liverpool
Consultant
Interventional
Radiologist
The Royal Liverpool University
Hospital
Liverpool
Consultant
Hepatobiliary
Surgeon
University Hospital Aintree,
Liverpool.
Ophthalmic Specialist Trainee,
Moorfields Eye Hospital, London
Patient Representative
Macmillan Consultant in Medical
Oncology, The Clatterbridge
Cancer Centre NHS Foundation
Trust, Liverpool
Patient Representative, Chair,
OcuMel UK*
Resigned
2012
October
Patient Representative
Professor in Experimental Cancer
Medicine Consultant in Medical
Oncology
Southampton
University
Hospitals
and
University of Southampton
Consultant Hepatobiliary and
Pancreatic Surgeon, University
Page 106 of 112
Uveal Melanoma Guidelines January 2015
Dr
Brian
Stedman
Mr
Sachin
Salvi
Dr
Peter
Szlosarek
Ms
Nancy
Turnbull
Hospital
Southampton,
Southampton
Consultant
Interventional
Radiologist
Southampton
University Hospitals NHS Trust,
Southampton
Consultant Ophthalmologist ,
Royal Hallamshire Hospital,
Sheffield
Consultant in Medical Oncology,
St Bartholomew's Hospital,
Clinical Senior Lecturer, Barts
Cancer Institute, Queen Mary,
University of London London
Project Manager; London
* Ms Curtis and Mr McGuirk shared attendance at GDG meeting. When neither could attend Mr Rob
Cheek, another member of OcuMel board, attended. Sadly, Kieran died in September 2014.
Page 107 of 112
Uveal Melanoma Guidelines January 2015
D- GDG Declarations of Interest tables
First Name
Last Name
DOI
last
updated
Personal Pecuniary
Non-personal pecuniary
National body
Stated personal
opinion
Editorial
Patents
Paul
Nathan
12/10/2014
Chief UK investigator on the
SUMIT study
Melanoma Focus Trustee
Member of NCRI Melanoma
Clinical Studies Group
Ex-secretary melanoma study
group
-
-
-
Victoria
Sarah
Cohen
Coupland
10/07/2013
10/07/2013
Member of advisory
committees
for
pharmaceutical
companies with drugs
in development for
melanoma
(GSK,
Roche, Astra Zeneca
and BMS) -Reported
at meeting 1
-
-
-
-
-
Kathryn
Bertil
Curtis
Damato
10/07/2013
02/04/2012
-
CRUK sponsorship for collection
of clinical samples collected
during the ITEM and SUAVE
studies (Novartis and Pfizer)
Reported at meeting 1
Have received support from
Bebig (manufacturing plaques),
Ellex (manufacturing ocular
ultrasound machines) and Optos
(manufacturing cameras).
Chair of trustees of OcuMel
See
PubMed
articles
Receive
royalties
for
textbooks
or
chapters
relating
to uveal
tumours.
-
Jonathan
Evans
07/08/2013
Involvement in the Delcath system Reported at meeting 1
Stephen
Lesley
Fenwick
Kirkpatrick
10/07/2013
10/07/2013
-
-
-
-
-
-
Page 108 of 112
Uveal Melanoma Guidelines January 2015
First Name
Last Name
DOI
last
updated
Personal Pecuniary
Non-personal pecuniary
National body
Stated personal
opinion
Editorial
Patents
Olivia
Ernie
Li
Marshall
01/03/2012
10/07/2013
-
Pharmaceutical
company
sponsored drug trials - ITEM and
SUAVE
NCRI, Melanoma CGG
Screening,
psychology and
treatment
-
-
Kieran
Bruce
Christian
McGuirk
Oliver
Ottensmeier
10/07/2013
04/03/2012
10/07/2013
Consulting for Bristol
Myers Squibb and
Novatis
Research funding for a clinical
trial for Ipilimumab for lung
cancer
Chair of trustees of OcuMel
-
-
-
Neil
Pearce
03/01/2012
Strong opinion
that
immunology
plays a role.
(Reported
at
meeting 1)
See above re
OcumelUK,
Brian
Stedman
27/04/2012
-
-
-
Sachin
Salvi
10/07/2013
-
-
-
I have written patient advice
for the OcumelUK website /
patient forum on surgical
aspects of management of
metastatic uveal melanoma
Sponsorship
from
radiology providers.
'Temmis'
Manufacturers,
DP
beamis/TACE, Medical
Advisor
for
and
sporsonship
from
SIRTX
-
-
-
-
National
Group
Ocular
Oncology
Page 109 of 112
Uveal Melanoma Guidelines January 2015
First Name
Last Name
DOI
last
updated
Personal Pecuniary
Non-personal pecuniary
National body
Stated personal
opinion
Peter
Szlosarek
15/6/14
-
-
-
Nancy
Turnbull
01/07/2013
Sponsored by BMI to
attend
ASCO
conference 2014
-
-
-
-
Editorial
Patents
-
-
Page 110 of 112
-
Uveal Melanoma Guidelines January 2015
E - Guideline Reviewers
Individuals and organisations involved in the care of patients with uveal melanoma were invited to review the
draft guideline.
The invitation to review the guideline was also posted on the Melanoma Focus website.
The GDG are grateful to the organisations and colleagues who took the not inconsiderable tiem to read the
guideline and provide comments. These were:
Organisations

British Society of Interventional Radiology

British Oculoplastic Surgery Society

EORTC Ocular Group

International society of ocular oncology

International Eye Cancer website

Melanoma Focus

OcuMel

The Royal College of Radiologists
Individuals
Dr
Ruth
Board
Dr
Richard
Carvajal
Dr
Pippa
Corrie
Consultant and Associate
Lecturer in Medical Oncology
Dr
Sarah
Danson
Medical Oncologist
Ms
Sheena
Dryden
Nurse specialist
Ms
Rhona
Jacques
Nurse specialis
Dr
Nasir
Khan
Interventional Radiologist
Prof
Tero
Kivela
Professor and Chair, Department
of Ophthalmology
Mr
Ali
Majeed
Liver Surgeon
Dr
Hardeep
Singh
Bruce
Mudhar
Consultant Ophthalmic
Histopathologist,
Patient
Mr
Oliver
Consultant medical oncologist
Lancashire teaching hospital.
Memorial Sloan-Kettering
Cancer Center New York USA
Cambridge University Hospitals
NHS Foundation Trust
(Addenbrooke's Hospital)
Royal Hallamshire Hospital,
Sheffield
NHS Lothian, Scotland
Royal Hallamshire Hospital,
Sheffield
Royal Marsden, London
Helsinki University Central
Hospital
Helsinki, Finland
Royal Hallamshire Hospital,
Sheffield
Royal Hallamshire Hospital,
Sheffield
Yorkshire
Page 111 of 112
Uveal Melanoma Guidelines January 2015
Mr
Mandeep Sagoo
Ocular Oncologist
St Bartholomew's and Moorfields
Eye Hospital, London
Mr
Arun
Singh
Ocular oncologist
Cleveland
Dr
Karen
Sisley
Senior Lecturer, Department of
Oncology
University of Sheffield
The following appendices are posted separately on the website of Melanoma Focus
http://melanomafocus.com/activities-2/um-guidelines-resources/.


Guideline Development Methodology
Summary of Information (for patients, carers and public)
Consultation Comments & GDG Responses
 Presentations of Evidence Used at GDG Meetings
 PowerPoint Presentation of Key Points (for use in training)

In addition the NICE accreditation application and report are publically
available from NICE.
Page 112 of 112