Uveal Melanoma Guidelines – Draft for Consultation
Uveal Melanoma National Guidelines
Draft for public consulation June 2014
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
1. Executive Summary ...... 6 1.1 Care Pathway ...... 6 1.2 Recommendations ...... 8 1.2.1 Patient Choice and Shared decision-making ...... 8 1.2.2 Service Configuration ...... 8 1.2.3 General Guidance...... 8 1.2.4 Primary management ...... 9 1.2.5 Prognostication ...... 11 1.2.6 Surveillance ...... 12 1.2.7 Metastatic disease ...... 13 2. Background ...... 15 2.1 Introduction ...... 15 2.2 Strengths and limitations of the evidence ...... 16 2.3 Risks versus benefits ...... 16 2.4 Scope and purpose ...... 16 2.4.1 Aim of the guideline ...... 16 2.4.2 Clinical areas covered by the guideline ...... 17 2.4.3 Target population and target audience ...... 17 2.5 Acknowledgements ...... 17 3. Methodology ...... 18 3.1 Levels of Evidence ...... 18 3.2 Grade of recommendations ...... 19 4. Management of the primary tumour ...... 19 4.1 Introduction ...... 19 4.2 Methods ...... 20 4.2.1 Questions addressed ...... 20 4.2.2 Inclusion and Exclusion criteria for selecting evidence ...... 21 4.2.3 Appraisal and Extraction ...... 21 4.3 Evidence Summary ...... 21
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4.3.1 Question 1. What are appropriate pre-operative investigations for the primary tumour? 21 4.3.2 Question 2. Should patients be staged before primary treatment? ...... 23 4.3.3 Question 3. What is the optimal primary treatment? ...... 25 4.4 Evidence Statements...... 37 4.4.1 Pre-operative investigations ...... 37 4.4.2 Staging before primary treatment ...... 38 4.4.3 Primary Treatment ...... 38 4.5 Recommendations ...... 39 4.6 Linking evidence to recommendations ...... 39 5. Prognostication ...... 40 5.1 Introduction ...... 40 5.2 Methods ...... 40 5.2.1 Questions addressed ...... 40 5.2.2 Inclusion and exclusion criteria for selecting evidence ...... 41 5.2.3 Appraisal and extraction ...... 41 5.3 Review of Evidence ...... 41 5.3.1 Is there a preferred prognostic tool? ...... 41 5.3.2 What is the role of prognostic biopsy? ...... 44 5.4 Evidence Statements...... 44 5.4.1 Prognostic factors/tool ...... 44 5.4.2 Prognostic biopsy ...... 44 5.5 Recommendations ...... 44 5.6 Linking Evidence to Recommendations ...... 45 6. Surveillance of patients at risk of recurrence ...... 45 6.1 Introduction ...... 45 6.2 Methods ...... 46 6.2.1 Questions addressed ...... 46 6.2.2 Inclusion and exclusion criteria for selecting evidence ...... 47 6.2.3 Appraisal and extractions ...... 47 6.3 Evidence summary ...... 47 6.3.1 Question 1: Should all patients be offered surveillance? ...... 47 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? ...... 48
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6.3.3 Question 3: What is the optimal imaging modality for surveillance, overall and of the liver? 49 6.3.4 Question 4: What is the optimal surveillance interval? ...... 50 6.3.5 Question 5: What is the duration of surveillance? ...... 50 6.4 Evidence Statements...... 51 6.5 Recommendations ...... 51 6.6 Linking evidence to recommendations ...... 51 7. Metastatic Disease ...... 52 7.1.1 Introduction ...... 52 7.2 Methods ...... 56 7.2.1 Questions addressed ...... 56 7.2.2 Inclusion and exclusion criteria for selecting evidence ...... 57 7.2.3 Appraisal and extraction ...... 58 7.3 Evidence summary ...... 58 7.3.1 Question 1. What is the optimal method of staging? ...... 58 7.3.2 Question 2. Is there a preferred prognostic method for a patient with metastatic disease 59 7.3.3 Question 3. What is the optimal management of systematic metastases? ...... 60 7.3.4 Question 4. What is the optimal treatment for oligometastatic disease outside the liver 61 7.3.5 Question 5. What is the optimal management of liver only metastases?...... 62 7.3.6 Question 6. Is regional liver therapy more effective than systemic therapy...... 63 7.3.7 Question 7. What is the role of surveillance following liver metastases treatment? .. 63 7.4 Evidence Statements...... 64 7.4.1 Staging ...... 64 7.4.2 Preferred prognostic method ...... 64 7.4.3 Management of systemic disease ...... 64 7.4.4 Management of oligometastatic-extrahepatic metastatic disease ...... 65 7.4.5 Management of liver disease ...... 65 7.4.6 Systemic versus targeted liver treatment ...... 65 7.4.7 Surveillance following liver treatment ...... 65 7.5 Recommendations ...... 65 7.6 Linking evidence to recommendations ...... 65 7.6.1 Staging ...... 65 7.6.2 Preferred prognostic method ...... 66 um_guideline_cons_draft_v2_23_6_14 Last saved by Nancy Turnbull Date 16 June 2014 Page 4 of 93
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7.6.3 Management ...... 66 7.6.4 Surveillance following liver treatment ...... 67 8. Using and implementing the guideline ...... 67 8.1 Potential organisational and financial barriers in applying its recommendation ...... 67 8.2 Audit criteria ...... 69 9. Review and updates ...... 71 10. Research recommendations ...... 71 References ...... 71 Appendices ...... 83
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1 1. Executive Summary
2 1.1 Care Pathway 3 For the flow chart in draft form, please refer to the version which is posted separately on the Melanoma Focus 4 website. This will be finalised following the consultation process and inserted into the final document. When 5 reading please refer to the three boxes below.
BOX 1 TREATMENT OPTIONS Treatment Used for Outcomes Complications Comments RADIOTHERAPY Brachytherapy Small/Medium Good local Loss of vision Dose and position of plaque can be Ruthenium 106 /Large uveal tumour Tumour adjusted to limit the loss of vision Iodine 125 melanoma <20mm in control recurrence basal diameter Proton Beam Medium to Large Good local Loss of vision Not available in all ocular oncology radiotherapy uveal melanoma tumour Loss of the eye units which can not be control from neovascular treated with glaucoma brachytherapy Stereotactic Juxta papillary uveal Good local Loss of vision Not available in all ocular oncology radiosurgery melanoma ; patients tumour Radiation related units unsuitable for control complications ruthenium plaque or unfit for surgery PHOTOTHERAPY Transpupillary Local recurrence and Improves Loss of vision Avoids radiotherapy complications thermotherapy of adjuvant therapy local Extraocular and may be useful when of uveal melnonma tumour tumour considering preservation of vision control recurrence for small melanoma nasal to the optic disc. However, it is no longer recommended as a sole primary treatment. Photodynamic Small amelanotic uncertain Tumour Avoids radiotherapy complications therapy melanoma recurrence New treatment option not widely used for uveal melanoma SURGERY Exoresection +/- Medium to large variable Retinal Always performed with plaque melanoma with a detachment brachytherapy to reduce the risk of narrow basal Loss of vision recurrence diameter Loss of the eye Tumour recurrence Endoresection +/- Toxic tumour variable Intraocular Rarely performed radiotherapy syndrome haemorrhage Tumour seeding Enucleation Large uveal 100% local Socket related Cosmetic results are reasonably melanoma tumour complications good with an orbital implant and Melanoma control if artificial eye associated with completely neovascular excised glaucoma +/- extensive retinal 6 detachment 7
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1 COMMISSIONING OF CARE BOX 2 PROGNOSTICATION The suspected diagnosis of uveal melanoma by the The following features should be recorded: referring clinician should follow the same pathways as any Age other suspected cancer. The ocular oncology centre Gender should be notified within 48 hours of presentation and the Tumour location patient should be seen by the specialist within two weeks. Tumour height Surgeons who see a patient with a recurrence who was Tumour Largest basal diameter treated elsewhere should inform the treating centre. Ciliary body involvement Extraocular melanoma growth Patients should be informed about and recruited into The following features should be recorded if clinical trials wherever possible. tissue is available: Supra-regional specialist multi-disciplinary teams (MDT), Cell type (modified Callendar using a network model, should be established that allow a system) coordinated approach for the care and follow-up of all Mitotic count (number/40 high patients with metastatic uveal melanoma. For advanced power fields in H&E stained disease a specialist oncology MDT should consist of a sections) medical or clinical oncologist, an interventional radiologist, Presence of extravascular matrix a histopathologist, a liver surgeon and a clinical nurse patterns (particularly closed specialist, all with experience in treating of uveal connective tissue loops; enhanced melanoma and with direct links to ocular surgical oncology with Periodic acid Schiff staining). centres. The MDT should make recommendations on an individual patient’s tumour staging and management, and A minimum dataset for uveal melanoma have available all treatments and trials locally or by from the Royal College of Pathology should referral. be recorded. A national register, based on a standardised minimum data Any molecular testing should be carried out set, should be established where details of every patient within an accredited laboratory with appropriate quality assurance in place to with a diagnosis of uveal melanoma are entered, with provide the standards of the diagnostic test. follow-up data collected at least annually.
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.
PATIENT INFORMATION AND
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.
SHARED DECISION MAKING
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1 1.2 Recommendations 2 Note: All of the recommendations are listed in this section and are not duplicated in the clinical chapter. 3 Within each clinical chapter there are hyperlinks to the relevant recommendations and a hyperlink to return to 4 the chapter.
5 The grading of the recommendations is detailed in the methodology section.
6 1.2.1 Patient Choice and Shared decision-making
7 1. All specialist ocular oncology multidisciplinary teams (MDTs) should collaborate to produce an 8 information leaflet on the options available nationally. [GPP]
9 2. All available procedural and treatment options, both local and national, should be discussed with 10 the patient. [GPP]
11 3. The risks and benefits of any procedures and treatments being considered should be fully discussed 12 with the patient, including their impact on quality of life. [GPP]
13 1.2.2 Service Configuration 14 4. Supra-regional specialist multi-disciplinary teams (MDT), using a network model, should be 15 established that promote a coordinated approach for the care and follow-up of all patients with 16 uveal melanoma. For advanced disease, a specialist oncology MDT should consist of a medical or 17 clinical oncologist, an interventional radiologist, a histopathologist, a liver surgeon and a clinical 18 nurse specialist, all with experience in treating uveal melanoma and with direct links to ocular 19 surgical oncology centres. The MDT should make recommendations on an individual patient’s 20 tumour staging and management, and have available all treatments and trials locally or by referral. 21 [GPP]
22 5. Any molecular testing should be carried out within an accredited molecular pathology laboratory 23 with appropriate quality assurance in place to provide the required standards and experienced 24 interpretation of the diagnostic test, in compliance with national requirements. [GPP]
25 6. A national register, based on a standardised minimum data set, should be established where details 26 of every patient with a diagnosis of uveal melanoma are entered, with follow-up data collected at 27 least annually. [GPP]
28 1.2.3 General Guidance 29 7. All local recurrences of the primary uveal melanoma should be reported to a surgical ocular 30 oncology centre. [GPP]
31 8. All Optometrists and Ophthalmologists should receive training in the recognition of uveal 32 melanoma, in order to allow earlier detection and timely referral of patients with uveal melanoma. 33 [GPP]
34 9. Each surgical ocular oncology centre should audit their results and share them nationally. [GPP]
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1 10. The suspected diagnosis of uveal melanoma by the referring clinician should follow the same 2 pathways as for any other suspected cancer. The ocular oncology centre should be notified within 3 48 hours of presentation and the patient seen by the specialist within two weeks. Grade C
4 11. Suspicious lesions or lesions diagnosed as uveal melanoma should be referred to a consultant 5 surgical ocular oncologist in one of the surgical oncology centres for ocular malignancies. Grade D
6 12. Specimens should be reported by an ophthalmic pathologist within a specialist centre. [GPP]
7 13. All patients with a new diagnosis of uveal melanoma should be offered referral to a medical or 8 clinical oncologist with a specialist interest in the disease. [GPP]
9 14. Patients should be informed about and recruited into clinical trials wherever possible. [GPP]
10 15. Patients should be offered the opportunity to participate in uveal melanoma specific research. With 11 patient consent, samples should be taken surplus to diagnostic requirements and stored in an 12 ethically-approved quality biobank for research purposes. [GPP]
13 1.2.4 Primary management
14 Pre-operative investigations 15 16. Make a diagnosis of uveal melanoma using ophthalmoscopy, fundus photography and conventional 16 ocular ultrasound. Grade A
17 17. Cillary body melanoma should be imaged with UBM or anterior segment OCT. Grade D
18 18. If the clinical diagnosis is uncertain following the above-mentioned techniques then diagnostic 19 biopsy should be considered and balanced against potential risks of the procedure [GPP]
20 19. Fine needle aspiration biopsy can be performed either with a direct transcleral approach or using a 21 transvitreal approach. Grade D
22 Staging before primary treatment 23 20. A decision on staging should be made based on the individual circumstances of the patient, but 24 staging should not delay the primary management of the tumour. [GPP]
25 21. Staging should be considered in the following circumstances:
26 The patient is at particularly high risk because of the clinical features of their presentation. 27 The patient is particularly anxious and requires reassurance [GPP]
28 Treatment of the primary tumour 29 22. Patients should be informed that there is no proven survival advantage between any of the offered 30 modalities. Grade A
31 23. Treat patients using table below
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Treatment Used for Outcomes Complications Comments Grade of recommendatio ns RADIOTHERAPY Brachytherapy Grade A Ruthenium 106 Small/Medium Good local Loss of vision Dose and position Iodine 125 /Large uveal tumour Tumour of plaque can be melanoma* control recurrence adjusted to limit <20mm in basal the loss of vision diameter
Proton Beam Medium to Good local Loss of vision Grade C radiotherapy Large uveal tumour Loss of the eye melanoma control from NVG which can not be treated with brachytherapy Stereotactic Juxta papillary Good local Loss of vision Grade C radiosurgery uveal tumour Radiation related melanoma ; control complications patients unsuitable for ruthenium plaque or unfit for surgery
PHOTOTHERAPY Transpupillary Local Improves Loss of vision Avoids radiotherapy Grade C thermotherapy recurrence and local tumour Extraocular complications and of adjuvant control tumour may be useful when therapy of recurrence considering uveal preservation of melnonma vision for small melanoma nasal to the optic disc. However, it is no longer recommended as a sole primary treatment. Photodynamic therapy Small Uncertain Tumour Avoids radiotherapy amelanotic recurrence complications melanoma New treatment option not widely used for uveal melanoma
SURGERY Exoresection +/- plaque Medium to Variable Retinal Always performed Grade C large detachment with brachytherapy melanoma with Loss of vision to reduce the risk of a narrow basal Loss of the eye recurrence diameter Tumour recurrence Endoresection +/- Toxic tumour Variable Transient Rarely performed Grade D um_guideline_cons_draft_v2_23_6_14 Last saved by Nancy Turnbull Date 16 June 2014 Page 10 of 93
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Treatment Used for Outcomes Complications Comments Grade of recommendatio ns radiotherapy Syndrome intraocular haemorrhage; Rarely tumour seeding
Enucleation Large uveal 100% local Socket related Cosmetic results Grade A melanoma tumour complications are reasonably Melanoma control if good with an associated with completely orbital implant and NVG +/- excised artificial eye extensive retinal detachment 1 * = as defined by (Diener-West, Hawkins et al. 1992)
2 Follow-up after primary treatment 3 24. Patients treated with plaque brachytherapy, proton beam radiotherapy or sterotactic radiotherapy 4 should be monitored for tumour regression intensively over the first two years following treatment. 5 Long-term follow up intervals depend of the response of the tumour to brachytherapy and the 6 radiotherapy complications experienced. [GPP]
7 Return to chapter by clicking HERE
8 1.2.5 Prognostication
9 Prognostic factors/tool 10 25. Prognostic factors of uveal melanoma are multi-factorial and include clinical, morphological and 11 genetic features. The following features should be recorded:
12 Age 13 Gender 14 Tumour location 15 Tumour height 16 Tumour Largest basal diameter 17 Ciliary body involvement 18 Extraocular melanoma growth (macroscopic) 19 The following features should be recorded if tissue is available:
20 Cell type (modified Callendar system) 21 Mitotic count (number/40 high power fields in H&E stained sections) 22 Presence of extravascular matrix patterns (particularly closed connective tissue loops; enhanced 23 with Periodic acid Schiff staining). Grade A 24 Presence of extraocular melanoma growth (size, presence or absence of encapsulation). [GRADE A]
25 Prognostic biopsy
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1 26. There should be a fully informed discussion with all patients, explaining the role of biopsy including 2 the benefits and risks. The discussion should include:
3 Risk of having the biopsy 4 Limitations of the investigation 5 Benefits for future treatments (including possible recruitment to trials) 6 Impact on quality of life 7 Recruitment to trials [GPP] 8
9 27. The minimum dataset for uveal melanoma from the Royal College of Pathology should be recorded. 10 http://www.rcpath.org/publications-media/publications/datasets/uveal-melanoma.htm Grade D
11 28. Tests for novel serological biomarkers should only be used within clinical trials or research 12 programmes. [GPP]
13 29. Consider collecting molecular genetic and/or cytogenetic data for research purposes where tumour 14 material is available and where patient consent has been obtained as part of an ethically approved 15 research programme. [GPP}
16 30. Use of the current (i.e. 7th) Edition of the TNM staging system for prognostication is highly 17 recommended. Grade A
18 31. Use of multifactorial prognostication models should be considered. Grade D
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20 1.2.6 Surveillance 21 32. Prognostication and surveillance should be led by a specialist multidisciplinary team that 22 incorporates expertise from ophthalmology, radiology, oncology, cancer nursing and hepatic 23 services. [GPP]
24 33. Prognosticon and risk prediction should be based on the best available evidence, taking into 25 account clinical, morphological and genetic cancer features. [GPP]
26 34. All patients, irrespective of risk, should have a holistic assessment to discuss the risk, benefits and 27 consequences of entry into a surveillance programme. The discussion should consider risk of false 28 positives, the emotional impact of screening as well as the frequency and duration of screening. An 29 individual plan should be developed. [GPP]
30 35. Patients judged at high-risk of developing metastases (Damato, Eleuteri et al. 2011),(Marshall, 31 Romaniuk et al. 2013) should have 6-monthly life-long surveillance incorporating a clinical review, 32 nurse specialist support and liver-specific imaging by a non-ionising modality. [GPP]
33 36. Liver function tests alone are an inadequate tool for surveillance. Grade C
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1 1.2.7 Metastatic disease
2 Staging 3 37. Patients should have whole body staging (chest, abdomen and pelvis) with CT scan or PET CT. 4 Grade D
5 38. Brain imaging should not be carried out in the absence of symptoms. [GPP]
6 39. Patients who have symptomatic bony pain should have a bone scan to assess the presence of bony 7 disease. [GPP]
8 40. Contract enhanced MRI with diffusion weight imaging should be used to stage liver disease when 9 assessing operability. Grade D
10 41. Contrast-enhanced CT scan should be used to stage extrahepatic disease. Grade D
11 Prognostic method 12 42. This minimum data set should be collected for all patients with systemic disease (Stage IV) for 13 future validation:
14 Metastatic Tumour Burden (site, volume, diameter and number), 15 LDH 16 ALP 17 GGT 18 Bilirubin 19 Presence or absence of ascites 20 Gender 21 Age 22 Performance status, 23 DFS following definitive primary therapy. [GPP] 24 25 43. A tissue sample should be taken to confirm the diagnosis of metastatic uveal melanoma unless 26 contraindicated. [GPP]
27 44. Curative (R0) resection is the most important positive prognostic factor following liver resection. 28 [GPP]
29 Management of systemic and oligometastatic-extrahepatic disease 30 45. Patients should be considered for clinical trials wherever possible and be informed of available trial 31 options at other centres.[GPP]
32 46. Patients with good performance status (PS 0-2) who decline trials or for whom no suitable clinical 33 trials are available should be offered systemic treatments and managed in specialist centres with 34 appropriate oncology expertise in uveal melanoma. [GPP]
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1 47. Specialist centres should be involved in treatment decisions and review, but a patient may prefer to 2 receive supportive care and systemic treatment locally. [GPP]
3 48. Patients with liver predominant disease should be considered for regional therapy. Grade D
4 49. Loco-regional treatment for the management of oligometastatic disease should be considered. This 5 may include surgery, stereotactic treatment or other forms of ablation.[GPP]
6 50. Ipilimumab can be offered in the UK following NICE approval of this drug for use in melanoma 7 generically.
8 Management of liver metastases 9 51. For patients with technically resectable disease, assessment for curative intent hepatic resection 10 should be offered. Grade D
11 52. Pre-operative diagnostic laparoscopy should be performed in patients with radiologically resectable 12 liver metastases, as many of these patients will have a miliary pattern of disease. Grade D
13 53. Regional or systemic treatments may be considered in patients with liver dominant disease where 14 resection is not suitable. [GPP]
15 Surveillance following liver treatment 16 54. Patients treated with curative intent should be followed with regular hepatic MRI and CT of chest, 17 abdomen and pelvis. [GPP]
18 55. Patient outcomes for this selected group should be collected centrally and prospectively. [GPP]
19 Return to chapter by clicking HERE
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1 2. Background
2 2.1 Introduction 3 Uveal melanoma has an incidence of approximately 6-9 per million per year in Caucasians; these tumours are 4 even less common in races with brown eyes. More than 90% involve the choroid, the remainder being 5 confined to iris and ciliary body. Both sexes are affected in equal numbers. (McLaughlin, Wu et al. 2005; 6 Damato and Damato 2012) The age at presentation peaks at approximately 60 years, except for iris 7 melanomas, which usually present at a younger age. (Damato and Damato 2012) (Shields, Shields et al. 2001) 8 Risk factors for uveal melanoma include light-coloured irides (Saornil 2004), congenital ocular melanocytosis 9 (Singh, De Potter et al. 1998), melanocytoma (Reidy, Apple et al. 1985) and neurofibromatosis (Singh, De 10 Potter et al. 1998). The role of sunlight is uncertain (Singh, Rennie et al. 2004). Familial cases are very rare but 11 some patients may have familial atypical mole and melanoma syndrome; these cases require monitoring by a 12 dermatologist as they are also at risk of cutaneous melanoma (Smith, Padnick-Silver et al. 2007). Rare families 13 carry germline mutations of the BAP1 gene on chromosome 3, which predisposes them to develop uveal 14 melanoma, mesothelioma and other cancers (Cheung, Talarchek et al. 2013).
15 Staging for uveal melanoma follows the American Joint Committee on Cancer (AJCC) Tumor-Node-Metastasis 16 (TNM) staging system for eye cancer (Finger and The 7th Edition AJCC-UICC Ophthalmic Oncology Task Force 17 2009). Outcomes for patients with uveal melanoma vary widely, but for patients with early tumours they are 18 excellent. In a cohort of 8033 patients, the 10-year metastatic rate for a 1-mm-thick uveal melanoma was 5%, 19 for a 2-mm-thick uveal melanoma it was 10%, and that for a 6-mm-thick uveal melanoma it was 30% (Diener- 20 West, Hawkins et al. 1992). When grouping 7621 uveal melanomas into small (0-3mm thick, 29.8%), medium 21 (3.1-8 mm thick, 49%) or large (>8 mm thick, 20.9%) tumours, the 10-year rates of detecting metastases were 22 11.5%, 25.5% and 49.2% respectively (Shields, Furuta et al. 2009).
23 An online tool, the Liverpool Uveal Melanoma Prognosticator Online (LUMPO), has been developed and is 24 freely available. It generates an all-cause mortality curve according to age, sex, AJCC TNM size category (based 25 on basal tumour diameter and tumour height), ciliary body involvement, melanoma cytomorphology, closed 26 loops, mitotic count, chromosome 3 loss, and presence of extraocular spread (www. 27 ocularmelanomaonline.com) (Damato, Eleuteri et al. 2011).
28 Cytogenetic and molecular genetic features of the uveal cells have been demonstrated to have strong 29 prognostication value in uveal melanoma. The most striking abnormality in uveal melanoma is the complete or 30 partial loss of chromosome 3. Other common genetic abnormalities of uveal melanoma include loss on the 31 short arm (p) of chromosome 1, and gains on 6p and 8q (see review, (Coupland, Lake et al. 2013). The above- 32 mentioned chromosomal alterations in primary UM are clinically relevant because of their correlation with the 33 risk of metastatic death. Chromosome 3 loss is associated with a reduction of the 5-year survival probability 34 from approximately 100% to about 50%. Similarly, chromosome 8 gains and loss of chromosome 1 significantly 35 correlate with reduced survival. Conversely, gains in chromosome 6p correlate with a good prognosis, 36 suggesting this aberration has a functionally protective effect.
37 The natural history of uveal melanoma is characterised by the frequent development of metastases and 38 patients develop metastatic disease at any time from the initial diagnosis of the primary to several decades 39 later (Kujala, Makitie et al. 2003; Diener-West, Reynolds et al. 2005; Marshall, Romaniuk et al. 2013). The risk
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1 of metastatic relapse for an individual varies greatly dependent on primary tumour characteristics and genetic 2 alterations.
3 Outcomes are poor once metastatic disease occurs. The median survival from the time of the development of 4 distant metastatic disease is 2 to 12 months and 1-year survival 10-15%. This range reflects a number of 5 prognostic factors including the burden of metastatic disease and the effect of metastatic screening 6 programmes (Augsburger, Correa et al. 2009).
7 The liver is the most common site for uveal melanoma metastases, with 50% of patients having liver-only 8 disease, and 90% of those with metastases elsewhere (bowel, bone, lung and lymph nodes) also having liver 9 metastases (Lorigan, Wallace et al. 1991; Collaborative Ocular Melanoma Study 2001). Liver disease is usually 10 multifocal, often in a miliary distribution, but some patients may develop isolated metastases, enabling 11 surgical removal. Liver involvement is the cause of death in most patients with metastatic uveal melanoma 12 (Collaborative Ocular Melanoma Study 2001). Most patients die from parenchymal liver failure, but 13 obstructive jaundice may result from liver metastases compressing the common hepatic or intrahepatic ducts 14 or, less commonly, from porta hepatis nodal disease compressing the extrahepatic duct.
15 2.2 Strengths and limitations of the evidence 16 Due to the rarity of uveal melanoma and associated poor prognosis, there is limited clinical evidence guiding 17 the optimal treatment of metastatic disease. Most reports in the literature are of small case series of ten or 18 fewer patients. Larger non-randomised studies were scrutinised carefully for a survival bias as mortality is so 19 high. With regard to treatment of primary tumours, each UK centre tends to have specific areas of interest 20 and no centre offers all potential treatment options. Whilst the centres compare their results in regular 21 meetings, there are no randomised comparative trials (RCT) from the UK. The COMS study (Collaborative 22 Ocular Melanoma Study (http://www.jhu.edu/wctb/coms/) in the US has provided a valuable sorce of data; 23 however, overall, the limitations of the evidence base in the literature are considerable. The COMS study is 24 discussed in more detail in section 4.
25 2.3 Risks versus benefits 26 In weighing up the risks and benefits of any intervention, the Guideline Development Group (GDG) has 27 concentrated on an analysis of clinical benefit and, where appropriate, toxicity. It has not performed any cost- 28 effectiveness analyses as this falls outside the remit of these guidelines.
29 2.4 Scope and purpose
30 2.4.1 Aim of the guideline 31 The aim of these guidelines is to optimise patient care by providing recommendations based on the best 32 available scientific evidence. These guidelines should assist the planning of patient care and provide an 33 indication of the likely clinical outcomes, as well as facilitating patient counselling and informed decision- 34 making. Where adequate evidence is lacking, the GDG has, where possible, arrived at an expert consensus. 35 The Group recognises, however, that each patient is an individual. These guidelines should therefore neither 36 be prescriptive nor dictate clinical care; however, where care significantly differs from the guidelines, it should 37 be justifiable. Our review also identifies gaps in current evidence, thereby defining scope for further research 38 and audit.
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1 The GDG has reviewed the evidence, where available, for the key areas of uncertainty in the field, which 2 include:
3 The use and effectiveness of new technologies such as cytogenetics/genetic analysis for 4 prognostication. 5 The appropriate pathway for the surveillance of patients following treatment for primary uveal 6 melanoma. 7 The use and effectiveness of new technologies in the treatment of hepatic recurrence. 8 The use of systemic treatments. 9
10 2.4.2 Clinical areas covered by the guideline 11 This guideline addresses the diagnosis and management of primary uveal melanoma, including iris and ciliary 12 body melanoma in adults (>16 years). It does not address conjunctival melanoma, which has a pathogenesis 13 and behaviour more in common with mucosal and cutaneous melanomas.
14 The guideline addresses four main clinical topics:
15 Management of the primary tumour 16 Prognostication 17 Surveillance of patients at risk of recurrence 18 Metastatic disease 19
20 2.4.3 Target population and target audience 21 The guideline is relevant to people with a confirmed or suspected diagnosis of uveal melanoma, as well as their 22 family and carers.
23 The guideline will be helpful to all health professionals who provide care for people with uveal melanoma. This 24 includes ophthalmologists, opticians, liver surgeons, radiologists, pathologists, specialist cancer nurses and 25 oncologists.
26 2.5 Acknowledgements 27 The GDG is grateful to Melanoma Focus for its support in funding the development of this guideline and for 28 hosting the consultation and the final product on its website. We would like to thank those people who 29 helped with the searches and review of the evidence. These include: the Royal College of Physicians Library 30 Services, who carried out the searches; Ruth Poulter, Clinical Trial Coordinator at University of Liverpool, who 31 obtained papers; and Dr Rachel O’Mahony, who reviewed and extracted the evidence where the members of 32 the GDG was unable to do so due to time constraints. The GDG members also express their gratitude to all 33 those colleagues worldwide who gave their constructive comments on the draft. See Appendix E for the names 34 of those who provided comments.
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1 3. Methodology 2 The guideline was convened under the UK Melanoma Study Group, a precursor of Melanoma Focus, now a 3 national charity with a professional core membership undertaking research and education in the field of 4 melanoma and skin cancers. The guideline and supporting documentation are available on the Melanoma 5 Focus website http://melanomafocus.com/activities-2/ocular-melanoma-project/). The development of the 6 guideline was led by Dr Paul Nathan, who is a trustee of Melanoma Focus and a medical oncologist with an 7 interest and expertise in the treatment metastatic melanoma. Other officers and trustees of Melanoma Focus 8 played no part in the development of the guideline and did not comment on the guideline prior to the public 9 consultation.
10 The number of health professionals who provide care to patients with uveal melanoma in the UK is relatively 11 small and the aim was to reflect the views of a significant proportion of these within the GDG. There are three 12 ocular oncology referral centres in England that deliver primary treatment (surgery) for patients with uveal 13 melanoma (Liverpool, London and Sheffield) while a handful of other centres have a specialist interest in the 14 treatment of uveal melanoma metastatic disease. GDG members were selected to represent these centres as 15 well as the professions involved in delivering care. In addition to the thirteen health professionals, including a 16 trainee, there were originally three patient representatives (one of whom resigned for personal reasons) and a 17 project manager on the GDG. The guideline was started in February of 2012, with the first Guideline 18 Development Group meeting held in April 2012; in all, seven GDG meetings were held over a period of two 19 years.
20 As the clinical area and the associated body of literature is small, it was decided to do one all-encompassing 21 initial literature search and then to sift references for each question within the database. The original search 22 was carried out by the Royal College of Physicians on 27 March 2012, with the search repeated to identify new 23 evidence on 21 June 2013 and again 16 April 2014. Questions were drafted based on input from GDG 24 members. Subgroups of content experts on the GDG worked on each topic, agreeing the criteria for including 25 papers, then appraising and extracting references using a ‘Scottish Intercollegiate Guidelines Network’ (SIGN) 26 checklist as a guide. However as most of the evidence consisted of small case series, for some questions 27 additional criteria were applied to appraise quality, in particular whether the case series included patients 28 from more that one centre. The sub-groups were supported and advised by a guideline methodologist. The 29 subgroups presented the evidence review and extraction tables to the full GDG at the group’s meetings. The 30 full GDG discussed the evidence and formulated evidence statements and recommendations. A great deal of 31 work was done electronically and following update search revisions all GDG members were sent several drafts 32 of chapters for comment.
33 The evidence was appraised and extracted into tables; see Appendix A, which includes many references that 34 were reviewed but not included in the final document.
35 A detailed description of the methodology is available in the document entitled Uveal Melanoma Guideline 36 Development Methodology at (weblink)
37 3.1 Levels of Evidence 38 The grading of the evidence is based on the Scottish Intercollegiate Guidelines Network (SIGN) grading system 39 1999-2012 http://www.sign.ac.uk/guidelines/fulltext/50/annexoldb.html
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1 1++ High quality meta-analyses, systematic reviews of RCTs, or RCTs with a very low risk of bias 2 1+ Well-conducted meta-analyses, systematic reviews, or RCTs with a low risk of bias 3 1- Meta-analyses, systematic reviews, or RCTs with a high risk of bias 4 2++ High quality systematic reviews of case control or cohort or studies. High quality case control or 5 cohort studies with a very low risk of confounding or bias and a high probability that the relationship 6 is causal 7 2+ Well-conducted case control or cohort studies with a low risk of confounding or bias and a moderate 8 probability that the relationship is causal 9 2- Case control or cohort studies with a high risk of confounding or bias and a significant risk that the 10 relationship is not causal 11 3 Non-analytic studies, e.g. case reports, case series 12 4 Expert opinion
13 3.2 Grade of recommendations 14 The grading of recommendations is also based on SIGN 199-2012: 15 A At least one meta-analysis, systematic review, or RCT rated as 1++, and directly applicable to the 16 target population; or A body of evidence consisting principally of studies rated as 1+, directly 17 applicable to the target population, and demonstrating overall consistency of results 18 B A body of evidence including studies rated as 2++, directly applicable to the target population, and 19 demonstrating overall consistency of results; or Extrapolated evidence from studies rated as 1++ or 1+ 20 C A body of evidence including studies rated as 2+, directly applicable to the target population and 21 demonstrating overall consistency of results; or Extrapolated evidence from studies rated as 2++ 22 D Evidence level 3 or 4; orExtrapolated evidence from studies rated as 2+ 23 GPP Recommended best practice based on the clinical experience of the guideline development group 24
25 4. Management of the primary tumour
26 4.1 Introduction 27 Most uveal melanoma patients present with symptoms, including blurred vision, visual field loss, distorted 28 vision, photopsia (i.e. flashing lights), visible tumour in iris or episclera, red eye and pain. In the UK 29 approximately 30%-40% of patients are asymptomatic, their tumour being detected on routine ophthalmic 30 examination by an optometrist or ophthalmologist (Damato 2001). Delay in referral leads to an increased 31 likelihood that the patient will require an enucleation (removal of the eye) and as the result of more advanced 32 disease stage at presentation (including disseminated melanoma) (Damato 2012).
33 Without timely treatment, uveal melanomas tend to make the eye blind, painful and unsightly as a result of 34 retinal detachment, NVG and uveitis. Despite successful ocular treatment, up to 50% of all patients with large 35 ciliary body melanoma develop metastatic disease, which almost always involves the liver and which is usually 36 fatal within a year of the onset of symptoms. With successful treatment of the primary, the outlook is 37 excellent for many patients with uveal melanoma. In a cohort of 8033 patients, the 10-year metastatic rate for 38 a 1-mm-thick uveal melanoma was 5%, while for a 2-mm-thick uveal melanoma it was 10%, and for a 6-mm- 39 thick uveal melanoma it was 30% (Diener-West, Hawkins et al. 1992). When grouping 7621 uveal melanomas 40 into small (0-3mm thick, 29.8%), medium (3.1-8 mm thick, 49%) or large (>8 mm thick, 20.9%) tumours, the 10- 41 year rates of detecting metastases were 11.5%, 25.5% and 49.2% respectively (Shields, Furuta et al. 2009). In 42 the COMS study, the five-year survival figures for medium-sized choroidal melanoma were 91% in a group of 43 patients randomized to radiotherapy and 89% in the group randomized to enucleation (Diener-West, Earle et 44 al. 2001).
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1 The objectives of ocular treatment are to attempt to prevent metastatic disease and if possible to conserve the 2 eye with as much useful vision as possible. Enucleation has therefore been replaced, whenever possible, by 3 various forms of external radiotherapy, phototherapy and local resection, which are administered either 4 individually or in combination. Many factors influence the choice of ocular treatment, including: tumour size 5 and location, visual acuity in the affected eye and the fellow eye, and the patient’s general health as well as 6 the patient’s visual needs, wishes and concerns.
7 4.2 Methods
8 4.2.1 Questions addressed 9 The following questions were addressed.
Question Population Intervention Comparator Outcome Q 1. What are Patients with Biopsy With each Selection of appropriate appropriate pre- possible B-ultrasound other/ With treatment modality (see operative primary uveal sonography (USS) observation Q 3) investigations for the melanoma Photography only primary tumour? Fluorescein angiogram Optical Coherence Tomography Q 2. Should patients Patients with Any staging No staging Change of treatment of be staged before primary uveal investigation primary tumour primary treatment? melanoma 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 Patients with Including: With each other Primary: optimal primary primary uveal • Enucleation or with usual 1. Survival/ Distal treatment? melanoma • Proton beam therapy care recurrence • Plaque therapy 2. Preserving eye • Endo-resection 3. Preserving vision • Trans-sceleral resection Secondary: • Stereotactic 1. Quality of life radiotherapy 2. Visual Acuity • Thermotherapy 3. Local recurrence 4. Side-effects /complications 10
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1 4.2.2 Inclusion and Exclusion criteria for selecting evidence 2 Inclusion Criteria for all sections were: All study types in humans were considered but case-series had to be 3 N>5. Older treatment forms, such as Xenon Arc photocoagulation that are no longer in use, were excluded.
4 4.2.3 Appraisal and Extraction 5 All references were sifted first by one individual. The primary reasons for excluding papers were that the 6 papers did not address the question, or the techniques are now obsolete due to more recent advances, where 7 techniques have changed, or that papers had been superseded by more contemporary results.
8 The four different reviewers (members of the GDG) appraised and reviewed the included papers, and the 9 quality of the studies was assessed using the modified SIGN checklists. Most of the studies were case-series 10 and, because SIGN does not have a quality checklist for this study type, additional criteria were used to assign 11 an overall quality rating to these studies.
12 Information from each of the studies was extracted and presented to the GDG for discussion with an update of 13 the evidence presented after an update search in June 2013. For full details of each of the included studies, 14 see the evidence tables in Appendix B.
15 4.3 Evidence Summary
16 4.3.1 Question 1. What are appropriate pre-operative investigations for the 17 primary tumour?
18 4.3.1.1 Choroidal melanoma 19 In most cases the diagnosis of choroidal melanoma is based on ophthalmoscopy, fundus photography and 20 conventional ocular ultrasound. An early report on the diagnostic accuracy of ophthalmoscopy, fundus 21 photography and conventional ocular ultrasound showed that the combination of these tests gave a diagnostic 22 accuracy of 99.52% (Albert and Marcus 1990).
23 Conventional A and B scan ocular ultrasound is key to making the diagnosis (Wang, Yang et al. 2003),(Romani, 24 Baldeschi et al. 1998). In the COMS trial, 99.7% (1559 of 1563) of ocular tumours were diagnosed to be 25 melanoma using ocular ultrasound alongside other features, a diagnosis that was later confirmed by pathology 26 (Collaborative Ocular Melanoma Study, Boldt et al. 2008). Uveal melanoma demonstrates ultrasonographic 27 hollowness, choroidal excavation and has a typical dome or ‘collar-stud’ configuration on B scan 28 ultrasonography. Ultrasonographic hollowness or low internal reflectivity is also a suspicious sign in atypical 29 choroidal naevi and helps to predict which naevi may progress to frank malignancy (Shields, Furuta et al. 30 2009). Evidence would suggest that ocular ultrasound sonography (USS) is better than computer tomography 31 (CT) or magnetic resonance imaging (MRI) at detecting extrascleral/orbital extension (Scott, Murray et al. 32 1998; Collaborative Ocular Melanoma Study, Boldt et al. 2008). Some have considered ocular positron 33 emission tomography (PET)/CT as a diagnostic investigation because cutaneous melanoma demonstrates high 34 metabolic activity and this can be demonstrated using Fludeoxyglucose positron emission tomography (FDG- 35 PET)/CT (Finger, Kurli et al. 2004; Reddy, Kurli et al. 2005). However, uveal melanoma shows variable 36 metabolic activity and, therefore, it is unlikely that an ocular PET/CT will be able to usefully distinguish 37 between naevi and melanoma (Finger, Kurli et al. 2004; Reddy, Kurli et al. 2005). The reason for poor FDG 38 uptake in uveal melanoma remains unknown (Strobel, Bode et al. 2009).
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1 Other tests scan be used to distinguish a choroidal naevus from a choroidal melanoma, tests that are especially 2 useful when considering small melanoma or amelanotic melanoma. Autofluorescence is a property of 3 lipofuscin (the orange pigment seen on top of melanoma which appears brown on the surface of an 4 amelanotic melanoma). Quantification of autofluorescence images can distinguish a choroidal melanoma from 5 a naevus with a sensitivity 89% and specificity of 93% (Albertus, Schachar et al. 2013). A study conducted by 6 Shields first described the presence of lipofuscin as a risk factor for predicting growth of small melanocytic 7 choroidal lesions (Shields, Shields et al. 1995). Other risk factors (tumour thickness>2mm; the clinical presence 8 of subretinal fluid; visual symptoms; and proximity to the optic disc <3mm) can all be determined with 9 ophthalmoscopy and conventional ocular ultrasound. The significance of subretinal fluid on Optical Coherence 10 Tomography (OCT) is yet to be determined, but OCT may be used to monitor suspicious choroidal lesions. As 11 enhanced depth imaging with OCT improves, it is likely that a better understanding of the choroidal 12 appearance of melanoma will be achieved, and this in turn is likely to assist in the differential diagnosis of 13 choroidal tumours.
14 4.3.1.2 Ciliary body and iris melanoma 15 The evidence for investigation with more recently developed diagnostic tools is based on comparative case 16 series. Bianciotto et al (Bianciotto, Shields et al. 2011) evaluated 200 iris and ciliary body tumours (47 were 17 melanomas): they reported that Anterior Segment Optical Coherence Tomography (AS-OCT) was useful for iris 18 melanoma but was not superior to Ultrasound Biomicroscopy (UBM) when considering ciliary body tumours. 19 AS-OCT suffers from optically-related image shadowing with large, pigmented lesions (Razzaq, Emmanouilidis- 20 van der Spek et al. 2011). Large iris pigment epithelium cysts and ciliary body lesions cannot be adequately 21 imaged with AS-OCT. Recent evidence suggests that small anterior iris melanoma can be adequately imaged 22 with AS-OCT (Hau et al in print). UBM with a 50MHz probe is considered to be the best tool to image the 23 ciliary body (Gunduz, Hosal et al. 2007). Further, Conway et al compared UBM with conventional A/B scan 24 ultrasound in 132 iris/ciliary body masses (55 were melanoma). They reported only 29% correspondence 25 between the anatomical structures invaded by melanoma as identified by B-scan verses disease extent defined 26 by UBM with UBM being superior(Conway, Chew et al. 2005). The disadvantages of UBM include patient 27 discomfort due to the eye contact with a water bath, and the increased time taken to perform this test. 28 However, more recent UBM machines are now fitted with probes that do not always require a waterbath.
29 4.3.1.3 Intraocular Biopsy for Diagnosis 30 If the diagnosis is still uncertain following the above investigations, then biopsy has a role in distinguishing 31 small melanomas from nevi and amelanotic melanomas from metastases. Various methods have been 32 described, using tools such as fine-needle aspiration, vitreous cutter and Essen Forceps. (Augsburger, Correa et 33 al. 2002; Sen, Groenewald et al. 2006; Bornfeld 2007; Shields, Ganguly et al. 2007; Konstantinidis, Roberts et 34 al. 2013). Biopsy is associated with a number of risks, which include: failure, especially with small tumours 35 (Cohen, Dinakaran et al. 2001; Augsburger, Correa et al. 2002); rhegmatogenous retinal detachment; and 36 rarely endophthalmitis (Kvanta, Seregard et al. 2005). Seeding to extraocular tissues can also occur but this is 37 exceptionally rare (Char, Kemlitz et al. 2006; Schefler and Abramson 2009; Caminal, Ribes et al. 2012).
38 Fine needle aspiration biopsy can be performed with a direct transcleral approach or using a transvitreal 39 approach. Cohen et al reported a cohort of 83 patients who underwent 25-gauge fine needle aspiration biopsy 40 for indeterminate choroidal lesions. Overall a diagnosis could be achieved in 88% but the small indeterminate 41 lesions did not always yield sufficient cells to make a diagnosis especially if less than 2mm in thickness (<2mm 42 40% diagnostic 2-4mm 90% diagnostic) (Cohen, Dinakaran et al. 2001). In a recent study of 39 patients
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1 undergoing an intraocular biopsy for clinically suspected metastatic disease, a tissue was achieved in all cases; 2 further, the site of origin was determined in 24 out of the 27 (88%) patients with an unidentified primary 3 tumour (Konstantinidis, Roberts et al. 2013). In another cohort study of 34 patients in the ‘naevus verses 4 melanoma category’ (1.5-3mm in thickness), who underwent a 25-gauge fine needle aspiration biopsy, the 5 diagnostic yield was 65% (Augsburger, Correa et al. 2002). Transcleral conventional biopsy is best suited for 6 anteriorly positioned tumours. Infrequent potential complications of biopsy include tumour seeding within 7 the eye or orbit, infection and intraocular haemorrhage, although the latter is usually only transient (Kvanta, 8 Seregard et al. 2005). Biopsy can be difficult to perform and the resulting specimen difficult to interpret. 9 Therefore, these surgical procedures should only be undertaken in a specialist surgical Ocular Oncology centre 10 by those with expertise and with the aid of a specialist ocular pathologist. (Cohen, Dinakaran et al. 2001; 11 Augsburger, Correa et al. 2002; Konstantinidis, Roberts et al. 2013).
12 4.3.2 Question 2. Should patients be staged before primary treatment?
13 4.3.2.1 Incidence of metastases at staging 14 In the majority of patients with uveal melanoma, metastatic disease is not detectable at diagnosis. It is a rare 15 finding at diagnosis being reported in less than 1% (70 out of 7,541) of patients screened for the COMS trial. 16 (Diener-West, Reynolds et al. 2004). However, this study has limitations as only liver function tests (LFTs) and 17 chest X-Rays (CXR) were used to stage patients. Using FDG-PET/CT, Finger et al. staged 52 patients with the 18 diagnosis of primary uveal melanoma, and metastases were only found in 2 patients (3.8%) (Finger, Kurli et al. 19 2004). More recently, Feinstein et al used abdominal CT to stage 91 patients with uveal melanoma, and 20 metastases were found in 3 patients (3.3%) (Feinstein, Marr et al. 2010).
21 There is evidence to suggest that the risk of detecting metastatic disease at diagnosis can be stratified 22 according to the size of the uveal melanoma. The incidence of liver metastases at diagnosis in 911 British 23 patients from 2007-2011 was only 0.6% in the small-to-medium uveal melanoma group compared to 7.7% in 24 those patients scheduled for enucleation [Papastefanou et al 2012, conference presentation]. These patients 25 were all staged with an abdominal ultrasound and LFTs: if an abnormality was detected, they had further 26 imaging with either PET/CT, CT or MRI of the abdomen. None of the patients with metastatic disease had a 27 normal abdominal ultrasound, although 40% of patients with CT-confirmed metastatic disease had normal 28 LFTs. This is in concordance with a large body of literature questioning the value of LFTs in uveal melanoma 29 staging and surveillance (see below and Chapter 6).
30 4.3.2.2 Staging investigations 31 If staging is performed, there is still debate regarding the optimum staging investigation to select and to date 32 no prospective trials have compared different staging systems. Unlike cutaneous melanoma, the liver is 33 almost always the first site where metastases are seen (Finger, Kurli et al. 2005). Therefore, imaging should be 34 targeted towards the liver.
35 Liver Function tests
36 Liver function tests are widely performed in staging of uveal melanoma. However, all authors accept the low 37 sensitivity of this blood test. In the COMS trial, an abnormal LFT was reported if it was at least twice the upper 38 limit of normal. This prompted liver imaging or a biopsy to confirm metastatic disease. The sensitivity and 39 specificity of at least one abnormal liver enzyme in predicting metastatic disease were 15% and 92% 40 respectively (Diener-West, Reynolds et al. 2004). Alkaline phosphase was suggested to be the enzyme with the
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1 highest diagnostic accuracy; however the combination of abnormal alkaline phosphase (ALP) and Gamma- 2 glutamyltransferase (GGT) raised the likelihood of detecting metastatic disease (Hicks, Foss et al. 1998). These 3 same authors however reported that LFTs had a positive predictive power of <50%, and therefore found them 4 of little value.
5 Kaiserman et al recorded serial LFTs in 30 uveal melanoma patients who subsequently developed metastases 6 and compared this group with 80 uveal melanoma patients without metastatic disease (Kaiserman, Amer et al. 7 2004). They found that liver enzymes rose 6 months prior to the detection of metastatic disease but 50% still 8 remained within normal limits. These authors recommended staging/screening with combined liver imaging 9 and sequential LFTs.
10 Abdominal Ultrasound
11 Eskelin et al recommended abdominal ultrasound combined with LFTs and a CXR. They reported that 12 abdominal USS revealed unequivocal hepatic metastases in 36 of 46 patients (78%) with metastatic disease, of 13 whom 12 (33%) had normal LFTs. Ultrasound was suggestive of metastases in 5 additional patients (11%), all 14 of whom were confirmed to have hepatic metastases by fine-needle aspiration biopsy, CT, or both. Liver USS 15 was negative (false negative) in only 2 patients (4%), both of whom had liver metastases and at least 1 16 abnormal LFT. Ultrasound is the preferred imaging modality in many centres due to its lower cost and ease of 17 accessibility (Eskelin, Pyrhonen et al. 1999). If an abnormality is detected in the liver on USS, further 18 qualification is performed with either CT or MRI. Staging with abdominal US and CXR was recommended by 19 Hicks et al who found the specificity and positive predictive power of abdominal ultrasound in detecting 20 metastatic disease to be 100% (Hicks, Foss et al. 1998).
21 Abdominal CT scan
22 Feinstein and associates reviewed the records of 91 patients who underwent CT scanning within 1 month of 23 uveal melanoma diagnosis. CT scan detected a large variety of benign hepatic lesions such as cysts and fatty 24 liver: 90% of hepatic lesions could be classified. The sensitivity, specificity, Positive Predictive Value (PPV) and 25 Negative Predictive Value (NPV) of a CT scan in detecting metastatic disease were 100%, 91%, 27%, and 100% 26 respectively. The low PPV was attributable to a variety of benign hepatic lesions detected with CT. Patients 27 with multiple lesions on abdominal CT scanning were significantly more likely to have metastatic disease 28 (Feinstein, Marr et al. 2010).
29 Abdominal MRI with or without contrast
30 There has been no published assessment of the value of an MRI of the liver for staging of patients presenting 31 with a primary uveal melanoma. In the follow up of patients with a ‘high risk’ of metastatic disease, MRI has 32 proved to be an accurate method for staging (Marshall, Romaniuk et al. 2013).
33 Fludeoxyglucose (FDG)-PET/CT
34 The value of FDG-PET in detecting metastatic disease in uveal melanoma remains uncertain. In a study of 27 35 patients 6/13 patients with liver metastases from UM were PET avid, whilst 7/13 were not (Strobel, Bode et al. 36 2009). In an earlier study 2/52 patients presenting with primary choroidal melanoma had FDG avid metastases 37 at diagnosis (Finger, Kurli et al. 2005). False positives were seen in 3/52 (3.8%) patients when further evaluated
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1 by histopathology and/or additional imaging; 7 patients (13.4%) had PET detected inflammatory or benign 2 lesions elsewhere. No comparison was made in this study with other imaging techniques, specifically high 3 resolution CT, MRI or USS. Further studies comparing PET/CT to other imaging modalities would be useful to 4 evaluate the detection rate and specificity of FDG-PET in the staging of uveal melanoma.
5 4.3.2.3 Does detection of metastatic disease at diagnosis influence management of the eye? 6 No evidence was found to address this question.
7 4.3.3 Question 3. What is the optimal primary treatment?
8 4.3.3.1 Enucleation 9 Prior to the advent of radiotherapy, the traditional treatment of choroidal melanoma was enucleation of the 10 affected eye as soon as the diagnosis was established with reasonable clinical certainty. The number of 11 patients needing enucleation has diminished with the availability of alternative globe-sparing treatment 12 options. In spite of this, enucleation is required in up to one-third of patients due to the tumour being too 13 large for treatment by other means, the potential complications of treatment being too great, or patient 14 choice. Enucleation entails the complete removal of the eyeball, thus avoiding any disturbance of the 15 intraocular tumour. In the event that there is extraocular spread, complete tumour excision should be 16 attempted where possible. If this is not achievable during surgery, adjuvant orbital radiotherapy is required.
17 Up to 50% of uveal melanoma patients develop metastatic disease because the tumour has disseminated at an 18 early stage before detection and treatment of the ocular tumour (Kujala, Makitie et al. 2003). Zimmerman et al 19 (Zimmerman, Mclean et al. 1978) previously suggested that enucleation surgery was associated with 20 acceleration of metastatic death. This hypothesis was not supported by the COMS report 24 (COMS and Group 21 2004), which indicated that pre-enucleation radiotherapy did not show an advantage. Gambrelle et al 22 (Gambrelle, Grange et al. 2007) found the 5-year melanoma-specific survival rate was around 32% after 23 primary enucleation (Isager, Ehlers et al. 2004).
24 After enucleation, there is an obviously reduced visual field to the side of the artificial eye along with loss of 25 depth perception. Many of the skills of depth perception are relearned with time and most patients continue 26 with their same jobs and activities without difficulty. Steeves et al (Steeves, Gonzalez et al. 2008) suggest that 27 one-eyed individuals maintain perfectly normal lives and are not limited by their lack of binocularity. Quality 28 of life studies have shown that following enucleation, patients have lower levels of anxiety compared to 29 patients treated with radiotherapy (Melia, Moy et al. 2006).
30 4.3.3.2 Brachytherapy 31 In most centres, brachytherapy is the first choice of treatment. The procedure involves suturing of a 32 radioactive plaque to the episclera (usually under general anaesthesia) and a second operation, following a 33 specific period of time during which the prescribed dose is delivered, to remove the plaque. Treatment is 34 completed once the plaque is removed. It may take up to 6 months before regression can be recorded. In 35 Europe, ruthenium-106 is the most popular isotope whereas in the USA iodine-125 is generally preferred. 36 Currently ruthenium-106 is the only radioisotope prescribed for the treatment of uveal melanoma in the UK, 37 and therefore these guidelines will consider, first, the published evidence for ruthenium-106 plaque 38 brachytherapy.
39 Ruthenium
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1 Ruthenium plaque brachytherapy can be used to treat small to medium sized melanoma, with excellent 5-year 2 local control rates of 95.6%, 93.6% and 98% being reported (Verschueren, Creutzberg et al. 2010; Marconi, de 3 Castro et al. 2013). However, no 10-year local control rates were reported in these studies. A meta-analysis of 4 1066 patients with uveal melanoma treated by ruthenium plaque brachytherapy recorded the 5-year mortality 5 for small/medium T1/T2 tumours (small tumours: height 1-3 mm, diameter more than 5mm; medium 6 tumours: height 2.5-10.0mm and diameter <=16 mm; T1, T2 and T3 reflect particular subcategories of the AJCC 7 TNM Staging system) as 6%, and for large T3 tumours (height >=10 mm or diameter >=16 mm) as 26% 8 (Seregard 1999). For the population as a whole, the 5- and 10-year mortalities were 14% and 22% respectively 9 (Seregard 1999). This reflects the tumour selection criteria for ruthenium plaque brachytherapy, as many 10 ocular oncologists do not select this treatment for larger tumours. Nevertheless ruthenium plaque 11 brachytherapy can be used for thick posterior uveal melanomas. In one small, non-randomised study, thick 12 posterior uveal melanomas were treated with enucleation or ruthenium plaque brachytherapy (Kaiserman, 13 Kaiserman et al. 2009). Despite a low 71% control rate in the ruthenium plaque group and the thicker tumours 14 being in the enucleation group (p<0.001), melanoma-related mortality rates were the same in both groups (at 15 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 16 ruthenium plaque brachytherapy is a safe alternative treatment that does not comprise survival (Kaiserman, 17 Kaiserman et al. 2009). Local tumour control is compromised when ruthenium plaque brachytherapy is 18 applied to thicker tumours, with control rates of 71%, 82% and 86% in three studies (Bergman, Nilsson et al. 19 2005; Kaiserman, Kaiserman et al. 2009; Ritchie, Gregory et al. 2012). Lack of response to ruthenium plaque 20 brachytherapy was associated with uveal melanomas >5mm in height (Papageorgiou, Cohen et al. 2011). The 21 selection criteria for ruthenium plaque brachytherapy vary between European centres but there is general 22 consenus that ruthenium plaque brachytherapy should be restricted to uveal melanoma below 7-8mm in 23 height (Bergman, Nilsson et al. 2005; Isager, Ehlers et al. 2006; Ritchie, Gregory et al. 2012). Other risk factors 24 for local recurrence/poor tumour control are large basal diameter, anterior location, young patient age and 25 foveal location (Isager, Ehlers et al. 2006; Papageorgiou, Cohen et al. 2011). Transpupillary thermotherapy TTT 26 can be combined with primary ruthenium plaque therapy to improve tumour control and globe preservation 27 rates (see section on TTT) (Yarovoy, Magaramov et al. 2012).
28 Visual complications from ruthenium plaque brachytherapy are less severe than those recorded from the 29 collateral damage of iodine plaque brachytherapy or proton beam radiotherapy (PBR). Patients are warned 30 about the risk of postoperative diplopia but the risk is very low. The incidence of ocular motility disorders 31 following ruthenium plaque brachytherapy in a cohort of uveal melanoma cases treated in London was rare at 32 1.7% over 8 years (Dawson, Sagoo et al. 2007). The incidence of radiation cataract is low at 16% (Marconi, de 33 Castro et al. 2013). The incidence of NVG is only 3% and related to the TNM stage of the tumour, i.e., it 34 increased after treatment of larger tumours (Summanen, Immonen et al. 1996; Marconi, de Castro et al. 35 2013). In the long term, radiation damage to the optic disc and macular can destroy central vision. Predictive 36 factors for visual deterioration from radiation maculopathy include: a) proximity of the posterior tumour 37 border to the fovea; b) poor presenting visual acuity; and c) age <40 years (Summanen, Immonen et al. 1996; 38 Rouberol, Roy et al. 2004; Bergman, Nilsson et al. 2005). Predictive factors for loss of light perception were 39 proximity to the optic disc and increasing size of the tumour (Summanen, Immonen et al. 1995). Visual 40 deterioration, cataract and vitreous haemorrhage is associated with increasing tumour height, as these 41 tumours require a higher dose of radiation to achieve tumour control (Summanen, Immonen et al. 1995; 42 Summanen, Immonen et al. 1996). The plaque can be positioned eccentrically with its posterior edge aligned 43 with the posterior tumour margin to reduce the radiation dose to the optic disc and fovea (Russo, Laguardia et
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1 al. 2012) Tumour control was not compromised using this technique even at 4 years follow up. However, in 2 general, good visual results are seen following ruthenium plaque brachytherapy, especially for anterior 3 tumours. Damato and his group (Damato, Kacperek et al. 2005) reported visual conservation of 20/40 or 4 better in 55% at 9 years; loss of vision correlated with: posterior tumour extension (p < 0.001), temporal 5 tumour location (p = 0.001), increased tumour height (p = 0.01), and older age (p < 0.01).
6 After plaque brachytherapy for uveal melanoma, ophthalmological follow up entails regular ocular 7 examinations and investigations for radiotherapy complications, which typically manifest 2-5 years after 8 primary treatment. Tumour regression is recorded with serial ocular ultrasound and dilated fundus 9 examination with visits to the respective Ocular Oncology service, especially in the first and second year after 10 completing primary treatment. Tumour regression rates are variable (Shields, Shields et al. 1998). Kivela and 11 associates were unable to correlate time to 25% or 50% reduction in tumour size following ruthenium plaque 12 brachytherapy with time to metastatic disease (Rashid and Kivela 2012). Therefore, it appears that tumour 13 response to brachytherapy cannot be relied upon with certainty as a prognostic indicator.
14 Iodine-125
15 I-125 episcleral plaque therapy is an effective, low morbidity treatment for medium and small sized but rapidly 16 growing choroidal melanomas (Vullaganti, DeVilliers et al. 2011). It can be a safe and effective alternative to 17 enucleation with regard to survival and local tumour control (Badiyan, Rao et al. 2012). It circumvents an 18 intraocular procedure and provides a margin of safety in the treatment of clinically undetectable disease 19 (Fernandes et al 2010). It provides a fair chance of preserving the eye with acceptable cosmesis and a 20 reasonable chance of conserving useful vision for 1 to 2 years. (Puusaari, Heikkonen et al. 2003; Krohn, Monge 21 et al. 2008).
22 The use of brachytherapy to treat choroidal melanoma is heavily influenced by evidence from COMS. There 23 were three main trial arms:
24 1. The COMS "Small" study: 204 patients with small choroidal melanomas (height 1-3 mm, diameter more 25 than 5mm) were prospectively observed. This study showed that with prospective follow-up, overall survival 26 was comparable to the general population (COMS report No 4 and 5) (Hawkins and Melia 1997; Melia, Diener 27 et al. 1997).
28 2. The COMS "Medium" randomized trial: 1317 patients with medium tumours (height 2.5-10.0mm and 29 diameter <=16 mm) were randomized to either treatment with I-125 plaque brachytherapy (85 Gy) or 30 enucleation. The overall survival and risk of death from metastatic disease were comparable between the two 31 groups, thus establishing plaque brachytherapy as a reasonable primary treatment for choroidal melanomas. 32 At 5, 10 and 12 years, the mortality rates for patients treated with brachytherapy were 10%, 18% and 21% and 33 for patients treated with enucleation, they were 11%, 17% and 17% respectively (COMS report 16,17,18, 28) 34 (Diener-West, Earle et al. 2001; Hawkins, Vine et al. 2001; Hawkins 2001; Melia, Abramson et al. 2001; 35 Hawkins 2006).
36 3. The COMS “Large” randomized trial: 1003 patients with large tumours (height >=10 mm or diameter >=16 37 mm) were randomized to pre-enucleation external beam radiation therapy (EBRT) 20/5 or enucleation only 38 without EBRT. This study showed that pre-enucleation radiotherapy does not provide any additional benefit 39 (COMS report 9, 10, 11, 15, 24) (Schachat 1998; Willson, Albert et al. 2001; Hawkins 2004).
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1 Treatment dose and parameters:
2 The American Brachytherapy Society recommends a minimum tumour I-125 dose of 85 Gy at a dose rate of 3 0.60-1.05 Gy/h. It has been shown that treatment of choroidal melanomas less than 5mm in apical height with 4 I-125 brachytherapy to the true apical height is equally effective when compared to treatment with 85Gy to 5 5.0mm (as performed in the COMS trial) and has a lower incidence of radiation-related complications 6 (Vullaganti, DeVilliers et al. 2011; Murray, Markoe et al. 2013).
7 Local control:
8 I-125 brachytherapy is effective in tumour control in 92-97%, allowing preservation of the eye and useful visual 9 function for the majority of patients. (Jensen, Petersen et al. 2005; Garcia-Alvarez, Saornil et al. 2012). It allows 10 for safe and effective therapy in patients with ocular melanoma of various sizes depending on location 11 (Fontanesi, Meyer et al. 1993).
12 Anterior location: The use of 125I plaque brachytherapy to treat melanomas situated anterior to the equator 13 allows good local and systemic control with a low rate of macular and optic disc complications. The most 14 frequent complication is cataract formation. (Lumbroso, Charif et al. 2004). Shields et al. have shown that 15 better visual outcomes are seen after plaque radiotherapy for choroidal melanoma in younger patients with 16 small tumours at sites remote from the optic disc and foveola (Baggetto, Gambrelle et al. 2005).
17 Juxtapapillary location: Sagoo et al demonstrated that juxtapapillary choroidal melanoma can be treated with 18 brachytherapy with 80% tumour control at 10 years and adjuvant TTT did not add to the success rate (Sagoo, 19 Shields et al. 2011). Krema et al showed that both I-125 brachytherapy and stereotactic radiotherapy 20 demonstrate comparable efficacy in the management of juxtapapillary choroidal melanoma. Stereotactic 21 radiotherapy (see section 4.6.3) showed statistically significantly higher radiation-induced ocular morbidities at 22 4 years post-radiotherapy but I-125 had higher recurrence rate (11% compared to 7%) (Krema, Heydarian et al. 23 2013), (Krema, Heydarian et al. 2013).
24 Melanomas with extraocular extension: Small and medium-sized ciliary body and choroidal melanoma with 25 clinically visible extraocular extension less than 3 mm in thickness can, in selected cases, be treated 26 successfully with plaque radiotherapy (Gunduz, Shields et al. 2000).
27 Melanomas with thickness between 5-7 mm: The management of choroidal melanoma with a thickness of 5-7 28 mm is controversial. Iodine seems to provide higher local tumour control, while ruthenium induces less 29 radiation complications. I-125 may represent a better option in this subgroup of tumours, especially for 30 preventing metastatic disease (Tagliaferri, Smaniotto et al. 2012).
31 Treatment failure:
32 There is a low risk of local treatment failure or secondary enucleation after definitive I125 brachytherapy for 33 choroidal melanoma. Jampol et al have shown the risk factors for local recurrence include older age at time of 34 treatment, greater apical height, and proximity to the foveal avascular zone (Jampol, Moy et al. 2002). Char et 35 al have also shown that late recurrence is possible five or more years later in patients treated with radioactive 36 plaque (Char, Kroll et al. 2002) Risk factors for enucleation following I-125 plaque radiotherapy in these studies 37 included: male gender; greater apical height of the tumour; longer basal dimension; poorer visual acuity in the
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1 tumour-containing eye at baseline; collar-button tumour shape; presence of retinal detachment over the 2 tumour; lower radiation dose to the tumour apex; and higher dose to the sclera. In patients with large 3 posterior uveal melanomas (> or =8-mm thick) the rate of enucleation was 24% at 5 years and 34% at 10 years 4 (Shields, Naseripour et al. 2002).
5 Visual loss after I-125 brachytherapy:
6 The COMS report number 16 showed that the visual acuity during the first 3 years after I-125 plaque 7 radiotherapy for choroidal melanoma declined on average at a rate of approximately two lines per year (Melia, 8 Abramson et al. 2001): 49% of patients had substantial loss of visual acuity at 3 years. High risk characteristics 9 for visual loss were: tumour height >5.0 mm; distance between tumour and foveal avascular zone <2.0 mm; 10 diabetes; non–dome-shaped tumour; and presence of tumour-associated retinal detachment. In patients with 11 large posterior uveal melanomas (> or =8-mm thick), Shields et al. have shown the most important risk factors 12 for poor visual acuity include retinal invasion by melanoma, increasing patient age, use of I- 125 isotope, and 13 <2 mm distance to the optic disc (Shields, Naseripour et al. 2002).
14 A study from New Zealand showed that a high percentage of patients retaining mobility vision following I-125 15 brachytherapy (>6/12 in 35% patients and >6/60 in 51% patients) (Stack, Elder et al. 2005).
16 Radiation retinopathy, neuropathy and cataract:
17 Radiation retinopathy and cataract formation are common toxicities 3 years following I-125 plaque 18 brachytherapy for medium-sized choroidal melanomas (i.e. mean tumour thickness and basal diameter = 5.0 19 mm and 12.1 mm)(Badiyan, Rao et al. 2013). Three-year rates of radiation retinopathy, radiation papillopathy, 20 and exudative retinal detachment were 45%, 14%, and 10%, respectively. The 3-year rates of cystoid macular 21 edema, vitreous hemorrhage, and enucleation due to radiation toxicity were 17%, 12%, and 4% respectively. 22 The risks of anterior segment complications were much higher in patients treated for large melanomas (i.e. 23 median tumour height and diameter = 10.7 mm and >16.5 mm). In these patients the 5-year rates of cataract 24 formation, neovascularization of the iris and NVG were 69%, 62% and 60%, respectively (Puusaari, Heikkonen 25 et al. 2004).
26 Development of complications was related to the tumour location and dose to non-tumour structures. A dose 27 of more than 90 Gy to the macula gave a 63% chance of developing maculopathy (P < 0.01). A tumour larger 28 than 4 mm significantly increased the risk of developing radiation maculopathy. Development of radiation 29 cataract was also dose-related; >25 Gy to the lens gave a 44% risk of cataract development (P < 0.001). For 30 tumours less than 4 mm from the disc margin there was a 50% risk of optic neuropathy (Stack, Elder et al. 31 2005).
32 Bianciotto et al showed that proliferative radiation retinopathy developed in 7% of eyes by 10 years after I-125 33 plaque radiotherapy for uveal melanoma. The main factors for development of proliferative radiation 34 retinopathy included young age, pre-existent diabetes mellitus and shorter tumour distance to the optic disc 35 (Bianciotto, Shields et al. 2010). The use of bevacizumab has reduced the need for enucleation due to I-125 36 radiation toxicity (Badiyan, Rao et al. 2013). Treatment modalities for radiation retinopathy include intravitreal 37 injections of triamcinolone and bevacizumab, laser photocoagulation, hyperbaric oxygen treatment, 38 photodynamic therapy and oral pentoxyphylline.
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1 Metastasis risk:
2 The risk of metastasis was found to be 10% at 5 years and 27% at 10 years in a study of patients treated with I- 3 125 (1163) In patients treated for large posterior melanomas (> or =8-mm thick), the tumour-related 4 metastases rate was 30% at 5 years and 55% at 10 years (Shields, Naseripour et al. 2002).
5 Other factors influencing choice of brachytherapy:
6 The COMS report number 3 looked at quality of life after I-125 brachytherapy or enucleation for choroidal 7 melanoma. Patients treated with brachytherapy reported significantly better visual function than patients 8 treated with enucleation with respect to driving and peripheral vision for up to 2 years following treatment. 9 This difference diminished by 3 to 5 years post-treatment, parallel-ing the decline in visual acuity in 10 brachytherapy-treated eyes. Patients treated with brachytherapy were more likely to have symptoms of 11 anxiety during follow-up than patients treated with enucleation. Given that no significant differences in 12 survival between enucleation and brachytherapy have been found, the differences demonstrated here for 13 driving and anxiety will allow the individual patient and physician to make informed choices regarding 14 treatment based on personal preferences (Melia, Moy et al. 2006).
15 Compared to ruthenium plaque treatment, the cost price of iodine treatment is much higher owing to the 16 requirement for frequent replacement of the iodine grains due to a short half-life of 60 days in comparison 17 with the 374 day half-life of ruthenium (Ru-106). The deeper penetration of the γ rays of I-125 (compared to β- 18 rays of Ru-106) allows treatment of larger and thicker tumours (up to 10mm height by I-126 compared to up to 19 5-7mm height by Ru-106), but at the cost of causing more radiation damage to healthy surrounding tissues, 20 hence optic neuropathy, maculopathy, and visual loss. Successful use of other isotopes, such as palledium, has 21 been demonstrated by Finger et al, and others (Shields, Cater et al. 2002; Finger, Chin et al. 2009).
22 4.3.3.3 Stereotactic radiosurgery 23 Stereotactic radiosurgery (SRS) usually consists of a single-session delivery of ionizing radiation to a 24 stereotactically localized volume of tissue. Certain centres use fractionated SRS for uveal melanoma (Muller, 25 Naus et al. 2012).
26 The patient receives standard retrobulbar anesthesia to prevent globe movement during SRS. Based on the 27 MRI, the target volume for each patient’s tumour is identified stereotactically and the radiation parameters 28 are calculated. A stereotactic frame is attached to the skull for the treatment and the entire treatment is 29 completed in a matter of hours. Advantages of this procedure are that it is minimally invasive (needing only 30 local anaesthesia); it is particularly useful in patients unfit for general anaesthesia as it does not involve any 31 surgery; and is performed as an outpatient.
32 SRS is particularly useful in juxtapapillary choroidal melanomas (Zorlu, Selek et al. 2009; Al-Wassia, Dal Pra et 33 al. 2011) and those tumours not suitable for ruthenium plaque therapy. Dunavoelgyi et al (Dunavoelgyi, 34 Dieckmann et al. 2011) have demonstrated an excellent local tumour control rate of 95.9% after 5 years and 35 92.6% after 10 years in patients with uveal melanoma treated with SRS.
36 In the UK, SRS has been used for the treatment of ocular melanomas since the 1990s at the Sheffield Ocular 37 Oncology Centre. In 1996, Rennie et al. published their initial experience in the use of SRS (Rennie, Forster et 38 al. 1996). The initial use of a high isodose at 70Gy was found to be effective but associated with a high
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1 incidence of radiation related adverse reactions. Reducing the isodose from 70 Gy to 35 Gy led to a dramatic 2 decrease in complications, vision loss and salvage enucleation, whilst not compromising patient survival. 3 Cohen et al (Cohen, Carter et al. 2003) have shown that the metastasis-free survival after SRS was comparable 4 to that after enucleation in patients treated at Sheffield (74% in the stereotactic treatment group versus 51% 5 in the enucleation treatment group at 5-years, with no significant difference after multi-variant analysis). A 6 retrospective analysis comparing the outcomes of patients from Sheffield treated with SRS versus proton 7 beam is currently under way.
8 In centrally-located choroidal melanomas, Dunavoelgyi et al demonstrated that hypo-fractionated SRS showed 9 a low to moderate rate of adverse long-term side effects comparable to those after PBR. Future fractionation 10 regimens should seek to further reduce adverse side effects rate while maintaining excellent local tumour 11 control. Suesskind et al (Suesskind, Scheiderbauer et al. 2013) found that SRS combined with tumour resection 12 might be associated with increased tumour control and fewer radiation complications than SRS alone as 13 monotherapy. However, the protocol was stopped after 3 unexplainable deaths following tumour resection 14 surgery.
15 Modorati et al (Modorati, Miserocchi et al. 2009), in a 12-year study from Italy have demonstrated a survival 16 rate with SRS of 81.9% at 5 years. The median tumour thickness reduction after treatment was 1.96 mm (- 17 32.1%). The most frequent treatment-related complications were: exudative retinopathy (33.3%), NVG 18 (18.7%), radiogenic retinopathy (13.5%) and vitreous haemorrhages (10.4%). A reduction of visual acuity was 19 observed but the eye was retained in 90% patients, and the authors concluded SRS should be considered as an 20 alternative to enucleation surgery. Chabert et al (Chabert, Velikay-Parel et al. 2004) demonstrated no 21 difference in quality of life scores between plaque brachytherapy and SRS for the treatment of uveal 22 melanoma.
23 4.3.3.4 Proton beam radiotherapy 24 PBR offers a more targeted delivery of radiation compared to conventional external beam radiotherapy. This 25 precision is achieved by the highly collimated beams with their destructive ionising radiation peaking at the 26 depth where the charged particles stop travelling (the ‘Bragg’ peak), hence it targets the discrete area with 27 limited damage to surrounding tissues. The treatment dose prescribed is fractionated, typically four sessions 28 are required and treatment is completed in one week. Treatment planning (simulation) is an important aspect 29 of proton beam radiotherapy that must be performed several weeks ahead. Tantalum markers are sutured to 30 the eye and intraoperative measurements are taken so that the tumour position and shape can be recorded. 31 An ocular X-ray reveals the location of the tantalum markers. Detailed ultrasound measurements of tumour 32 height are required for accurate modification of the proton beam. PBR is custom-designed for each individual 33 patient with uveal melanoma.
34 Protons achieve high rates of local tumour control in patients considered unsuitable for other forms of 35 conservative treatment. Multiple studies are consistent in demonstrating this high rate of local control of PBR: 36 between 87% and 96% at 5 years (Damato, Kacperek et al. 2005; Dendale, Lumbroso-Le Rouic et al. 2006; Aziz, 37 Taylor et al. 2009; Caujolle, Mammar et al. 2010), and between 92.1%-96.8%% at 10 years (Mosci, Polizzi et al. 38 2001; Damato, Kacperek et al. 2005; Caujolle, Mammar et al. 2010). There is only one publication to date 39 comparing local tumour control following PBR, ruthenium and iodine plaque brachytherapy. Wilson et al 40 reported that patients treated with ruthenium plaque brachytherapy had significantly greater risk of local 41 tumour recurrence than did those patients treated with either 125-Iodine plaque brachytherapy (P = 0.0133;
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1 confidence interval [CI], 1.26-7.02; risk ratio, 2.97) or proton beam radiotherapy (P = 0.0097; CI, 1.30-6.66; risk 2 ratio, 2.94) (Wilson and Hungerford 1999). There was no significant difference in tumour control between PBR 3 and 125- Iodine plaque brachytherapy. Risk factors for failure of local tumour control following PBR were 4 identified as a reduction of the safety margin, large tumours infiltrating the ciliary body, the presence of an 5 eyelid within the irradiation field, inadequate delimitation of the tumour border by tantalum clips, and male 6 gender (Egger, Schalenbourg et al. 2001).
7 Metastasis-free survival after PBR was 88.3% at 5 years and 76.4% at 10 years (Caujolle, Mammar et al. 2010), 8 (Damato, Kacperek et al. 2005). Similarly, Dendale et al (Dendale, Lumbroso-Le Rouic et al. 2006) showed 5- 9 year overall survival and metastasis-free survival rates were 79% and 80.6% respectively. When considering 10 patients with large choroidal melanoma, there was no significant difference between enucleation or PBR for 11 cumulative all-cause mortality, melanoma-related mortality and metastasis-free survival (log-rank test, p = 12 0.56, p = 0.99 and p = 0.25, respectively) (Mosci, Lanza et al. 2012).
13 Another survival study on the relative rates of metastatic death, cancer death, and all cause mortality between 14 enucleation and PBR revealed a statistically significant survival benefit in the PBR group in the first two years of 15 treatment. However, by the sixth year the survival benefit was not maintained. Results suggest that treatment 16 choice has little overall influence on survival in patients with uveal melanoma (Seddon, Gragoudas et al. 1990).
17 4.3.3.5 Complications of Proton Beam Radiotherapy (PBR) 18 One early main complication after PBR is intraocular inflammation. Lumbroso et al (Lumbroso, Desjardins et al. 19 2001) found 28% of patients developed ocular inflammation. Inflammation following PBR is not unusual, but is 20 usually limited to mild anterior uveitis, which rapidly resolves with topical steroids and cycloplegics. It is 21 correlated with larger initial tumours (tumour height and irradiation of a large volume of the eye) and may be 22 related to an exudative retinal detachment and tumour necrosis, both of which in turn are thought to lead to 23 an associated release of cytokines and neovascular glaucoma (NVG) (termed, ‘toxic tumour syndrome’). The 24 good local control results are tempered somewhat by the appreciable ocular morbidity, which may necessitate 25 removal of the eye (secondary enucleation) usually as a result of NVG. Secondary enucleation rates following 26 PBR correlate strongly with tumour size (Foss, Whelehan et al. 1997; Damato, Kacperek et al. 2005). The 27 overall eye retention rate in 2648 uveal melanoma patients (tumour diameter 4mm-27.5 mm and tumour 28 height 0.9-15.6 mm) treated with proton beam radiotherapy was 88.9% at 5 years, 86.2% at 10 years and 29 83.7% at 15 years (Egger, Zografos et al. 2003). After optimization of the technique, retention rates at 5 years 30 increased from 97.1% to 100% for small tumours, from 86.7% to 99.7% for medium, and from 71.1% to 89.5% 31 for large tumours (Egger, Zografos et al. 2003). Similar rates from Scotland were reported for ciliary body and 32 choroidal melanomas, where proton beam treatment is mainly used in the treatment of medium and large 33 uveal melanomas. Of the 147 patients identified, 22.4% required enucleation (Macdonald, Cauchi et al. 2011). 34 Mean time to enucleation was 23.8 months and the main reasons were suspected recurrence (48%) and NVG 35 (42%). The actuarial 5-year eye retention rate was 71.3% (Macdonald, Cauchi et al. 2011). In a larger study of 36 1406 patients with uveal melanoma treated by proton beam radiotherapy, the 5-year enucleation rate for 37 complications was 7.7%, the main indication being NVG. Independent prognostic factors for enucleation for 38 complications of PBR were tumour thickness (p < 0.0001) and lens volume receiving at least 30 Cobalt Gray 39 Equivalent (CGE)(p = 0.0002) (Dendale, Lumbroso-Le Rouic et al. 2006). Foss et al demonstrated that the 40 presence of retinal detachment and large tumour dimensions, i.e., those tumours too large to be treated by 41 ruthenium plaque, are important risk factors in predicting NVG (Foss, Whelehan et al. 1997). If both are
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1 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 2 no risk of developing NVG.
3 An alternate to enucleation in the event of ‘toxic tumour syndrome’ development following PBR secondary 4 include local resection and endoresection (Cassoux, Cayette et al. 2013); (Konstantinidis, Groenewald et al. 5 2014); (McCannel 2013). These procedures have been introduced recently by a few ocular oncology centres 6 with good effect.
7 Prognosis for vision is rather more positive: 18.5% of patients had vision less than 3/60 pre-treatment, 8 compared to 74% post-irradiation (p < 0.0001) (Aziz, Taylor et al. 2009). Preservation of acuity is influenced by 9 the stage of the tumour. Results from Genoa show that visual acuity better than 2/10 was 30% in T1 and T2 10 tumours, and 21% in T3 tumours (Mosci, Polizzi et al. 2001). An early report on 538 patients treated with high 11 energy proton beam showed one-third of patients with adequately scored visual acuity pre- and post- 12 treatment had stable, if not improved vision, and half the patients retained useful vision post-treatment, 13 despite two-thirds having posterior pole tumours (Courdi, Caujolle et al. 1999; Mosci, Polizzi et al. 2001). In 14 Liverpool, of 349 patients with choroidal melanoma treated with PBR, 79.1% had post-treatment vision of 15 counting fingers or better, 61.1% had vision of 20/200 or better and 44.8% achieved 20/40 or better. Visual 16 loss can be unpredictable due to toxic tumour syndrome (Damato, Kacperek et al. 2005). Progressive visual 17 field deficits have also been reported following PBR for parapapillary choroidal melanoma, and not 18 unexpectedly, the scotoma usually correlates with the area of the retina exposed to irradiation (Park, Walsh et 19 al. 1996).
20 A systematic review and meta-analysis of PBR concluded that a strong recommendation favouring PBR above 21 enucleation or plaque brachytherapy could not be made from the currently published evidence (Wang, 22 Nabhan et al. 2013). The overall quality of the evidence was low (Wang, Nabhan et al. 2013). Other important 23 factors need to be considered for comparative effectiveness decisions. Patients’ opinions and preferences 24 should heavily influence the decision, including their feelings about enucleation, their willingness to try a 25 therapy without extensive prospective outcome data (PBR), their willingness to travel to tertiary care centres, 26 and in some cases their financial and other resources. In Europe, the availability of PBR is currently limited to a 27 few tertiary care centres.
28 4.3.3.6 Transpupillary thermotherapy 29 Transpupillary thermotherapy (TTT) is another method of treating uveal melanaoma. The heat from a laser 30 induces ischaemia, free radical damage and tumour necrosis. The treatment is delivered in the clinic using a 31 modified infrared diode laser at 810 nm with an adjustable beam width of 1.2 mm, 2.0 mm and 3.0 mm. The 32 infrared delivery system is adapted to a slit-lamp biomicroscope and delivered through a contact lens. The end 33 point of treatment is a colour change in the tumour, and this is best seen at the first treatment of a pigmented 34 uveal melanoma. Intravenous indocyanine green can be given just before TTT to increase the laser energy 35 uptake by amelanotic uveal melanoma (Sagoo, Shields et al. 2011).Intravenous indocyanine green 36 administration before TTT does not alter the tumour regression pattern (De Potter and Jamart 2003). Several 37 treatment sessions are required to achieve total tumour destruction (Kociecki, Pecold et al. 2002).
38 TTT has been used as primary treatment for small uveal melanoma with some success. Shields et al reported 39 4% recurrence at 1 year, 12% at 2 years, and 22% at 3 years (Shields, Shields et al. 2002). Of serious concern is 40 that there have been accounts of extraocular extension following primary TTT (Shields, Shields et al. 2002). It
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1 is vital therefore that tumours are carefully selected for this primary treatment. The following maximum cut 2 off values for selecting tumours for primary TTT have been recommended: tumour height not greater than 3.0 3 mm, basal diameter not greater than 10 mm and maximum systolic velocity of the tumour on doppler 4 ultrasound not greater than 11.7 cm/s (Yarovoy, Magaramov et al. 2010). Other risk factors for local 5 recurrence include amelanotic pigmentation, presence of subretinal fluid, tumours abutting or overhanging 6 the optic disc, tumour requiring more than 3 sessions of TTT and incomplete regression following primary TTT 7 (Shields, Shields et al. 2002; Parrozzani, Boccassini et al. 2009; Yarovoy, Magaramov et al. 2010).
8 Transpupillary thermotherapy can cause damaging effects to the retina, leading to visual loss shortly after 9 treatment. Shields et al. reported visual outcomes in their first 100 cases (Sagoo, Shields et al. 2011).The visual 10 acuity was worse in 42 eyes (42%). The main reason for poor vision was treatment of a subfoveal tumour with 11 induction of a visual scotoma in the treated area (Kociecki, Pecold et al. 2002). Retinal traction was seen in 12 10% of cases. It was most frequently associated with treatment of uveal melanoma distal and temporal to the 13 optic disc (Shields et al 2011). Other visual threatening complications include macular pucker 11%, macular 14 oedema 4%, vitreous haemorrhage 3%, vein occlusion 8%, exudative retinal detachment and NVG in 3% 15 (Kociecki, Pecold et al. 2002; Parrozzani, Boccassini et al. 2009).
16 The concern about poor local control rates and extraocular recurrence with primary TTT led researchers to 17 suspect that the depth of penetration of the diode laser was insufficient to treat the majority of uveal 18 melanomas. Deeper tumour necrosis at the base of the uveal melanoma was more likely to be achieved with 19 simultaneous plaque radiotherapy (Kociecki, Pecold et al. 2002). Hence TTT is widely used in conjunction with 20 plaque brachytherapy, known as ’sandwich‘ therapy to improve local tumour control (Gragoudas, Li et al. 21 2002); (Shields, Cater et al. 2002). 5-year recurrence rates as low a 3% have been achieved using ’sandwich‘ 22 therapy (Gragoudas, Li et al. 2002), (Shields, Cater et al. 2002). This combination treatment appears to provide 23 better 5-year local tumour control (96% verses 83% p=<0.034), a better globe preservation (98% verses 87% 24 p=<0.024) and recurrence free survival rate (89% verses 67% p=<0.017) than ruthenium plaque brachytherapy 25 alone (Yarovoy, Magaramov et al. 2012). There was no difference in overall patient survival/metastatic rate 26 (Yarovoy, Magaramov et al. 2012). TTT is widely used to manage radiotherapy complications such as ‘toxic 27 tumour syndrome’ (see above under 4.3.3.5) and local tumour recurrence (Yarovoy, Magaramov et al. 2012). 28 When early plaque brachytherapy-related vision loss is accounted for, the addition of TTT did not result in 29 significantly worse visual acuity (Drury, Chidgey et al. 2012). However at 1 and 4 years follow up, the visual 30 outcome was worse in patients who had received ’sandwich‘ therapy compared to those who had received 31 plaque brachytherapy alone (Drury, Chidgey et al. 2012). Adjuvant TTT did not improve the local tumour 32 control of juxtapapillary uveal melanoma treated by Iodine-125 plaque brachytherapy (Sagoo, Shields et al. 33 2011).
34 TTT has also been used in conjunction with PBR: in a randomized study of 151 patients, PBR was combined 35 with TTT for the treatment of large uveal melanomas (Desjardins, Lumbroso-Le Rouic et al. 2006). Patients 36 who received adjuvant TTT had a significantly lower risk of secondary enucleation (p=0.02) and had a more 37 marked reduction in tumour thickness (p=0.06). No statistically significant difference was observed between 38 the 2 groups in terms of cataracts, maculopathy, papillopathy and glaucoma.
39 4.3.3.7 Exoresection 40 Exoresection (also termed ‘local resection’ or ‘choroidectomy’) involves removal of the tumour ‘en bloc’ 41 through a large sclera opening. Previously, full-thickness sclera excision was advocated but this has been
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1 replaced by methods using a lamellar sclera flap to close the eye. Exoresection of choroidal melanomas is a 2 difficult procedure, demanding considerable surgical experience. Furthermore, it requires significant systemic 3 hypotension to control haemorrhage. For these reasons, this operation is performed by only a very few 4 surgeons around the world. Exoresection of small, ciliary body tumours (cyclectomy) is less difficult and is 5 therefore undertaken more widely. Exoresection of iris melanomas (iridectomy) is in turn easier than either of 6 the above procedures, but is increasingly being replaced by radiotherapy (e.g. PBR and ruthenium plaques; see 7 below).
8 The largest exoresection series reported to date was published by Damato et al over 20 years ago (Damato, 9 Paul et al. 1993). In 163 completed resections, the tumours had a mean diameter of 13.3 mm and a mean 10 thickness of 7.4 mm, with 38 tumours extending to within 1 disc diameter (DD) of the optic disc, fovea or both. 11 Cox multivariate analysis showed that the most significant preoperative factors for predicting retention of 12 good vision (6/12 or better) were nasal tumour location (p = 0.002) and distance of more than 1 DD between 13 the tumour and the optic disc or fovea (p = 0.010). The most significant predictive risk factor for severe visual 14 loss (hand movements or worse) was posterior tumour extension to within 1 DD of the optic disc and/or fovea 15 (p = 0.009). One year post-operatively, all 28 patients with medial tumours not extending to within 1 DD of the 16 optic disc or fovea retained the eye with 57% having vision of 6/12 or better and 93% having vision of counting 17 fingers or better. In 68 patients with lateral tumours, 90% retained the eye at 1 year with preservation of 18 vision of counting fingers or better in 82% of 56 eyes without posterior tumours extension and in 50% of 12 19 eyes with posterior tumour extension (Damato et al 1993). There were 24 patients (14%) with residual tumour 20 in this cohort. Forward stepwise logistic regression analysis indicated that posterior extension to within 1 DD 21 of the optic disc or fovea was the sole best indicator of the risk of residual disease (p < 0.001). After excluding 22 these cases, 286 patients were studied for the development of delayed local recurrence, which occurred in 57 23 cases. Forward stepwise multivariate analysis showed statistically significant predictors for recurrent tumour 24 to be epithelioid cellularity (p = 0.002), posterior tumour extension to < 1 disc diameter of disc of fovea (p = 25 0.002), large tumour diameter > or = 16 mm (p = 0.019) and lack of adjunctive plaque radiotherapy (p = 0.018) 26 (Damato, Paul et al. 1996). Rhegmatogenous retinal detachment occurred in 28 (18%) eyes and was 27 significantly more common in patients with thick tumours (Cox univariate analysis, P = 0.001) and in males 28 (Cox univariate analysis, P = 0.013), with posterior tumour extension being of borderline significance (Cox 29 univariate analysis, P = 0.069). Surgical treatment of the retinal detachment was performed in 25 patients. 30 Anatomic success was achieved in 21 (84%) of these 25 patients, with 7 patients retaining counting fingers 31 vision, and 3 seeing 6/60 or better. Ten eyes treated for retinal detachment were enucleated because of 32 recurrent tumour (four eyes), retinal detachment (three eyes), wound dehiscence (one eye), phthisis (one 33 eye), and poor visual acuity (one eye). Eleven eyes known to have a retinal tear underwent prophylactic 34 vitreoretinal surgery at the end of the local resection, with only one (9%) of these subsequently developing 35 retinal detachment (Damato, Groenewald et al. 2002).
36 Technical improvements have occurred more recently (Damato 2012; Damato 2012). Techniques have been 37 developed for conserving the integrity of the ciliary epithelium over the pars plana and for ‘top-slicing’ tumour 38 adherent to retina, dramatically reducing rates of retinal detachment (Damato 2012; Damato 2012). Rates of 39 local tumour control have improved greatly, as a result of adjunctive brachytherapy with a 25 mm ruthenium 40 plaque in all cases (Damato 1997). Such routine adjunctive brachytherapy has reduced the need for wide 41 surgical margins. These measures have significantly improved ocular outcomes, particularly conservation of
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1 vision (Damato 1997). Outcomes of local resection of uveal melanoma depend greatly on the experience of 2 the surgeon and on the anaesthetist’s ability to provide profound hypotensive anaesthesia.
3 Even with earlier resection techniques, various authors have shown that with large uveal melanomas, the 4 results of local resection are superior to those achieved with radiotherapy (Shields, Cater et al. 2002; Shields, 5 Naseripour et al. 2002; Puusaari, Damato et al. 2007; Bechrakis, Petousis et al. 2010).
6 4.3.3.8 Endoresection 7 With endoresection, the choroidal melanoma is removed piecemeal, using a vitreous cutter. This is done either 8 through a retinotomy over the tumour or after raising a retinal flap. The technique is evolving, with advances 9 such as bimanual surgery and the use of heavy liquids. Endolaser treatment is applied to destroy any residual 10 tumour and to achieve retinopexy. The eye is filled with silicone, which is removed after twelve weeks. 11 Adjunctive radiotherapy can be applied, either in all patients or if histology and genetic studies indicate that 12 the tumour is aggressive. Some centres perform endoresection only after neo-adjuvant radiotherapy, because 13 of concerns about iatrogenic tumour seeding (Bechrakis and Foerster 2006; Schilling, Bornfeld et al. 2006).
14 In a series of 52 endoresections by Damato, the tumours had a mean largest basal diameter of 8.2 mm and a 15 mean tumour thickness of 3.9 mm (Damato, Groenewald et al. 1998). Forty tumours extended to within 2 disc 16 diameters of the optic disc, with 17 involving the disc. Follow-up ranged from 40 days to 7 years (median 20 17 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 18 counting fingers (18), hand movements (nine), and light perception (four). The main complications were 19 retinal detachment in 16 and cataract in 25 patients. Secondary endoresection (n=11) was performed after 20 plaque radiotherapy (four), photocoagulation (four), trans-scleral local resection (two), and PBR (one), with 21 retention of the eye in nine cases. By the close of the study, no patients developed definite local tumour 22 recurrence but one died of metastatic disease 41 months postoperatively. The Liverpool Ocular Oncology 23 Centre experience in local resection of an additional 71 patients is reported in a recent publication 24 (Konstantinidis, Groenewald et al. 2014).
25 The only other major series is that reported by Garcia et al in 2008 (Garcia-Arumi, Zapata et al. 2008). In a 26 series of 38 patients, the authors reported outcomes after a follow-up time ranging from 23 to 129 months 27 (mean 70.63 months). Preoperative visual acuity ranged from ’hand-movements‘ to 20/20 (mean, 20/60). In 28 primary cases, mean tumour thickness was 10.1 mm and mean base diameter 9.9 mm. At the latest visit, 29 92.1% patients still retained the eye. Final visual acuity ranged from ’no light perception‘ to 20/30 (mean 30 20/300). Two patients experienced local recurrence before 3 years of follow-up. Metastatic disease was 31 found in two patients at 5 years of follow-up. Kaplan-Meier survival analysis for all causes was 88.2% at 5 32 years. Specific survival was 90.9% at 5 years.
33 4.3.3.9 Treatment of Iris Melanoma 34 These tumours have the best survival outcomes, if the ciliary body is not involved the 10-year survival data is 35 close to 100%. Nevertheless, treatment is still recommended as an enlarging iris tumour will produce ocular 36 complications.
37 Resection of small iris tumours is a very successful treatment option especially if there is no ciliary body 38 involvement. Iris sector defects can result in visual side effects such as photophobia, glare and halo formation 39 around lights, which make night driving difficult. Pupilloplasty (i.e. reconstruction of the iris) can be performed 40 to minimise this problem. PBR has been used but in this subgroup of patients the eye retention rates are
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1 worse than for ciliary body or choroidal melanoma. In a recent review of 15 cases, eye retention following PBR 2 was 80% (Rundle, Singh et al. 2007). 53% of patients with iris melanomas following proton beam treatment 3 had glaucoma, although this was a pre-existing condition in 33% of the original group of 15 patients (Rundle, 4 Singh et al. 2007). Damato et al reported complication rates from a larger series of 88 patients with iris 5 melanomas. Glaucoma was present before treatment in 13 patients and developed after treatment in another 6 3, and in several patients it was difficult to control (Damato, Kacperek et al. 2005). Post-irradiation cataract is 7 a common although treatable complication following PBR of iris melanoma. Lumbroso et al found 45% of 8 these patients developed cataract within 24 months of treatment (Lumbroso-Le Rouic, Delacroix et al. 2006). 9 In another series of 78 iris melanomas treated by PBR, 51% developed cataract (8873). Both Damato et al 10 (Damato, Kacperek et al. 2005) and Rundle et al (Rundle, Singh et al. 2007) found 20% of patients developed 11 cataract following proton beam irradiation for iris melanomas, and the latter group also reported 27% of 12 patients developed dry eye.
13 Ruthenium plaque brachytherapy resulted in 100% tumour control in a series of 15 pure iris melanomas from 14 London with a long median follow-up of 96 months (Tsimpida, Hungerford et al. 2011). The eye retention rate 15 was also 100%, as no cases of NVG were reported. Like PBR cataract was reported in 60% and dry eyes were 16 seen in 20% of patients. Slightly higher rates of cataract formation have been recorded following Iodine plaque 17 brachytherapy.
18 4.4 Evidence Statements
19 4.4.1 Pre-operative investigations 20 Uveal melanoma is a rare cancer and the combination of a multi-disciplinary skill set together with specialist 21 expertise is required. Level 4 - Government advice
22 Delay in referral results in more advanced disease at presentation and an increased likelihood that the patient 23 will require an enucleation. Level 3
24 The diagnosis of uveal melanoma made using ophthalmoscopy, fundus photography and conventional ocular 25 ultrasound has an accuracy of 99.52%. Level 1-
26 Conventional A and B scan ocular ultrasound is key to making the diagnosis. Level 3
27 Ocular Oncology Centres tend to have more experienced ocular ultrasonographers and better ultrasound 28 equipment. Level 4
29 The evidence for investigation with more recently developed diagnostic tools, based on comparative case 30 series, demonstrate that anterior segment OCT is useful for iris melanoma but is not superior to UBM when 31 considering ciliary body tumours. Level 3
32 UBM with a 50MHz probe is the best tool to image the ciliary body. Level 3
33 The disadvantage of UBM includes patient discomfort due to the eye contact with a waterbath and the 34 increased time taken to perform this test. Level 4
35 If the diagnosis is still uncertain then biopsy has a role. Level 3
36 Small indeterminate lesions may not yield sufficient cells to make a diagnosis especially if less than 2mm in 37 thickness. Level 2+
38
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1 4.4.2 Staging before primary treatment 2 The incidence of metastases at diagnosis of the primary tumour can be use to aid patient stratification 3 according to tumour size. Level 2+
4 Knowledge of the presence of metastatic disease only affects management of the primary tumour when 5 considering enucleation of a painless asymptomatic eye. In this situation, it may be appropriate after careful 6 counselling of the patient to postpone primary treatment or to not perform the operation, to avoid needless 7 mutilation. Level 4
8 LFTs are highly specific but not sensitive in detecting metastatic disease. Level 2+
9 When evaluating biochemical markers of liver function combined GGT and ALP were the most helpful in 10 predicting patients with metastatic disease. Level 3
11 A rising trend in liver enzyme levels over time is more important than the absolute value, which may be within 12 the normal range. Level 2-
13 Abdominal ultrasound, abdominal CT and PET/CT have been used to stage uveal melanoma patients at the 14 time of diagnosis of the primary tumour. Level 2
15 Although there is evidence that MRI is the best imaging modality for assessing the volume and distribution of 16 liver metastatic disease once it has occurred (Level 2), no reports were found that evaluated the use of MRI to 17 stage uveal melanoma patients at diagnosis of the primary tumour.
18 4.4.3 Primary Treatment 19 Choice of primary treatment has not been demonstrated to have a significant impact upon patient survival in 20 uveal melanoma. Level 1
21 There was no significant difference for cumulative all-cause mortality, melanoma-related mortality and 22 metastasis-free survival (log-rank test, p = 0.56, p = 0.99 and p = 0.25, respectively) in patients with large 23 choroidal melanoma after primary treatment with enucleation compared to PBR. Level 2+
24 Five-year local control rates of over 95% have been reported for Ruthenium plaque brachytherapy. Level 2-
25 Risk factors for local recurrence/poor tumour control include large basal diameter, anterior location, young 26 patient age and foveal location. Level 3
27 Visual complications of ruthenium plaque brachytherapy are less severe than those recorded from the 28 collateral damage of iodine plaque brachytherapy or PBR. Level 3
29 Visual deterioration, cataract and vitreous haemorrhage is associated with increasing tumour height following 30 brachytherapy, as these tumours require a higher dose of radiation to achieve tumour control. Level 3
31 Tumour response to brachytherapy may not be a reliable prognostic indicator. Level 3
32 There is a risk of later extraocular extension following primary TTT, particularly in larger tumours. Level 3
33 TTT used in conjunction with plaque brachytherapy, known as “sandwich” therapy, provides better 5-year local 34 tumour control (96% verses 83% p=<0.034), a better globe preservation (98% verses 87% p=<0.024) and 35 recurrence free survival rate (89% verses 67% p=<0.017) than ruthenium plaque brachytherapy alone but 36 there was no difference in overall patient survival/metastatic rate. Level 2+
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1 At 1- and 4-years follow-up the visual outcome was worse in patients who had received ’sandwich‘ therapy 2 compared to those who had received plaque brachytherapy alone. Level 2+
3 In patients with tumour diameter ranging from 4 to 27.5 mm, and tumour height from 0.9 to 15.6 mm 4 receiving PBR, the overall eye retention rate post-treatment at 5 years was 88.9%, 86.2% at 10 years and 5 83.7% at 15 years. Level 3
6 Eye retention rates following PBR are lower for iris melanoma with a higher incidence of post-irradiation 7 cataract and NVG. Level 2
8 4.5 Recommendations 9 Refer to recommendations related to this chapter which in Section 1.2 by clicking HERE
10 4.6 Linking evidence to recommendations 11 In formulating these recommendations, the GDG appraised the data where available. Where data were 12 lacking, the GDG considered how best to combine what data were available with data and experience from 13 similar situations in other oncological areas, as well as their own experience of managing the disease. The GDG 14 did not formally assess the cost of any of the recommendations as the focus of these guidelines is on the 15 identification of those clinical management changes that could be: a) clinically justified; and b) lead to 16 improved health outcomes. However, the GDG was generally aware that recommendations need to be 17 practical if they are able to result in a change of practice. An example was discussions regarding imaging 18 technology to stage patients presenting with ‘high risk’ primary uveal melanomas. Whilst we agreed that 19 contrast-enhanced MRI is the optimal modality for assessing the burden of metastatic liver disease, many 20 centres perform an initial hepatic assessment using USS performed by highly experienced operators and only 21 progress to other modalities when USS-detected abnormalities are seen. Whilst the GDG agreed that USS 22 provides less accurate information regarding disease burden than MRI, using it as an initial screening tool may 23 be entirely reasonable if it has a low false negative rate. USS also has major advantages regarding speed of 24 assessment and cost, and without evidence that patients were at a disservice by having an MRI scan only 25 following an abnormal ultrasound, the GDG was unable to recommend MRI staging for all ‘high risk’ patients. 26 This is an area that would benefit from further investigation.
27 The GDG believes that our recommendations regarding patient access to information about options available 28 at each of the surgical centres, the development of a national uveal melanoma database, education of health 29 care professionals who are likely to detect primary uveal melanoma, and timely referral to medical oncology 30 will combine to significantly improve the quality of patient care.
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1 5. Prognostication
2 5.1 Introduction 3 Uveal melanoma can arise in the iris, ciliary body and the choroid, with the latter being the most common site. 4 Despite successful treatment of the primary tumours in most cases, approx. 40%-50% of patients will develop 5 disseminated disease, predominantly in the liver, but also in the lungs, bone and elsewhere. Early surgical 6 removal of metastases has improved patient survival in some cases (Frenkel, Nir et al. 2009; Mariani, Piperno 7 et al. 2009); however, in general, the prognosis of UM patients with metastatic disease is currently poor 8 because of the lack of effective systemic agents.
9 Several parameters have been identified in the literature, which have prognostic significance with varying 10 degrees of strength that predict metastasis and therefore survival in uveal melanoma patients. These can be 11 grouped into: a) clinical-; b) histomorphological-; c) immunohistochemical-; d) genetic; and e) serological- 12 features (see references below). Some of these have been reviewed in depth by the AJCC TNM staging 13 committee and have been included into this staging system for prognostication purposes (Finger and The 7th 14 Edition AJCC-UICC Ophthalmic Oncology Task Force 2009; Kivela and Kujala 2013). Others have undergone 15 extensive analysis using large data sets, either as part of a one-centre or multicentre analysis either as single 16 parameters or in combination. Finally, other prognostic parameters noted in the literature have undergone 17 less robust evaluation and their true significance remains unclear. The purpose of the following Chapter is to 18 review the proposed prognostic parameters, determine whether there is a preferred prognostic tool and to 19 suggest the role for prognostic biopsy.
20 5.2 Methods
21 5.2.1 Questions addressed 22 The questions that the developer(s) aimed to address were:
Question Population Intervention Comparator Outcome
Is there a • Patients with Clinical variables Each other Survival (hazard preferred diagnosed primary Histomorphological ratio for prognostic tool? uveal melanoma features prognostic factors) with and without Immunohistochemical clinical evidence of features metastatic disease Genetic data Serological markers What is the role Patients with uveal Intraocular biopsy With no biopsy Patient surveys of the prognostic melanoma with and and satisfaction biopsy? without clinical evidence of metastatic disease
23
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1 5.2.2 Inclusion and exclusion criteria for selecting evidence 2 All papers regarding prognostic parameters predicting survival outcome described for primary uveal melanoma 3 were included. Preclinical and animal studies, in vitro cytogenetic markers and cell line studies, single centre 4 unvalidated series and single case reports were excluded.
5 5.2.3 Appraisal and extraction 6 Information from each of the investigation was extracted and presented to the Guideline Development Group 7 for discussion on July 10 2013, with an update of the evidence presented after the update search. Tables 1-4 8 show the papers that were reviewed. For full details of each of the included studies, see the evidence tables in 9 Appendix A.
10 All references were sifted initially by one individual, and grouped according to whether the prognostic 11 parameter(s) described was/were of the following types: a) clinical; b) histomorphological; c) 12 immunohistochemical; d) genetic; or e) serological. Where several or combinations of prognostic parameters 13 described, these were also evaluated. The primary reasons for excluding papers were that they did not 14 address the question. The reviewer appraised and reviewed the included papers, and the quality of the 15 studies was assessed using the SIGN checklists as a guide.
16 5.3 Review of Evidence
17 5.3.1 Is there a preferred prognostic tool? 18 When evaluating the literature with respect to this question, it became apparent that the definition of the 19 word ’tool‘ had to be addressed. Ultimately, it was decided that the word ’tool‘ had several meanings but 20 principally referred to a ’method‘ or ’methods‘, including clinical, histomorphological, immunohistochemical, 21 genetic, serological and ‘combined’ methods, which had been applied to determine the prognosis of uveal 22 melanoma patients.
23 Clinical factors that have been consistently demonstrated in the literature to have strong statistical significance 24 when predicting the risk of metastasis (and therefore have a role in prognostication) include:
25 1. Patient age (Seddon, Albert et al. 1983);.(Folberg, Rummelt et al. 1993; Hawkins 2006; 26 Damato, Duke et al. 2007; Virgili, Gatta et al. 2008; Shields, Furuta et al. 2009; Shields, Kaliki 27 et al. 2013).
28 2. Patient gender (Folberg, Rummelt et al. 1993; Virgili, Gatta et al. 2008; Damato and Coupland 29 2012).
30 3. Tumour height (Diener-West, Hawkins et al. 1992; Shields, Furuta et al. 2009 ; Shields, Kaliki 31 et al. 2013).
32 4. Tumour basal diameter (Seddon, Albert et al. 1983 ; Folberg, Rummelt et al. 1993; Hawkins 33 2006; Damato and Coupland 2009; Shields, Furuta et al. 2009; Kivela and Kujala 2013; 34 Shields, Kaliki et al. 2013).
35 5. Tumour location – i.e. ciliary body involvement (Seddon, Albert et al. 1983; Damato and 36 Coupland 2009; Shields, Furuta et al. 2009; Kivela and Kujala 2013).
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1 6. Presence and extent of extraocular melanoma growth (Seddon, Albert et al. 1983; Group 2 1998; Coupland, Campbell et al. 2008; Kivela and Kujala 2013; Shields, Kaliki et al. 2013).
3 Most of these parameters have been included in the 7th Edition of the AJCC TNM staging system 4 (Kivela and Kujala 2013).
5 Histomorphological factors shown in numerous papers to be prognostic significance comprise:
6 1. Tumour cell type (McLean, Foster et al. 1982; McLean, Foster et al. 1983; Damato, Duke et al. 7 2007)2. Mitotic count (on haematoxylin staining only) (Folberg, Rummelt et al. 1993; Collaborative 8 Ocular Melanoma Study 2003 ; Damato, Duke et al. 2007; Coupland and Damato 2009; Damato, 9 Dopierala et al. 2010).
10 3. Mean diameter of ten largest nucleoli (McLean, Keefe et al. 1997; Al-Jamal and Kivela 2006; 11 Al-Jamal, Toivonen et al. 2010).
12 4. Presence of extravascular matrix patterns, particularly ‘closed loops’ (Folberg, Rummelt et al. 13 1993; Rummelt, Folberg et al. 1995; McLean, Keefe et al. 1997; Damato, Duke et al. 2007).
14 5. Microvascular density (Foss, Alexander et al. 1996; Schaling and Pauwels 1996; Lane, Egan et 15 al. 1997; Makitie, Summanen et al. 1999; Chen, Maniotis et al. 2002).
16 6. Presence and size of extraocular melanoma growth (Seddon, Albert et al. 1983; Group 1998; 17 Coupland, Campbell et al. 2008; Kujala, Damato et al. 2013; Shields, Kaliki et al. 2013).
18 Immunohistochemical parameters described to be of prognostic significance in uveal melanoma include:
19 1. Tumour cell proliferation markers (Ki-67, PCNA/PC-10, Ser10/PHH3) (Mooy, Luyten et al. 20 1995; Seregard, Spangberg et al. 1998; Al-Jamal and Kivela 2006; Onken, Worley et al. 2010; 21 Angi, Damato et al. 2011).
22 2. Density of tumour-infiltrating macrophages (Folberg, Rummelt et al. 1993; Whelchel, Farah 23 et al. 1993; de Waard-Siebinga, Hilders et al. 1996; Makitie, Summanen et al. 2001; 24 Toivonen, Makitie et al. 2004; Mougiakakos, Johansson et al. 2010).
25 3. Density of tumour-infiltrating lymphocytes (de la Cruz, Specht et al. 1990; Durie, Campbell et 26 al. 1990; Tobal, Deuble et al. 1993; de Waard-Siebinga, Hilders et al. 1996; 1998; Maat, Kilic 27 et al. 2008; Bronkhorst, Vu et al. 2012; Herwig, Bergstrom et al. 2013).
28 Cytogenetic and molecular genetic features of the tumour cells have been demonstrated to have strong 29 prognostication value in uveal melanoma. The most striking abnormality in uveal melanoma is the complete or 30 partial loss of chromosome 3. Other common genetic abnormalities of uveal melanoma include loss on 1p, 6q, 31 8, and 9p as well as gain on 1q, 6p, and 8q (see review, (Coupland, Lake et al. 2013). The above-mentioned 32 chromosomal alterations in primary uveal melanoma are clinically relevant because of their correlation with 33 the risk of metastatic death. Chromosome 3 loss is associated with a reduction of the 5-year survival 34 probability from approximately 100% to about 50% (Prescher, Bornfeld et al. 1992; Prescher, Bornfeld et al. 35 1994; Damato, Duke et al. 2007; Onken, Worley et al. 2007; Shields, Ganguly et al. 2007; Young, Burgess et al. 36 2007; Young, Rao et al. 2007; Damato and Coupland 2009; Damato, Dopierala et al. 2010; Onken, Worley et al.
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1 2012; Singh, Aronow et al. 2012; Thomas, Putter et al. 2012; Vaarwater, van den Bosch et al. 2012). Similarly, 2 chromosome 8 gains and loss of chromosome 1 significantly correlate with reduced survival (Sisley, Rennie et 3 al. 1990; Damato, Duke et al. 2007; Damato, Dopierala et al. 2010). Both chromosome 3 loss and polysomy 8q 4 are also associated with other poor prognostic factors, including increasing tumour basal diameter, ciliary body 5 involvement, presence of epithelioid cells, high mitotic count, and closed connective tissue loops (Scholes, 6 Damato et al. 2003; Damato, Duke et al. 2007; Damato, Dopierala et al. 2010). Conversely, gains in 7 chromosome 6p correlate with a good prognosis, suggesting this aberration has a functionally protective effect 8 (White, Chambers et al. 1998; Damato, Duke et al. 2007; Damato, Dopierala et al. 2010).
9 Different methods (i.e. techniques or ’tools‘) can be applied to assess the genetic alterations of uveal 10 melanomas. The most commonly used tests are fluorescent in situ hybridization (FISH), multiplex ligation 11 dependent probe amplification (MLPA), microsatellite analysis (MSA), single nucleotide polymorphisms (SNP) 12 array (aSNP) and a PCR-based 12-gene assay based on gene expression profiling (GEP) (see Review by 13 (Coupland, Lake et al. 2013)). The latter technique divides uveal melanoma into two ‘classes’ on the basis of 14 an mRNA expression signature: class 1 and class 2 (Onken, Worley et al. 2010; Onken, Worley et al. 2012). 15 Essentially, ‘Class 1’ uveal melanoma often show 6p and 8q gain. ‘Class 2’ uveal melanoma tend to show more 16 aneuploidy with 1p loss, 3 loss, 8p loss, and 8q gain. Class 2 UM are also strongly associated with inactivating 17 mutations of ‘BRCA1-associated protein-1 (BAP1), located at 3p21 (see below) (Harbour, Onken et al. 2010). 18 The GEP-based test has been patented (DecisionDx-UM; www.castlebiosciences.com/test_UM.html). To date, 19 there has been a paucity of studies that directly compare prognostic techniques in uveal melanoma (Singh, 20 Aronow et al. 2012). Only limited comparative analyses have been performed (Onken, Worley et al. 2007; 21 Young, Burgess et al. 2007), (Young, Rao et al. 2007; Petrausch, Martus et al. 2008; Onken, Worley et al. 2012; 22 Singh, Aronow et al. 2012; Vaarwater, van den Bosch et al. 2012; Coupland, Damato et al. 2013; Coupland, 23 Lake et al. 2013), each with their respective flaws, and therefore no statement regarding superiority of a 24 particular technique over another can be made.
25 Some serological markers have been proposed to be associated with poorer prognosis and ‘high-risk’ uveal 26 melanoma: these include MIA-1 (Schaller, Bosserhoff et al. 2002; Reiniger, Schaller et al. 2005; Barak, Frenkel 27 et al. 2007; Missotten, Korse et al. 2007); S-100B (Missotten, Beijnen et al. 2003; Barak, Frenkel et al. 2007; 28 Missotten, Korse et al. 2007), osteopontin (Kadkol, Lin et al. 2006) ,(Barak, Frenkel et al. 2007); TPS (Barak, 29 Frenkel et al. 2007); GDF-15 (Suesskind, Ulmer et al. 2011); B2-microglobulin (Triozzi, Achberger et al. 2012); 30 and circulating cell free DNA (Metz, Scheulen et al. 2013). Most of these serological biomarkers are being 31 investigated as a research tool but to date are not being used to influence clinical management.
32 Combined prognostic models have been designed and validated by some ocular oncology centres (Taktak, 33 Fisher et al. 2004; Kaiserman, Rosner et al. 2005; Damato, Eleuteri et al. 2008; Damato, Eleuteri et al. 2011). 34 The prognostic models take into account a number of the stronger prognostic parameters in uveal melanoma, 35 which have been incorporated into statistical systems (e.g. conditional hazard estimating neural network; 36 artificial neural networks; and accelerated failure time) using test and validation sets, for individualised 37 prediction of prognosis. It has been demonstrated that these models increase the accuracy of prognosis 38 prediction rather than using one single prognostic parameter. In some centres, the prognostication model is 39 being used for patient counselling and to determine screening frequency and the ultimate modality for 40 screening (e.g. MRI versus ultrasound) applied (Marshall, Romaniuk et al. 2013).
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1 5.3.2 What is the role of prognostic biopsy? 2 The proposed roles of prognostic biopsy are:
3 1. The identification of a high-risk group allows for: a) determination of liver scan frequencies and 4 studies comparing screening methodologies; b) early surgical intervention of metastatic disease; and c) 5 development of systemic adjuvant therapies using either two-stage or multistage phase II studies (Whitehead, 6 Tishkovskaya et al. 2012).
7 Whilst genetic testing may alter management of patients at ocular oncology centres (Damato, Eleuteri et al. 8 2011), to date there is only one documented prospective single-arm study in the literature, whereby those 9 asymptomatic uveal melanoma patients with a predicted 5-year mortality of greater than 50% underwent 6- 10 monthly screening using MRI (Marshall, Romaniuk et al. 2013). This resulted in metastases being detected 11 before symptoms in 83 (92%) of 90 patients developing systemic disease, with 49% of these having less than 12 five hepatic lesions all measuring less than 2 cm in diameter. Of these 90 patients, 12 (14%) underwent 13 hepatic resection, all surviving for at least a year afterwards. Whether this results in prolongation of life after 14 taking lead-time bias into account, requires further follow-up and investigation.
15 2. Aid patient counselling – Patient demand is increasing for prognostication biopsies in uveal 16 melanoma. Some studies (Beran, McCannel et al. 2009; Cook, Damato et al. 2009) have demonstrated that one 17 of the main benefits perceived by patients is that they would have greater control knowing the genetic ‘type’ 18 of their tumour, and that screening for metastatic disease and early treatment might enhance chances of 19 survival. Further, psychological status did not vary significantly as a function of cytogenetic test result. 20 Prognostic information was important to patients with choroidal melanoma, even in the absence of 21 prophylactic measures that might improve prognosis (Beran, McCannel et al. 2009).
22
23 5.4 Evidence Statements
24 5.4.1 Prognostic factors/tool 25 Prognostic factors of uveal melanoma are multi-factorial and include clinical, morphological, 26 immunohistochemical and genetic features. Level 1++ 27 There are a number of different cytogenetic and molecular techniques for evaluating genetic changes 28 in uveal melanoma but there is insufficient comparative data. No evidence was found that 29 demonstrated one technique was superior to another. Level 1+ 30 A number of novel serological biomarkers are being investigated but not informed clinical 31 management. Level 2-
32 5.4.2 Prognostic biopsy 33 Biopsy provides powerful prognostic information but there is as yet inadequate evidence to 34 demonstrate that changing management as a result of this information affects survival. Level 4
35 5.5 Recommendations 36 Refer to recommendations related to this chapter, which are in Section 1.2 by clicking HERE
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1 5.6 Linking Evidence to Recommendations 2 The GDG had a lengthy discussion regarding the risks and benefits of a prognostic biopsy. Some of the 3 clinicians regarded the biopsy as collecting information for research purposes only, with no therapeutic 4 benefit; others were of the opinion that a biopsy assists in identifying patients at ‘high risk’ of metastasis and 5 who could benefit from more intensive follow-up with the aim of potentially detecting metastases earlier. 6 There was additional prolonged discussion on how to define a ‘high risk’ uveal melanoma patient (with respect 7 to the development of metastasis) given the variety of genetic testing methods and their varying degrees of 8 accuracy. Further, the GDG discussed what the definition of a ‘high risk’ uveal melanoma patient would be 9 without the genetic data.
10 Currently two of the three ocular oncology referral centres in the UK do not routinely perform prognostic 11 biopsy as it does not alter patient management in those two particular centres. There is some concern about 12 the accuracy of the results and about the risks of the procedure. These include the risk of tumour seeding, 13 intraocular haemorrhage as well as the possibility of a non-diagnostic result. This is in contrast to the third 14 centre (Liverpool) where routine prognostication has been part of patient management since 1996, and where 15 considerable expertise has been accumulated.
16 The discussion focused on patient preferences. The patient representatives were in favour of patients being 17 informed about and being offered an intraocular biopsy, as this gave them more information on which to base 18 decisions including future treatment options. They argued that if the biopsy is not performed, this information 19 would not be available at a later date, particularly if the uveal melanoma was treated by radiotherapy in the 20 absence of tissue sampling. Without accurate genotyping of their tumours through a biopsy, patients may not 21 be eligible to be recruited into clinical trials. This was regarded by the patient representatives as a major 22 handicap. There was a discussion about whether all patients wanted to know the results of the intraocular 23 biopsies. Experience at the Liverpool Ocular Oncology Centre (and elsewhere) would suggest that most 24 patients do; however, this information is only incorporated into the pathology reports, if the patient has 25 consented for the prognostic testing to be done. It was agreed that there should be an informative and 26 neutral discussion between the patient and ocular oncologist about the risks of intraocular biopsy prior to 27 treatment of the primary tumour, and these were to be considered against the potential benefits.
28
29 6. Surveillance of patients at risk of recurrence
30 6.1 Introduction 31 Uveal melanoma is a rare cancer, with a propensity for liver metastasis. Management of localised disease with 32 either surgery or radiotherapy achieves a high rate of local control; however, about 50% of patients relapse 33 with predominantly liver metastases. The risk of metastatic disease can be predicted relatively accurately 34 through the use of clinicopathological features and molecular genetics (see above). Prognosis in the 35 metastatic setting remains poor, with a median survival of less than 6 months. Surgical management of liver 36 metastases offers the only real likelihood of long-term disease control at present (Frenkel, Nir et al. 2009; 37 Mariani, Piperno-Neumann et al. 2009), particularly as there are currently no proven systemic therapies that 38 change outcome in patients with disseminated uveal melanoma. This has led to the introduction of 39 surveillance programmes for patients with a high-risk of developing disease, with the aim of identifying
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1 metastases early, allowing for resection or clinical trial entry. It has been previously shown that surveillance 2 allows early detection of metastases prior to the development of symptoms, and that this facilitates trial entry 3 and surgery in a limited proportion of patients. Although a survival benefit to screening has not been proven, 4 many centres (nationally and internationally) now perform periodic screening of patients with high-risk uveal 5 melanoma, and screening is now considered to be good clinical practice. However the optimal screening 6 method (e.g. CT scanning, MRI, US), timing, patient selection and overall advantage of surveillance remain 7 under debate. More sensitive imaging modalities such as PET/CT and contrast-enhanced MRI have been 8 proposed and are increasingly used internationally. This has been on the assumption that such technologies 9 improve the detection and expedite detection of metastases and improve resection and hence survival. 10 However this benefit remains to be demonstrated, and there are clear financial and clinical implications.
11
12 Aim – purpose is to identify patients who have relapsed. – i.e. who have developed 13 metastatic disease.
14 The GDG agreed that the aim is to detect small volume, pre-clinical disease rather than first identifying large 15 volume, clinically detectable, metastatic disease.
16 Aim – to detect metastatic disease as early as possible.
17 The GDG agreed that there is a need to assess whether early detection makes a difference. There is evidence 18 in Section 7 that small volume treatment has better outcome. Early treatment potentially may influence 19 benefit and number of lines of treatment.
20 6.2 Methods
21 6.2.1 Questions addressed 22 1. Should all patients be offered surveillance? 23 2. Should there be a risk-adapted strategy for surveillance? 24 3. What is the optimal imaging modality for surveillance? 25 4. What is the interval? 26 5. What is the duration of surveillance? 27
Question Population Test/Intervention Comparator Outcome
Should all patients be Patients who have LFT With each other Metastasis offered surveillance? been treated for a USS Survival primary uveal MRI (liver, contrast melanoma enhanced) Laparoscopy Should there be a Patients who have LFT Comparing Sensitivity and risk-adapted strategy been treated for a USS different risk levels specificity of for surveillance? primary uveal MRI (liver, contrast to each other metastasis melanoma, and enhanced) detection who have a ‘high Laparoscopy risk’ of developing Survival metastatic disease, according to
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clinical, histomorphological and genetic features. What is the optimal Patients who have USS Compared to each Sensitivity and imaging modality for been treated for a MRI (liver, contrast other specificity of surveillance? primary uveal enhanced) metastasis What is the interval? melanoma detection
Survival
What is the duration Patients who have USS Compared to each Sensitivity and of surveillance? been treated for a MRI (liver, contrast other specificity of primary uveal enhanced) metastasis melanoma 5 years versus 10 detection years versus life- long Survival
1
2 6.2.2 Inclusion and exclusion criteria for selecting evidence 3 Included were Case control studies, Case series >3 patients and Review articles combined with case reports. 4 Only studies with adult patients were included. Preclinical and animal studies were excluded, as were case 5 reports (1-3 cases) and review articles without any original case information.
6 6.2.3 Appraisal and extractions 7 All references were sifted first by one individual. Two reviewers appraised and reviewed the included papers, 8 and the quality of the studies was assessed using the modified SIGN checklists as a guide.
9 Most of the studies were case reports (close to 30%) with only about 10% representing descriptive case series.
10 Information from each of the studies was extracted and presented to the Guideline Development Group for 11 discussion on March 14 2014 with an update of the evidence presented after the update search. For full details 12 of each of the included studies, see the evidence tables in Appendix A.
13 No studies were found that addressed the duration of surveillance review question.
14 6.3 Evidence summary
15 6.3.1 Question 1: Should all patients be offered surveillance? 16 A recent and very detailed review of studies that investigated periodic surveillance from 1980 to 2009 by 17 Augsburger et al. (Augsburger, Correa et al. 2011) failed to find evidence of a survival benefit associated with 18 regular surveillance. Therefore it could be argued that it is futile offering uveal melanoma patients 19 surveillance examinations to detect metastatic disease. However, the majority of the studies reported in this 20 review (n = 31 in total) were small, retrospective, and from single institutions. In addition, a wide and very 21 variable range of screening methods and strategies were described, further complicating the comparison. 22 Notably, none of the articles was a report of a randomized or nonrandomized comparative clinical trial of total 23 post-treatment survival in subgroups assigned to regular periodic surveillance for metastasis versus no 24 surveillance testing (Augsburger, Correa et al. 2011).
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1 On the other hand, several studies having clearly demonstrated that periodic liver imaging allows the 2 identification of liver metastases prior to the development of symptoms (Eskelin, Pyrhonen et al. 1999; Maeda, 3 Tateishi et al. 2007; Kim, Lane et al. 2010; Marshall, Romaniuk et al. 2013). For example, in the study by 4 Marshall et al. 92% of patients who developed metastases, were asymptomatic at the time of diagnosis using 5 6-monthly non-contrast MRI surveillance (Marshall, Romaniuk et al. 2013). Furthermore, liver surveillance 6 allowed detection of liver metastases in the majority of patients prior to changes in serum biochemistry.
7 Liver metastasectomy is currently only possible in approximately 10% of cases using historical screening 8 programmes (Sato 2010; Marshall, Romaniuk et al. 2013) and reflecting the burden of disease at diagnosis of 9 metastases. However, the resection rate may be increased with strategic planning of screening, using more 10 sensitive tools.
11 6.3.2 Question 2: Should there be a risk-adapted strategy for surveillance? If so, 12 what is a high-risk and or low-risk uveal melanoma? 13 As mentioned above in the “Prognostication” section (section 5), the risk of metastatic relapse in uveal 14 melanoma is determined by multiple factors, including clinicopathological features such as tumour size and 15 location (Shields, Furuta et al. 2009) and molecular genetic abnormalities, most notably the loss of 16 chromosome 3 (Prescher, Bornfeld et al. 1996; Damato, Eleuteri et al. 2011). In addition, the risk of metastatic 17 disease may be assessed using multigene expression assays (Onken, Worley et al. 2010). This has enabled the 18 development of sophisticated prognostic tools, which allow the identification of patients with a high risk of 19 developing metastases, (Onken, Worley et al. 2010) for whom surveillance is most likely to be beneficial. For 20 example, the Liverpool Uveal Melanoma Prognosticator Online (LUMPO) is used on a routine basis to stratify 21 uveal melanoma patientsinto low- and high-risk groups, and is used in patient counselling, management and 22 screening (www. ocularmelanomaonline.com) (Damato, Eleuteri et al. 2011).
23 Targeted screening, in the highest risk patients with the greatest needs, also offers a practical setting where 24 clinical trials may be most helpful in elucidating the role of follow-up. In the study by Marshall et al (Marshall, 25 Romaniuk et al. 2013) for example, only patients with monosomy 3 were enrolled, thus limiting surveillance to 26 patients with a high risk of recurrence, which is reflected in the development of metastases in 48% of patients, 27 after a median follow-up period of approximately 29 months. Conversely, patients for whom relapse is very 28 unlikely may be reassured and discharged early. However, the level of risk that is employed as a cutoff is 29 clearly subject to debate. The risk-versus-benefit ratio of screening in ‘low metastatic risk’ disease poses 30 additional challenges and must be carefully weighed against potential harm from false positive findings, 31 potential radiation exposure, psychological morbidity and the economic impact.
32 The definition of ‘high risk’ uveal melanoma poses difficulties since not all centres apply the molecular genetic 33 testing, or only in very few selected cases, e.g. enucleation samples. Consequently, a definition of ‘high risk’ 34 cannot in the UK be based only on molecular genetic abnormalities, but must include clinical and 35 histomorphological features of the tumours, when assessable. A ‘high risk group’ may therefore entail 36 inclusion of uveal melanomas with:
37 a. Large tumour size (based on a TNM cutoff - e.g. T2) (Finger and The 7th Edition AJCC-UICC Ophthalmic 38 Oncology Task Force 2009; Kivela and Kujala 2013)
39 b. with or without (+/-) Ciliary body involvement
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1 d. +/- Closed connective tissue loops
2 e. +/- High mitotic count (>5 per 40 HPF)
3 f. +/- Monosomy 3
4 g. +/- Polysomy 8
5 h. +/- GEP Class 2.
6 i. +/- A risk of death of 30% at 5 years or higher.
7 Discussion is required to agree on this definition before any prospective study addressing the usefulness of 8 surveillance in uveal melanoma subgroups can be commenced. Further, the endpoints of this study would 9 have to be carefully considered: e.g. time to detection of metastases, time to resection, survival outcomes.
10 6.3.3 Question 3: What is the optimal imaging modality for surveillance, overall 11 and of the liver? 12 Many different imaging modalities are in use or have been suggested including, but not limited to, liver 13 imaging with USS, CT or MRI (with or without contrast enhancement) or body imaging with CT or PET-CT. The 14 choice of imaging modality currently reflects local practice access, and also whether or not to exclusively 15 image the liver or include extrahepatic sites.
16 The principal hypothesis behind screening in the surveillance of uveal melanoma patients is the detection of 17 resectable liver metastases, based on the assumption that a significant proportion of patients have liver-only 18 metastases at first relapse. Consequently, this has led to the use of liver imaging as the primary modality used 19 for screening. In an imaging study of 110 uveal melanoma patients at different time points following diagnosis 20 of the primary tumour, 55% had liver-only metastases, and the liver was involved in 92% overall (Lorigan, 21 Wallace et al. 1991). Several other studies have similarly reported high rates of liver involvement (Einhorn, 22 Burgess et al. 1974; Gragoudas, Egan et al. 1991). However, in a series evaluating distribution of metastases at 23 death, the liver was involved in 93%, with 87% of cases showing multiple sites of metastases (Collaborative 24 Ocular Melanoma Study 2001). Other autopsy series showed liver-only metastases in between 22%-30% of 25 patients with other sites being affected in up to 90% of patients. (Patel, Didolkar et al. 1978; Borthwick, 26 Thombs et al. 2011).
27 Therefore, in advanced metastatic disease liver-only uveal melanoma metastases are less common; 28 extrahepatic metastases at first relapse in the presence of liver metastases can occur (Lorigan, Wallace et al. 29 1991), but the frequency is unclear. Recent case series utilising PET-CT have illustrated that UM metastases 30 can be widely disseminated and include unusual sites such as cardiac, muscle, and thyroid etc. (Klingenstein, 31 Haug et al. 2010) and (Kurli, Reddy et al. 2005). Extrahepatic relapse in the absence of liver metastases 32 appears uncommon. Prolonged survival has been described following solitary extrahepatic metastatectomy 33 (Aoyama, Mastrangelo et al. 2000). The low frequency of isolated extrahepatic relapse would not appear to 34 justify routine imaging beyond the liver: this would require long-term CT follow-up, which is potentially 35 associated with harmful radiation effects.
36 Liver imaging: Although there has been very limited formal evaluation of imaging in uveal melanoma, a meta- 37 analysis in gastrointestinal cancer reported the highest weighted sensitivity in the detection and assessment of 38 liver metastases with either MRI or PET-CT (Niekel, Bipat et al. 2010). Two uveal melanoma-specific studies 39 suggest that MRI may be superior to PET-CT in detecting small hepatic metastases (lesions <10 mm in
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1 diameter) (Servois, Mariani et al. 2010; Orcurto, Denys et al. 2012). However, MRI still remains an imperfect 2 preoperative modality, given the pattern of miliary liver metastases that can be seen in uveal melanoma. 3 Contrast-enhanced MRI can further increase high spatial resolution and sensitivity and is the preferred liver- 4 imaging technique for potentially operable malignant liver disease. The role in routine surveillance is less clear 5 and potentially offset by high costs, long procedure time and a recognised but low incidence of potentially 6 adverse reactions. A direct comparison between MRI with and without contrast has not been published in 7 uveal melanoma. Investigation into the utility of PET-MRI in this setting is also required. This is a relatively 8 new technology that is not in general use at present. However, PET-MRI has potential advantages, most 9 notably a lower dose of ionising radiation in comparison to PET-CT.
10 The choice of modality clearly has implications on the cost-effectiveness of any surveillance programme. The 11 current estimated costs to the NHS are £85-£125, £380, £370, £450 and £900 for liver USS, contrast CT, non- 12 contrast MRI, contrast MRI and PET-CT, respectively. In the absence of cost-effectiveness data, the choice of 13 modality has been based upon a relatively subjective assessment of efficacy in relation to cost and the scope 14 of the surveillance programme (all patients versus a targeted high-risk population).
15
16 6.3.4 Question 4: What is the optimal surveillance interval? 17 There is very little evidence on which to base decisions regarding either frequency or duration of follow-up.
18 In a study by Eskelin et al. (Eskelin, Pyrhonen et al. 1999) surveillance was performed annually using liver USS 19 and 59% of metastases were detected at an asymptomatic stage. The authors hypothesised that 6-monthly 20 imaging would increase the percentage of asymptomatic detection to 95%. In the study by Marshall et al. (in 21 which surveillance was performed every 6 months), 92% of patients were detected before the development of 22 symptoms (Marshall, Romaniuk et al. 2013).
23 Nonetheless, the general consensus in the field is that 6-monthly imaging is preferable. Advice must take into 24 account the individual’s risk weighted against the cost and resource implications of shorter scanning intervals 25 as well as the possible psychological impact on patient and family from more frequent (e.g. 3monthly) testing.
26 6.3.5 Question 5: What is the duration of surveillance? 27 Uveal melanoma may continue to relapse for many decades following primary diagnosis, with 20%-33% of 28 deaths attributed to metastatic recurrence even at 15-42 years (Coupland, Sidiki et al. 1996; Kujala, Makitie et 29 al. 2003). The Liverpool dataset suggests an almost linear continuation of recurrence over time and beyond 10 30 years without a visible plateau in risk of recurrence. (Damato and Damato 2012) The role of lifelong screening 31 is unknown, but it is pertinent to note that surgical resection series report that the outcome appears most 32 favourable in later relapsing patients, perhaps arguing for prolonged follow-up in some instances. Lifelong 33 screening in all patients would appear unjustified and expensive, and supports the concept of targeted 34 screening of higher risk subgroups. Marshall et al. reported that 65% of high-risk patients had relapsed at 5 35 years on non-contrast liver MRI surveillance, and thus focusing surveillance on this period would appear 36 sensible (Marshall, Romaniuk et al. 2013). However, a further period of screening, may also prove to be of 37 value in the detection of resectable disease.
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1 6.4 Evidence Statements 2 To date, an effect of screening on survival of uveal melanoma patients has not been demonstrated. 3 Level 2- 4 If a substantial and clinically meaningful survival benefit were truly associated with periodic 5 surveillance testing for uveal melanoma metastases, such benefit would be demonstrated most 6 convincingly by means of a prospective comparative clinical trial in which subgroups of patients with 7 uveal melanoma (after treatment of their primary intraocular tumour) were subjected to either 8 regular periodic surveillance testing by some consistent regimen or no surveillance testing at all and 9 then followed until death from any cause. It seems unlikely that this could be tested practically. 10 Level 4 11 Despite the lack of evidence there is general consensus that surveillance testing is not worthless, and 12 indeed is performed in virtually all centres in a periodic manner using differing methods for differing 13 lengths of periods. Level 4 14 Surveillance clearly identifies many patients with metastasis at a substantially less advanced disease 15 burden than would occur if only postsymptomatic testing were employed. Level 2 16 Targeted surveillance is likely to bring more benefit. A consensus definition of ‘high-risk’ uveal 17 melanoma is required, incorporating clinical, histomorphological and genetic features of the tumours. 18 Level 4 19 Most surveillance testing for metastatic uveal melanoma concentrates on the liver, with the effect 20 that highly-sensitive modalities for liver imaging are chosen. Level 2 21 The role of extrahepatic imaging in surveillance is unclear, particularly as the frequency of 22 extrahepatic metastatic relapse remains unknown. Level 2 23 Hepatic surveillance of uveal melanoma has resulted in an increased detection rate of metastases in 24 the liver, resulting in increased locoregional treatment in some centres and trial recruitment. Level 2 25 Surveillance is intuitively advantageous, allowing locoregional management of liver-only metastases, 26 and facilitating early systemic treatment and particularly trial enrolment before the disease burden 27 causes deteriorations in general health and performance status. Level 4 28 Additionally, surveillance facilitates patient follow-up, provides a link with oncology services and 29 allows a more holistic approach to cancer patients that includes early access to cancer nurse 30 specialists and smooth transition to services such as palliative care at an appropriate stage. Level 2 31 No evidence was found with respect to the duration of surveillance. 32
33 6.5 Recommendations 34 Refer to recommendations related to this chapter which in Section 1.2 by clicking HERE
35 6.6 Linking evidence to recommendations 36 The GDG discussed the reasoning and strategy for surveillance of uveal melanomas at length.
37 With respect to the question “Should all patients should be offered surveillance”, there was consensus 38 amongst the GDG that whilst the evidence in the literature would suggest that this practice is futile, all three 39 ocular oncology centres and their associated general oncologists supported the concept of conducting 40 surveillance, with an emphasis on liver screening. This was supported by studies demonstrating that periodic
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1 liver imaging allows the identification of liver metastases prior to the development of symptoms and/or 2 change in blood values.
3 Regarding the question “Should there be a risk-adapted strategy for surveillance?”, there was no consensus in 4 the GDG, due to the inability to agree on a definition of ‘high metastatic risk’, reflecting the varying 5 approaches between the centres to prognostication. Whilst some centres would employ MRI with or without 6 contrast in ‘high-risk’ uveal melanoma, others indicated that they would remain with the initial hepatic 7 assessment using USS and only progress to other modalities when USS-detected abnormalities are seen. It was 8 suggested that due to the insufficient evidence comparing and contrast screening modalities in uveal 9 melanoma patients, a prospective trial for uveal melanoma surveillance is required before any change of local 10 practice would be undertaken.
11 Consensus was achieved amongst the GDG for 6-monthly liver screening in all uveal melanoma patients for the 12 first 5 years, despite the lack of evidence in the literature supporting this practice. However, no consensus was 13 reached between GDG members with respect to the duration of surveillance. This is another area that would 14 benefit from further investigation.
15 The patient representatives were in favour of the uveal melanoma patients being informed of the strengths 16 and weaknesses of differing screening methodologies, and being involved in the decision-making process of 17 what screening method was chosen in their particular case.
18
19 7. Metastatic Disease
20 7.1.1 Introduction 21 As discussed above, the natural history of uveal melanoma is characterised by the frequent development of 22 metastases. Close to 50% of patients develop metastatic disease at any time from the initial diagnosis of the 23 primary to several decades later (Kujala, Makitie et al. 2003; Diener-West, Reynolds et al. 2005). The risk of 24 metastatic relapse for an individual can vary greatly dependent upon a number of primary tumour 25 characteristics, including genetic alterations (see section 5 above). Outcomes are poor once metastatic disease 26 occurs, and the median survival from the time of development of distant metastatic disease is 2 to 12 months 27 and 1-year survival 10%-15%. This range reflects a number of prognostic factors, including the burden of 28 metastatic disease and the effect of metastatic screening programmes (Augsburger, Correa et al. 2009).
29 Metastatic disease almost always involves the liver and is rarely detectable using imaging techniques, at the 30 time of primary tumour management (<5%). The pattern of disease is distinct from that of cutaneous 31 melanoma. The liver may be the only metastatic site in a significant percentage of patients although lung, bone 32 and skin metastases are also well described (Collaborative Ocular Melanoma Study 2001). Brain metastases 33 are extremely uncommon.
34 Patients with metastatic uveal melanoma are typically managed by oncologists and palliative care teams as 35 part of skin melanoma services and guided by skin melanoma guidelines in the absence of standards for 36 staging investigations, metastatic biopsy and treatment.
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1 A broad spectrum of therapies have been reported and reflect the presenting pattern of metastatic disease. 2 Treatment may include best supportive care, systemic therapies (chemotherapy, biological therapies) or liver- 3 directed therapies (chemotherapy, radiotherapy or surgery). Systemic chemotherapy results in an objective 4 response rate that ranges from 5% to 15% and without any strong evidence that conventional chemotherapy 5 prolongs survival. Access to clinical trials is limited and patients with metastatic uveal melanoma are often 6 specifically excluded from clinical trials in skin melanoma.
7 In the absence of a proven standard of care or clinical trial in the UK, many patients with metastatic uveal 8 melanoma currently receive best supportive care or dacarbazine chemotherapy for 4-6 cycles. Unlike skin 9 melanoma, mutations in the BRAF gene are rare and thus for these patients BRAF-directed therapies 10 unhelpful. The anti-CTLA4 agent, Ipilimumab has National Institute for Health and Care Excellence (NICE) 11 approval for previously treated advanced (unresectable or metastatic) melanoma based upon clinical trials in 12 skin melanoma. http://publications.nice.org.uk/ipilimumab-for-previously-treated-advanced-unresectable-or- 13 metastatic-melanoma-ta268
14 The vast majority of patients with metastatic uveal melanoma have liver involvement and often as the first site 15 of metastatic relapse. Some patients appear to relapse with liver only disease and may represent a distinct 16 subgroup who may benefit from regional approaches to therapy. This chapter focuses on the management of 17 all patients who present with distant metastatic recurrence irrespective of the site and aims to give guidance 18 on:
19 Q1. What is the optimal method of staging?
20 Q2. What is the most robust prognostication (known prognostic factors for survival)?
21 Q3. What is the optimal management of systemic metastases?
22 Q4. What is the optimal management of oligometastatic disease outside the liver?
23 Q 5.What is the optimal management of liver only metastases?
24 Q 6. Is regional liver therapy more effective than systemic therapy?
25 Q7. What is the role of surveillance following metastatic treatment?
26 Staging
27 Staging is performed once the patient has been found to have clinical, biochemical or radiological evidence of 28 metastatic disease. Some centres use a surveillance program, which varies depending on the predicted risk of 29 developing metastases following the primary treatment (Marshall, Romaniuk et al. 2013). The aim of staging is 30 to identify all sites of metastatic disease in order to determine the most appropriate treatment plan for an 31 individual patient. For instance, if a patient has multiple lung metastases and lymph node disease within the 32 abdomen, there is unlikely to be any survival benefit in performing a liver resection for liver metastases.
33 Cross sectional imaging with CT or MRI are the most commonly used imaging modalities for staging metastatic 34 disease. MRI of the liver is more sensitive than CT in lesion detection (Niekel, Bipat et al. 2010) and the use of 35 liver specific MRI contrast agents can increase the number of visualised liver metastases. More recently MRI 36 diffusion-weighted imaging (DWI) has been shown to increase the detection rate of colorectal liver metastases
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1 (Koh, Collins et al. 2012) and (Kim, Yu et al. 2012). CT has better spatial resolution than MRI, and is more 2 sensitive for detection of extrahepatic disease. Uveal melanoma metastases greater than 1 cm are usually seen 3 on PET-CT, but small liver metastases are frequently missed (Orcurto, Denys et al. 2012). Despite significant 4 improvements in cross sectional imaging, miliary and sub-capsular liver metastases, and serosal small bowel 5 metastases are still commonly missed (Servois, Mariani et al. 2010). This supports the need for pre-operative 6 staging laparoscopy.
7 Prognostication
8 Prognostic factors are critically important in the selection of patients for therapy and in guiding decision 9 making for both patients and professionals. Although multiple prognostic factors have been reported in the 10 setting of metastatic uveal melanoma, these often arise from case series and univariate analysis. Prognostic 11 factors have been described specifically in the setting of disseminated metastatic disease (e.g., LDH, tumour 12 burden, Performance status) as well as liver-only disease.
13 Management
14 Systemic chemotherapy has been the standard treatment for most patients with liver metastases, with or 15 without extrahepatic disease. Treatment protocols have often arisen from experience in cutaneous melanoma 16 despite a lack of uveal melanoma-specific clinical trial evidence. Indeed, previous evidence base is almost 17 entirely based upon retrospective case series and a small number of uncontrolled phase II clinical trials that 18 are compounded by case selection. In the absence of an evidence-based standard of care, dacarbazine has 19 emerged as the standard control arm in a number of recently completed and ongoing randomised clinical trials 20 (Carvajal 2013; Sacco, Nathan et al. 2013). Progress in basic science and cancer biology has highlighted an 21 increasing number of potential novel therapeutic targets in uveal melanoma. This has created a momentum in 22 new clinical trials that are evaluating a wide range of targetedtreatments and immunotherapy. Furthermore, 23 and importantly, the evaluation of new therapies has been underpinned by robust clinical trial design with 24 clear eligibility and prospective data collection in both national multicentre and international collaboration.
25 The delivery of systemic therapies in liver-only metastatic disease has been based on the assumption that liver 26 resection is unlikely to offer a curative resection, as there are often more metastases within the remnant liver 27 and occult extra-hepatic micrometastatic disease. In addition the post-operative recovery period could be a 28 significant proportion of the patient’s remaining life. As morbidity and mortality from liver surgery has 29 reduced, and more complex resection techniques have evolved, surgery may have a greater role to play in the 30 future. Wedge resections and other adjunctive therapies can be used to treat small metastases in the remnant 31 liver, either at the time of primary liver resection or at a later time.
32 Regional liver therapies have been extensively reported in the setting of liver-only disease; however, the 33 reports are similarly flawed by the low quality of retrospective case series and uncontrolled single arm clinical 34 trials. There is no doubt that interventional radiology has developed rapidly over the last two decadesand 35 offers potential therapeutic options for selected patients with liver-only metastatic uveal melanoma.
36 Targeted treatment can be delivered to liver metastases using two different approaches: 1) Percutaneous 37 thermal needle-based techniques include radiofrequency, laser, microwave and cryo-ablation which are all 38 capable of treating liver metastases up to 3 cm in diameter with curative intent (Lencioni, Della Pina et al. 39 2005; Hamada, Yamakado et al. 2012). Recently non-thermal ablation, using irreversible electroporation, has
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1 entered clinical practice. This technique involves passing a high voltage current between two or more needles 2 placed around the metastasis, producing pores within the cell membrane, leading to cell death. 2) Trans- 3 arterial treatments take advantage of the dual blood supply to the liver. The portal vein provides up to 80% of 4 blood to the normal liver while most liver metastases, especially highly vascular tumours such as melanoma, 5 recruit a blood supply from the hepatic artery branches. Delivering treatments through the hepatic artery will 6 therefore treat liver metastases while sparing normal liver. Historically intra-arterial chemotherapy infusions 7 have been used after surgical placement of a catheter within the hepatic artery (Cantore, Fiorentini et al. 8 1994). Clearly the benefit over systemic chemotherapy relies on the liver chemotherapy retention during the 9 ‘first passage’ of the injected agent through the liver. A significant portion of the chemotherapy, however, will 10 pass through the liver and reach the venous circulation, giving no additional benefit over systemic 11 chemotherapy.
12 Conventional chemoembolisation involves injecting a combination of chemotherapy and an embolic agent 13 through a temporary catheter placed in the hepatic artery, thus slowing transit of the chemotherapy through 14 the liver and blocking the blood/oxygen supply to the tumour. More recently, drug-eluting beads (Martin, Joshi 15 et al. 2011) and radiolabelled beads (Van Hazel, Blackwell et al. 2004) have become available to use within the 16 liver to treat primary and secondary liver cancers. The bead becomes trapped within the tumour 17 microvasculature where the chemotherapy agent or β radiation, respectively, is maintained in close proximity 18 to the tumour.
19 Immunoembolisation replaces the chemotherapy component with an immune modulating agent such as 20 granulocyte macrophage colony-stimulating factor. In addition to the ischaemic effect of the embolisation, 21 there is stimulation of antigen presenting cells leading to a possible increased systemic immunity to cancer 22 cells (Yamamoto, Chervoneva et al. 2009).
23 Another arterial delivered treatment termed ‘isolated hepatic perfusion’ involves saturating the liver with high 24 doses of chemotherapy by occluding the venous outflow from the liver for approximately 30 minutes. The 25 drug-filled venous effluent is removed from the body and passes through an extra-corporeal filter to remove 26 the chemotherapy before the blood is returned to the patient (Zager and Nutting 2012).
27 Despite more aggressive liver surgery and new interventional techniques, it is the diffuse infiltrative nature of 28 ocular melanoma liver metastases that continues to provide the greatest challenge in disease control. The rare 29 nature of this uveal melanoma means that most publications consist of small case series, often mixed with 30 cutaneous melanoma liver metastases, or metastases from other primary tumours. Comparisons are often 31 made with historical data sets.
32 Surveillance
33 Following any metastatic therapy imaging is performed more frequently, initially to assess treatment response 34 and then to look for early recurrence. The modality (CT, MRI, PET) of choice will be largely guided by the 35 pattern of metastases and need for comparison with pre treatment assessment. The potential benefit of 36 follow-up imaging is dependent on the availability of subsequent therapeutic options and patient wishes. 37 Early, presymptomatic detection of relapse or progression may offer the possibility of subsequent treatment 38 or clinical trial entry but currently there is a lack of evidence base and decisions are most appropriately made 39 on an individual basis. Patients who have undergone a potential curative liver resection represent a highly 40 selected subgroup with respect to ongoing surveillance. By virtue of the fact these patients have already
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1 developed liver metastases they are in a particularly high-risk group, and so imaging frequency should increase 2 compared to the surveillance group who have yet to develop metastases. It is not clear how long after liver 3 treatment a patient should return to a surveillance program. As with pre-operative staging, imaging can be 4 performed with MRI or CT, supplemented by PET-CT. Following ablation treatments the ablated area should be 5 larger than the underlying metastasis, and should have sharply defined margins with the adjacent liver. There 6 will be a rim of hyperaemic normal liver adjacent to the periphery of the ablation site within the first week or 7 so, and it is important that this is not misinterpreted for residual tumour. Post ablation liver imaging at around 8 four weeks is generally regarded as an appropriate interval to assess treated metastases.
9 Following intra-arterial treatments imaging assessment is more difficult as the distinction between necrotic 10 tumour and viable tumour is not always clear. The classic Response Evaluation Criteria In Solid Tumors (RECIST) 11 method of assessing tumour response almost always underestimates the effectiveness of treatment, as the 12 size of the treated metastasis may not change. As ablation techniques aim to destroy a rind of normal liver at 13 least 5mm beyond the margin of the metastasis, the RECIST assessment would regard this as progression of 14 disease. The modified RECIST criteria (Lencioni and Llovet 2010), recently introduced to accommodate newer 15 treatment techniques, incorporate the reduction of tumour enhancement, following intravenous contrast 16 administration, as an indicator of response.
17 7.2 Methods
18 7.2.1 Questions addressed 19 The following questions were addressed
Question Population Intervention Comparator Outcome
LFT USS Patients with Q. 1 CT chest abdo pelvis uvealmelanoma What is the MRI (whole body, liver, Assess the extent with suspected With each other optimal method of contrast enhanced) of disease metastatic staging? FDG PET CT disease Bone scan Laparoscopy Q2. What is the Patients with Clinicopathological Each other Survival (hazard most robust uveal melanoma variables; ratio for prognostication withmetastatic Performance status prognostic factors) (known prognostic disease CRP factors for Platelet/lymphocyte ratio survival)? Other Treatment variables: Regional therapy Systemic therapy Q3. What is the Patients with Surgery With each other Primary - Overall optimal uveal Ablation survival management of melanoma with Regional therapy eg. liver Progression free systemic systemic +/-liver isolation perfusion, TACE, survival metastases? metastatic other Disease free disease Systemic therapy survival Combination of the above Response rate Best supportive care Toxicity Quality of life
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Second line treatment
Q4. What is the Patients with Surgery With each other Response optimal uveal RFA toxicity, management of melanoma with Radiotherapy QOL, oligometastatic oligometastatic PFS, disease outside disease outside Overall survival the liver? the liver Quality of life Second line treatment
response rate, PFS, OS Primary - Overall survival Surgery Progression free Patients with Ablation Q5.What is the survival uveal Regional therapy eg. liver optimal Disease free melanoma with isolation perfusion, TACE, management of With each other survival liver only other liver only Response rate metastatic Systemic therapy metastases? Toxicity disease Combination of the above Quality of life Best supportive care Second line treatment Primary - Overall survival Surgery Progression free Patients with Ablation survival Q6. Is regional uveal Regional therapy eg. liver Disease free liver therapy more melanoma with isolation perfusion, TACE, With each other survival effective than liver +/- systemic other Response rate systemic therapy? metastatic Systemic therapy Toxicity disease Combination of the above Quality of life Second line treatment
Q7. What is the Patients with Survival role of uveal melanoma USS Ability to identify surveillance following CT Each other disease recurrence following resection or MRI or new metastatic metastatic regional disease treatment? treatment
1
2 7.2.2 Inclusion and exclusion criteria for selecting evidence 3 Included were all human, adult only, Phase I/II/III studies. All study types were included except for case 4 reports. Studies relating to prognostic factors in advanced disease and imaging for advanced disease were 5 included. Studies relating to in vitro cytogenetic markers and cell line studies were excluded.
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1 7.2.3 Appraisal and extraction 2 Information from each of the studies was extracted and presented to the GDG for discussion, with an update 3 of the evidence presented after the update search. For full details of each of the included studies, see the 4 evidence tables in Appendix B.
5 All references were sifted first by a GDG member with expertise in the topic. The primary reasons for 6 excluding papers were that they did not address the question.
7 The reviewers appraised and reviewed the included papers, and the quality of the studies was assessed using 8 the SIGN checklists as a guide. Most of the studies were case series and because SIGN does not have a quality 9 checklist for this study type, the guideline developers used additional criteria to assign an overall quality rating 10 to these studies. The quality rating was as follows: those with a larger number of subjects and where subjects 11 were recruited from more than one centre, were considered as being of better quality.
12
13 7.3 Evidence summary
14 7.3.1 Question 1. What is the optimal method of staging? 15 Systemic: There are no randomised controlled trials evaluating staging investigations in metastatic uveal 16 melanoma. Most reports consist of small patient numbers from institutional series only and often based upon 17 retrospective review.
18 The prevalence and location of metastases from uveal melanoma was reported in 110 patients at the MD 19 Anderson Cancer Centre (Lorigan, Wallace et al. 1991). In 55% of patients, the liver was the only organ 20 affected. Extrahepatic metastases included lung, bone, skin and lymph nodes were noted but were rare in the 21 absence of liver involvement (8%). Brain and adrenal metastases were seen in <5% of cases.
22 Patel et al (Patel, Winston et al. 2011) reported on the CT characteristics in biopsy-proven liver metastases 23 from uveal melanoma. Seventy-six patients were identified over an 11-year review period. Radiographic 24 evidence of extrahepatic metastases was evident in 53% of cases that represented advanced malignancy with 25 high liver tumour burden. In this cohort, overall survival correlated with tumour volume, hepatomegaly and 26 ascites.
27 Liver: Several small case series (Servois, Mariani et al. 2010; Orcurto, Denys et al. 2012) report that PET-CT is 28 not able to detect metastases less than 12mm. MRI is able to detect the majority of liver metastases even as 29 small as 5mm. Contrast-enhanced MRI was compared with PET CT in the preoperative stage of known liver 30 metastases in 15 uveal melanoma patients (Servois, Mariani et al. 2010). All patients proceeded to 31 laparotomy. MRI was superior to PET CT for staging liver metastases. MRI was also more sensitive for 32 detecting small liver metastases in a second small study (Orcurto, Denys et al. 2012).
33 While the available evidence for optimal staging of uveal melanoma liver metastases is small, the findings are 34 consistent with the much larger experience with colorectal liver metastases where MRI with liver specific 35 contrast is the most sensitive imaging modality for pre-operative staging. This concordance fits with what we 36 already know about the sensitivity of PET CT. Similarly the false positive rate of PET CT for extrahepatic disease 37 is as much a problem in ocular melanoma staging (Finger, Kurli et al. 2005) as it is with more common tumour 38 groups such as colorectal cancer. um_guideline_cons_draft_v2_23_6_14 Last saved by Nancy Turnbull Date 16 June 2014 Page 58 of 93
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1 On balance, uveal melanoma liver metastases are best staged with liver specific contrast-enhanced MRI 2 (Servois, Mariani et al. 2010; Orcurto, Denys et al. 2012) and extrahepatic disease with PET CT (Kurli, Reddy et 3 al. 2005). As sub centimetre extrahepatic metastases can be missed on PET CT and some metastases can be 4 PET-negative (Strobel, Bode et al. 2009), a contrast enhanced CT scan, either in addition or as part of PET CT, 5 may increase the identification of small extrahepatic metastases.
6 One study (Strobel, Bode et al. 2009) showed that 50% of liver metastases were FDG PET negative. It also 7 showed that if the liver metastases were PET negative, then so were the extrahepatic metastases. This would 8 suggest that patients with PET-negative liver metastases need whole body CT for complete staging.
9 No studies were identified concerning the role of biopsy and histological confirmation in suspected metastatic 10 uveal melanoma.
11 7.3.2 Question 2. Is there a preferred prognostic method for a patient with 12 metastatic disease 13 Many of the published therapeutic studies incorporate prognostic factor evaluation using univariate and/or 14 multivariate analysis. This most often represented institutional case series. Factors identified included tumour 15 burden (maximum diameter of largest tumour, percentage of liver involvement, tumour volume, 16 hepatomegaly, ascites), performance status, LFTs (e.g. ALP, LDH), gender, pattern of metastases and surgical 17 resection outcome (R0 resection).
18 Several institutional series report on variates of survival and potential prognostic indices. (Eskelin, Pyrhonen et 19 al. 2003) defined a potential prognostic model in 91 consecutive patients combining performance status, 20 tumour diameter and ALP.
21 Retrospective review of 119 patients managed over a 10-year period at Memorial Sloan Kettering Cancer 22 Centre identified five variates of survival: age < 60 years, long disease-free interval from initial diagnosis to 23 metastatic disease, treatment with surgery or intrahepatic therapy, lung/soft tissue as the only site of disease 24 and female gender (Rietschel, Panageas et al. 2005).
25 None of the putative prognostic factors have been formally evaluated or validated in prospective randomised 26 controlled trials.
27 Three papers (Kodjikian, Grange et al. 2005; Frenkel, Nir et al. 2009; Patel, Winston et al. 2011), looking at 28 prognostic factors in patients with metastatic liver disease, all found a correlation between liver metastatic 29 burden and survival. Each paper measured the disease burden in different ways: greater than 10 metastases in 30 one paper (Kodjikian, Grange et al. 2005), and a volume greater than 100cm3 of the largest metastasis in 31 another (Patel, Winston et al. 2011) and found that both of these measures were poor prognostic indicators 32 for survival. In addition to these, two other studies (Kodjikian, Grange et al. 2005; Patel, Winston et al. 2011) 33 showed that involvement of the ciliary body at the time of primary diagnosis and the presence of ascites and 34 hepatomegaly were independent negative prognostic factors. It was not stated whether the ascites was 35 malignant or related to liver failure.
36 7.3.2.1 Following surgery 37 A clear resection margin has a significant impact on survival. The overall median survival in one study (Mariani, 38 Piperno-Neumann et al. 2009) was 14 months following liver resection, but in the R0 group median survival
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1 was 68 months. Similarly, the median survival in another study (Frenkel, Nir et al. 2009) rose from 16.6 months 2 to 65.6 months, when comparing R1/R2 with R0 resections, respectively.
3 Interestingly, the presence of extrahepatic disease was not found to correlate with a worse survival in one of 4 the studies (Patel, Winston et al. 2011).
5
6 7.3.2.2 Following non-surgical liver treatment 7 Three studies (Gupta, Bedikian et al. 2010; Huppert, Fierlbeck et al. 2010; Heusner, Antoch et al. 2011)) found 8 that tumour burden (>9 metastases, >75 % liver replacement and >25% liver replacement respectively) was a 9 poor prognostic factor in patients who underwent transarterial chemoembolization (TACE) (Gupta, Bedikian et 10 al. 2010; Huppert, Fierlbeck et al. 2010) and isolated hepatic perfusion (IHP) (Heusner, Antoch et al. 2011). The 11 baseline LDH level was also a negative prognostic factor in one of the TACE studies (Gupta, Bedikian et al. 12 2010).
13 The angiographic appearances of the liver metastases seen at the time of TACE have been shown to correlate 14 with both the primary tumour location and with survival (Dayani, Gould et al. 2009). Compared to a nodular 15 pattern of contrast distribution at angiography, an infiltrative pattern tends to be seen with primary tumours 16 involving the ciliary body or those with extra-scleral spread (p=0.01). The nodular appearance is also 17 significantly associated with improved survival following TACE (12.7 months) compared to the infiltrative 18 pattern (3.7 months).
19
20 7.3.3 Question 3. What is the optimal management of systematic metastases?
21 7.3.3.1 Systemic Therapy 22 The evidence base reviewed consists of a heterogeneous collection of reports including single arm prospective 23 clinical trials, retrospective single institution case series and subset analysis in unselected metastatic 24 melanoma trials. Two of the largerlargest uveal-specific trials included 48 patients (Becker, Terheyden et al. 25 2002; Schmittel, Schmidt-Hieber et al. 2006). The majority of studies evaluated conventional chemotherapy 26 with a smaller number of reports including biological therapies, including immunotherapy.
27 Schmittel et al reported a progression-free benefit in the first and only published randomised phase II trial 28 evaluating treosulfan versus gemcitabine and treosulfan in 48 patients (Schmittel, Schmidt-Hieber et al. 2006). 29 No overall survival data were presented.
30 The objective response rate to systemic therapy was very low with stable disease most often reported. Despite 31 this low response rate, single case responders were not uncommon irrespective of the therapy under 32 evaluation. Progression-free and overall survival was not consistently reported with a range of PFS (1.5- 33 3months) and OS (6-12months) reflecting heterogeneity of cases. The largest published case series of 201 34 uveal melanoma patients represents retrospective data from a single institutional experience and reported 1% 35 response rate to systemic chemotherapy (Bedikian, Legha et al. 1995). Only 1 published randomised phase II/ 36 III trials evaluating systemic therapy against regional therapies or surgery was identified (Leyvraz, Piperno- 37 Neumann et al. 2014).
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1 7.3.3.2 Emerging therapies 2 Two randomised clinical trials in patients with metastatic uveal melanoma confined to the liver have been 3 completed although only one has been published following peer review. A randomised trial comparing 4 percutaneous hepatic perfusion (PHP) of melphalan compared to best active care (BAC) (including systemic 5 therapy) reported at the annual meeting of the American Society for Clinical Oncology (ASCO), patients in the 6 PHP arm had a median PFS of 6.1 months compared with just 1.6 months with BAC (P≤0.001) (Pingpank, 7 Hughes et al. 2010). Improvement in PFS did not appear to extend to overall survival (OS), which at 12 months 8 was 26% with BAC and 29% with PHP. Median survival was 9.9 months versus 11.4 months respectively.
9 The EORTC 18021 trial is the largest prospective clinical trial completed to date in metastatic uveal melanoma 10 and compared intrahepatic chemotherapy versus intravenous treatment (Leyvraz, Piperno-Neumann et al. 11 2014). Between February 2005 and February 2011, 171 patients were randomized (Hepatic intra-arterial (HIA): 12 86, Intravenous (IV): 85). Due to poor accrual, an interim analysis was performed after 134 deaths in order to 13 test futility (power=79%). Intra-arterial chemotherapy led to a higher overall response rate (ORR) (12% versus 14 2%) and longer PFS (HR=0.62; 6-month rate 41% versus 27%; 1-year rate: 19% versus 8%) compared to IV 15 administration but did not translate into an improvement in OS (median ~ 13.5 months).
16 Data from the SUAVE trial, a randomised study comparing sunitinib with dacarbazine in 74 patients, showed 17 no significant difference in PFS or OS. Results were presented at ASCO 2013 (Sacco, Nathan et al. 2013).
18 7.3.3.3 Biological Therapies 19 Uveal melanoma is a unique clinical and molecular subtype of melanoma that has no known effective therapy 20 in the metastatic setting. The increasing understanding of the underlying biology of uveal melanoma has led to 21 the identification of a number of novel and promising therapeutic strategies that warrant investigation. 22 Currently, an increasing number of novel agents are under evaluation in well designed prospective and uveal- 23 specific phase II clinical trials. A randomised phase II study in 98 patients compared selumetinib versus 24 temozolamide has reported improved response rate and doubling of PFS (15.9 versus 7 weeks) (Carvajal 2013). 25 A number of case series have now reported on the activity of ipilimumab in patients with metastatic uveal 26 melanoma. Luke et al (Luke, Callahan et al. 2013) reported 2 out of 34 patients having a radiological response 27 with a median overall survival of 9.6 months. Maio et al (Maio, Danielli et al. 2013) also reported a 5% 28 response rate in 84 patients with a median overall survival of 6 months, and Kelderman et al (Kelderman, van 29 der Kooij et al. 2013) 1 patient out of 22 having a radiological response and a median overall survival of 5.2 30 months.
31 7.3.4 Question 4. What is the optimal treatment for oligometastatic disease 32 outside the liver 33 A single retrospective series in 12 patients undergoing metastatectomy reported two patients with lung 34 metastases and one patient with brain metastasis (Aoyama, Mastrangelo et al. 2000). Median recurrence-free 35 and overall 5-year survival was 15.6% and 53.3%, respectively for the whole series. A single case report of a 36 solitary pulmonary metastatectomy was also identified (Komatsu, Sowa et al. 2013). The surgical cases were 37 characterised by a long interval from initial diagnosis (median 8 years) and incidental detection in 38 asymptomatic patients.
39
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1 7.3.5 Question 5. What is the optimal management of liver only metastases? 2 Intra-arterial treatments (chemotherapy infusion, chemoembolization, immunoembolisation). 3 There is one randomised controlled trial evaluating optimal management with intra-arterial treatments. 4 Studies are mostly small case series (Egerer, Lehnert et al. 2001), (Farolfi, Ridolfi et al. 2011), some comparing 5 response rates with escalating doses of chemotherapy (Agarwala, Panikkar et al. 2004), others using different 6 sorts of chemotherapy (Gupta, Bedikian et al. 2010) or combination chemotherapy (Melichar, Voboril et al. 7 2009). All case series made comparison with historical data sets. These studies provide preliminary support for 8 the concept that regional therapy produces a higher response rate than systemic chemotherapy. The largest 9 multi-centre case series (Peters, Voelter et al. 2006) of 101 patients receiving repeated intra-arterial 10 fotemustine administrations, showed a median survival of 15 months and 2-year survival of 29%. In a small 11 study (Fiorentini, Aliberti et al. 2009) assessing a series of 10 patients, irinotecan drug-eluting beads showed a 12 response rate in up to 80 % of patients, with a similar number experiencing an improvement in quality of life. 13 Response rates were measured using modified RECIST. The results of another study (Yamamoto, Chervoneva 14 et al. 2009) suggest that immunoembolisation may increase PFS of extrahepatic sites but the numbers are 15 small. 16 The single published randomised controlled trial (Leyvraz, Piperno-Neumann et al. 2014) compared intra- 17 arterial fotemustine with IV fotemustine in first line treatment of ocular melanoma liver metastases. Whilst 18 there was no overall survival difference there was an increased response rate and liver PFS in the intra-arterial 19 arm.
20 7.3.5.1 Radioembolisation (selective internal radiation therapy) 21 No randomised controlled trials have been conducted for this relatively new technique. Two papers reported 22 on radioembolisation, one a single-centre case series (Gonsalves, Eschelman et al. 2011), the other a multi- 23 centre retrospective case series (Kennedy, Nutting et al. 2009). Both studies showed a response or stabilisation 24 of disease in 63-100% of patients. This included heavily pre-treated patients (chemoembolization, 25 immunoembolisation) in the larger study (32 patients) (Kennedy, Nutting et al. 2009; Gonsalves, Eschelman et 26 al. 2011). The overall median survival was 10 months (PFS of hepatic metastases 4.7 months). A smaller pre- 27 treatment liver tumour volume (<25%) improved survival (10.5 months) compared to patients who had >25% 28 liver replacement (3.9 months). When compared to historical data sets, extrahepatic disease progression was a 29 more prominent feature in this series of patients, presumably due to slowing of disease progression in the 30 liver. The smaller study (Kennedy, Nutting et al. 2009) showed a high response rate (1 complete response, 6 31 partial responses, 1 stable disease, 1 progressive disease) at 3 months, with 80% survival at 1 year.
32 7.3.5.2 Percutaneous Isolated Hepatic Perfusion 33 There have been several technical papers reporting the development of isolated hepatic perfusion (IHP) to 34 treat a variety of secondary liver tumours including uveal melanoma liver metastases (Alexander, Libutti et al. 35 2003; van Etten, de Wilt et al. 2009; Alexander 2012; Lindner, Rizell et al. 2012; Zager and Nutting 2012). 36 Registry data from Sweden (Olofsson, Cahlin et al. 2014), which included 34 patients with uveal melanoma 37 liver metastases who were treated with IHP, showed a median overall survival of 27 months, a 14 month 38 improvement over historical patients not treated with IHP.
39 A randomised controlled cross-over trial (Alexander 2012) of 93 patients with ocular or cutaneous melanoma 40 liver metastases comparing IHP with BAC demonstrated a median hepatic progression free-survival of 8.0 41 months with IHP melphalan versus 1.6 months with BAC. Up to 6 treatments were given every 4-8 weeks. The
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1 cross over design of the study meant that 57% of the BAC patients were also treated with IHP, which made 2 survival benefit difficult to evaluate.
3 7.3.5.3 Surgery 4 Seven case series (Hsueh, Essner et al. 2004; Pawlik, Zorzi et al. 2006; Herman, Machado et al. 2007; Frenkel, 5 Nir et al. 2009; Mariani, Piperno-Neumann et al. 2009; Caralt, Marti et al. 2011), mostly retrospective single 6 centre studies, showed that in a highly selective patient group there is a survival benefit with surgery. The 7 selection criteria include the absence of extra-hepatic disease after evaluation with CT/MRI and FDG-PET 8 scans; disease-free interval longer than 24 months after the resection of the primary melanoma; presumed 9 completely resectable lesions; low tumour burden; absence of clinical co-morbidities. One study (Pawlik, Zorzi 10 et al. 2006), in 16 patients, showed that patients eligible for liver surgery based on performance status, no 11 extrahepatic disease, and a favourable liver disease distribution had a significantly longer PFS and median 12 overall survival (9 months and 29 months respectively). Many of the studies, however, included patients who 13 received adjuvant chemotherapy.
14 Another study (Mariani, Piperno-Neumann et al. 2009) demonstrated that at >24 months from the primary 15 resection, an R0 resection, < 5 metastases and absence of miliary disease were consistently found to be good 16 prognostic factors. Some studies identified more extensive liver disease or unexpected extrahepatic disease in 17 up to 44% at the time of surgery (Herman, Machado et al. 2007). Accurate staging is therefore vitally 18 important to try to exclude these inoperable cases. In a large single centre surgical series 255 patients 19 (Mariani, Piperno-Neumann et al. 2009), the R2 resection rate was 62%, which probably accounted for the 20 post resection overall median survival being only 14 months. In the same study, the median survival of the R0 21 resections rose to 27 months. This would suggest that there is no role for debulking surgery for ocular 22 melanoma liver metastases.
23 7.3.6 Question 6. Is regional liver therapy more effective than systemic therapy 24 The question of optimal therapy for liver-only disease remains unanswered but of great relevance to both 25 patients and clinicians. Whilst many studies combined systemic therapy with liver surgery or targeted liver 26 intervention there were only a few papers that directly compared systemic treatment with liver treatment for 27 patients with liver only metastatic disease. Two small randomised trials (Pingpank, Hughes et al. 2010; Leyvraz, 28 Piperno-Neumann et al. 2014) have been completed and have been described above. Neither study was able 29 to identify a survival advantage despite improved response rate and PFS. Furthermore, no data on quality of 30 life is available from these studies.
31 7.3.7 Question 7. What is the role of surveillance following liver metastases 32 treatment? 33 Despite improved overall survival following liver metastatectomy, the majority of patients will relapse a 34 second time; thus patients who undergo R0 resection remain at high risk of further hepatic and extrahepatic 35 relapse. No published studies were found addressing the question of continued surveillance in this highly 36 selected population.
37
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1 7.4 Evidence Statements
2 7.4.1 Staging 3 Contrast enhanced MRI is superior to PET in staging liver disease.Level 2+ 4 Intrahepatic metastases less than 12 mm are often not detected on PET CT. Level 3 5 Extrahepatic metastases less than 10 mm are often not detected on PET CT. Level 3 6 Liver metastases can be PET-negative in up to 50% of patients. Level 3 7 When liver metastases are PET-negative then so are the extrahepatic metastases. Level 3 8 Small subcapsular or miliary liver metastases may not be detected on MRI. Level 3 9 PET/CT can identify extra hepatic disease. Level 3 10 No evidence was found that the FDG component of PET was useful in adding increased sensitivity for 11 staging. Level 3 12 There is insufficient evidence that any imaging technique is superior to any other in identifying extra- 13 hepatic disease. Level 3 14
15 7.4.2 Preferred prognostic method 16 Metastatic Tumour Burden (volume, diameter and number), LDH, ALP, gender, age, performance 17 status, DFS have been shown to be prognostic factors. Level 3 18 Limited evidence suggests that cilary body involvement in the primary may have prognostic relevance 19 in metastatic disease. Level 3 20 The absence of liver disease (soft tissue metastasis) appears favourable to outcome. Level 3 21 Post-treatment survival (surgical and non-surgical) is worse in patients with a greater liver tumour 22 burden. Level 3 23 Liver disease presenting <24 months after primary diagnosis has a worse prognosis. Level 3 24 Following treatment
25 The presence of ascites at the time of surgery is associated with a worse prognosis. Level 3 26 R0 resection achieves a significantly better prognosis than R1 or R2 resections. Level 3 27 Post treatment survival (surgical and non-surgical) is worse in patients with a greater liver tumour 28 burden. Level 3 29 Ciliary body involvement is associated with a worse post resection prognosis. Level 3 30 High pre-operative LDH levels are associated with a worse post resection prognosis. Level 3 31 Defined tumours have a better prognosis than miliary tumours. Level 3
32 7.4.3 Management of systemic disease 33 Response rates to chemotherapy are very low. Level 3 34 No high quality evidence was found showing improved survival or quality of life following systemic 35 therapies. 36 A small subset of patients may have prolonged stable disease irrespective of the therapy delivered. 37 Level 3 38 There is no evidence that one chemotherapy regimen is superior to another in terms of outcome or 39 quality of life. Level 3
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1 Unpublished but presented data suggests MEK inhibitors are an area requiring further evaluation. 2 Occasional patients appear to have benefit from treatment with ipilimumab. Level 3
3 7.4.4 Management of oligometastatic-extrahepatic metastatic disease 4 Highly selected patients presenting with oligometastatic disease having had a significant disease-free 5 interval may benefit from resection of metastasis. Level 3
6 7.4.5 Management of liver disease 7 No evidence was identified for ablative techniques. 8 In selected patients, curative liver resection is associated with longer survival in case series. Level 3 9 There is no role for debulking liver surgery. Level 3 10 All the regional non-surgical techniques can reduce measurable tumour burden, but there is 11 inadequate evidence to demonstrate an overall improvement in survival. Level 1- 12 The data does not enable a differentiation that one intervention is superior to another in terms of 13 outcomes. Level 3
14 7.4.6 Systemic versus targeted liver treatment 15 There is no evidence that liver targeted treatment produces a better overall survival than systemic 16 therapies.
17 7.4.7 Surveillance following liver treatment 18 No evidence was found.
19 7.5 Recommendations 20 Refer to recommendations related to this chapter, which are in Section 1.2 by clicking HERE
21 7.6 Linking evidence to recommendations
22 7.6.1 Staging 23 There was insufficient evidence to compare and contrast staging modalities in advanced uveal melanoma 24 patients. In the absence of evidence, the view of the GDG was that the pattern of relapse in uveal melanoma 25 metastatic disease should include imaging of the chest, abdomen and pelvis. Because of the low incidence of 26 CNS metastases, the GDG were of the opinion that that routine brain imaging in the absence of symptoms was 27 not justified. As bone metastases occur in a minority of patients the GDG thought that routine imaging with 28 bone scan was not required in the absence of progressive symptoms.
29 There was evidence that PET CT can detect uveal melanoma metastases but as there was no strong evidence 30 that this influences management or adds additional information above and beyond CT, the GDG did not 31 recommend this. Whilst PET CT can detect metastases at all sites within the body it has a relatively high false 32 negative rate due to either lesion size (<12 mm) or lack of FDG-avidity. Contrast-enhanced CT, which is also 33 more widely available than PET CT, should be able to detect metastases below 10 mm in diameter at all sites 34 imaged.
35 Liver surgery should only be considered when there is no evidence of extrahepatic disease, so accurate staging 36 with imaging and pre-operative laparoscopy is vitally important. MRI for liver staging in other cancer groups is
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1 generally accepted to be the most accurate imaging modality. From the low volume of evidence availaible for 2 the detection of uveal melanoma liver metastases, the GDG were of the opinion that contrast-enhanced MRI 3 with the addition of DWI offers the best available non-user dependent imaging modality at present.
4 Overall the GDG felt that the combination of contrast enhanced MR liver and contrast-enhanced CT of the 5 chest, abdomen and pelvis is the best and most easily available, at present, to stage a patient thought to have 6 metastatic uveal melanoma.
7 7.6.2 Preferred prognostic method 8 No evidence was found to define a single validated prognostic tool for advanced uveal melanoma. A number 9 of putative factors have been described but require validation in future prospective trials. In the absence of 10 evidence, the view of the GDG was that prospective collection of these factors is recommended. Outside 11 clinical trials, specialist centres should collaborate with the aim of developing a common central database that 12 incorporates primary tumour details, staging information, treatment and outcomes, in order to collect data for 13 future research to improve care.
14 Prognosis is likely to be related to a combination of factors: tumour biology, host immune response, disease 15 volume, achievement of clear resection margins. Recognised poor prognostic indicators in patients with ocular 16 melanoma liver metastases– e.g. tumour volume, ascites, early (<24 months) liver involvement following 17 primary diagnosis and ciliary body involvement - are all apparent at the time of surgical assessment. They 18 should be viewed as contraindications to liver surgery.
19 Liver resection, in carefully selected patients, gives the best chance of prolonged survival. R0 resection, 20 however, is only determined following pathological review of the resected liver specimen. In the reviewed 21 surgical studies, R0 resection was highly significant and the main determinant for prolonged survival.
22 7.6.3 Management 23 There was no evidence that current therapies impact on survival or quality of life for most patients with 24 advanced uveal melanoma. Because of the current absence of evidence, the GDG were of the opinion that 25 emphasis should be placed on developing and conducting well-designed clinical trials as a priority for all 26 patients, particularly as there are a number of emerging novel therapies that hold promise but that require 27 further validation before these can be considered as standards. Outside the clinical trial setting, conventional 28 chemotherapy delivered according to local protocol or best supportive care remain valid options for selected 29 patients following a full discussion with the patient of their own potential to benefit.
30 As in all studies, there was evidence that a small subset of patients may achieve protracted stable disease 31 irrespective of the therapy; in the view of the GDG conventional chemotherapy should be reserved for patients 32 with good performance status (PS 0-21) who may benefit. Good performance status patients should be 33 managed in specialist centres with appropriate oncology expertise in uveal melanoma and that collaborate 34 with hepatobiliary and interventional radiology services.
35 Liver surgery offers the best chance for long-term survival, but patient selection is vitally important to avoid R2 36 resections. Pre-operative laparoscopy may detect additional disease and should be performed in all patients. 37 There is no evidence at present that de-bulking liver resection offers any survival benefit.
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1 Whilst there is a trend towards improved survival with non-surgical treatments, the evidence is poor quality 2 and low in volume. If the patient understands the palliative intent of the selected treatment, and is fully 3 informed about the potential side effects, then liver targeted treatments could be considered. The available 4 options have varying degrees of invasiveness, side effects, cost and need for repeated treatments. The choice 5 of treatments offered varies between and across countries. Published studies are mostly based on case series 6 with their inherent biases. Despite the fact that two small RCTs have failed to show a survival benefit for 7 regional therapies over systemic therapy, in the absence of firmer evidence the GDG regarded regional 8 therapy is a viable option to be considered for patients with liver predominant disease.
9 The GDG thought that, as a minimum, all patients treated with surgical or liver targeted interventions should 10 be entered on a registry with an accompanying minimum data set. Ideally every patient should become part of 11 a well-constructed clinical trial. All patients should be discussed at a specialist multidisciplinary team meeting 12 and treatment should take place at recognised centres.
13
14 7.6.4 Surveillance following liver treatment 15 No evidence was identified to demonstrate whether a surveillance programme is useful following treatment 16 for uveal melanoma metastases. It would seem reasonable to perform cross-sectional imaging soon after a 17 surgical or non-surgical liver procedure (4-6 weeks) to assess treatment response. Thereafter, appropriate 18 post-treatment imaging should be performed to identify disease recurrence at an early stage, which may be 19 suitable for further intervention. It is recommended that the same imaging modality is used each time to aid 20 the assessment of treatment response; contrast-enhanced MRI with DWI is thought to be the optimal choice.
21 8. Using and implementing the guideline
22 8.1 Potential organisational and financial barriers in applying its 23 recommendation 24 The GDG recognises that the lack of evidence base is a significant challenge in defining standards in the context 25 of a rare cancer. The GDG strongly supports the concept of greater specialisation to facilitate research and 26 prospective audit and collaboration. Against this background, few barriers to implementation are anticipated 27 amongst those who specialise in this condition. Where patients choose to receive local care, it is possible that 28 individual trusts may view some aspects of follow up (eg surveillance) as an added resource pressure. The GDG 29 considers this a potential barrier to implementation but are aware of the emerging consensus concerning 30 follow-up imaging in high risk cutaneous melanoma, the very low incidence of uveal melanoma and the 31 opportunity to support an element of centralised follow up in specialist centres.
32 The delivery of highly specialist regional therapies merits specific comment. The GDG does not consider the 33 potential of curative liver surgery to be a barrier given existing resources and standards of care within NHS 34 specialist hepatobiliary surgical teams. This is not the case with respect to the availability of regional 35 interventional therapies, which are considered options within the guideline. At present there is no nationally 36 agreed funding stream within the NHS specialist commissioning for this aspect of care resulting in a lack of 37 equity of access or agreed standards. The GDG recognise the critical importance of collaboration amongst 38 specialist centres to facilitate research and evidence base in this area.
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1 The NHS England Commissioning through Evaluation programme provides one platform to commission novel 2 therapies and the GDG encourage all specialist uveal melanoma centres to engage and develop opportunities 3 within this framework.
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1 8.2 Audit criteria Guidance Audit standard reference Exceptions Comments
All patients with a diagnosis of melanoma enrolled on a national Patient consent withheld 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 None All patients with a diagnosis or a suspected diagnosis of ocular Documented patient refusal melanoma are referred to one of the three specialist centres Documentation of a fully informed discussion with all patients, None 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: None 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: Cell type (modified Callendar 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 um_guideline_cons_draft_v2_23_6_14 Last saved by Nancy Turnbull Date 16 June 2014 Page 69 of 93
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acid Schiff staining). 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 Documented patient refusal 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
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 No appropriate trial Document type of trial entered (surgical, trials and informed of available trial options at other centres. available, but consideration cytotoxic agent, targeted therapy, immune documented therapy, other biological)
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1
2 9. Review and updates 3 The guideline was published on ****** and a full copy of the guideline and appendices is available on (Link), 4 There will be a full review of the guideline in three years’ time. In the interim GDG members will alert the 5 chairman of any new evidence that would new evidence that may make any aspect of the guideline unsafe and 6 a decision will be taken. Updates of the guideline should follow the methodology detailed in in Uveal 7 Melanoma Guideline Development Methodology (Link), which also contains further details of the update 8 methods.
9 10. Research recommendations 10 Linking the primary tumour genetics to metastatic genetics 11 Establishment of a register to study the disease 12 The sensitivity and specificity of liver ultrasound compared to MRI for screening for metastatic 13 disease as part of primary treatment 14 Role of a prognostic biopsy - does it identify the right group of patients to follow up the more 15 intensively? There is a need to identify the risk at each stage, and then quantify the benefit.
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1 Damato, B., A. Eleuteri, et al. (2011). "Estimating prognosis for survival after treatment of choroidal 2 melanoma." Prog Retin Eye Res 30(5): 285-295. 3 Damato, B., C. Groenewald, et al. (1998). "Endoresection of choroidal melanoma." Br J Ophthalmol 82(3): 213- 4 218. 5 Damato, B., C. P. Groenewald, et al. (2002). "Rhegmatogenous retinal detachment after transscleral local 6 resection of choroidal melanoma." Ophthalmology 109: 2137-2143. 7 Damato, B., A. Kacperek, et al. (2005). "Proton beam radiotherapy of choroidal melanoma: the Liverpool- 8 Clatterbridge experience." Int J Radiat Oncol Biol Phys 62(5): 1405-1411. 9 Damato, B., A. Kacperek, et al. (2005). "Proton beam radiotherapy of iris melanoma." Int J Radiat Oncol Biol 10 Phys 63(1): 109-115. 11 Damato, B. E. (2001). "Detection of uveal melanoma by optometrists in the United Kingdom." Ophthalmic & 12 Physiological Optics 21: 268-271. 13 Damato, B. E. (2012). "Local resection of uveal melanoma." Dev Ophthalmol 49: 66-80. 14 Damato, B. E. (2012). "Local resection of uveal melanoma." Current Concepts in Uveal Melanoma 15 Developments in Ophthalmology. 49(pp:66-80): 66-80. 16 Damato, B. E. and S. E. Coupland (2012). "Differences in uveal melanomas between men and women from the 17 British Isles." Eye (Lond) 26(2): 292-299. 18 Damato, B. E., J. Paul, et al. (1993). "Predictive factors of visual outcome after local resection of choroidal 19 melanoma." Br J Ophthalmol 77(10): 616-623. 20 Damato, B. E., J. Paul, et al. (1996). "Risk factors for residual and recurrent uveal melanoma after trans-scleral 21 local resection." British Journal of Ophthalmology 80: 102-108. 22 Damato, E. M. and B. E. Damato (2012). "Detection and time to treatment of uveal melanoma in the United 23 Kingdom: an evaluation of 2,384 patients." Ophthalmology 119(8): 1582-1589. 24 Dawson, E., M. S. Sagoo, et al. (2007). "Strabismus in adults with uveal melanoma following episcleral plaque 25 brachytherapy." J AAPOS 11(6): 584-588. 26 Dayani, P. N., J. E. Gould, et al. (2009). "Hepatic metastasis from uveal melanoma: angiographic pattern 27 predictive of survival after hepatic arterial chemoembolization." Arch Ophthalmol 127(5): 628-632. 28 de la Cruz, P. O., Jr., C. S. Specht, et al. (1990). "Lymphocytic infiltration in uveal malignant melanoma." Cancer 29 65(1): 112-115. 30 De Potter, P. and J. Jamart (2003). "Adjuvant indocyanine green in transpupillary thermotherapy for choroidal 31 melanoma." Ophthalmology 110(2): 406-413; discussion 413-404. 32 de Waard-Siebinga, I., C. G. Hilders, et al. (1996). "HLA expression and tumor-infiltrating immune cells in uveal 33 melanoma." Graefes Arch Clin Exp Ophthalmol 234(1): 34-42. 34 Dendale, R., L. Lumbroso-Le Rouic, et al. (2006). "Proton beam radiotherapy for uveal melanoma: results of 35 Curie Institut-Orsay proton therapy center (ICPO)." Int J Radiat Oncol Biol Phys 65(3): 780-787. 36 Desjardins, L., L. Lumbroso-Le Rouic, et al. (2006). "Combined proton beam radiotherapy and transpupillary 37 thermotherapy for large uveal melanomas: a randomized study of 151 patients." Ophthalmic Res 38 38(5): 255-260. 39 Diener-West, M., J. D. Earle, et al. (2001). "The COMS randomized trial of iodine 125 brachytherapy for 40 choroidal melanoma, II: characteristics of patients enrolled and not enrolled. COMS Report No. 17." 41 Arch Ophthalmol 119(7): 951-965. 42 Diener-West, M., J. D. Earle, et al. (2001). "The COMS randomized trial of iodine 125 brachytherapy for 43 choroidal melanoma, III: initial mortality findings. COMS Report No. 18." Arch Ophthalmol 119(7): 44 969-982. 45 Diener-West, M., B. S. Hawkins, et al. (1992). "A review of mortality from choroidal melanoma. II. A meta- 46 analysis of 5-year mortality rates following enucleation, 1966 through 1988." Arch Ophthalmol 110(2): 47 245-250. 48 Diener-West, M., S. M. Reynolds, et al. (2004). "Screening for metastasis from choroidal melanoma: the 49 Collaborative Ocular Melanoma Study Group Report 23." J Clin Oncol 22(12): 2438-2444. 50 Diener-West, M., S. M. Reynolds, et al. (2005). "Development of metastatic disease after enrollment in the 51 COMS trials for treatment of choroidal melanoma: Collaborative Ocular Melanoma Study Group 52 Report No. 26." Arch Ophthalmol 123(12): 1639-1643. 53 Drury, B., A. Chidgey, et al. (2012). "The effect of supplemental transpupillary thermal therapy on visual 54 outcomes in choroidal melanoma." Clinical and Experimental Ophthalmology Conference: 44th 55 Annual Scientific Congress of the Royal Australian and New Zealand College of Ophthalmologists, 56 RANZCO 2012 Melbourne, VIC Australia. Conference Start: 20121124 Conference End: 20121128. 57 Conference Publication:(var.pagings): 40. um_guideline_cons_draft_v2_23_6_14 Last saved by Nancy Turnbull Date 16 June 2014 Page 74 of 93
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1 Dunavoelgyi, R., K. Dieckmann, et al. (2011). "Local tumor control, visual acuity, and survival after 2 hypofractionated stereotactic photon radiotherapy of choroidal melanoma in 212 patients treated 3 between 1997 and 2007." Int J Radiat Oncol Biol Phys 81(1): 199-205. 4 Durie, F. H., A. M. Campbell, et al. (1990). "Analysis of lymphocytic infiltration in uveal melanoma." Invest 5 Ophthalmol Vis Sci 31(10): 2106-2110. 6 Egerer, G., T. Lehnert, et al. (2001). "Pilot study of hepatic intraarterial fotemustine chemotherapy for liver 7 metastases from uveal melanoma: a single-center experience with seven patients." International 8 Journal of Clinical Oncology 6: 25-28. 9 Egger, E., A. Schalenbourg, et al. (2001). "Maximizing local tumor control and survival after proton beam 10 radiotherapy of uveal melanoma." Int J Radiat Oncol Biol Phys 51(1): 138-147. 11 Egger, E., L. Zografos, et al. (2003). "Eye retention after proton beam radiotherapy for uveal melanoma." 12 International Journal of Radiation Oncology, Biology, Physics 55: 867- 880. 13 Einhorn, L. H., M. A. Burgess, et al. (1974). "Metastatic patterns of choroidal melanoma." Cancer 34(4): 1001- 14 1004. 15 Eskelin, S., S. Pyrhonen, et al. (2003). "A prognostic model and staging for metastatic uveal melanoma." Cancer 16 97(2): 465-475. 17 Eskelin, S., S. Pyrhonen, et al. (1999). "Screening for metastatic malignant melanoma of the uvea revisited." 18 Cancer 85(5): 1151-1159. 19 Farolfi, A., L. Ridolfi, et al. (2011). "Liver metastases from melanoma: Hepatic intra-arterial chemotherapy. a 20 retrospective study." Journal of Chemotherapy 23(5): 300-305. 21 Feinstein, E. G., B. P. Marr, et al. (2010). "Hepatic abnormalities identified on abdominal computed 22 tomography at diagnosis of uveal melanoma." Arch Ophthalmol 128(3): 319-323. 23 Finger, P. T., K. J. Chin, et al. (2009). "Palladium-103 ophthalmic plaque radiation therapy for choroidal 24 melanoma: 400 treated patients." Ophthalmology 116(4): 790-796, 796 e791. 25 Finger, P. T., M. Kurli, et al. (2005). "Whole body PET/CT for initial staging of choroidal melanoma." Br J 26 Ophthalmol 89(10): 1270-1274. 27 Finger, P. T., M. Kurli, et al. (2004). "Whole body PET/CT imaging for detection of metastatic choroidal 28 melanoma." Br J Ophthalmol 88(8): 1095-1097. 29 Finger, P. T. and The 7th Edition AJCC-UICC Ophthalmic Oncology Task Force (2009). "The 7th edition AJCC 30 staging system for eye cancer: an international language for ophthalmic oncology." Arch Pathol Lab 31 Med 133(8): 1197-1198. 32 Fiorentini, G., C. Aliberti, et al. (2009). "Intra-arterial hepatic chemoembolization (TACE) of liver metastases 33 from ocular melanoma with slow-release irinotecan-eluting beads. Early results of a phase II clinical 34 study." In Vivo 23(1): 131-137. 35 Folberg, R., V. Rummelt, et al. (1993). "The prognostic value of tumor blood vessel morphology in primary 36 uveal melanoma." Ophthalmology 100(9): 1389-1398. 37 Fontanesi, J., D. Meyer, et al. (1993). "Treatment of choroidal melanoma with I-125 plaque." Int J Radiat Oncol 38 Biol Phys 26(4): 619-623. 39 Foss, A. J., R. A. Alexander, et al. (1996). "Microvessel count predicts survival in uveal melanoma." Cancer Res 40 56(13): 2900-2903. 41 Foss, A. J., I. Whelehan, et al. (1997). "Predictive factors for the development of rubeosis following proton 42 beam radiotherapy for uveal melanoma." Br J Ophthalmol 81(9): 748-754. 43 Frenkel, S., I. Nir, et al. (2009). "Long-term survival of uveal melanoma patients after surgery for liver 44 metastases." Br J Ophthalmol 93(8): 1042-1046. 45 Gambrelle, J., J. D. Grange, et al. (2007). "Survival after primary enucleation for choroidal melanoma: changes 46 induced by the introduction of conservative therapies." Graefes Arch Clin Exp Ophthalmol 245(5): 47 657-663. 48 Garcia-Alvarez, C., M. A. Saornil, et al. (2012). "Episcleral brachytherapy for uveal melanoma: analysis of 136 49 cases." Clin Transl Oncol 14(5): 350-355. 50 Garcia-Arumi, J., M. A. Zapata, et al. (2008). "Endoresection in high posterior choroidal melanomas: long-term 51 outcome." Br J Ophthalmol 92(8): 1040-1045. 52 Gonsalves, C. F., D. J. Eschelman, et al. (2011). "Radioembolization as salvage therapy for hepatic metastasis of 53 uveal melanoma: a single-institution experience." AJR Am J Roentgenol 196(2): 468-473. 54 Gragoudas, E., W. Li, et al. (2002). "Evidence-based estimates of outcome in patients irradiated for intraocular 55 melanoma." Arch Ophthalmol 120(12): 1665-1671. 56 Gragoudas, E. S., K. M. Egan, et al. (1991). "Survival of patients with metastases from uveal melanoma." 57 Ophthalmology 98(3): 383-389; discussion 390. um_guideline_cons_draft_v2_23_6_14 Last saved by Nancy Turnbull Date 16 June 2014 Page 75 of 93
Uveal Melanoma Guidelines – Draft for Consultation
1 Group, C. O. M. S. (1998). "Histopathologic characteristics of uveal melanomas in eyes enucleated from the 2 Collaborative Ocular Melanoma Study. COMS report no. 6." Am J Ophthalmol 125(6): 745-766. 3 Gunduz, K., B. M. Hosal, et al. (2007). "The use of ultrasound biomicroscopy in the evaluation of anterior 4 segment tumors and simulating conditions." Ophthalmologica 221(5): 305-312. 5 Gunduz, K., C. L. Shields, et al. (2000). "Plaque radiotherapy for management of ciliary body and choroidal 6 melanoma with extraocular extension." Am J Ophthalmol 130(1): 97-102. 7 Gupta, S., A. Y. Bedikian, et al. (2010). "Hepatic artery chemoembolization in patients with ocular melanoma 8 metastatic to the liver: response, survival, and prognostic factors." Am J Clin Oncol 33(5): 474-480. 9 Hamada, A., K. Yamakado, et al. (2012). "Radiofrequency ablation for colorectal liver metastases: prognostic 10 factors in non-surgical candidates." Jpn J Radiol 30(7): 567-574. 11 Harbour, J. W., M. D. Onken, et al. (2010). "Frequent mutation of BAP1 in metastasizing uveal melanomas." 12 Science 330(6009): 1410-1413. 13 Hawkins, B. A., A. K. Vine, et al. (2001). "The COMS randomized trial of iodine 125 brachytherapy for choroidal 14 melanoma, II: Characteristics of patients enrolled and not enrolled: COMS report no. 17 " Archives of 15 Ophthalmology 119: 951-965. 16 Hawkins, B. S. (2001). "The COMS randomized trial of iodine 125 brachytherapy for choroidal melanoma, III: 17 Initial mortality findings: COMS report no. 18 " Archives of Ophthalmology 119: 969-982. 18 Hawkins, B. S. (2004). "The Collaborative Ocular Melanoma Study (COMS) randomized trial of pre-enucleation 19 radiation of large choroidal melanoma: IV. Ten-year mortality findings and prognostic factors. COMS 20 report number 24." American Journal of Ophthalmology 138: 936-951. 21 Hawkins, B. S. (2006). "The COMS randomized trial of iodine 125 brachytherapy for choroidal melanoma: V. 22 Twelve-year mortality rates and prognostic factors: COMS report no. 28." Archives of Ophthalmology 23 124(12): 1684-1693. 24 Hawkins, B. S. and M. Melia (1997). "Mortality in patients with small choroidal melanoma: COMS report no. 4." 25 Archives of Ophthalmology 115: 886-893. 26 Herman, P., M. A. Machado, et al. (2007). "Selected patients with metastatic melanoma may benefit from liver 27 resection." World J Surg 31(1): 171-174. 28 Herwig, M. C., C. Bergstrom, et al. (2013). "M2/M1 ratio of tumor associated macrophages and PPAR-gamma 29 expression in uveal melanomas with class 1 and class 2 molecular profiles." Exp Eye Res 107: 52-58. 30 Heusner, T. A., G. Antoch, et al. (2011). "Transarterial hepatic chemoperfusion of uveal melanoma metastases: 31 survival and response to treatment." Rofo 183(12): 1151-1160. 32 Hicks, C., A. J. Foss, et al. (1998). "Predictive power of screening tests for metastasis in uveal melanoma." Eye 33 (Lond) 12 ( Pt 6): 945-948. 34 Hsueh, E. C., R. Essner, et al. (2004). "Prolonged survival after complete resection of metastases from 35 intraocular melanoma." Cancer 100(1): 122-129. 36 Huppert, P. E., G. Fierlbeck, et al. (2010). "Transarterial chemoembolization of liver metastases in patients with 37 uveal melanoma." Eur J Radiol 74(3): e38-44. 38 Isager, P., N. Ehlers, et al. (2004). "Prognostic factors for survival after enucleation for choroidal and ciliary 39 body melanomas." Acta Ophthalmol Scand 82(5): 517-525. 40 Isager, P., N. Ehlers, et al. (2006). "Visual outcome, local tumour control, and eye preservation after 106Ru/Rh 41 brachytherapy for choroidal melanoma." Acta Oncol 45(3): 285-293. 42 Jampol, L. M., C. S. Moy, et al. (2002). "The COMS randomized trial of iodine 125 brachytherapy for choroidal 43 melanoma: IV. Local treatment failure and enucleation in the first 5 years after brachytherapy. COMS 44 report no. 19." Ophthalmology 109(12): 2197-2206. 45 Jensen, A. W., I. A. Petersen, et al. (2005). "Radiation complications and tumor control after 125I plaque 46 brachytherapy for ocular melanoma." Int J Radiat Oncol Biol Phys 63(1): 101-108. 47 Kadkol, S. S., A. Y. Lin, et al. (2006). "Osteopontin expression and serum levels in metastatic uveal melanoma: a 48 pilot study." Investigative ophthalmology & visual science 47(3): 802-806. 49 Kaiserman, I., R. Amer, et al. (2004). "Liver function tests in metastatic uveal melanoma." Am J Ophthalmol 50 137(2): 236-243. 51 Kaiserman, I., M. Rosner, et al. (2005). "Forecasting the prognosis of choroidal melanoma with an artificial 52 neural network." Ophthalmology 112(9): 1608. 53 Kaiserman, N., I. Kaiserman, et al. (2009). "Ruthenium-106 plaque brachytherapy for thick posterior uveal 54 melanomas." Br J Ophthalmol 93(9): 1167-1171. 55 Kelderman, S., M. K. van der Kooij, et al. (2013). "Ipilimumab in pretreated metastastic uveal melanoma 56 patients. Results of the Dutch Working group on Immunotherapy of Oncology (WIN-O)." Acta Oncol 57 52(8): 1786-1788. um_guideline_cons_draft_v2_23_6_14 Last saved by Nancy Turnbull Date 16 June 2014 Page 76 of 93
Uveal Melanoma Guidelines – Draft for Consultation
1 Kennedy, A. S., C. Nutting, et al. (2009). "A first report of radioembolization for hepatic metastases from ocular 2 melanoma." Cancer Invest 27(6): 682-690. 3 Kim, H., J. S. Yu, et al. (2012). "Diffusion-weighted imaging versus superparamagnetic iron oxide (SPIO)- 4 enhanced MRI: exclusive and combined values in the assessment of hepatic metastases." Magn Reson 5 Imaging 30(4): 554-561. 6 Kim, I. K., A. M. Lane, et al. (2010). "Survival in patients with presymptomatic diagnosis of metastatic uveal 7 melanoma." Arch Ophthalmol 128(7): 871-875. 8 Kivela, T. and E. Kujala (2013). "Prognostication in eye cancer: the latest tumor, node, metastasis classification 9 and beyond." Eye (Basingstoke) 27(2): 243-252. 10 Klingenstein, A., A. R. Haug, et al. (2010). "Whole-body F-18-fluoro-2-deoxyglucose positron emission 11 tomography/computed tomography imaging in the follow-up of metastatic uveal melanoma." 12 Melanoma Res 20(6): 511-516. 13 Kociecki, J., K. Pecold, et al. (2002). "Clinical and histopathological findings after transpupillary thermotherapy 14 of malignant choroidal melanoma." Medical Laser Application 17: 321-329. 15 Kodjikian, L., J. D. Grange, et al. (2005). "Prognostic factors of liver metastases from uveal melanoma." Graefes 16 Arch Clin Exp Ophthalmol 243(10): 985-993. 17 Koh, D. M., D. J. Collins, et al. (2012). "Combining diffusion-weighted MRI with Gd-EOB-DTPA-enhanced MRI 18 improves the detection of colorectal liver metastases." Br J Radiol 85(1015): 980-989. 19 Komatsu, T., T. Sowa, et al. (2013). "A case of solitary pulmonary metastasis of choroidal melanoma with an 20 exceptionally long disease-free period." International Journal of Surgery Case Reports 4(10): 849-851. 21 Konstantinidis, L., C. Groenewald, et al. (2014). "Long-term outcome of primary endoresection of choroidal 22 melanoma." Br J Ophthalmol 98(1): 82-85. 23 Konstantinidis, L., C. Groenewald, et al. (2014). "Trans-scleral local resection of toxic choroidal melanoma after 24 proton beam radiotherapy." Br J Ophthalmol 98(6): 775-779. 25 Konstantinidis, L., D. Roberts, et al. (2013). "Whole anterior segment proton beam radiotherapy for diffuse iris 26 melanoma." Br J Ophthalmol 97(4): 471-474. 27 Krema, H., M. Heydarian, et al. (2013). "A comparison between (1)(2)(5)Iodine brachytherapy and stereotactic 28 radiotherapy in the management of juxtapapillary choroidal melanoma." Br J Ophthalmol 97(3): 327- 29 332. 30 Krema, H., M. Heydarian, et al. (2013). "A comparison between 125Iodine brachytherapy and stereotactic 31 radiotherapy in the management of juxtapapillary choroidal melanoma." The British journal of 32 ophthalmology 97(3): 327-332. 33 Krohn, J., O. R. Monge, et al. (2008). "Posterior uveal melanoma treated with I-125 brachytherapy or primary 34 enucleation." Eye (Lond) 22(11): 1398-1403. 35 Kujala, E., B. Damato, et al. (2013). "Staging of ciliary body and choroidal melanomas based on anatomic 36 extent." J Clin Oncol 31(22): 2825-2831. 37 Kujala, E., T. Makitie, et al. (2003). "Very long-term prognosis of patients with malignant uveal melanoma." 38 Invest Ophthalmol Vis Sci 44(11): 4651-4659. 39 Kurli, M., S. Reddy, et al. (2005). "Whole body positron emission tomography/computed tomography staging 40 of metastatic choroidal melanoma." Am J Ophthalmol 140(2): 193-199. 41 Kvanta, A., S. Seregard, et al. (2005). "Choroidal biopsies for intraocular tumors of indeterminate origin." Am J 42 Ophthalmol 140(6): 1002-1006. 43 Lane, A. M., K. M. Egan, et al. (1997). "An evaluation of tumour vascularity as a prognostic indicator in uveal 44 melanoma." Melanoma Res 7(3): 237-242. 45 Lencioni, R., C. Della Pina, et al. (2005). "Percutaneous image-guided radiofrequency ablation in the 46 therapeutic management of hepatocellular carcinoma." Abdom Imaging 30(4): 401-408. 47 Lencioni, R. and J. M. Llovet (2010). "Modified RECIST (mRECIST) assessment for hepatocellular carcinoma." 48 Semin Liver Dis 30(1): 52-60. 49 Leyvraz, S., S. Piperno-Neumann, et al. (2014). "Hepatic intra-arterial versus intravenous fotemustine in 50 patients with liver metastases from uveal melanoma (EORTC 18021): a multicentric randomized trial." 51 Annals of Oncology 25: 742-746. 52 Lindner, P., M. Rizell, et al. (2012). "Isolated Hepatic Perfusion (IHP) for metastases of ocular malignant 53 melanoma." European Journal of Surgical Oncology Conference: 32nd Congress of the European 54 Society of Surgical Oncology, ESSO 32 Valencia Spain. Conference Start: 20120919 Conference End: 55 20120921. Conference Publication:(var.pagings): 38. 56 Lorigan, J. G., S. Wallace, et al. (1991). "The prevalence and location of metastases from ocular melanoma: 57 imaging study in 110 patients." AJR Am J Roentgenol 157(6): 1279-1281. um_guideline_cons_draft_v2_23_6_14 Last saved by Nancy Turnbull Date 16 June 2014 Page 77 of 93
Uveal Melanoma Guidelines – Draft for Consultation
1 Luke, J. J., M. K. Callahan, et al. (2013). "Clinical activity of ipilimumab for metastatic uveal melanoma: a 2 retrospective review of the Dana-Farber Cancer Institute, Massachusetts General Hospital, Memorial 3 Sloan-Kettering Cancer Center, and University Hospital of Lausanne experience." Cancer 119(20): 4 3687-3695. 5 Lumbroso-Le Rouic, L., S. Delacroix, et al. (2006). "Proton beam therapy for iris melanomas." Eye (Lond) 20(11): 6 1300-1305. 7 Lumbroso, L., L. Desjardins, et al. (2001). "Intraocular inflammation after proton beam irradiation for uveal 8 melanoma." Br J Ophthalmol 85(11): 1305-1308. 9 Lumbroso, L. R., C. M. Charif, et al. (2004). "125I plaque brachytherapy for anterior uveal melanomas." Eye 18: 10 911-916. 11 Maat, W., E. Kilic, et al. (2008). "Pyrophosphorolysis detects B-RAF mutations in primary uveal melanoma." 12 Invest Ophthalmol Vis Sci 49(1): 23-27. 13 Macdonald, E. C., P. Cauchi, et al. (2011). "Proton beam therapy for the treatment of uveal melanoma in 14 Scotland." Br J Ophthalmol 95(12): 1691-1695. 15 Maeda, T., U. Tateishi, et al. (2007). "Magnetic resonance screening trial for hepatic metastasis in patients with 16 locally controlled choroidal melanoma." Japanese Journal of Clinical Oncology 37(4): 282-286. 17 Maio, M., R. Danielli, et al. (2013). "Efficacy and safety of ipilimumab in patients with pre-treated, uveal 18 melanoma." Ann Oncol 24(11): 2911-2915. 19 Makitie, T., P. Summanen, et al. (1999). "Microvascular density in predicting survival of patients with choroidal 20 and ciliary body melanoma." Invest Ophthalmol Vis Sci 40(11): 2471-2480. 21 Makitie, T., P. Summanen, et al. (2001). "Tumor-infiltrating macrophages (CD68(+) cells) and prognosis in 22 malignant uveal melanoma." Invest Ophthalmol Vis Sci 42(7): 1414-1421. 23 Marconi, D. G., D. G. de Castro, et al. (2013). "Tumor control, eye preservation, and visual outcomes of 24 ruthenium plaque brachytherapy for choroidal melanoma." Brachytherapy 12(3): 235-239. 25 Mariani, P., S. Piperno-Neumann, et al. (2009). "Surgical management of liver metastases from uveal 26 melanoma: 16 years' experience at the Institut Curie." Eur J Surg Oncol 35(11): 1192-1197. 27 Mariani, P., N. S. Piperno, et al. (2009). "Surgical management of liver metastases from uveal melanoma: 16 28 years' experience at the Institut Curie." European Journal of Surgical Oncology 35(11): 1192-1197. 29 Marshall, E., C. Romaniuk, et al. (2013). "MRI in the detection of hepatic metastases from high-risk uveal 30 melanoma: A prospective study in 188 patients." British Journal of Ophthalmology 97(2): 159-163. 31 Martin, R. C., J. Joshi, et al. (2011). "Hepatic intra-arterial injection of drug-eluting bead, irinotecan (DEBIRI) in 32 unresectable colorectal liver metastases refractory to systemic chemotherapy: results of multi- 33 institutional study." Ann Surg Oncol 18(1): 192-198. 34 McCannel, T. A. (2013). "Post-brachytherapy tumor endoresection for treatment of toxic maculopathy in 35 choroidal melanoma." Eye (Lond) 27(8): 984-988. 36 McLaughlin, C. C., X. C. Wu, et al. (2005). "Incidence of noncutaneous melanomas in the U.S." Cancer 103(5): 37 1000-1007. 38 McLean, I. W., W. D. Foster, et al. (1982). "Uveal melanoma: location, size, cell type, and enucleation as risk 39 factors in metastasis." Hum Pathol 13(2): 123-132. 40 McLean, I. W., W. D. Foster, et al. (1983). "Modifications of Callender's classification of uveal melanoma at the 41 Armed Forces Institute of Pathology." Am J Ophthalmol 96(4): 502-509. 42 McLean, I. W., K. S. Keefe, et al. (1997). "Uveal melanoma. Comparison of the prognostic value of fibrovascular 43 loops, mean of the ten largest nucleoli, cell type, and tumor size." Ophthalmology 104(5): 777-780. 44 Melia, B. M., D. H. Abramson, et al. (2001). "Collaborative ocular melanoma study (COMS) randomized trial of 45 I-125 brachytherapy for medium choroidal melanoma. I. Visual acuity after 3 years COMS report no. 46 16." Ophthalmology 108(2): 348-366. 47 Melia, B. M., W. M. Diener, et al. (1997). "Factors predictive of growth and treatment of small choroidal 48 melanoma: COMS report no. 5." Archives of Ophthalmology 115: 1537-1544 49 Melia, M., C. S. Moy, et al. (2006). "Quality of life after iodine 125 brachytherapy vs enucleation for choroidal 50 melanoma: 5-year results from the Collaborative Ocular Melanoma Study: COMS QOLS Report No. 3." 51 Arch Ophthalmol 124(2): 226-238. 52 Melichar, B., Z. Voboril, et al. (2009). "Liver metastases from uveal melanoma: clinical experience of hepatic 53 arterial infusion of cisplatin, vinblastine and dacarbazine." Hepatogastroenterology 56(93): 1157- 54 1162. 55 Metz, C. H., M. Scheulen, et al. (2013). "Ultradeep sequencing detects GNAQ and GNA11 mutations in cell-free 56 DNA from plasma of patients with uveal melanoma." Cancer medicine 2: 208-215. 57 Missotten, G. S., J. H. Beijnen, et al. (2003). "Proteomics in uveal melanoma." Melanoma Res 13(6): 627-629. um_guideline_cons_draft_v2_23_6_14 Last saved by Nancy Turnbull Date 16 June 2014 Page 78 of 93
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1 Schachat, A. P. (1998). "The Collaborative Ocular Melanoma Study (COMS) randomized trial of pre- enucleation 2 radiation of large choroidal melanoma III: Local complications and observations following enucleation 3 COMS report no. 11." American Journal of Ophthalmology 126: 362-372. 4 Schaling, D. F. and E. K. Pauwels (1996). "The clinical role of immunoscintigraphy for the detection of ocular 5 melanoma." Q J Nucl Med 40(4): 335-340. 6 Schaller, U. C., A. K. Bosserhoff, et al. (2002). "Melanoma inhibitory activity: a novel serum marker for uveal 7 melanoma." Melanoma Res 12(6): 593-599. 8 Schefler, A. C. and D. H. Abramson (2009). "Should evisceration ever be done in a blind, painful eye?" Archives 9 of Ophthalmology 127(2): 211-212. 10 Schilling, H., N. Bornfeld, et al. (2006). "[Endoresection of large uveal melanomas after pretreatment by single- 11 dose stereotactic convergence irradiation with the leksell gamma knife--first experience on 46 12 cases]." Klin Monbl Augenheilkd 223(6): 513-520. 13 Schmittel, A., M. Schmidt-Hieber, et al. (2006). "A randomized phase II trial of gemcitabine plus treosulfan 14 versus treosulfan alone in patients with metastatic uveal melanoma." Ann Oncol 17(12): 1826-1829. 15 Scholes, A. G., B. E. Damato, et al. (2003). "Monosomy 3 in uveal melanoma: correlation with clinical and 16 histologic predictors of survival." Invest Ophthalmol Vis Sci 44(3): 1008-1011. 17 Scott, I. U., T. G. Murray, et al. (1998). "Evaluation of imaging techniques for detection of extraocular extension 18 of choroidal melanoma." Arch Ophthalmol 116(7): 897-899. 19 Seddon, J. M., D. M. Albert, et al. (1983). "A prognostic factor study of disease-free interval and survival 20 following enucleation for uveal melanoma." Arch Ophthalmol 101(12): 1894-1899. 21 Seddon, J. M., E. S. Gragoudas, et al. (1990). "Relative survival rates after alternative therapies for uveal 22 melanoma." Ophthalmology 97(6): 769-777. 23 Sen, J., C. Groenewald, et al. (2006). "Transretinal choroidal tumor biopsy with a 25-gauge vitrector." 24 Ophthalmology 113(6): 1028-1031. 25 Seregard, S. (1999). "Long-term survival after ruthenium plaque radiotherapy for uveal melanoma. A meta- 26 analysis of studies including 1,066 patients." Acta Ophthalmol Scand 77(4): 414-417. 27 Seregard, S., B. Spangberg, et al. (1998). "Prognostic accuracy of the mean of the largest nucleoli, vascular 28 patterns, and PC-10 in posterior uveal melanoma." Ophthalmology 105(3): 485-491. 29 Servois, V., P. Mariani, et al. (2010). "Preoperative staging of liver metastases from uveal melanoma by 30 magnetic resonance imaging (MRI) and fluorodeoxyglucose-positron emission tomography (FDG- 31 PET)." Eur J Surg Oncol 36(2): 189-194. 32 Shields, C. L., J. Cater, et al. (2002). "Combined plaque radiotherapy and transpupillary thermotherapy for 33 choroidal melanoma: tumor control and treatment complications in 270 consecutive patients." Arch 34 Ophthalmol 120(7): 933-940. 35 Shields, C. L., M. Furuta, et al. (2009). "Choroidal nevus transformation into melanoma: Analysis of 2514 36 consecutive cases." Archives of Ophthalmology 127(8): 981-987. 37 Shields, C. L., M. Furuta, et al. (2009). "Metastasis of uveal melanoma millimeter-by-millimeter in 8033 38 consecutive eyes." Arch Ophthalmol 127(8): 989-998. 39 Shields, C. L., A. Ganguly, et al. (2007). "Chromosome 3 analysis of uveal melanoma using fine-needle 40 aspiration biopsy at the time of plaque radiotherapy in 140 consecutive cases." Transactions of the 41 American Ophthalmological Society 105(pp:43-52): 43-52. 42 Shields, C. L., S. Kaliki, et al. (2013). "Iris nevus growth into melanoma: Analysis of 1611 consecutive eyes: The 43 ABCDEF guide." Ophthalmology 120(4): 766-772. 44 Shields, C. L., M. Naseripour, et al. (2002). "Plaque radiotherapy for large posterior uveal melanomas (> or =8- 45 mm thick) in 354 consecutive patients." Ophthalmology 109(10): 1838-1849. 46 Shields, C. L., J. A. Shields, et al. (1998). "Radiation therapy for uveal malignant melanoma." Ophthalmic Surg 47 Lasers 29(5): 397-409. 48 Shields, C. L., J. A. Shields, et al. (1995). "Risk factors for growth and metastasis of small choroidal melanocytic 49 lesions." Ophthalmology 102(9): 1351-1361. 50 Shields, C. L., J. A. Shields, et al. (2001). "Iris melanoma: risk factors for metastasis in 169 consecutive patients." 51 Ophthalmology 108(1): 172-178. 52 Shields, C. L., J. A. Shields, et al. (2002). "Primary transpupillary thermotherapy for small choroidal melanoma 53 in 256 consecutive cases: outcomes and limitations." Ophthalmology 109: 225-234. 54 Singh, A. D., M. E. Aronow, et al. (2012). "Chromosome 3 status in uveal melanoma: a comparison of 55 fluorescence in situ hybridization and single-nucleotide polymorphism array." Invest Ophthalmol Vis 56 Sci 53(7): 3331-3339.
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1 Singh, A. D., P. De Potter, et al. (1998). "Lifetime prevalence of uveal melanoma in white patients with 2 oculo(dermal) melanocytosis." Ophthalmology 105(1): 195-198. 3 Singh, A. D., I. G. Rennie, et al. (2004). "Sunlight exposure and pathogenesis of uveal melanoma." Surv 4 Ophthalmol 49(4): 419-428. 5 Sisley, K., I. G. Rennie, et al. (1990). "Cytogenetic findings in six posterior uveal melanomas: involvement of 6 chromosomes 3, 6, and 8." Genes Chromosomes Cancer 2(3): 205-209. 7 Smith, J. H., L. Padnick-Silver, et al. (2007). "Genetic study of familial uveal melanoma: association of uveal and 8 cutaneous melanoma with cutaneous and ocular nevi." Ophthalmology 114(4): 774-779. 9 Stack, R., M. Elder, et al. (2005). "New Zealand experience of I125 brachytherapy for choroidal melanoma." 10 Clin Experiment Ophthalmol 33(5): 490-494. 11 Steeves, J. K., E. G. Gonzalez, et al. (2008). "Vision with one eye: a review of visual function following unilateral 12 enucleation." Spat Vis 21(6): 509-529. 13 Strobel, K., B. Bode, et al. (2009). "Limited value of 18F-FDG PET/CT and S-100B tumour marker in the 14 detection of liver metastases from uveal melanoma compared to liver metastases from cutaneous 15 melanoma." Eur J Nucl Med Mol Imaging 36(11): 1774-1782. 16 Suesskind, D., J. Scheiderbauer, et al. (2013). "Retrospective evaluation of patients with uveal melanoma 17 treated by stereotactic radiosurgery with and without tumor resection." JAMA Ophthalmol 131(5): 18 630-637. 19 Suesskind, D., A. Ulmer, et al. (2011). "Circulating melanoma cells in peripheral blood of patients with uveal 20 melanoma before and after different therapies and association with prognostic parameters: a pilot 21 study." Acta Ophthalmol 89(1): 17-24. 22 Summanen, P., I. Immonen, et al. (1995). "Visual outcome of eyes with malignant melanoma of the uvea after 23 ruthenium plaque radiotherapy." Ophthalmic Surg Lasers 26(5): 449-460. 24 Summanen, P., I. Immonen, et al. (1996). "Radiation related complications after ruthenium plaque 25 radiotherapy of uveal melanoma." Br J Ophthalmol 80(8): 732-739. 26 Tagliaferri, L., D. Smaniotto, et al. (2012). "Brachytherapy with iodine 125 or ruthenium 106 for treatment of 27 choroidal melanomas measuring 5-7 mm in thickness." Radiotherapy and Oncology Conference: 28 World Congress of Brachytherapy, WCB 2012 Barcelona Spain. Conference Start: 20120510 29 Conference End: 20120512. Conference Publication:(var.pagings): 103-S164. 30 Taktak, A. F., A. C. Fisher, et al. (2004). "Modelling survival after treatment of intraocular melanoma using 31 artificial neural networks and Bayes theorem." Phys Med Biol 49(1): 87-98. 32 Thomas, S., C. Putter, et al. (2012). "Prognostic significance of chromosome 3 alterations determined by 33 microsatellite analysis in uveal melanoma: a long-term follow-up study." Br J Cancer 106(6): 1171- 34 1176. 35 Tobal, K., K. Deuble, et al. (1993). "Characterization of cellular infiltration in choroidal melanoma." Melanoma 36 Res 3(1): 63-65. 37 Toivonen, P., T. Makitie, et al. (2004). "Microcirculation and tumor-infiltrating macrophages in choroidal and 38 ciliary body melanoma and corresponding metastases." Invest Ophthalmol Vis Sci 45(1): 1-6. 39 Triozzi, P. L., S. Achberger, et al. (2012). "The association of blood angioregulatory microRNA levels with 40 circulating endothelial cells and angiogenic proteins in patients receiving dacarbazine and interferon." 41 J Transl Med 10: 241. 42 Tsimpida, M., J. Hungerford, et al. (2011). "Plaque radiotherapy treatment with ruthenium-106 for iris 43 malignant melanoma." Eye (Lond) 25(12): 1607-1611. 44 Vaarwater, J., T. van den Bosch, et al. (2012). "Multiplex ligation-dependent probe amplification equals 45 fluorescence in-situ hybridization for the identification of patients at risk for metastatic disease in 46 uveal melanoma." Melanoma Res 22(1): 30-37. 47 van Etten, B., J. H. de Wilt, et al. (2009). "Isolated hypoxic hepatic perfusion with melphalan in patients with 48 irresectable ocular melanoma metastases." Eur J Surg Oncol 35(5): 539-545. 49 Van Hazel, G., A. Blackwell, et al. (2004). "Randomised phase 2 trial of SIR-Spheres plus fluorouracil/leucovorin 50 chemotherapy versus fluorouracil/leucovorin chemotherapy alone in advanced colorectal cancer." J 51 Surg Oncol 88(2): 78-85. 52 Verschueren, K. M., C. L. Creutzberg, et al. (2010). "Long-term outcomes of eye-conserving treatment with 53 Ruthenium(106) brachytherapy for choroidal melanoma." Radiother Oncol 95(3): 332-338. 54 Virgili, G., G. Gatta, et al. (2008). "Survival in patients with uveal melanoma in Europe." Arch Ophthalmol 55 126(10): 1413-1418. 56 Vullaganti, S., P. DeVilliers, et al. (2011). "GNAQ gene status in cellular blue nevi, spitzoid and spindle cell 57 melanomas." Laboratory Investigation Conference: United States and Canadian Academy of um_guideline_cons_draft_v2_23_6_14 Last saved by Nancy Turnbull Date 16 June 2014 Page 82 of 93
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1 Pathology Annual Meeting, USCAP 2011 San Antonio, TX United States. Conference Start: 20110226 2 Conference End: 20110304. Conference Publication:(var.pagings): 91-127A. 3 Wang, T., C. Yang, et al. (2003). "Characteristic ultrasonographic findings of choroidal tumors " Journal of 4 Medical Ultrasound 11: 55-59. 5 Wang, Z., M. Nabhan, et al. (2013). "Charged particle radiation therapy for uveal melanoma: a systematic 6 review and meta-analysis." Int J Radiat Oncol Biol Phys 86(1): 18-26. 7 Whelchel, J. C., S. E. Farah, et al. (1993). "Immunohistochemistry of infiltrating lymphocytes in uveal malignant 8 melanoma." Invest Ophthalmol Vis Sci 34(8): 2603-2606. 9 White, V. A., J. D. Chambers, et al. (1998). "Correlation of cytogenetic abnormalities with the outcome of 10 patients with uveal melanoma." Cancer 83(2): 354-359. 11 Whitehead, J., S. Tishkovskaya, et al. (2012). "Devising two-stage and multistage phase II studies on systemic 12 adjuvant therapy for uveal melanoma." Invest Ophthalmol Vis Sci 53(8): 4986-4989. 13 Willson, J. K. V., D. M. Albert, et al. (2001). "Assessment of metastatic disease status at death in 435 patients 14 with large choroidal melanoma in the collaborative ocular melanoma study coms report no. 15." 15 Archives of Ophthalmology 119: 670-676. 16 Wilson, M. W. and J. L. Hungerford (1999). "Comparison of episcleral plaque and proton beam radiation 17 therapy for the treatment of choroidal melanoma." Ophthalmology 106(8): 1579-1587. 18 Yamamoto, A., I. Chervoneva, et al. (2009). "High-dose immunoembolization: survival benefit in patients with 19 hepatic metastases from uveal melanoma." Radiology 252(1): 290-298. 20 Yarovoy, A. A., D. A. Magaramov, et al. (2010). "Which choroidal melanoma should be treated with primary 21 transpupillary thermotherapy? Our experience from 78 patients." Eur J Ophthalmol 20(1): 186-193. 22 Yarovoy, A. A., D. A. Magaramov, et al. (2012). "The comparison of ruthenium brachytherapy and simultaneous 23 transpupillary thermotherapy of choroidal melanoma with brachytherapy alone." Brachytherapy 24 11(3): 224-229. 25 Young, T. A., B. L. Burgess, et al. (2007). "High-density genome array is superior to fluorescence in-situ 26 hybridization analysis of monosomy 3 in choroidal melanoma fine needle aspiration biopsy." 27 Molecular Vision 13(pp:2328-2333): 2328-2333. 28 Young, T. A., N. P. Rao, et al. (2007). "Fluorescent In Situ Hybridization for Monosomy 3 via 30-Gauge Fine- 29 Needle Aspiration Biopsy of Choroidal Melanoma In Vivo." Ophthalmology 114(1): 142-146. 30 Zager, J. and C. Nutting (2012). "Chemosaturation therapy with percutaneous hepatic perfusions of melphalan 31 versus standard of care in patients with hepatic metastases from melanoma: A randomized 32 multicenter phase 3 study." Journal of Vascular and Interventional Radiology Conference: 37th 33 Annual Scientific Meeting of the Society of Interventional Radiology, SIR 2012 San Francisco, CA 34 United States. Conference Start: 20120324 Conference End: 20120329. Conference 35 Publication:(var.pagings): 23. 36 Zimmerman, L., I. Mclean, et al. (1978). "Does enucleation of the eye containing a malignant melanoma 37 prevent or accelerate the dissemination of tumour cells?" British Journal of Ophthalmology 62: 420- 38 425. 39 Zorlu, F., U. Selek, et al. (2009). "Initial results of fractionated CyberKnife radiosurgery for uveal melanoma." J 40 Neurooncol 94(1): 111-117.
41
42
43 Appendices 44 A – Extraction tables of Evidence (separate document)
45 B - Glossary and Acronyms
Anti-angiogenic Inhibiting the formation and differentiation of blood vessels. Ascites Accumulation of fluid in the spaces between tissues and organs in the abdomen Brachytherapy Targeted radiotherapy when the radiation is placed in or near to the
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tumour. Choroid A vascular membrane between the retina and the sclera of the eye containing large branched pigment cells. Choroidectomy Removal of choroidal melanomas. Ciliary body 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. Computed Tomography (CT) A method to use X-rays to give a high resolution pictures of the inside of the body. CyberKnife A particular brand of equipment to deliver stereotactic radiosurgery (SRS). Cyclectomy Removal of small, ciliary body tumours. Debulking Removal of most or all of the tumour, thus reducing the size. Embolisation Introduction of pellets into the circulatory system in order to occlude blood vessels supplying the tumour. Endoresection The surgical removal of part of an organ or tumour from within. Enucleation Removal of the eye. Exoresection Removal of the tumour ‘en bloc’ through a large sclera opening. Extrahepatic Outside of the liver (commonly used for metastasis outside of the liver). Exudative retinopathy 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. Fractionate Splitting of a whole into different parts. Fractionated stereotactic radiation Treatments of moderately high doses of radiation usually given over treatments/therapy three to eight sessions (fractions). Fundus of the eye The interior surface of the eye, opposite the lens. It includes the retina, optic disc, macula and fovea, and posterior pole. GammaKnife A particular brand of equipment to deliver stereotactic radiosurgery (SRS). Hepatomegaly Enlargement of the liver. Hypofractionated radiotherapy Radiation treatment split into large doses per timepoint (fraction) but treatment giving less treatment doses (fractions) than with standard fractionation. A particular way to improve efficacy of radiation treatment. Intraocular Located within the eye. Intraocular haemorrhage Bleeding within the eye. Iridectomy Removal of the iris or parts of the iris to treat iris melanoma. Iris 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. Ischaemia A reduction of blood supply resulting from the blocking of an artery. Laproscopy Looking inside of the abdomen using a laparoscope. Magentic Resonance Imaging (MRI) A non-invasive diagnostic technique that produces computerized images of internal body tissues. It uses magnetic signals rather than X rays. Miliary spread of melanoma A large number of small nodules of melanoma that resemble grains of small seeds (of millet). Monosomy 3 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. Neovascular glaucoma The abnormal production of new blood vessels causing increased um_guideline_cons_draft_v2_23_6_14 Last saved by Nancy Turnbull Date 16 June 2014 Page 84 of 93
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pressure in the eye. Oedema Swelling caused by fluid accumulating particularly in the abdomen. Ophthalmoscopy 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. Parenchyma The functional part of an organ such as the liver. Pars plana Translates as ‘flat part’ – the outer ring of the ciliary body. Pars plana vitrectomy Surgical removal of vitreous body from the eye, with introduction of the instruments via the pars plana of the ciliary body. Percutaneous 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). Percutaneous ablative techniques Removal or destruction of metastases using a percutaneous approach. This is usually the case for microwave and radiofrequency ablation or cryothearapy. Plaque therapy 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. Porta hepatis 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). Proton beam therapy A type of radiation treatment. Beams of particles, called protons, are aimed at the cancer bearing part of the eye. R0 resection 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. R1 resection 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. R2 resection After surgery visible residual tumour following is left behind. Radiogenic retinopathy Long term damage of the retina caused as a side effect of radiation treatment. Resectable When surgical removal of the tumour is possible. Retina The light-sensitive layer of tissue, lining the inner surface of the eye. Retinopexy A procedure to seal the retina to the surface beneath to stop it detaching. Retinotomy A surgical incision through the retina. Sclera The tough white outer layer of the eyeball. Stereotactic 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. Stereotactic Radiosurgery 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. Stereotactic resection The removal of the tumour using microsurgery with the aid of the stereotactic techniques. Surgical Ocular Oncology Centre 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. um_guideline_cons_draft_v2_23_6_14 Last saved by Nancy Turnbull Date 16 June 2014 Page 85 of 93
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Thermotherapy The use of heat to treat a tumour. Transcatheter arterial Injection of small particles coated with chemotherapeutic chemoembolization / Transarterial drugs directly into an artery supplying a tumour. This restricts the Chemoembolization (TACE) tumour's arterial blood supply and delivers chemotherapy directly to the target tissue. Tumour seeding 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). Uvea The middle layer of the eye including the iris and ciliary body as well as the choroid. Vitreous body The clear jelly-like structure that fills the posterior part of the eyeball. Vitreous haemorrhage Bleeding into the vitreous body. 1
ALP Alkaline phospatase BAC Best Available Care BCNU Carmustine (bis-chloroethylnitrosourea) CT Computed Tomography CGE Cobalt Gray Equivalent DFS Disease free survival DTIC Trade name for Dacarbazine DWI Density weighted imaging ELND Elective Lymph Node Dissection FNAB Fine Needle Aspiration Biopsy fSRT Fractionated Stereotactic Radiation Therapy IE or CE Immunoembolization/Chemoembolization IFN or INF Interferon Alfa-2b IHP Isolated Hepatic Perfusion IL-2 Interleukin-2 IND Investigational New Drug Intron-A Interferon Alfa-2b LDH Lactate Dehydrogenase LFT Liver Function Test MFS Metastatic Free Survival MRI Magnetic Resonance Imaging NED No Evidence of Disease OCT Optical Coherence Tomography OS Overall Survival PBR Proton Beam Radiotherapy PET Positron Emission Tomography RCT Randomised control trials RECIST Response Evaluation Criteria in Solid Tumours RFA Radiofrequency Ablation SIRT Selective Internal Radiation Therapy SLN Sentinel Lymph Node SNB or SLNB Sentinel Node Biopsy/Sentinel Lymph Node Biopsy SRS Stereotactic Radiosurgery TACE Transcatheter Arterial Chemoembolization/ Transarterial Chemoembolization TNF Tumour Necrosis Factor TNM Tumor Node Metastasis staging system UBM Ultrasound Biomicroscopy US Ultrasound WLE Wide Local Excision 2
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1 C - Lists of Guideline Development Group members
Dr Paul Nathan Consultant Medical Oncologist Mount Vernon Cancer Centre Northwood, Middlesex Miss Victoria Cohen Consultant Ocular Oncologist Lead Clinician Ocular Oncology Service St Bartholomew's and Moorfields Eye Hospital London Prof Sarah Coupland George Holt Chair of Pathology and Deputy Head of Department Molecular and Clinical Cancer Medicine Honorary Consultant in Pathology University of Liverpool Ms Kathryn Curtis Patient Representative OcuMel UK* Prof Bertil Damato Moved to USA and Hon. Professor of did not attend Ophthalmology meetings after May Royal Liverpool University 2013, but contributed Hospital’ to the guideline Liverpool electronically. Dr Jonathan Evans Consultant Interventional Radiologist The Royal Liverpool University Hospital Liverpool Mr Stephen Fenwick Consultant Hepatobiliary Surgeon University Hospital Aintree, Liverpool. Dr Olivia Li Methodologist and Trainee Ophthalmic Surgeon, London Dr Lesley Kirkpatrick Patient Representative Dr Ernie Marshall Macmillan Consultant in Medical Oncology, The Clatterbridge Cancer Centre NHS Foundation Trust, Liverpool Mr Kieran McGuirk Patient Representative, Chair, OcuMel UK* Mr Bruce Oliver Resigned October Patient Representative 2012 Prof Christian Ottensmeier Professor in Experimental Cancer Medicine Consultant in Medical Oncology Southampton University Hospitals and University of Southampton Mr Neil Pearce Consultant Hepatobiliary and Pancreatic Surgeon, University Hospital Southampton, Southampton
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Dr Brian Stedman Consultant Interventional Radiologist Southampton University Hospitals NHS Trust, Southampton Mr Sachin Salvi Consultant Ophthalmologist , Royal Hallamshire Hospital, Sheffield Dr Peter Szlosarek Consultant in Medical Oncology, St Bartholomew's Hospital, Clinical Senior Lecturer, Barts Cancer Institute, Queen Mary, University of London London Ms Nancy Turnbull 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.
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1 D- GDG Declarations of Interest tables
First Name Last Name DOI last Personal Pecuniary Non-personal pecuniary National body Stated personal Editorial Patents updated opinion Paul Nathan 30/01/2012 Member of advisory Chair rare melanoma sub- - - - committees for group of NCRI rare melanoma pharmaceutical group companies with drugs Ex-secretary melanoma study in development for group melanoma (GSK, Roche, BMS) - Reported at meeting 1 Victoria Cohen 10/07/2013 ------Sarah Coupland 10/07/2013 - CRUK sponsorship for collection - - - - of clinical samples collected during the ITEM and SUAVE studies (Novartis and Pfizer) Reported at meeting 1 Kathryn Curtis 10/07/2013 - - Chair of trustees of OcuMel - - - Bertil Damato 02/04/2012 Have received support from See PubMed Receive royalties Bebig (manufacturing plaques), articles for textbooks or Ellex (manufacturing ocular chapters relating to ultrasound machines) and uveal tumours. Optos (manufacturing cameras).
Jonathan Evans 07/08/2013 Involvement in the Delcath system Reported at meeting 1 Stephen Fenwick 10/07/2013 ------Lesley Kirkpatrick 10/07/2013 ------
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First Name Last Name DOI last Personal Pecuniary Non-personal pecuniary National body Stated personal Editorial Patents updated opinion Olivia Li 01/03/2012 ------Ernie Marshall 10/07/2013 - Pharmaceutical company NCRI, Melanoma CGG Screening, sponsored drug trials - ITEM psychology and and SUAVE treatment
Kieran McGuirk 10/07/2013 - - Chair of trustees of OcuMel - - - Bruce Oliver 04/03/2012 ------Christian Ottensmeier 10/07/2013 Consulting for Bristol Research funding for a clinical Strong opinion Myers Squibb and trial for Ipilimumab for lung that Novatis cancer immunology plays a role. (Reported at meeting 1) Neil Pearce 03/01/2012 I have written patient advice See above re for the OcumelUK website / OcumelUK, patient forum on surgical aspects of management of metastatic uveal melanoma
Brian Stedman 27/04/2012 Sponsorship from - - - - - radiology providers. 'Temmis' - Manufacturers, DP beamis/TACE, Medical Advisor for and sporsonship from SIRTX Sachin Salvi 10/07/2013 - - National Ocular Oncology - - - Group Peter Szlosarek 15/6/14 Sponsored by BMI to - - - - attend ASCO um_guideline_cons_draft_v2_23_6_14 Last saved by Nancy Turnbull Date 16 June 2014 Page 91 of 93
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First Name Last Name DOI last Personal Pecuniary Non-personal pecuniary National body Stated personal Editorial Patents updated opinion conference 2014 Nancy Turnbull 01/07/2013 ------
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1 The following appendices will be posted separately on the website at the time of 2 publication.
3 List of reviewers of the guideline
4 Ocular Melanoma Guideline Development Methodology
5 Patient information
6 Table of consultation comments and GDG responses
7 PowerPoint Presentations of evidence from meetings
8 NICE accreditation application and report (publically available from NICE)
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