Uveal Melanoma Guideline Update 2022 & 2023: Methodology and Key Recommendations

Uveal Melanoma Guideline Update 2022 &2023 melanomafocus.org

Methodology • Open recruitment of Guideline Development Group • Clinical questions • Literature search • Evidence review • Discussion and agreement of recommendations • Drafting • Consultation • Write-up and publications Funded by Melanoma Focus & OcuMel UK

Timeline • 2015 First publication of the guideline • 2022 Update of out-of-date sections of the guideline • 2023 Update of Surveillance

Guideline Development Group 2022 Mt Vernon Cancer Centre, Northwood Prof Paul Nathan (Chairman) Coupland Medical Oncologist George Holt Chair in Pathology, University of Liverpool Prof Sarah Histopathologist Bartholomew's Hospital, Barts Health NHS Trust Dr Dr Rachel Sachin Lewis Modi Clinical Oncologist Interventional Radiologist University Hospital Southampton Bartholomew's Hospital, Barts Health NHS Trust Dr Sukaina Retired Rashid January 2021 Medical Oncologist The Clatterbridge Cancer Centre & University of Liverpool Dr Joe Sacco Medical Oncologist Department of Oncology and Metabolism University of Sheffield Francis Crick Institute Dr Karen Sisley Senior Lecturer Dr Dr Ms Dr Samra Matthew Wheater Audrey Jack Turajlic Medical Oncologist Medical Oncologist Patient Representative Medical Oncology Research Fellow Project Manager University Hospital Southampton Colchester Woraker Broadfoot University Hospital Southampton London Mrs Nancy Turnbull

Guideline Development Group 2023 • Dr Matthew Wheater Medical Oncologist (Chairman) Sarah Coupland Histopathologist Bertil Damato Ophthalmologist University Hospital Southampton • Prof • Prof George Holt Chair in Pathology, University of Liverpool Consultant Ocular Oncologist, St Erik’s Eye Hospital & Karolinska Institutet, Stockholm Chester Aintree University Hospital, Liverpool University of Birmingham/Queen Elizabeth Hospital Devonshire University Hospital Southampton Moorfields Eye Hospital London University College London Hospital OcuMel UK • Ms • Mr • Dr • Ms • Dr • Mr • Dr • Ms • Ms Helen Stephen Fenwick Hepatobiliary Surgeon Leila Khoja Medical Oncologist Tracey Krausa Patient Representative Sachin Modi Interventional Radiologist Guy Negretti Ophthalmologist Heather Shaw Medical Oncologist Reta Sowton Oncology Nurse Nancy Turnbull Project Manager Evans Patient Representative • Ms Susanna Daniels Chief Executive Melanoma Focus Observer

What’s new? • Patient information and support (revised 2022) • Genetic and molecular features (new 2022) • Adjuvant therapy • Systemic adjuvant therapy after surgery (new 2022) • Radiation therapy as adjuvant treatment to the orbit (new 2022) • Surveillance • Ocular (new 2023) • Liver (updated 2023) • Treatment options for macroscopic orbital recurrence (new 2022) • Metastatic disease • Systemic therapy (revised 2022) • Impact of molecular features on choice of therapy (new 2022) • Loco-regional management of hepatic predominant disease (revised 2022) • Surveillance following liver treatment (updated 2023)

Patient information and support (2022) 1. Information should be offered throughout the patient pathway in an individualised manner and provided as needed. Ideally, this should adhere to these quality standards (https://pifonline.org.uk/pif-tick/). 2. Patients should be encouraged to record their consultations, with the knowledge of the clinician and staff. 3. Patients should be given the time and opportunity to discuss their condition and treatment on each visit. This should include: risks and benefits of investigations, procedures and treatments the treatment options available locally and at other centres the ‘pros’ and ‘cons’ of prognostication, including the role of tumour biopsy timely information on the roles of other teams in their care signposting to other high-quality resources, for example Melanoma Focus, OcuMel UK, Cancer Research UK, MacMillan and Maggie’s. • • • • •

Patient information and support cont. 4. Each patient should have a named keyworker, with contact details including telephone and e- mail address, who is responsible for communication between the different cancer centre teams caring for the patient and between the cancer centre and primary and secondary care. Ideally, this should be a Clinical Nurse Specialist. 5. Patients should be given scan results as early as possible to mitigate anxiety. 6. Standard care available to all patients nationwide should include: information on the side effects of local or systemic treatment advice for patients and families regarding signs and symptoms that may indicate that the cancer has recurred the offer of psychological support easy access to out-patient review or remote consultation the opportunity to have a family member with them at consultations. This may be done remotely, if necessary the offer of early referral to services, for example, enhanced supportive care, palliative care support services and support groups. • • • • • •

Prognostic factors/tool Prognostic factors/tool (2022) 28. and genetic features. The following features should be recorded: • Patient age • Patient sex • Tumour location (i.e. involvement of ciliary body or not) • Tumour height • Tumour largest basal diameter • Ciliary body involvement • Extraocular melanoma growth (macroscopic and microscopic). The following features should be recorded if tissue is available: • Cell type (modified Callender system) • Mitotic count (number/40 high power fields in H&E-stained sections) • Presence of extravascular matrix patterns (particularly ‘closed loops’) • Presence of extraocular melanoma growth (size in mm; presence/absence of encapsulation; relation to surgical margin) • Positive or negative expression of nuclear BAP1 protein in the tumour cells. Prognostic factors of uveal melanoma are multi-factorial and include clinical, morphological

Prognostic factors/tool cont. Prognostic factors/tool cont. 29. The following features should be recorded if cytology of tumour is available: • Confirmation of melanoma cells (i.e., exclude differential diagnoses, particularly metastatic carcinoma) – immunocytology may be required for this, but is not always necessary. • Cell type (modified Callender system), if possible.

Prognostic biopsy (2022) 30. There should be a fully informed discussion with all patients, explaining the role of biopsy including the benefits and risks. The discussion should include: • Enabling prognostication and allow tailored follow-up • Allowing recruitment into adjuvant trials • Risks of having the biopsy • Limitations of the investigation • Effects of prognostication information on quality of life. 31. The minimum dataset for uveal melanoma from the Royal College of Pathology (or national official equivalents) should be recorded in the pathology reports. See: https://www.rcpath.org/profession/publications/cancer-datasets.html 32. Use the most up-to-date edition of the TNM staging system for prognostication and include in pathology/clinical reports.

Prognostic biopsy cont. 33. Collect molecular genetic and/or cytogenetic data for research and prognostication purposes, where tumour material is available and where patient consent has been obtained, as part of an ethically-approved research programme. 34. The use of multifactorial prognostication models incorporating clinical, histological, immunohistochemical and genetic tumour features should be considered. 35. Where available the results of state-of-the-art molecular analysis should be combined with clinical features and standard anatomical and pathological staging for prognostication. 36. Tests for novel circulating blood-borne biomarkers should only be used within clinical trials or research programmes.

Adjuvant therapy (2022) Systemic adjuvant therapy after surgery 37. The availability of prognostic tools that allow identification of high-risk primary disease, and the poor outcomes for metastatic uveal melanoma support an adjuvant approach. In the absence of proven therapy, adjuvant systemic therapy should only be given within a well-designed clinical trial. Radiation therapy as adjuvant treatment to the orbit 38. There is very limited evidence for adjuvant radiation therapy to the orbit after definitive surgical treatment of primary disease. It is an option that can be considered for patients deemed to be at high risk of local relapse (e.g., greater than 5mm tumour extra-ocular extension in enucleation samples). Toxicity should be balanced against lack of evidence for efficacy and patients should be counselled on the benefits and risks of radiation therapy. 39. When radiation therapy is indicated, due to the relative radio resistance of melanoma, doses greater than 2Gy per fraction are recommended with a total does of 45-50Gy/20#.

Ocular Surveillance (2023) 40. Patients should be offered surveillance of the eye initially every 6 months for 2-5 years and then annually depending on response to therapy and individual patient factors. If there is doubt over stability, then the interval between follow-ups can be reduced to allow for a period of closer follow up to either confirm or refute stability. • Surveillance can be carried out locally by colour photography if there is a clear view of the whole tumour. Ocular oncologists should only monitor patients who cannot safely be monitored close to their home. Ocular oncologists should encourage local healthcare workers to send images of the lesion if they have any uncertainty • Some patients whose whole tumour is not visible with colour photography can be monitored adequately in certain local centres with good access to ocular ultrasound or with shared care between ocular oncology / local centres. If the tumour has completely regressed the patient may be discharged to their local optometrist. • Patients who have had enucleation and all of the tumour is removed (R0 resection) can be discharged to an optometrist when the socket is healed. 41. Prior to discharge from the Ocular Oncologist, patients should have a clear plan in place for metastatic surveillance see the section which follows.

Ocular Surveillance cont.. 42. Ongoing eye surveillance, where needed, can be carried out by a general Ophthalmologist or an Optometrist who has appropriate expertise. This should generally be for life. • Patients should be copied into correspondence between Ocular Oncologist and local hospital with a summary of the follow-up plan and how local ophthalmologists can access Prof Damato’s booklet Essential Ocular Oncology https://melanomafocus.org/for-professionals/educational- resources/essential-ocular-oncology-a-guide-for-practitioners-2/ • Patients should be advised that if they have not heard from the onward care team within 2 month’s they should contact the referring centre. 43. Management of ocular morbidities may require advisory input from the Ocular Oncologist. 44. Future work: The UK Ocular Oncology Centres should produce a consensus patient information sheet on the risks and benefits of intra-ocular biopsy.

Liver Surveillance (2023) 45. Patients should be offered a discussion with an oncologist or other appropriately trained healthcare professional to discuss the relative merits of metastatic surveillance. For patients who commence surveillance this should be co-ordinated through secondary care and not primary care. 46. A multi-parameter prognostic model (e.g. LUMPO3) should be used in discussion with uveal melanoma patients with respect to their individual metastatic risk, and value of liver surveillance during follow up. 47. For patients without genetic analyses, modelling with LUMPO3 to estimate risk with or without monosomy 3 may inform discussion around risk of recurrence and value of imaging surveillance. 48. Patients who are considered to have a less than 10% metastatic risk within a 10-year period as calculated by a multi-parameter prognostic model (e.g. LUMPO3) should not be recommended for regular liver surveillance. 49. Patients with a small tumour (T1) and favourable histological and genetic analyses, have an excellent outcome and may not need imaging surveillance. (Genetic factors that suggest low risk include tumours having either disomy chromosome 3 or class 1 (GEP); absence of BAP1 loss or SF3B1 gene mutation (SS and NGS) or nuclear protein expression of BAP1). 50. The decision to start surveillance and the duration should be individualised based on factors such as co- morbidity and fitness to act on the results of scan findings.

Liver Surveillance cont (2023) 51.Standard surveillance should be for 10 years from the initial ocular diagnosis. This should be every 6 months for 5 years and then annually to 10 years. The choice of imaging modality should be discussed with the patient but should be focused on the liver. 52. When available, patients with a known somatic SF3B1 mutation (not routinely tested at the time of this guidance) may benefit from extending surveillance for 15 years. 53.US and MRI generally are equally effective for clinical decision making for surveillance. However, individual patient factors (e.g., BMI, pacemakers, prior liver-directed therapy) and availability may influence choice of modality. [2023] 54.When MRI is the chosen modality for imaging surveillance non-contrast examinations utilizing Diffusion Weighted Imaging (DWI ) are recommended and contrast agents used only at baseline and where indicated by the reporter for lesion characterisation. 55.When ultrasound is used for surveillance, it should be performed by an experienced operator. A MRI scan should be scheduled urgently if any new lesion is detected on ultrasound.

Liver Surveillance cont (2023) 55.When ultrasound is used for surveillance, it should be performed by an experienced operator. A MRI scan should be scheduled urgently if any new lesion is detected on ultrasound. 56. FDG PET-CT scans and CT are not recommended for liver surveillance.] 57.Liver function tests are an inadequate tool for surveillance for uveal melanoma metastases and should not be part of routine surveillance. 58.All patients should be offered access to psychological services including those who are not being offered surveillance. 59.Patients who have completed a liver surveillance programme and been discharged to the General Practitioner or Ophthalmologist should be referred to a medical or clinical oncologist should any concerns of metastatic recurrence arise. Note: The guideline development group acknowledge that patients on an existing liver surveillance pathway may find it difficult to transition to the new guidelines. The new data supporting the update should be discussed with patients before considering modifying their follow up plan and appropriate support be given where needed.

Treatment options for macroscopic orbital recurrence (2022) 60. For local macroscopic recurrence in the orbit, there should be a discussion at MDT to discuss surgical and radiotherapy options. 61. When radiation therapy is indicated, due to the relative radio resistance of melanoma, doses greater than 2Gy per fraction are recommended with a total does of 45-50Gy/20#.

Metastatic disease (2022) Systemic therapy 68. Pending availability consider offering tebentafusp to HLA-A*02:01 positive fit patients with metastatic disease. 69. Patients should be considered for clinical trials wherever possible and be informed of available trial options at other centres. 70. Patients with good performance status (PS 0-2) who decline trials or for whom no suitable clinical trials are available should be offered systemic treatments and managed in specialist centres with appropriate oncology expertise in uveal melanoma. 71. Specialist centres should be involved in treatment decisions and review, but a patient may prefer to receive supportive care and systemic treatment locally if possible.

Metastatic disease cont. 72. Systemic immune checkpoint inhibitors (ICI) can be considered in the absence of relevant clinical trials. Without clear evidence of superiority, treatment decisions between single agent and combination ICI require careful discussion regarding the risk of significant toxicity and modest potential additional benefits. 73. For patients with liver only or liver predominant disease, local or locoregional therapy may also be considered. 74. Chemotherapy has limited, if any, efficacy in uveal melanoma, and as such should only be used in the absence of other options and with full discussion of risks and impact on quality of life. 75. Targeted therapy should only be used in the context of a clinical trial.

Impact of molecular features on choice of therapy 76. Screen fit patients for HLA-A*02:01 to identify those who may benefit from tebentafusp 77. Bio-banking and similar efforts in UM should conform to agreed best practices that ultimately could allow for pooling of molecular and clinical data collected in clinical trials and routine care to maximise the likelihood of successfully validating predictive biomarkers.

Loco-regional management of hepatic predominant disease 78. For patients with technically resectable disease, assessment for hepatic resection should be offered where complete macroscopic clearance (RO) can be achieved. 79. Patient selection to ensure complete macroscopic clearance is important to exclude surgery without benefit, including consideration of early interval imaging, in order to exclude rapidly emerging disease. Patent selection should consider these criteria: • The extent of liver involved with tumour • No more than one site of extra-hepatic disease which is either stable or with an alternative treatment strategy for that site • ECOG PS >= 1 • Functionally significant underlying liver disease. 80. Laparoscopic assessment should be performed in patients with radiologically resectable liver metastases, as many of these patients will have a miliary pattern of disease. 81. Liver directed and/or systemic treatments should be considered in selected patients with liver dominant disease where resection is not suitable.

What’s not new? • Service configuration • Primary management

Supporting information Available on the Melanoma Focus Website https://melanomafocus.org/for- professionals/rare-melanoma-guidelines/uveal-melanoma-guidelines/ • Recommendations - Executive summary https://melanomafocus.org/files/pdfs/uveal- melanoma/executive-summary.pdf • Care pathway https://melanomafocus.org/files/pdfs/uveal-melanoma/care-pathway.pdf • Reviews of evidence and development group summaries - https://melanomafocus.org/files/pdfs/uveal-melanoma/guideline.pdf • Methodological detail • Appendices 2022 https://melanomafocus.org/files/pdfs/uveal-melanoma/appendix-to-guideline-2022.pdf • Appendices 2015 https://melanomafocus.org/files/pdfs/uveal-melanoma/appendix-to-guideline-2015.pdf • Patient & Carer Information https://melanomafocus.org/about-melanoma/types-of- melanoma/uveal-melanoma/ • Consultation comments and responses - https://melanomafocus.org/files/pdfs/uveal- melanoma/consultation.pdf • This slide set - https://melanomafocus.org/files/pdfs/uveal-melanoma/slide-set.pdf

Uveal Melanoma Guideline Update 2022 & 2023: Methodology and Key Recommendations