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The Role of Radiotherapy in Melanoma

The Role of Radiotherapy in Melanoma. Dr Jenny Nobes Norfolk and Norwich University Hospital Oct 2012. Indications. Primary Regional Palliative WBRT ? Combination with immunotherapy. Neurotropic Melanomas. Use of adjuvant radiotherapy controversial Commonly used H&N region

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The Role of Radiotherapy in Melanoma

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  1. The Role of Radiotherapy in Melanoma Dr Jenny Nobes Norfolk and Norwich University Hospital Oct 2012

  2. Indications • Primary • Regional • Palliative • WBRT • ? Combination with immunotherapy

  3. Neurotropic Melanomas Use of adjuvant radiotherapy controversial Commonly used H&N region Thick tumours (>4mm) Narrow surgical margins (<1cm path) Benefit on retrospective data 3

  4. ANZMTG 01/09 - A randomised phase III trial of postoperative radiation therapy following wide excision of neurotropic melanoma of the head and neck (RTN2)PI: Dr Matthew Foote, Princess Alexandra Hospital, QLD, AU

  5. RTN2 - Study Design Localised Neurotropic Melanoma of Head and Neck  Surgical Excision (1 cm macroscopic margin, flap or graft)  Initial Observation Radiation Therapy 48Gy in 20#  No local recurrence Local recurrence  Restage + re-excise 1 : 1 5

  6. RTN2 - Endpoints and Statistics Primary: Time to in-field relapse Secondary: Progression- free survival Overall survival Patterns of relapse Late toxicity Quality of life n= 100 patients LRF 65% control VS 83% up-front RT 80% power, 2 sided testing 2 interim analyses planned 6

  7. RTN2 Accrual & Sites 15/100 to date 12 Australian Sites Interested international sites include Norfolk and Norwich University Hospital UK Waitemata Specialist Center NZ University Clinic of Padova Italy Princess Margaret Hospital Canada 7

  8. Adjuvant radiotherapy to regional nodes

  9. Regional nodal RT – Case 1 • 50 year old man • 1.7mm melanoma epigastrium 2007 • Right axillary recurrence 2008 • 2/15 nodes • AVAST-M trial, completed 12 months Bevacizumab • Left axillary recurrence July 2010 • 2/19 nodes, largest 11mm, no ECS

  10. Regional nodal RT – Case 1 • Would you offer adjuvant radiotherapy to left axilla?

  11. Regional nodal RT – Case 1 • 48Gy/20# Aug 2012 • G1 acute dermatitis • No lymphoedema • Disease free at 2 years • BRAF positive

  12. Regional nodal RT – Case 2 • 75 year old man • 6.5mm melanoma right flank Nov 2011 • Palpable right axillary nodes Jan 2012 • 17/30 nodes • 4 apical axillary nodes • ECS • Post op restaging CT clear • BRAF wild type

  13. Regional nodal RT – Case 2 • Would you offer adjuvant radiotherapy to the right axilla?

  14. Regional nodal RT – Case 2 • 48Gy/20# March 2012 • G2 acute dermatitis • May 2011 • Disseminated disease • Liver, lungs, spleen • Died June 2012

  15. ANZMTG 01/02 - Adjuvant radiotherapy improves nodal field control in melanoma patients after lymphadenectomy: Results of an Intergroup Randomised TrialBurmeister and Henderson; The Lancet OncologyMay 9, 2012DOI:10.1016/S1470-2045(12)70138-9

  16. Background • Retrospective series from several large melanoma centres: RT improves regional control after nodal dissection • RTOG 93.02 • Randomised trial on the role of RT • Failed to recruit • No results reported

  17. Background TROG 96.06, single arm phase II trial of adjuvant radiotherapy after nodal dissection : 234 patients Radiotherapy: 48 Gy in 20 fraction High rate of regional control when compared with surgery alone series Acceptable toxicity Multicentre study across Australia and New Zealand was feasible Burmeister et al., Radiotherapy and Oncology; 2006

  18. Eligibility Criteria • Surgical Procedure: Minimum lymph node numbers harvested • Parotid & Neck: 2 – 25 (depending on type of dissection) • Axilla: 10 • Groin: 6 • At ‘significant’ risk of lymph node field relapse No of positive lymph nodes: • Parotid (1) • Neck, axilla (2) • Groin ( 3) OR Maximum positive lymph node size • Parotid, Neck , Axilla (3 cm) • Groin ( 4 cm) OR Extra-nodal spread

  19. Trial Schema Surgery for Lymph Node Field Recurrent Melanoma • Main Eligibility Criteria • Completely resected, palpable, nodal metastatic melanoma • No previous or concurrent local, in transit or distant metastatic relapse • At significant risk for lymph node field relapse StratificationInstitutionNodal Region Number of positive nodesMetastatic node sizeExtent of extra-nodal spread RANDOMISATION Adjuvant Radiotherapy (48 Gy in 20 F) Observation

  20. Trial Endpoints • Primary Endpoint: • Regional nodal field relapse (as a first relapse) • Secondary Endpoints: • Relapse free survival • Overall survival • Pattern of relapse • Late toxicity • Quality of life

  21. Statistics

  22. Time to lymph node field relapse

  23. Relapse-free survival

  24. Overall survival

  25. Early Radiotherapy Toxicity: Grade 3 No grade 4 early RT toxicities No information on late toxicities/lymphoedema

  26. ANZMTG 01.02 Conclusions Radiotherapy improves lymph node field control There is no evidence for a difference in RFS/OS Local control is important even in presence of systemic disease Avoid morbidity of nodal recurrence Early radiotherapy toxicity appears minimal

  27. Protocol in Development ANZMTG - Radiotherapy followed by nodal dissection for high volume nodal melanoma PI: Dr Matthew Foote, Princess Alexandra Hospital, QLD

  28. Background Stage IIIb-c disease has 5 year risk of relapse at any site of 70-85% Approx 30% nodal relapse and >50% with distant metastatic disease The timing of relapse often within the first year after nodal surgery Romano E, Scordo M, Dusza S, Coit D and Chapman P. Site and Timing of First Relapse in Stage III Melanoma Patients: Implications for Follow-up Guidelines. Journal of Clinical Oncology 2010; 28(18): 3042-47.

  29. Background For patients with high volume stage III disease surgery or radiotherapy unlikely to impact on OS Attain good regional control with least morbidity

  30. Background – Pilot 12 patients IIIb, IIIc and selected stage IV Pre-operative radiotherapy 48Gy/20# Pre/post treatment PET Planned nodal dissection at 12 weeks Foote, Burmeister, Dywer et al. An innovative approach for locally advanced stage III cutaneous melanoma: radiotherapy followed by nodal dissesction. Melanoma Research 2012

  31. Pilot Results (n=12)

  32. Results 9/10 primary closure was attained 1/10 had local myocutaneous flap Acute surgical morbidity 4/10 had post-op collection/infection requiring re-admission for drainage and Ab’s. 1/10 small wound dehiscence treated conservatively Two patients (17%) avoided the morbidity of surgery due to the rapid development of distant metastatic disease Shada A, Walters D, Tierney S et al. Surgical resection for bulky or recurrent axillary metastatic melanoma. J Surg Oncol 2012; 105:21-25.

  33. Phase II Proposal - Design Phase II non-randomized Preoperative RT followed by nodal dissection Patients with bulky and/or inoperable nodal melanoma (‘high volume nodal disease’) Stage IIIb (N2b) any node ≥ 6cm in maximum diameter or ≥ 4 nodes in the nodal basin ≥ 2 of which 3-6 cm in maximum diameter. Stage IIIc (N3) matted nodes Stage IV disease that meets nodal criteria but with limited distant disease such that the patient’s prognosis is at least 6 months (excluding brain metastases).

  34. Phase II Study Design & Stats Pre-treatment PET scan Radiotherapy (48-50Gy in 20#) PET scan 10-12 weeks post RT Planned nodal dissection 12 weeks n=30 patients Based on 1 yr local control of 40% (surgery) vs 75% (surgery and RT) 2-sided testing at the (alpha) 10% significance level and with a power of 80% Consideration to conduct a Ph III RCT afterwards

  35. Objectives Primary Effectiveness of approach Regional control rate (1 yr) Secondary Acute and late RT and Surgery morbidity Assess PET predictive values for response Melanoma specific QOL (EORTC MOD) Proportion of patients with change in planned surgery as determined by MDT Translation arm – genetic signatures of response and relapse patterns

  36. Whole Brain Radiotherapy

  37. WBRT - Case • 50 year old man • No history of melanoma • Cerebellar symptoms • 4.2 x 3.3cm mass • Biopsy = metastatic melanoma • No extra-cranial disease • Debulking Nov 2011

  38. WBRT - Case • Would you offer adjuvant whole brain RT?

  39. WBRT - Case • 30Gy/10# Jan 2012 • WBRT trial • Died Feb 2012 • Intracranial progression

  40. ANZMTG 01/07 - Whole Brain Radiotherapy following local treatment of intracranial metastases of melanoma - A randomised phase III trialPI: Dr Gerald Fogarty, Mater and St Vincents Hospital, Sydney

  41. WBRT Mel Trial Schema 8 weeks ≥ 6 weeks 4 weeks • Follow up schedule (every 8 weeks / MRI every 12 weeks) • Patients followed up for life; data collected includes: intra / extra cranial disease burden, performance status, QOL, NCF

  42. WBRT Mel Trial Overview • 90 patients randomised as of 30 Sept 2012 • First analysis planned 1 year following 100th randomised patient • Full study: From July 2011 • 200 patients • 26 sites: • 16 AU sites, 8 UK sites, 1 Norwegian site, 1 US site, 1 Brazilian site • Pilot phase COMPLETED: December 2008 – June 2011 • 60 patients • 15 sites (14 AU sites, 1 Norwegian site) Right: WBRT Mel Study Chair Dr Gerald Fogarty with Dr Angela Hong (MIA) and Dr Jenny Nobes (Norwich UK)

  43. WBRT Mel Trial Endpoints Primary • Distant intracranial failure at 12 months, as assessed by MRI Secondary • Time to intracranial failure (local, distant and overall (local+ distant)) as assessed by MRI • Deterioration in quality of life (EORTC QLQC30 & BM20) • Deterioration of performance status (ECOG) • Deterioration of neurocognitive function (NCF assessments) • Progression-free and overall survival • Death from neurological causes or not

  44. WBRT Mel Trial - Eligibility Criteria • Inclusion Criteria • 1-3 intracranial melanoma metastases on MRI, locally treated with either surgical excision and/or stereotactic irradiation. • Life expectancy of at least 6 months • ECOG score of 2 or less at randomisation • WBRT must begin within 8 weeks of localised treatment and 4 weeks of randomisation • eGFR is adequate and capable of having gadolinium-containing contrast medium for MRI • CT scan (chest, abdomen & pelvis) within 12 weeks of randomisation • Serum LDH ≤ 2xULN Neurocognitive Function and Quality of Life Components • Patients will be excluded from the NCF and QOL aspects of the study if their fluency (oral and written) is less than a year 8 standard.

  45. WBRT Mel Trial - Eligibility Criteria • Exclusion Criteria • Any untreated intracranial disease • Previous treatment (surgical excision / SRS / WBRT) for brain mets • Leptomeningeal disease • Prior cancers except: • Cancers diagnosed > 5 years ago with no evidence of recurrence • Successfully treated BCC and SCC • Carcinoma in-situ of the cervix • A medical or psychiatric condition that compromises ability to give informed consent or complete the protocol

  46. WBRT Mel Planned Secondary Studies WBRT Mel MRI discrepancy audit • Is there a significance difference in reporting of intracranial failure between local radiologists and subspecialist neuro-radiologists? Hippocampal metastases retrospective audit • Determine the number of cases with metastases in and within 5mm of the hippocampus • Single centre (MIA) WBRT health economic evaluation • Determine the cost-effectiveness of WBRT compared to observation from the perspective of: • Health system • Patients incurring out-of-pocket expenses • Australian quality adjusted life year (QALY) weights

  47. WBRT Mel Consumer Education Video http://www.youtube.com/watch?v=7gxrA7vNWPE DVDs now available via ANZMTG

  48. RADVAN - Study Summary A randomised, double-blind, placebo-controlled multi-centre phase II study Melanoma with brain metastases 6 patients from a single site in a non-randomised safety phase 80 additional patients from 10 UK sites Projected recruitment period of 24 months An analysis will be performed when approximately 74 brain progression/death events have occurred 49

  49. RADVAN - Study Schema Radiotherapy + Vandetanib Safety Cohort 6 patients Analysis of safety cohort Randomised trial Randomisation Radiotherapy + Vandetanib Radiotherapy + Placebo 80 patients, ratio 1:1 50

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