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
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
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
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
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
Regional nodal RT – Case 1 Would you offer adjuvant radiotherapy to left axilla?
Regional nodal RT – Case 1 48Gy/20# Aug 2012 – G1 acute dermatitis – No lymphoedema Disease free at 2 years BRAF positive
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
Regional nodal RT – Case 2 Would you offer adjuvant radiotherapy to the right axilla?
Regional nodal RT – Case 2 48Gy/20# March 2012 – G2 acute dermatitis May 2011 – Disseminated disease – Liver, lungs, spleen Died June 2012
ANZMTG 01/02 - Adjuvant radiotherapy improves nodal field control in melanoma patients after lymphadenectomy: Results of an Intergroup Randomised Trial Burmeister and Henderson; The Lancet Oncology May 9, 2012 DOI:10.1016/S1470-2045(12)70138-9
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
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
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
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 Stratification Institution Nodal Region Number of positive nodes Metastatic node size Extent of extra-nodal spread RANDOMISATION Adjuvant Radiotherapy (48 Gy in 20 F) Observation
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
Statistics Target sample size220 patients CriteriaNodal field relapse rate difference = 15% (15% versus 30% at 1 year) with 80% power Statistical methodsLog rank comparison of time to nodal field relapse curves (Kaplan-Meier) IDMCThree international experts (surgeon, radiation oncologist, statistician) AmendmentSample size increased to 250 to compensate for eligibility infringements
Early Radiotherapy Toxicity: Grade 3 H&N (n=31)Axilla (n=50)Groin (n=34) 2 weeks post-RT Radiation dermatitis3105 Pain-2- 6 weeks post-RT Radiation dermatitis-5- Pain-11 Fatigue-1- No grade 4 early RT toxicities No information on late toxicities/lymphoedema
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
Protocol in Development ANZMTG - Radiotherapy followed by nodal dissection for high volume nodal melanoma PI: Dr Matthew Foote, Princess Alexandra Hospital, QLD
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.
Background For patients with high volume stage III disease surgery or radiotherapy unlikely to impact on OS Attain good regional control with least morbidity
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
Pilot Results (n=12) PatientClinical Response (In-field)FDG-PET ResponsePathological Response 1SD IR 2PR NR 3PRND* 4PDND* 5SD IR 6CR 7SDPRIR 8PRNDCR 9PRNDPR 10PRSDIR 11PRNDN/A 12PRNDNR
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.
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).
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
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
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
WBRT - Case Would you offer adjuvant whole brain RT?
WBRT - Case 30Gy/10# Jan 2012 WBRT trial Died Feb 2012 Intracranial progression
ANZMTG 01/07 - Whole Brain Radiotherapy following local treatment of intracranial metastases of melanoma - A randomised phase III trial PI: Dr Gerald Fogarty, Mater and St Vincents Hospital, Sydney
WBRT Mel Trial Schema 8 weeks 6 weeks4 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 ≥
90 patients randomised as of 30 Sept 2012 First analysis planned 1 year following 100 th 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) WBRT Mel Trial Overview Right: WBRT Mel Study Chair Dr Gerald Fogarty with Dr Angela Hong (MIA) and Dr Jenny Nobes (Norwich UK)
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 WBRT Mel Trial Endpoints
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. 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 WBRT Mel Trial - Eligibility Criteria
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: i.Health system ii.Patients incurring out-of-pocket expenses iii.Australian quality adjusted life year (QALY) weights
WBRT Mel Consumer Education Video http://www.youtube.com/watch?v=7gxrA7vNWPE DVDs now available via ANZMTG
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
RADVAN - Study Schema 50 Safety Cohort Radiotherapy + Vandetanib Analysis of safety cohort Randomisation Radiotherapy + Vandetanib Radiotherapy + Placebo Randomised trial 6 patients 80 patients, ratio 1:1
RADVAN - Stratification Patients will be stratified by RTOG RPA score 1 or 2 RPA classification – Class 1: Patients with Karnofsky Performance Score (KPS) ≥70%, age <65 years, controlled primary and no extracranial metastases – Class 2: All others – Class 3: (patient excluded from study) Patients with KPS <70% 51
Objectives and Endpoints Primary objective: – To assess the efficacy of vandetanib in combination with radiotherapy, compared with radiotherapy alone, in the treatment of patients with brain metastases from melanoma Primary endpoint: – Progression Free Survival in brain (PFS brain) as assessed by MRI scan 52
Objectives and Endpoints Secondary objectives – To assess the safety and tolerability of vandetanib + radiotherapy vs radiotherapy alone Secondary endpoints – Maintenance of cognitive function (as assessed by neurocognitive tests) – PFS brain at 6 months – Overall survival (OS) – Adverse events (using NCI CTCAE version 4.0) 53
33 y/o woman with recurrent melanoma Progressed on ipilimumab for 1 year Required palliative radiotherapy Responded outside of radiation field after 4 months Response has been durable with continued ipilimumab Postow M, Callahan M, Barker C, et al. New Engl J Med 2012
Preclinical evidence for immunologic effects of RT implicated in the abscopal effect Early evidence for clinical synergy of immunotherapy (IL-2) and RT* Anecdotal clinical evidence of ipilimumab and RT synergy as described with immunologic observations Summary *Seung, et al. Sci Transl Med 2012
Prospective evaluation – Ludwig Institute for Cancer Research Phase II Trial – RTOG Phase II trial Additional correlative analyses, including biopsies RT and other emerging immunomodulatory strategies (PD-1, OX40, CD137) Ongoing work
Eligibility Unresectable metastatic melanoma At least 2 measurable sites by irRC and mWHO One lesion in need of radiotherapy A Phase II Randomized Study to Evaluate the Efficacy of Combining Ipilimumab (3mg/kg) with Different Doses/Schedules of External Beam Radiotherapy Participating Sites Memorial Sloan-Kettering Cancer Center, Stanford University, University of Chicago, NCI, Penn State, Mt. Vernon Cancer Center and NNUH, UK Randomize Conventional 30Gy (3Gy x 10 fractions) Starting between 1 st and 2 nd dose of ipi Complete standard ipi induction High Dose Per Fraction 24Gy (8Gy x 3 fractions) Starting between 1 st and 2 nd dose of ipi Complete standard ipi induction Primary Endpoint Disease control rate (SD, PR, CR) at week 18 by mWHO Michael Postow Christopher Barker Jedd Wolchok