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
– Thick tumours (>4mm)
– Narrow surgical margins (<1cm path)
• Benefit on retrospective data
3
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
RTN2 - Study Design
Localised Neurotropic Melanoma of Head
and Neck

Surgical Excision (1 cm macroscopic margin, flap or graft)
1:1

Initial Observation

Radiation Therapy 48Gy in 20#

No local recurrence
5

Local recurrence 

Restage +
re-excise
RTN2 - Endpoints and Statistics
• Primary:
• Secondary:
Time to in-field relapse
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
RTN2 Accrual & Sites
• 15/100 to date
• 12 Australian Sites
• Interested international sites include
–
–
–
–
7
Norfolk and Norwich University Hospital UK
Waitemata Specialist Center NZ
University Clinic of Padova Italy
Princess Margaret Hospital Canada
Adjuvant radiotherapy to
regional nodes
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 size
220 patients
Criteria
Nodal field relapse rate difference = 15%
(15% versus 30% at 1 year) with 80% power
Statistical methods
Log rank comparison of time to nodal field relapse
curves (Kaplan-Meier)
IDMC
Three international experts (surgeon, radiation
oncologist, statistician)
Amendment
Sample size increased to 250 to compensate for
eligibility infringements
Time to lymph node field relapse
Relapse-free survival
Overall survival
Early Radiotherapy Toxicity: Grade 3
H&N (n=31) Axilla (n=50) Groin (n=34)
2 weeks post-RT
Radiation dermatitis
3
10
5
Pain
-
2
-
Radiation dermatitis
-
5
-
Pain
-
1
1
Fatigue
-
1
-
6 weeks post-RT
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 7085%
• 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)
Patient
Clinical Response (In-field)
FDG-PET Response
Pathological Response
1
SD
SD
IR
2
PR
PR
NR
3
PR
ND*
ND*
4
PD
ND*
ND*
5
SD
SD
IR
6
CR
CR
CR
7
SD
PR
IR
8
PR
ND
CR
9
PR
ND
PR
10
PR
SD
IR
11
PR
ND
N/A
12
PR
ND
NR
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
• Primary
Objectives
– 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
Whole Brain Radiotherapy
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
RANDOMISATION
Local treatment
Treat existing
melanoma
brain metastases w
surgical excision
and/or stereotactic
irradiation
- consent to study
- confirm eligibility
Stratified by
- Number of cerebral
metastases (1, >1)
- Presence or absence of
extracranial disease
- Centre
- Gender
- Planned radiotherapy
dose (30gy/10# or higher)
- Age (<65 or ≥=65 yrs)
6 weeks
WBRT
(at least 30 Gy over 10#)
Follow Up
and
Outcome
Assessment
Observation only
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
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)
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
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.
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 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
Radiotherapy
+
Vandetanib
Safety Cohort
6 patients
Analysis of safety cohort
Randomised trial
Randomisation
Radiotherapy
+
Vandetanib
Radiotherapy
+
Placebo
80 patients, ratio 1:1
50
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
The Abscopal Effect in Melanoma
Patients
What does “abscopal” mean?
“ab” away
“scopus” target for shooting
Prior to RT
2.5 years later
O’Connell British Journal of Radiology 1989
Ipilimumab + ????
chemotherapy?
targeted therapy?
other immunotherapy?
radiation therapy?
Ipilimumab + ????
chemotherapy?
targeted therapy?
other immunotherapy?
radiation therapy?
• 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
Postow M , Callahan M, Barker C, et al. New Engl J Med 2012
Postow M , Callahan M, Barker C, et al. New Engl J Med 2012
28.5 Gy/3 fractions
Postow M , Callahan M, Barker C, et al. New Engl J Med 2012
Postow M , Callahan M, Barker C, et al. New Engl J Med 2012
Postow M , Callahan M, Barker C, et al. New Engl J Med 2012
Postow M , Callahan M, Barker C, et al. New Engl J Med 2012
Summary
• 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
*Seung, et al. Sci Transl Med 2012
Ongoing work
• 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)
A Phase II Randomized Study to Evaluate the Efficacy of Combining
Ipilimumab (3mg/kg) with Different Doses/Schedules of External Beam
Radiotherapy
Eligibility
•Unresectable metastatic melanoma
•At least 2 measurable sites by irRC and mWHO
•One lesion in need of radiotherapy
Randomize
Conventional
30Gy (3Gy x 10 fractions)
Starting between 1st and 2nd dose of ipi
Complete standard ipi induction
High Dose Per Fraction
24Gy (8Gy x 3 fractions)
Starting between 1st and 2nd 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
Participating Sites
Memorial Sloan-Kettering Cancer Center, Stanford University, University of
Chicago, NCI, Penn State, Mt. Vernon Cancer Center and NNUH, UK