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

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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

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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

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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

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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

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


• Would you offer adjuvant radiotherapy to left axilla?


• 48Gy/20# Aug 2012– G1 acute dermatitis– No lymphoedema

• Disease free at 2 years

• BRAF positive


• 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


• Would you offer adjuvant radiotherapy to the right axilla?


• 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, 2012DOI: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 relapseNo 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 SchemaSurgery 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

StratificationInstitution

Nodal RegionNumber of positive nodes

Metastatic node sizeExtent 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 -

6 weeks post-RT

Radiation dermatitis - 5 -

Pain - 1 1

Fatigue - 1 -

No grade 4 early RT toxicitiesNo 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)

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

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

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

Local treatment

Treat existing melanomabrain metastases w surgical excision and/or stereotactic irradiation

- consent to study- confirm eligibility

WBRT(at least 30 Gy over 10#)

Observation only

Follow Up and

Outcome Assessment

RANDOMISATION

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)

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

≥

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)

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 StudiesWBRT 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 systemii. Patients incurring out-of-pocket expensesiii. Australian quality adjusted life year (QALY) weights

WBRT Mel Consumer Education Videohttp://www.youtube.com/watch?v=7gxrA7vNWPEDVDs now available via ANZMTG

http://www.youtube.com/watch?v=7gxrA7vNWPE

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

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RADVAN - Study Schema

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Safety CohortRadiotherapy

+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%

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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

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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)

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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?

• 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

28.5 Gy/3 fractions


• 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 SitesMemorial Sloan-Kettering Cancer Center, Stanford University, University of Chicago, NCI, Penn State, Mt. Vernon Cancer Center and NNUH, UK

Randomize

Conventional30Gy (3Gy x 10 fractions)

Starting between 1st and 2nd dose of ipiComplete standard ipi induction

High Dose Per Fraction24Gy (8Gy x 3 fractions)

Starting between 1st and 2nd dose of ipiComplete standard ipi induction

Primary EndpointDisease control rate (SD, PR, CR) at week 18 by mWHO

Michael PostowChristopher BarkerJedd Wolchok

the role of radiotherapy in melanoma

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