THE IMPACT OF LESION NUMBER AND TREATMENT …...IN MELANOMA BRAIN METASTASES TREATED WITH STEREOTACTIC RADIOSURGERY (SRS) Shelly X Bian 1, David Routman 1, Jonathan Liu 1, Lingyun

THE IMPACT OF LESION NUMBER AND TREATMENT VOLUME AND AGE ON SURVIVAL IN MELANOMA BRAIN METASTASES TREATED WITH STEREOTACTIC RADIOSURGERY (SRS)

Shelly X Bian1, David Routman1, Jonathan Liu1, Lingyun Ji4, Susan Groshen4, Gabriel Zada2, Michael K Wong3, Michael Apuzzo2, Cheng Yu1, Eric L Chang1

Department of Radiation Oncology1, Neurosurgery2, Medical Oncology3

, and Biostatistics4

Keck Medical Center and Norris Comprehensive Cancer Center,University of Southern California, Los Angeles, CA, USA

• None

Conflict of Interest Disclosure

2

• 76,000 new cases, 10,000 deaths/year in the US• 132,000 new cases worldwide• Second most frequent invasive cancer in

individuals < 39 years• Incidence has doubled over the past 40 years• 15 % develop metastatic disease• Accounts for ~10% of brain metastases

Background: Melanoma

3

State of California, United StatesMelanoma of the skin incidence rate 21.1 per 100,000Source: U.S. Cancer Statistics Working Group 1999-2012

4

• Stereotactic radiosurgery (SRS) is becoming more prevalent in the treatment of brain metastases (BM)

Background

5

6

• Stereotactic radiosurgery (SRS) is becoming more prevalent in the treatment of brain metastases (BM)• Lower risk of cognitive side effects than WBRT• High rates of local control (LC) than WBRT• Lower complications than surgical resection

Background

7

8Chang EL. Lancet Oncol 2009;10(11):1037-44.

http://www.lancet.com/journals/lanonc/issue/current

http://www.lancet.com/journals/lanonc/issue/current

• Particularly important for radioresistanthistologies: melanoma, RCC, sarcoma• Conventional fractionation results in low rates of LC

Background

9

• Lesion number is routinely used to evaluate a patient’s candidacy for SRS

• Upper limit usually set at 3 or 5 lesions• However, recent studies suggest that lesion

number may not be a significant prognostic factor for overall survival (OS)

Background

10

Reference n Study Type OS influenced by lesion number

Yamamoto, Lancet 2014 1194 Prospective NoLikhacheva, IJROBP 2012 251 Retrospective No

Chang, JNS 2010 323 Retrospective NoBhatnagar, IJROBP 2006 205 Retrospective No

Background: lesion number

11





12

No difference in survival between• 2-4 lesions (10.8mo)• 5+ lesions (10.8mo)





13

On multivariate analysis, predictors of OS were:• Extracranial disease• Total tumor volume > 2cm3

• Age >60 years• Diagnosis-specific graded prognostic assessment (GPA)





14

No difference in survival between• 1–5 lesions (10mo)• 6–10 lesions (10mo)• 11–15 lesions (13mo)

Faster development of BM in 15+ lesions





15

On multivariate analysis, prognostic factors for OS were:• Total treatment volume• Age• Recursive Partitioning Analysis (RPA)• Marginal dose


% Melanoma

Yamamoto, Lancet 2014 1194 Prospective No <3%Likhacheva, IJROBP 2012 251 Retrospective No <30%

Chang, JNS 2010 323 Retrospective No <15%Bhatnagar, IJROBP 2006 205 Retrospective No 17%


16

However, the majority of patients on these studies had lung or breast cancer histologies, and included a minority of patients with melanoma, which are historically more radioresistant

• To evaluate survival in patients with metastatic melanoma with single versus 2-4 lesions, versus 5+ BM treated with SRS

• To investigate the association between lesion number, total intracranial treatment volume, age and OS

Study Objectives

17

• Retrospective review of patients treated at USC Center for Radiosurgery

Methods

18

19

• 392 consecutive patients with 971 lesions from metastatic melanoma treated from 1994 to 2013 at Keck Medicine of USC

• All patients were treated with • Gamma Knife Model U (1994 – 2000)• Gamma Knife Model C (2000 – 2008)• Gamma Knife Perfexion (2008 – present)

• Survival data obtained from cancer registry

Methods

• Patients were grouped according to:• Number of lesions treated• Total volume of lesions treated• Age

• OS was calculated from the day of SRS to the date of last follow-up or date of death

• Analysis included Kaplan-Meier curves and Cox proportional hazard models

Methods

20

N %Lesion Number

1 183 47%2-4 171 44%5+ 34 9%

Lesion Volume<5cc 241 62%

5-10cc 73 19%10-20cc 54 14%

>20cc 20 5%Age

<50 112 28%50-59 107 28%60-69 86 22%≥70 83 21%

Patient Characteristics

21

• Median OS was 7.5 months for the entire cohort (95% CI, [6.7 - 8.1]).

• Median follow-up was 44.1 months(Range 1mo - 17 years) for patients alive at time of analysis.

Results

22

• On multivariable trend analysis, all 3 factors had significant associations with OS• Lesion number (p≤0.001)• Total tumor volume (p≤0.001)• Age (p≤0.017)

Results

23

• OS by Lesion Number

Results

24

Lesion Number HR for risk of death

95% CI

1 12-4 1.4 1.1 – 1.75+ 1.9 1.3 – 2.8

OS by Lesion Number

25

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

OS

Prob

abili

ty

0 1 2 3 4 5 6Time in Years from Treatment

Lesion number: 1 (n=183)Lesion number: 2-4 (n=171)Lesion number: >=5 (n=34)

p<0.001

• OS by Treatment Volume

Results

26

Treatment Volume HR for risk of death

95% CI

<5cc 1.0

5-10cc 1.3 0.99 - 1.7

10-20cc 1.7 1.2 - 2.3

>20cc 2.2 1.4 - 3.6

OS by Treatment Volume

27

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

OS

Prob

abili

ty


0-5 (n=241)5-10 (n=73)10-20 (n=54)>=20 (n=20)

p<0.001

• OS by Age

Results

28

Age HR for risk of death

95% CI

<50 1.0

50-59 1.4 1.0 – 1.8

60-69 1.3 1.0 – 1.8

≥70 1.5 1.1 – 2.0

OS by Age

29

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

OS

Prob

abili

ty


<50 (n=112)50-59 (n=107)60-69 (n=86)>=70 (n=83)

p=0.013

• Strongest determinants for shortened OS

Results

30

Risk factor Hazard Ratio (HR) for risk of death

95% Confidenceinterval (CI)

Tumor volume >20cc 2.2 *Ref group 1-5cc

1.4 - 3.6

5+ lesions 1.9*Ref group 1 lesion

1.3 - 2.8

1st Author(Journal, year)

Year Institution n # of BM

Marginal Dose

Survival based on lesion #

Median OS

Mingione(JNS 2002)

1989-1999 Univ of Virginia 45 92 13-25Gy 1: 14.5mo2+: 7.6mo

10.5mo

Selek(IJROBP 2004)

1991-2001 MD Anderson 103 153 10-24Gy 1: 7.2mo2+: 5.0mo

6.7mo

Radbill(Cancer 2004)

1996-2001 Univ of Alabama 51 188 10-21Gy 1: 18mo2+: 4.7mo

6.1mo

Gaudy-Marqueste(IJROBP 2006)

1997-2003 Hopital la Timone, Marseille, France

106 221 14-40Gy 1: 5.5mo2+: 4.6mo

5.9mo

Skeie(World NSG 2007)

1996-2006 Haukeland UnivHospital, Norway

77 143 15-25Gy 1: 10mo2+: 6mo

7.0mo

Liew(JNS 2011)

1987-2008 Univ of Pittsburgh 333 1570 10-22Gy 1-2: 6.7mo3-6: 4.3mo7+: 2.8mo

5.6mo

Bian(current study)

1994-2013 Univ of Southern California

392 971 12-22Gy 1: 8.5mo2-4: 7.1mo5+: 4.5mo

7.5mo

Putting Our Study into Context:Selected Melanoma SRS Series

31

Prognostic factors in melanoma SRS

32Radbill AE. Cancer 2004;101(4):825-833.


33Gaudy-Marqueste C. IJROBP 2006; 65(3):809-816.


34Skeie BS. World Neurosurgery 2010;75(5-6):684-691.


35Liew DN. J Neurosurg 2011; 114(3):769-779.

• As one of the largest melanoma SRS series conducted to date, our study suggests prognostic significance for OS for:1) Total lesion number 2) Total tumor volume 3) Age

• Worse survival outcomes were associated with 5+ lesions, lesion volume >20cc, and age >50

Conclusion

36

• Evaluation of more prognostic factors including whole brain radiation, RPA, GPA

• Possible synergistic interactions of novel systemic agents with SRS • Ipilimumab, B-RAF inhibitors, anti-PD-1 agents

Future Directions

37

Mentor• Eric L. Chang

GK and Melanoma Team• Cheng Yu• Gabriel Zada• Michael Apuzzo• Michael K Wong

Acknowledgements

38

Statistics• Lingyun Ji• Susan Groshen

Medical Students• David Routman• Jonathan Liu

Thank you for your attention!

39

40

Documents

THE IMPACT OF LESION NUMBER AND TREATMENT …...IN MELANOMA BRAIN METASTASES TREATED WITH STEREOTACTIC RADIOSURGERY (SRS) Shelly X Bian 1, David Routman 1, Jonathan Liu 1, Lingyun