Badakhshi Cancer with oligometastases 2016

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Personalized adaptive
Radiotherapy
(PART )

The dialectics of cure and palliation

Cancer with oligometastases

Facts
Theory
History

28 % 26 %
Male Female
Lung
9% 15%
Lung
BreastProstate
8% 9%
7% 7%Pancreas Pancreas
5% 5% OvarLiver, gallbladder
Cancer Statistics 2015, Siegel & Jemal CA Cancer
Survival
ColorectalColorectal

H a r u n . B a d a k h s h i + +Cancer Statistics 2015, Siegel & Jemal CA Cancer
Lung cancer
Breast cancer
Colorectal cancer

Lung cancer
Prostate cancer
Colorectal cancer

Cancer
Cancer
Accidents
Heart
40-59
60-79
> 80
Accidents
Mortality

Highest mortality in 40-80 y individuals is caused by cancer
Mortality

UK
RadioTherapy *
*
* * *
Mortality in UK

Access at 29.12.2015
17,74829,713
14,75213,772
12,20012,975
7,936 8,181
5,770 5,646
Mortality in Germany

Mortality

Lung cancer

18% @ 5 y
6 % in 35 y

What kills patients ?

Metastases = Organ failure
Bleeding
Thromboses

Cancer 1973
*

Cancer 1973

Study Infection Lung Liver Brain Bleeding HyperCa n
Hagemeister
1980, MCA 24 % 26 % 14 % 9 % 9 % 3 % 166
Cho
1980, MCA 24 % - - - 9 % - 144
Dvoretsky 1988,
Ovar 17 % 21 % - - - - 100

Volumen of Metastasen = Tumor burden

1-cm
increase risk of progression 4.5%
increase risk of death
5%
n= 124
Tumor burden:
independent prognostic
factor in metas. renal cell
carcinoma
Lacovelli 2012
ResultsStudy

MTV is signiﬁcantly associated
with
OS
HR for 1-unit increase of
ln(MTV(WB)) of 1.40/1.32 (P = .
004/.039)
n=104
Prognostic value of
metabolic tumor burden
from FDG PET in
surgical patients with
NSCLC.
Zhang 2013
ResultsStudy

Median OS: 48.9 m
5-year OS: 45.4%.
Number of pulmonary mets.
was the most important
important factor affecting the
outcome
The role of hepatic metastases
and pulmonary tumor burden
in predicting survival after
complete pulmonary resection
for colorectal cancer.
Scalafani 2013
Study Results

Quantiﬁed pathologic response
is a predictor of RFS in patients
with rectal adenocarcinoma
after
chemoradiotherapy
n=251
Pathol. response in patients
with rectal cancer
Agarwal 2013
Study Results

Cure Palliation ?
Metastases

OligometastasesConcept

Cancer comprises a biologic
spectrum extending from a
disease that remains
localized to one that is
systemic when ﬁrst detectable
but with many
intermediate states.
Oligometastases is
not just a stochastic
oddity, but a
state of limited
metastatic capacity

State of
Oligometastases
Dialectic synthesis
Systemic disease
Contiguous growth
1894
1980
1995

Cure Palliation
Transitional zone
Aggressive treatment
of oligometastases

Mehta N, Mauer AM, Hellman S, et al:
Analysis of further disease progression in metastatic
non-small cell lung cancer: Implications for locoregional
treatment. 2004
Stage IV NSCLC :
74% mets in one to two organs
50% had three metastatic sites lung primary tumor.
Torok J, Kelsey CR, Salama JK:
Patterns of distant metastases in surgically managed early
stage NSCLC. 2013
n=1700
Stage I-II NSCLC with later progression
33% solitary mets
19% limited to two to three mets
Singh D, Yi WS, Brasacchio RA, et al: Is there
a favorable subset of patients with prostate cancer
who develop oligometastases? 2004
Prostate cancer with later Recently reported phase II and III
studies of modern systemic therapies including more than 2,500
Albanien 2008
Bergh 2012
Tawﬁk 2013
Hurvitz 2013 Breast cancer studies
Gianni 2013
Modern systemic therapies n=2,500 pats
43% to 77% had disease limited to two metastases

Colorectal cancer (mCRC)
38% limited to one metastatic site
55% to 85% had disease limited to two sites
Hutwitz 2004 NEJM
Douillard 2010 JCO
Van Cutsem 2011 JCO
Max Mustermann Lancet 2016 ?

Unknown photographer/artist - National Cancer Institute via Stanford University, image number AV-5700-3472
Gordon Isaac
with
Retinoblastoma
1957
Stanford, CA, USA

Technology and Innovationen
High resolution IGRTMultileaf collimator
First Linac
3D CT planning
1960 1970 1980 1990 2000 2010
IMRT
dose-painting
Standard
collimator
Cerrobend
blocks
Shaped
electron fields
Image
Fusion
Robot Stereotactic
Radiotherapy
Particle
Therapy
Courtesy Gillies McKenna
Concept and Innovationen

Aggressive treatment
for oligometastases
„Stage IV“ is not
helpful
Tumor volume
Number of metastases
Palliative treatment for
all metastases
Stage IV is a
„natural law“
Therapeutic nihilism
Just RCT
Cancer is always systemic
?

KonzeptWan 2013, Nature
Fidler 2003, Nature Rev.

Konzept

Local treatments for metastases
Brain
Lung
Liver

CNS < 5 small metastases

Stereotactic radiosurgery Microsurgery

HarunBadakhshi ++ move ideas
single metastatic
lesion
Primary
tumor

A randomized trial of surgery in the treatment
of single metastases to the brain.
N= 48
Local control: 80 % (vs 48%)
OS: median 40 m (vs 15 m)
Practice
Patchel 1990, NEJM
OP+ WBRT
WBRT
vs
1 metastasis in ZNS

Postoperative radiotherapy in
the treatment of single metastases to the brain:
a randomized trial.
N= 95
Med FU= 48 w
Local control: 90% vs 54%
Patchell 1998, JAMA
OP+ WBRT*
vs
OP
1 metastasis in ZNS Practice

Rades 2009
Matched pair analysis.
N= 104
Local control: 82 % vs 66 %
OS: median 56 m vs 47 m
< 5 metastases in CNS
OP+ WBRT
SRS+ WBRT
vs
Practice

SRS
SRS+WBRT
vs
Aoyama 2006, 2015
n=132
Kombination war besser
——————————-
EORTC 22952, Kocher 2011
n=359
Kombination war besser
Practice< 5 metastases in CNS

Lee 2008
Rades 2008*
Rades 2007
Kocher 2004
Wang 2002
LC at 1 y: 66 % (vs 19%) 0.04
OS at 1 y: 40 % (vs 17%) 0.001
WBRT
SRS
vs
Practice

SRS
Unsere Gruppe, Rad Onc 2015
n= 90
med FU= 14 m
ZNS Mets des Lungenkarzinoms
OS: 51 % after 6 months and 29.9 % after 12
months.
Histology (adeno)
Higher Karnofsky
The presence of extracranial metastases
Practice< 5 kleine Metastasen im ZNS

In oligometastatic state (< small lesions)
in brain the prognosis improves by
local treatment

Lung lesions

The International Registry of Lung
Metastases.
_ ab 1991
18 Institutionen
N= 5206
5y OS: 36%
Metastases in the lung
* J Thorac Cardiovasc Surg. 1997 Jan;113(1):37-49.
OP
Practice

Nine studies with 796 patients
VATS: higher odds of 1, 3 and 5 year survival with OR of 1.53, 1.69 and 1.41
respectively.
VATS: higher odds of 1, 3 and 5 year recurrence free survival with OR
of 1.29, 1.54 and 1.54 respectively.
Overall pulmonary recurrence had lower odds in the VATS group with an OR
of 0.55

24 studies with 2925 patients
Multiple mets. were associated with an increased risk of death (HR 2.04, 95 % CI 1.72–2.41).

OS @ 5 y: 36 %
Surgery

Lung

Lung
Stereotactic ablative body radiotherapy
SABR

n= 121
Breast cancer
2 y OS: 74%, 6y: 47%
2 y FFDM: 52%, 6y: 36%
2 y LC: 87 %, 6 y 87%
Milano 2012
SABR
Metastases in the lung Practice

Empirie *
*Milano 2012
SABR

n=110
Med FU= 43 m
2 y LC
SABR: 94%, OP: 90%
3 y OS: SABR: 60%, OP: 62%
5 y OS: SABR: 49%, OP: 41 %
Widder 2013
SABR
oder
OP
Metastases in the lung Practice

n=76
Med FU= 20 m
Local control
1 y 95%,
2 y 95%,
3 y 89%
OS
1 y 84.1%
2 y 84.1%
3 y 73 %
Navarria, 2014
SABR
< 5 metastases in the lung Practice

2010
n= 334 with SABR
2-year local control: 77.9%.
2-year overall survival: 53.7%

move ideas
OS @ 5 y: 48 %
SABR for the lung

in the lung prognosis improves by
local treatment

Liver lesions

move ideas
Primary
tumor
single metastatic lesion

Association Francaise de
Chirurgie _ ab 1987
85 Institutionen
N= 1568 / 1955
1350:1-3 lesions (86%)
183: 4 lesions
2 y OS: 64%
5 y OS: 28 %
Metastases in the liver
*Nordlinger 1996
OP
Practice

North Hampshire Hospital
ab 1987
N= 1005
1-3 lesions (66%)
5 y OS: 36%
Sloan-Kettering NYC
ab 1985
N=1001
5 y OS for 1 lesion (n=517): 44 %
5 y OS for 2-3 lesion (n=330): 32 %
*Rees 2008, Fong 1999
OP
Metastases in the liver Practice

26 % @ 3 J.,Leporrier 2006
Systematic Review
Spelt 2012,
16 Analysen
Prospektive Analysen
Konopke 2009 (n=201)
Rees 2008 (N=1005)
Mingawa 2007 (n=369)
Malik 2007 (N=687)
Volume
Number
Metastases in the liver Practice

Retrospektive Analysen
Nordlinger 1996 (n=1568)
Fong 1999 (n=1001)
Zakaria 2007 (n=662)
Yamagushi 2008 (n=380)
Iwatsuki 1999 (n=305)
Practice
Volume
Number
Metastases in the liver

OS @ 5 y: 45 %
LiverSurgery

in the liver prognosis improves by
local treatment

Cure Palliation
Metastases

What to do?

Cure ? Palliation
Oligometastasized
1-5 lesions
< 3 cm, each
Poly-metastasized
> 5 lesions

1-4 lesions
< 3 cm, each
Karnofsky Index > 60 %
Inclusion criteria
Synchronous:
Treatable primary tumor +
Metastases in less that three sites
Metachronous:
Stable primary tumor
(local control: no tumor
or no progress)

Lung < 4 lesions
< 3 cm (each)
VATS-surgery
Radiosurgery 3 x 20 Gy
4 x 12 Gy
8 x 7,5 Gy
Bone < 4 leasions
Surgery
Kyphoplasty
Leber < 4 Läsionen
Surgery
4 x 12 Gy
8 x 7,5 Gy
Brain < 4 lesions
< 3 cm (each)

5 x 7 Gy
+/- WBRT
Surgery
Biologicals
Targeted
Immunotherapy
Chemotherapy
Time?

Theory

Practice
Empiric actions *
Abstraction
Action **
Concept
*Neccessary ** Study u. standards

Practice
Empiric action
Abstraction
Action
Concept
Episteme*
Data**
Obstructions***
*Foucault ** Kuhn *** Bachelard

Concept

Wan 2013, Nature
Concept

Konzept
Wan 2013, Nature
Concept

History

Medizin 500VC bis 1700 NC

Practice
local treatment
breast tumor
Concept
Ibn Sina (Avicenna)
980-1037
1030 ad

Practice
omnis cellula e cellula
Concept
Rudolph Virchow (1902)
Klassiﬁkation
Diagnostik

PracticeConcept
New York Times_1902

Stephen Paget (1921)
Seed and Soil
Concept Practice

Seed and Soil

Cancer spread is orderly,
extending in a contiguous
fashion from the primary
tumor through the lymphatics
to the lymph nodes and then
to distant sites.
William
Halsted
(1921)
Concept Practice

1882 ﬁrst surgery
1894-1914 consolidation
1992 NIH-declaration *
Radical mastectomy
*NIH Development Conference on the treatment
of early-stage breast cancer, Bethesda, MD, June
18-21, 1990. J Natl Cancer Inst Monogr . 1992;11:1-187.
Contiguous growth
100 years of …
Cancer’s
„local“ hypothesis

Kontinuitätstheorie
Small tumors:
Early cancer manifestation
From 1920
Lumpectomy + radiation
Geoffrey Keynes (1982)
PracticeContiguous growth

Cancer’s
„systemic“ hypothesis
Cancer is a systemic disease . . .
and that variations in effective
local regional treatment are
unlikely to affect survival
substantially
Bernard Fisher
Concept

Samuel Helmann

Cancer comprises a biologic
spectrum extending from a
disease that remains
localized to one that is
systemic when ﬁrst detectable
but with many
intermediate states.
Oligometastases is
not just a stochastic
oddity, but a
state of limited
metastatic capacity
Concept Cancer’s
„spectrum“ hypothesis

The clinical implication of this
hypothesis is that
localized forms of cancer
treatment may be effective
Concept Cancer’s
„spectrum“ hypothesis

Present

Take home
Selection (Tumor’s variables, patient’s variables)
Predictors (genetic, epigenetic, serologic)

Take home
Local therapy can be curative in
metastasized cancer

Personalisierte adaptive
Radiotherapie
(PART )

Badakhshi Cancer with oligometastases 2016

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