ICARO Advances in Radiation Oncology Vienna, April 2009 Biological - - PowerPoint PPT Presentation
International Conference on ICARO Advances in Radiation Oncology Vienna, April 2009 Biological [i.e. non-technical] approach to [understand and] reduce late radiation toxicities Jens Overgaard Department of Experimental Clinical Oncology,
Biological [i.e. non-technical] approach to [understand and] reduce late radiation toxicities
International Conference on Advances in Radiation Oncology Vienna, April 2009 Jens Overgaard
Department of Experimental Clinical Oncology, Aarhus University Hospital, Denmark
jens@oncology.dk – www.oncology.dk
from the early days of high voltage irradiation when a new technology was just introduced – and used with excitement.
Secondary cancer Pancreas 7 Colon 4 Bladder 2 Basal cell 2 Unknown primary 2 Kidney 1 Sarcoma 1
1 9 6 6 1 9 6 6
Radiotherapy of testicular cancer
94 pts. treated 1964-71
neurological symptoms (latency 10-20 years)
cancer in the irradiated fields
Co-60 Ant.-post. fields treated on alternating days.
Knap et al. Acta Oncol 2007
A few ”other problems”
Arteriosclerosis 9 pt. all diagnosed < 60 years Gastrointestinal: 4 necrosis of small intestine (3 dead) 4 gastric ulcer 3 surgery for ileus/stenosis 2 severe malabsorbtion Kidney: 2 nephrectomy due to radiation induced nephritis 1 dead of malignant hypertention
6% 6% 40% 40% 8% 8% 32% 32% 13% 13% 1% 1%
Estimated global cancer burden 2008
12.5 mio new cases – 7.6 mio deaths – 28 mio living with cancer
Estimated Global Cancer Burden
(Numbers of new cases of cancer per annum)
5,000,000 10,000,000 15,000,000 20,000,000 25,000,000 30,000,000 1975 1985 2000 2008 2020 2030
More and older people
What do we have?
What do we have?
More new cancer patients than ever before. More patients treated with radiotherapy – and cured.
More patients at risk for late effects.
we need?
we need?
Identify and measure the extend and nature of the problem. Describe the relationship to
avoidance and/or modification. Investigate into the underlying biology and look for targets for avoidance.
RECORDING OF MORBIDITY
JO-99/7
SOMA - LENT CONSORT STATEMENT
DEVELOPMENT IN RECORDING OF MORBIDITY
Established system Own graded system Sporadic None
0% 20% 40% 60% 80%
1985 1988 1998 2008
Reporting clinical results of radiotherapy
1985-88: Data from IJRO and Radiother. Oncol. (Dische at al.) 1998, 2008: Data from Radiotherapy & Oncology
If morbidity is so important, how come we ignore to record it?
morbidity in clinical trials
we have to explain why things when wrong
arguments for getting new fancy technology
Morbidity and its recording
By far most of the press and public awareness about radiotherapy is related to side effects and treatment related complications
(Nobody cares that it’s because more pts. are long-time survivors)
Our ”Interaction” with the public
The (curative) response to radiotherapy depends on dose
in the critical surrounding normal tissues.
Dose-Response in RADIOTHERAPY
30 40 50 60 70 80 90
DOSE
0% 20% 40% 60% 80% 100%
PROBABILITY risk of complication tumor control
JO-97/1
CANCER TREATMENT
In most situations the amount of side effects is considered a limiting factor (tolerance). However, the magnitude of this tolerance depends
Thus, in smaller tumors with good prognosis less risk is accepted as compared to more advanced cases.
JO-98/9
"TOLERENCE" IS RELATIVE
"Tolerance dose”
Rubin& Casarett 1970
"estimate injurious doses for various
basis of personal experience..“ Rubin& Casarett 1970
The most cited paper in the radiotherapeutic journals:
Emami et al. IJRO 1991
The most cited paper in radiotherapy
Emami et al. IJRO 1991
Emami et al. IJRO 1991
Dose - volume relationship
Lyman, Burman and others
Radiation dose (Gy) P r
a b i l i t y
c
p l i c a t i
( % ) 5 % 100% 33% 67% 5%
(partial volume irradiated)
CAN WE TRUST THE MODELS?
Ellis formula: Total dose = NSD x N 0.22 T 0.11 Ellis formula: Total dose = NSD x N 0.24 T 0.11
Long week-end!
High dose per fraction increase late radiation damage
ERYTHEMA (ACUTE) FIBROSIS (LATE) 0% 20% 40% 60% 80%
COMPLICATIONS (%)
Overgaard et al. 1987
5 Fx 5 Fx 2 Fx 2 Fx
Dose per fraction
vs acute and late
radiation complications
Postmastectomy radiotherapy - 2 vs 5 Fractions/Week
Postmastectomy radiotherapy - 2 vs 5 Fractions/Week (Ellis’ equavalent)
High dose per fraction increase late radiation damage
ERYTHEMA (ACUTE) FIBROSIS (LATE) 0% 20% 40% 60% 80%
COMPLICATIONS (%)
Overgaard et al. 1987
5 Fx 5 Fx 2 Fx 2 Fx
50 Gy / 25 fx 42 Gy / 12 fx
Postmastectomy radiotherapy - 2 vs 5 Fractions/Week (Ellis’ equavalent)
Same expected morbidity
(according to NSD model prediction)
Don’t trust the models
(especially if they are extrapolated)
With such past history, one can be a bit nervous about the late outcome of the current increased use of hypofractionation in curative intended radiotherapy. Do we really know what we are doing – or have we just forgotten the past?
Late effects are like footprint on the beach – they become deeper and more pronounced with time.
Herman D Suit
FACTORS INFLUENCING RADIATION RELATED MORBIDITY
Factors influencing radiotherapy morbidity
Important radiation related morbidity
Marie 2001/09
Breast cancer
Arm edema. Impairment of shoulder movement. Brachial plexus damage. Telangiectasia. Breast appearence. Subcutaneous fibrosis. Rib fractures Pneumonitis and lung fibrosis. Ischemic heart disease. Secondary malignancy
Does the sensitivity for development of e.g. fibrosis correlate with other (late) normal tissue endpoints ? i.e. an assay predictive for one (late responding) tissue/endpoint will be predictive for (all) other (late) endpoints.
Photon field without bolus ”Scar” photon field with bolus Chest wall electron field
DBCG 77 radiotherapy technique
Telangiektasia versus fibrosis No correlation
Sensitive Resisaent Sensitive Resistant
Fibrosis - Field II Telangiektasia
Telangiektasia versus telangiektasia Correlation
Bentzen, Overgaard & Overgaard. Eur J Cancer, 1993
Sensitive Resistant Sensitive Resistant
Telangiektasia - Field II Telangiektasia
Intra- and Inter-patient variation in radiation induced late effects
There is no relationship between early and late radiation reactions - and no relationship between different late radiation reactions. If there is a genetic underlying component, it is not clinically expressed in “normal” persons.
The development of late radiation related side-effects is dependent of:
influence of (external) factors in that period
There is not (necessarily) a correlation between different types of late damage in the same patients.
Factors influencing radiotherapy morbidity
EBCTCG overview, Lancet 2000
Excess death due to ischemic heart disease
Excess heart disease after 15+ years
Late cardiac mortality in breast cancer patients – the European magnitude: 4 mio. ”cured” breast cancer patients alive.
Excess ”vascular death” (according to EBCTCG): 4% Thus, up to 80.000 patients living in Europe may eventually die from radiation induced late morbidity
Hooning et al JNCI 2007
no RT RT RT+CT
Risk
congestive heart failure
Risk of Lung Cancer
Factors influencing radiotherapy morbidity
Factors influencing radiotherapy morbidity
Frequency of arm edema (%) 5 10 15 20 25 30 35 No axillary RT Axillary RT 0 - 3 4 - 9 >10 _
Arm edema vs. Lymph-nodes excised and Radiotherapy
Surgery interacts with radiotherapy
Johansen et al Acta Oncol
RT no RT
Factors influencing radiotherapy morbidity
Chemo-radiation is not good for all
compliance is poor !
Pignon et al. IJRO 2007 Machtay al. JCO 2008
Chemo-radiation enhance late morbidity
Trotti Lancet Oncol 2007 Bentzen and Trotti JCO 2007 Chemo-RT schedules RT alone schedules
I f t h e b u r d e n
( a c u t e ) m
b i d i t y b e c
e t
a r g e i t w i l l e s p e c i a l l y h i t t h e w e a k ( e l d e r l y ) p a t i e n t s w i t h c
b i d i t y
Factors influencing radiotherapy morbidity
CAN WE PREDICT AND PREVENT RADIATION RELATED MORBIDITY
Prediction and Prevention
radiotherapy (within normal range)
More sensitive More resistant Using clinical data and m olecular pathology to identify genetic risk factors ( dose m odification) and targets for intervention
Prediction
Sensitive profile Resistant profile
Metallothioneins SODs ECM rem odeling
Alsner et al (2007) Radiother Oncol 83:261–266
Differentially expressed genes in fibroblasts after in vitro irradiation
Radiation dose (Gy)
(equivalent dose of 2 Gy per fraction)
30 40 50 60 70 80 90
Moderate/severe fibrosis (%)
20 40 60 80 100
Radiation dose (Gy)
(equivalent dose of 2 Gy per fraction)
30 40 50 60 70 80 90
Moderate/severe fibrosis (%)
20 40 60 80 100
Resistant profile Sensitive profile
Prediction
Enhancement ratio
1.25 (1.12-1.40)
Alsner et al (2007) Radiother Oncol 83:261–266
Ingenuity pathway analysis
www.ingenuity.com
TNFα
Molecular pathology
ROS (Reactive Oxygen Species) Cascade of cytokine activity Fibrosis Superoxide dismutases Metallothioneins Ionizing radiation CTGF family e.g. TGFβ1 (SMADs) Others Others Others TGFβ1 Adlican, Lumican, Fibroblast activating protein WISP2 TNFα
Days 25 50 75 100125150175200225 Severe fibrosis (%) 20 40 60 80 100 Control (N=14) +/‐ buffer or siRNA mismatch P=0.00003 siRNA TNFa (N=11)
#6, day 125 Control #21, day 125 Treated
Intervention (siRNA)
Reduced morbidity
Dose (Gy) 35 40 45 50 55 60 65 70 Response (%) 10 20 30 40 50 60 70 80 90 100
siRNA Control TCD50 (95% CI) Enhancement ratio (95% CI) 0.97 (0.88‐1.08) 57.8 56.2Same tumor response We can identify a biological target which can be suppressed and in turn selectively prevent development of Radiation Induced Fibrosis
Current status: Radiation induced morbidity are
complex and involve multiple factors related to:
volume, technique.
therapy).
diabetes).
response and/or the subsequent pathogenesis related to the side-effect in question.
we need to do?
We have now an understanding
late morbidity – and is about to understand the underlaying mechanisms. We need more treatment data (dose and target), biological material and careful long-term clinical recordings. We can only achieve this in a joint collaborative effort (involving patients and professionals)