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, Aarhus University Hospital, Denmark jens@oncology.dk – www.oncology.dk
A story from the early days of high voltage irradiation when a new technology was just introduced – and used with excitement.
Radiotherapy of testicular cancer e h t f o % 0 Co-60 Ant.-post. fields treated on alternating days. 6 d n u o r A A few ”other problems” d e p Arteriosclerosis o l e v 1 9 6 6 1 9 6 6 e d 94 pts. treated 1964-71 s t n e i t a 9 pt. all diagnosed < 60 years p • 7 patients with late Gastrointestinal: s t c e f f e e t a l ocurring severe s 4 necrosis of small intestine (3 dead) u o i r e t e l e d 4 gastric ulcer neurological symptoms e n o n 3 surgery for ileus/stenosis d n (latency 10-20 years) a – ) l a t a f % 2 severe malabsorbtion 9 1 ( • 19 pts. with secondary Kidney: y b d e cancer in the irradiated t c e t 2 nephrectomy due to radiation induced e d e r e w fields nephritis Secondary cancer p u 1 dead of malignant hypertention Pancreas 7 w o l l o f e Colon 4 n i t u o r Bladder 2 Basal cell 2 Unknown primary 2 Kidney 1 Knap et al. Acta Oncol 2007 Sarcoma 1
Estimated global cancer burden 2008 13% 13% 32% 32% 40% 40% 6% 6% 8% 8% 1% 1% 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) 30,000,000 More and older people 25,000,000 20,000,000 15,000,000 10,000,000 5,000,000 0 1975 1985 2000 2008 2020 2030
What do we have?
More new cancer patients What do we than ever before. have? More patients treated with radiotherapy – and cured. More patients at risk for late effects.
-and what do we need?
Identify and measure the extend and nature of the problem. Describe the relationship to our practice and means of avoidance and/or modification. -and what do Investigate into the underlying biology and look for targets for we need? avoidance.
RECORDING OF MORBIDITY
CONSORT STATEMENT SOMA - LENT JO-99/7
DEVELOPMENT IN RECORDING OF MORBIDITY Reporting clinical results of radiotherapy 1985-88: Data from IJRO and Radiother. Oncol. (Dische at al.) 1998, 2008: Data from Radiotherapy & Oncology 1985 80% 1988 1998 60% 2008 40% 20% 0% Established system Own graded system Sporadic None
Morbidity and its If morbidity is so important, how come we ignore to recording record it? - but we do not record it - we only care about morbidity in clinical trials routinely - or when it’s too late, and we have to explain why things when wrong -and/or when we need arguments for getting new fancy technology
Our ”Interaction” with the public 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)
Dose-Response in RADIOTHERAPY The (curative) response 100% to radiotherapy 80% depends on dose PROBABILITY tumor control 60% risk of complication - so does the morbidity 40% in the critical 20% surrounding normal 0% 30 40 50 60 70 80 90 DOSE tissues.
CANCER TREATMENT The limiting factor in cancer treatment is the "tolerance" of the normal tissue. JO-97/1
"TOLERENCE" IS RELATIVE In most situations the amount of side effects is considered a limiting factor (tolerance). However, the magnitude of this tolerance depends on the risk and consequences of treatment failure. Thus, in smaller tumors with good prognosis less risk is accepted as compared to more advanced cases. JO-98/9
"Tolerance Rubin& Casarett 1970 dose”
"Tolerance dose" "estimate injurious doses for various organs on the basis of personal experience..“ Rubin& Casarett 1970
The most cited paper in the radiotherapeutic journals:
The most cited paper in radiotherapy Emami et al. IJRO 1991
Emami et al. IJRO 1991
Emami et al. IJRO 1991
Dose - volume relationship ) % ( n o CAN WE TRUST THE MODELS? i t a c i l p m o c f o y 100% t 67% i 33% % l i b 5% 0 a 5 b o (partial volume irradiated) r P Radiation dose (Gy) Lyman, Burman and others
Something about MODELS and the impact on clinical practice (in the past).
NSD CRE TDF ret
Ellis formula: Ellis formula: Total dose = NSD x N 0.22 T 0.11 Total dose = NSD x N 0.24 T 0.11 Long week-end! F. Ellis: Clin. Radiol. 1969
High dose per fraction increase late radiation damage Postmastectomy radiotherapy - 2 vs 5 Fractions/Week (Ellis’ equavalent) 80% Overgaard et al. 1987 2 Fx Dose per fraction 60% vs acute and late COMPLICATIONS ( %) radiation 40% complications 2 Fx 5 Fx 20% Postmastectomy radiotherapy - 2 vs 5 5 Fx Fractions/Week 0% ERYTHEMA (ACUTE) FIBROSIS (LATE)
High dose per fraction increase late radiation damage Postmastectomy radiotherapy - 2 vs 5 Fractions/Week (Ellis’ equavalent) 80% Same expected morbidity Overgaard et al. 1987 Don’t trust the models 2 Fx (according to NSD model prediction) (especially if they are extrapolated) 60% COMPLICATIONS ( %) 42 Gy / 12 fx 40% 2 Fx 5 Fx 50 Gy / 25 fx 20% 5 Fx 0% ERYTHEMA (ACUTE) FIBROSIS (LATE)
With such past history, one can be a bit Most late morbidity is due to nervous about the late outcome of the current large dose per fraction (often increased use of hypofractionation in curative due to uncritical application of intended radiotherapy. Do we really know what we are doing models) – or have we just forgotten the past? - and/or the use of poor radio- therapy technique.
The road of hypo- fraction
FOLLOW-UP TIME Late effects are like footprint on the beach – they become deeper and more pronounced with time. Herman D Suit
Children get late, late problems - because the live longer
FACTORS INFLUENCING RADIATION RELATED MORBIDITY
Factors influencing radiotherapy morbidity • Volume and target • Interaction with systemic therapy • Interaction with surgery • Dose and fractionation • Treatment technique •Others (e.g. comorbidity) • Individual radiosensitivity
Breast cancer Important radiation related morbidity 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 � Marie 2001/09
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.
DBCG 77 radiotherapy technique Photon field without bolus ”Scar” photon field with bolus Chest wall electron field
Intra- and Inter-patient variation in radiation induced late effects There is no relationship between early and late radiation reactions - and no relationship between Telangiektasia - Field II Resisaent Fibrosis - Field II Resistant If there is a genetic underlying component, it is different late radiation reactions. not clinically expressed in “normal” persons. Sensitive Sensitive Sensitive Resistant Sensitive Resistant Telangiektasia - Field I Telangiektasia - Field I Telangiektasia Telangiektasia versus versus telangiektasia fibrosis Correlation No correlation Bentzen, Overgaard & Overgaard. Eur J Cancer, 1993
There is not (necessarily) a correlation between different types of late damage in the same patients. The development of late radiation related side-effects is dependent of: 1. Tissue, organ, endpoint 2. Time to develop damage (latency) and influence of (external) factors in that period 3. Co-morbidity (tissue dependent)
Factors influencing radiotherapy morbidity • Volume and target • Interaction with systemic therapy • Interaction with surgery • Dose and fractionation • Treatment technique •Others (e.g. comorbidity) • Individual radiosensitivity
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. 2. mio. (at least) has been irradiated. Excess ”vascular death” (according to EBCTCG): 4% Thus, up to 80.000 patients living in Europe may eventually die from radiation induced late morbidity
RT+CT Risk of congestive heart failure RT no RT Hooning et al JNCI 2007
Risk of Lung Cancer
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