STUDIES OF LOW-DOSE RADIATION AND CANCER. E. Lubin

Transcription

1 STUDIES OF LOW-DOSE RADIATION AND CANCER E. Lubin 1

2 RELEVANT DATA BEIR VII 2006 UNSCEAR 2000 ICRP PIERCE D. PRESTON DL Japanese survivors. CARDIS E. IARC occupational exposure. BRENNER D. CT exposure and calculated risk. 2

3 In a lifetime, approximately 42 (solid circles) of 100 people will be diagnosed with cancer from causes unrelated to radiation. The calculations in this report suggest approximately one cancer (star) in 100 people could result from a single exposure 100 msv of low- LET radiation. 3

4 Beir VII Population = 100 (all ages) Exposure = 0.10 Sv=10 cgy Cancer incidence = 43 Cancer expected = 42 Relative Risk: RR-10R 43/42 = Excessive Relative Risk: ERR-10R 1/42 =

5 ICRP TO BEIR VII RECOMMENDS THAT FOR EXPOSURES BELLOW 20 cgy OR BELLOW 10 R/H, THE LINEAR RISK ESTIMATES OBTAINED FROM HIGH DOSES BE REDUCED BY A DDREF OF 2. 5

6 ICRP 6

7 Risk Estimates for Cancer Incidence from Studies of Radiation Exposure: Colon Cancer Study Mean dose (Sv) EXTERNAL LOW-LET LET EXPOSURES Average excess relative risk at 1 Sv Incidence Life Span Study Age at exposure <20 yrs >20 yrs All ( ) 7

8 Risk Estimates for Cancer Incidence from Studies of Radiation Exposure: Thyroid Cancer Study Life Span Study Age at exposure 0-9 yrs Life Span Study Israeli Tinea Capitis New York Tinea Capitis yrs yrs >30 yrs Age at exposure 0-19 yrs Gothenburg Skin Haemangioma Mean dose Sv EXTERNAL LOW-LET LET EXPOSURES Incidences Cohort studies of children Average excess relative risk at 1 Sv ( ) 34 (23-47) 7.7 (<0-60) (95% CI: )

9 Fatal Cancer Risk as Function of Age for 100 cgy Exposure Age Life-time probability of fatal cancer %/100 cgy (Dendy P.) 9

10 Pierce D Radiation-related Cancer Risk at Low Doses Among Atomic Bomb Survivors Within 3000 mt of Hypocenter Results provide useful risk estimates for doses Sv There is a significant risk in the range of Sv, and an upper confidence limit on any possible threshold computed as 0.06 Sv Rad. Res 154 (2000) 10

11 Cardis 2007 Our results are consistent with Beir VII. This study however, cannot address effects at very low doses of the order of tens of msv (10m Sv = 1 RAD) 11

12 Cardis 2007 Significant association found between Radiation Dose and mortality Increase in All Cancer Mortality (ERR/Sv 0.97) Due to Increase in Lung Cancer Mortality (ERR/Sv 1.86) 12

13 Cardis 2007 If Lung Cancer would be removed because of lack of smoking data Then Mortality for All Cancer would be ERR/Sv 0.59 not significant 13

14 Brenner D Cancer risk attributable to low doses of Ionizing Radiation assessing what we really know What is the lowest dose of X-ray or of Gamma Radiation for which good evidence exists of increased cancer risk in humans? msv (1-5 R) for acute exposure (Atomic bomb survivors) msv (5-10 R) for protracted exposure (Radiation workers) Proc. Natl. Acad. Sci (Nov) (2003) 14

15 Not statistically significant Statistically significant [p<0.05] Estimated excess relative risk of mortality ( ) 1997) from solid cancers among groups of survivors in the LSS cohort of atomic bomb survivors 15

16 Estimated Dependence of Lifetime Radiation-Induced Risk of Cancer on Age at Exposure for Two of the Most Common Radiogenic Cancers 16

17 Radiation Induced Cancer Calculated (Virtual) Cases After Exposure to 10 msv 1 RAD INCIDENCE MORTALITY All Ages 1/ /1000 Children 2/1000 1/1000 Cancer Cases Unrelated To Radiation All Ages 420/ /1000 (1/ cgy) (5/ cgy) 17

18 RADIATION DOSIMETRY ADULTS Organ Target Dose cgy Effective Dose REM Bone 99m Tc MDP 6.9 bone 0.90 Kidney 99m Tc DTPA 3.3 bladder m Tc MAG3 5.1 bladder 0.44 Thyroid 99m Tc 2.3 thyroid Iodine 39.0 thyroid 1.20 Cardiology 99m Tc MIBI 4.2 gallbladder Tl 5.1 kidneys

19 RADIATION DOSIMETRY CHILDREN 5 yrs./20 kg Bone 99m Tc MDP Kidney 99m Tc DTPA 99m Tc MAG3 Thyroid 99m Tc 131 Iodine Organ Target Dose cgy 4.8 bone 0.60 bladder 1.9 bladder 0.47 thyroid 32 thyroid Effective Dose REM

20 Reduced Radiation Dose Limits Risk of Pediatric CT Radiologists must understand strategies for minimizing exposure in children. D.P. Frush,, MD, Division Chief of Pediatric Radiology at Duke University Hospital, Durham. NC L.F. Donnelly, MD, Associate Director of Radiology at Children s s Hospital Medical Center, Cincinnati, OH 20

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22 Mammography Screening For Breast Cancer 1000 Women From Age 50 On Radiation Exposure To Breast 2mSv x 10 Studies 20mSv 22

23 Benefit Reduction In Breast Cancer Deaths Mortality Year % The reduction in mortality due to early diagnosis and improved treatment 23

24 Risk 1000 Women From Exposure To 20mSv ERR/20mSv = 0.02 Incidence of breast cancer None exposed 100 Exposed to 20mSv

25 Conclusion In 1000 women screened annually for 10y Benefit Death reduction 20 cases Risk Estimate - Due to radiation 2 cases (estimate from ERR/Gy = 1) 25

26 Mammography In High Risk For Breast Cancer Women Age 30y or younger 31y-34y 34y Risk > Benefit Risk = Benefit Risk < Benefit? 35y and older Risk < Benefit? MRI recommended for young high risk women. (BRCA is a radiation repair gene that when inactivated could increase radiation sensitivity) 26

27 PET/CT Radiation Exposure Effective Dose For Adults msv 18-FDG CT High Res. Low Res C-Choline Choline In the oncology patients benefit far outweighs risks. 27

28 THYROID CANCER TREATMENT 131I CONSIDERATIONS

29 ASSESSMENT OF METASTASIS IN THYROID CANCER Thyroglobulin (TG) Suppressed 131 I WBS 5mCi 55% Positive Positive 33% Positive Negative 12% Negative Negative Lubin E,

30 THERAPY 131 I INDIVIDUALIZED Ablation 30,000 cgy to remnant Metastasis Cancericidal >8500 cgy at more than 60 cgy/hour Palliative >2000 cgy Bone marrow dose <200 cgy 30

31 TREATMENT CASE - METASTASIS For a dose of 150 mc 131 I - Biol. T½T - 3 days - Uptake should be >0.3%/gr. metast. - To deliver >8500 cgy (124 I is now being considered as a positron emitter to better calculate uptake) 31

32 RADIATION DOSE TO BONE MARROW FOLLOWING TREATMENT cgy/100 mci 131 I Thyroid Children Adults No uptake or less than 5% % uptake % uptake (EANM Guidelines, ICRP)

33 FATAL CANCER RISK AS FUNCTION OF AGE FOR 100 cgy EXPOSURE Age Life-time probability of fatal cancer %/100 cgy (Dendy P.) 33

34 SECOND PRIMARY MALIGNANCIES AFTER THYROID CANCER NIH (Ronckers C.M. 2005) EUROPE (Rubino C. 2003) No patients Mean follow-up years

35 SECOND PRIMARY MALIGNANCIES AFTER THYROID CANCER NIH EUROPE 131 I Treated All Sites Leukemia SIR (301)* (12) I Treated/Non 131 I Treated All Sites Leukemia * Statistically significant RR * * 35

36 NEJM Nov 18, 1971 Judah Folkman, M.D. 36

37 NEJM Nov 18,

38 De Vita 38

39 De Vita 39

40 De Vita 40

41 De Vita 41

42 TYROSINE KINASE RECEPTORS INHIBITION TKR PHOSPHORYLATION IS INHIBITED BY SMALL MOLECULES SIMILAR TO ATP THAT ATTACH TO TKR AND PREVENT PHOSPHORYLATION AND THUS GROWTH FACTOR SIGNALING 42

43 TYROSINE KINASE RECEPTOR INHIBITORS IN THYROID CANCER METASTASIS WITH NO RADIOIODINE CONCENTRATION SUNITINIB 50mg/day 4 weeks yes 2 weeks no ASCO 2008 Ezra Cohen Chicago Response % Partial Response 13 Stable Disease 68 Progressive Disease 10 43

44 HYPERTHYROIDISM I131 TREATMENT Case: 15 years old 150gr thyroid weight 50% uptake 50 mci Effective Dose 50 cgy Risk estimate of fatal cancer death: 6% above non-exposed (21%) Difficult decision in young patients with very large goiter. 44

45 BEIR VII CONCLUSIONS The current evidence is consistent with the hypothesis that there is a linear no threshold dose-response relationship between exposure to Ionizing Radiation and the development of cancer in humans. 45

46 BEIR VII UNCERTAINTIES ESTIMATING RISK AT LOW DOSES AND DOSE RATES ARE LARGE AND FOR SITE-SPECIFIC SPECIFIC CANCERS ARE SPECIALLY LARGE. 46

47 Is Linearity Between Cancer Induced by More than 10 cgy and Cancer Induced by 1 cgy Justified? From radiation protection and human diagnostic exposure YES (Alara( Alara) From epidemiological studies and radiobiological data MANY QUESTIONS STILL OPEN 47

48 Justification Optimization 48

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53 INITIAL DOSE RATES, CUMULATIVE DOSES AND EFFECTIVE DOSES FOR PRACTICAL CLINICAL CONDITIONS FOLLOWING ADMINISTRATION OF 5.5 GBq 131 I Biological half-life life (days) Long Effective half-life life (days) Uptake %/g MBq/g Initial dose rate (Gy/h) Cummulative dose and (effective dose) in Gy (2) 152 (3) (34) 92 (47) 130 (66) 190 (96) 304 (154) (68) 138 (93) 195 (131) 285 (192) 456 (306) (134) 230 (184) 324 (218) 470 (315) 760 (510) (301) 460 (414) 648 (583) 941 (847) (1370) 53 (Schlesinger T., 1989)

54 NEOPLASTIC ANGIOGENESIS The Vascular Endothelial Growth Factor (VEGF) leads to: Endothelial Cell proliferation Migration Invasion Capillary tube formation Unregulated VEGF signaling leads to tumor angiogenesis and tumor growth. 54