1. UAB Measuring Normal Tissue Effects of Radionuclide Therapy Ruby Meredith, M.D., Ph.D. Department of Radiation Oncology University of Alabama at Birmingham

2. UAB What is the Tolerance of Normal Organs to Radiation ? Usually more tolerance for radionuclides than external beam - but not well studied

3. UAB Organ Tolerance Data Comparison External Beam Radionuclide TD5/5, TD 50/5any toxicity Severe Late complications acute + late # patients reportedusually < 50 +/- surgeryfailed multiple therapies

4. UAB Organ Tolerance Data Comparison External BeamRadionulcide 2Gy/d x 5/weeksingle dose >1 MeVlower energy High dose ratelow dose rate Whole/partial organmostly whole

5. UAB Normal Organ Tolerance to Radiation (cGy)

6. UAB Normal Organ Tolerance to Radiation (cGy)

7. UAB Normal Organ Tolerance to Radiation (cGy)

8. UAB How Accurate are Radionuclide Dose Estimates and Comparison Between Studies? 1.Radionuclide dosimetry is less accurate than external beam. 2.How accurate are tracer studies? 3.Calculated dose is  biologic dose. 4.How accurate are comparisons of radionuclide dose estimates?

9. UAB Radionuclide Dosimetry Is Less Accurate Than External Beam Radionuclide = less precise. e.g. parenchymal lung tumor difference in attenuation between lung vs. more dense tissue, *immediate full dose

10. UAB How Accurate Are Tracer Studies? Comparison of tracer-predicted vs. therapeutic radiation doses measured

11. UAB Calculated Dose Is  Biologic Dose Physical/biologic interaction factors heterogeneous distribution dose rate effects effective range of radiation RBE, other characteristics

12. UAB Biologic Factors Affecting Tolerance age, prior therapies, time since prior Rx, disease status-e.g. anemia, marrow replacement; genetic factors and/or physiologic conditions - hypoxia that affect radio-sensitivity & repair

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14. Biologic Effectiveness of Radionuclide Therapy Agents/factors not contributing to radiation dose estimates. Chemotherapy, other biologic response modifiers  Radiosensitizers, Cytokines Growth Factor Inhibitors BuDR IL-1, IL-2anti-EGFr

15. UAB 90 Y-ChL6 Therapy of Breast Cancer Xenografts DeNardo et al., PNAS 1997

16. UAB How Accurate are Comparisons of Radionuclide Dose Estimates? Variance in Dosimetry Methods Include: a)Measured organ volume as used in myeloablative studies (U. Washington) vs Phantom MIRD model b) Do calculations use computer programs- MIRDOSE 2 or MIRDOSE 3

17. UAB How Accurate are Comparisons of Radionuclide Dose Estimates? Variance in Dosimetry Methods: c)Was attenuation correction applied for imaged ROI or a transmission scan technique used d)Was background subtraction correction performed e)What was the frequency & appropriateness of data collection, if peak concentration missed  lower dose estimate

18. UAB How Accurate are Doses Reported - Wessels: marrow +/-700% in 1980’s, 200% in 1990’s, now ~30% reports of 7 institutions vs. his recalculationof their data  -35% - +6% AAPM-Sgouros method, 0.19 blood in marrow  ~ 200 cGy vs. report whole blood had marrow dose ~600 cGy

19. UAB When Does Imaging/Dosimetry Potential Have Great Impact ?  Good correlation of data with organ toxicity and/or anti-tumor effects.  When normal organ that can be “accurately” assessed is dose limiting. e.g.– myeloablative, lung, liver

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22. When Does Imaging/Dosimetry Potential Have Great Impact ?  Tumor adjacent critical organ  Distribution – highly variable - 131 I-anti-CEA  >2x faster T1/2 colorectal  Unknown distribution

23. UAB Loculation, Then Resolved

24. UAB Catheter Eroded into Bowel

25. UAB RIT + External Beam RT  Hepatoma: 2100cGy + concurrent  Adr/alternating 5-Fu + Flagyl,  2 months  dose chemo.  93-157mCi 131 I-anti-ferritin  400-1000cGy to nl liver (Order)

26. UAB Myeloablative RIT + XRT  Leukemia: ( U. Washington) 76-612 mCi 131 I-anti-CD45 CY + 1200cGy TBI, MTD liver 1050cGy  Breast, Prostate Ca 131 I-anti-TAG-72 CY + 1320cGy TBI +/- Thiotepa, 131 I- Ab  142-990cGy to liver,  LFT also chemo only regimens (UAB)

27. UAB Tissue Tolerance to Re-Irradiation Acutely Responding Tolerate Full 2 nd Course (Months) Late Responding Vary- No Recovery: Heart, Bladder, Kidney. Partial Recovery: Skin, Mucous, Lung, Spinal Cord Sem Rad Onc 10(3): 200-209; 2000

28. UAB Tolerance for 2nd Radiation Course - May be Close to that of Initial for Some Tissues

29. UAB Radionuclide Re-treatment  89 Sr > 5x, > 6 wk  90 Y2B8 40mCi(3 pt.) unfavorable factors  131 I-LYM-1, 177 Lu-CC49, 131 I-CC49  Trend = longer recovery, mildly increased toxicity with re-treatment at short interval

30. UAB Summary & Conclusions  More radionuclide data needed to improve dose/toxicity relationships.  improved data collection/processing methods will increase accuracy of dose estimates.

31. UAB Summary & Conclusions  Modifiers  chemotherapy- other radiosensitizing agents  prior Rx, disease status affect toxicity & tumor response without changing dose estimates