Therapeutic Ratio


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  • Therapeutic Ratio

    1. 1. Therapeutic Ratios <ul><li>Dose Response Relationships and Therapeutic Ratio </li></ul><ul><li>Normal Tissue Responses </li></ul><ul><ul><li>Alpha/Beta </li></ul></ul><ul><ul><li>Overall Time Factor </li></ul></ul><ul><ul><li>Tissue Organization </li></ul></ul><ul><li>Alternative Fractionation Schemes </li></ul><ul><ul><li>Predicting Responses </li></ul></ul><ul><li>Increasing Therapeutic Ratios </li></ul>
    2. 2. Dose-Response Relationships
    3. 3. Dose-Response Relationships
    4. 4. TISSUE CLASIFICATIONS Low Intermediate High Very High Mature red cells, muscle cells, mature connective tissues, mature bone and cartilage, ganglion cells Endothelium, growing bone and cartilage, fibroblasts, glial cells, glandular epithelium of breast, pulmonary epithelium, renal epithelium, hepatic epithelium, pancreatic epithelium, thyroid epithelium, adrenal epithelium Urinary bladder epithelium, esophageal epithelium, gastric mucosa, mucous membranes, epidermal epithelium, epithelium of optic lens Lymphocytes, immature hematopoietic cells, intestinal epithelium, spermatogonia, ovarian follicular cells
    5. 5. TISSUE CLASIFICATIONS <ul><li>TISSUE TYPE </li></ul><ul><li>Highly Differentiated Tissues </li></ul><ul><ul><li>Little or no mitotic activity </li></ul></ul><ul><ul><li>Closed static population </li></ul></ul><ul><li>Self-renewing tissue </li></ul><ul><ul><li>Mitosis-Mediated Effects </li></ul></ul><ul><ul><li>Rate of renewal (expression time) </li></ul></ul><ul><li>TOXICITY MECHANISM </li></ul><ul><li>Cell Killing Mediated </li></ul><ul><ul><li>Inherent Radiosensitivity </li></ul></ul><ul><ul><li>Response Related to Tissue Growth Kinetics </li></ul></ul><ul><ul><li>Tissue Organization Important </li></ul></ul><ul><li>Not Obviously Mediated by Cell Killing </li></ul><ul><ul><li>Nausea/Vomiting </li></ul></ul><ul><ul><li>Fatigue, Somnolence </li></ul></ul><ul><ul><li>Acute Edema </li></ul></ul><ul><ul><li>Erythema </li></ul></ul>
    6. 6. Early Effects <ul><li>Early or acute effects occur within a few days of irradiation </li></ul><ul><li>Early or acute effects result from the death of large numbers of cells </li></ul><ul><li>Response is determined by a hierarchical cell lineage composed of stem cells and their differentiated offspring </li></ul><ul><li>Time to onset correlates with the relatively short lifespan of the mature functional cells </li></ul><ul><li>The target cell is usually obvious </li></ul><ul><li>Examples include skin epidermis, GI epithelium, and hematopoietic system </li></ul>
    7. 7. Late Effects <ul><li>Late or chronic effects appear after a delay of months </li></ul><ul><li>Late effects occur predominately in slowly proliferating tissues </li></ul><ul><li>Late damage is usually not completely reversible </li></ul><ul><li>Targets for late damage include vascular and parenchymal cells </li></ul><ul><li>Examples include lung, kidney, heart, liver and CNS </li></ul>
    8. 8. Dose-Response Curves
    9. 9. Dose-Response Curves Withers, 1982
    10. 10. Early and Late Effects
    11. 11. Four R’s of Radiotherapy <ul><li>Reoxygenation </li></ul><ul><li>Reassortment of cells within the cell cycle </li></ul><ul><li>Repair of Sublethal Damage </li></ul><ul><li>Repopulation </li></ul>
    12. 12. Overall Time Factor Extra dose required to counteract proliferation does not become significant until ~2 weeks after the start of daily fractionation Delay – population turnover time Delay reflect mitotic death? Steep Rise, not T 0.11 Denekamp, 1973 (Gray Lab)
    13. 13. Population Turnover Time <ul><li>Therefore, effect of time in allowing sparing by cell proliferation is large during RT for early responding tissues but absent or small for the late-responding organs </li></ul>Treatment protocols are never sufficiently long to include proliferation of late-responding tissues
    14. 14. Accelerated Repopulation 28 Days Withers: head and neck cancers Dashed line: predicted from a constant 2 month clonogen doubling rate
    15. 15. Summary : Overall Time Effect <ul><li>Prolonged radiotherapy schedules: </li></ul><ul><ul><li>Spare acute reactions and tumors but not late complications </li></ul></ul><ul><li>Shortened radiotherapy schedules: </li></ul><ul><ul><li>Will give more tumor cell kill, but the acute reactions will also be more severe so that total dose must be reduced to some extent. Late reactions should not be worse </li></ul></ul>
    16. 16. Functional Subunits in Tissues <ul><li>Can be structurally defined: </li></ul><ul><ul><li>Survival of unit depends on the survival of one or more clonogenic cells within unit </li></ul></ul><ul><ul><li>Small units more sensitive to radiation (smaller #s of clonogens) </li></ul></ul><ul><ul><li>Examples: Kidney nephron, Liver lobule </li></ul></ul><ul><li>Can have no clear anatomic demarcation </li></ul><ul><ul><li>Clonogenic cells can migrate from one unit to another </li></ul></ul><ul><ul><li>Tissue-rescue units </li></ul></ul><ul><ul><li>Examples: Bone marrow, Skin, Mucosa, Spinal cord </li></ul></ul>
    17. 17. Volume Effect <ul><li>The larger the irradiated volume of an organ that is divided in FSUs, the greater the likelihood of knocking out enough subunits to effect the overall functioning of the tissue, and consequently, the lower the tolerance dose. </li></ul><ul><li>Serial arrangement </li></ul><ul><ul><li>Steep dose response </li></ul></ul><ul><ul><li>Example: spinal cord </li></ul></ul><ul><ul><ul><li>Loss of one FSU leads to myelopathy </li></ul></ul></ul><ul><li>No serial arrangement </li></ul><ul><ul><li>Less steep dose response </li></ul></ul><ul><ul><li>More usual condition </li></ul></ul>
    18. 19. Volume Effect <ul><li>Clinical tolerance depends strongly on volume irradiated in: </li></ul><ul><ul><li>Spinal cord, Kidney, Lung </li></ul></ul><ul><li>Skin </li></ul><ul><ul><li>No well defined FSU but respond similar to where FSUs are in parallel </li></ul></ul><ul><ul><ul><li>Severity is dose independent </li></ul></ul></ul><ul><ul><ul><li>Larger area – potentially more problems </li></ul></ul></ul><ul><ul><ul><ul><li>Infection, prolonged healing time </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Not based on increased probability of injury </li></ul></ul></ul></ul>
    19. 20. Increasing Therapeutic Ratio <ul><li>Changing Dose/Fraction </li></ul><ul><ul><li>Often leads to change in overall treatment time </li></ul></ul><ul><ul><li>With fast-growing tumors, overall time may be more important than fraction number </li></ul></ul><ul><ul><li>Between 5 and 7 weeks after the start of a fractionated regimen, the dose equivalent of regeneration with protraction of treatment is ~0.5 Gy/day (3 Gy/week). </li></ul></ul>
    20. 21. Alternative Fractionation Schemes <ul><li>Hyperfractionation </li></ul><ul><li>Accelerated Treatment </li></ul><ul><li>Continuous Hyperfractionation with Accelerated RT </li></ul><ul><li>Accelerated Hyperfractionation RT while Breathing Carbogen and with the Addition of Nicotinamide </li></ul><ul><li>Hypofractionation </li></ul>
    21. 22. Using Linear-Quadratic Concept to Calculate Effective Doses <ul><li>Emphasizes differences between early and late effects </li></ul><ul><li>Never possible to match two different fractionation regimens to be equivalent for both </li></ul><ul><li>Useful guide but not a substitute for clinical judgment and experience </li></ul>
    22. 24. Biologically Equivalent Doses (BED) <ul><li>BED is the quantity by which different fractionation regimens are compared. </li></ul><ul><ul><li>Extrapolated tolerance dose </li></ul></ul><ul><li>Effect (e.g. cell kill) = n(  d +  d ²) </li></ul><ul><li>E/  = nd(1+ d/(  )) </li></ul><ul><ul><li>(1+ d/(  )) is the relative effectiveness term </li></ul></ul><ul><ul><li>E/  (biologically equivalent dose)  is the dose in Gy required to produce some given endpoint such as tissue tolerance or complication rate of 5% </li></ul></ul>
    23. 25. Predict the Effect of Hyperfractionation <ul><li>Conventional Treatment : 30 fractions of 2-Gy given one fraction per day, 5 days per week for an overall treatment time of 6 weeks. </li></ul><ul><ul><li>30F X 2Gy/6 weeks </li></ul></ul><ul><li>E/  = nd(1+ d/(  )) </li></ul>
    24. 26. <ul><li>Conventional Treatment : </li></ul><ul><ul><li>30F X 2Gy/6 weeks </li></ul></ul><ul><ul><li>E/  = nd(1+ d/(  )) </li></ul></ul><ul><li>Early effects: </li></ul><ul><ul><li>E/  = 60(1+ 2/(10)) = 72 Gy 10 </li></ul></ul><ul><li>Late effects: </li></ul><ul><ul><li>E/  = 60(1+ 2/(3)) = 100 Gy 3 </li></ul></ul>
    25. 27. Predict the effect of hyperfractionation <ul><li>Hyperfractionation : </li></ul><ul><ul><li>70F X 1.15 Gy twice daily/7 weeks </li></ul></ul><ul><ul><li>E/  = nd(1+ d/(  )) </li></ul></ul><ul><li>Early effects: </li></ul><ul><ul><li>E/  = 80.5(1+ 1.15/(10)) = 89.8 Gy 10 </li></ul></ul><ul><li>Late effects: </li></ul><ul><ul><li>E/  = 80.5(1+ 1.15/(3)) = 114 Gy 3 </li></ul></ul>
    26. 28. ([35F X 1.8 Gy] + [12F X 1.5 Gy])/6 weeks <ul><li>Early effects: </li></ul><ul><ul><li>E/  = 54(1+ 1.8/(10)) + 18(1+ 1.5/(10)) = </li></ul></ul><ul><ul><li>84.4 Gy 10 </li></ul></ul><ul><li>Late effects: </li></ul><ul><ul><li>E/  = 54(1+ 1.8/(3)) + 18(1+ 1.5/(3)) </li></ul></ul><ul><ul><li>113.4 Gy 10 </li></ul></ul>Concomitant Boost:
    27. 29. <ul><li>N = N 0 e  t </li></ul><ul><ul><li>N = number of clonogens at time t </li></ul></ul><ul><ul><li>N 0 = initial number of clonogens </li></ul></ul><ul><ul><li> = constant related to Tpot </li></ul></ul><ul><ul><ul><li> =log e ²/Tpot = 0.693/Tpot </li></ul></ul></ul><ul><li>E/  = nd(1+ d/(  )) – (0.693/  )(t/Tpot) </li></ul><ul><ul><li>(0.693/  )(t/Tpot) = log e ²/  (# of cell doublings) </li></ul></ul>Correction for Tumor Proliferation
    28. 30. <ul><li>Assume  = 0.3 ± 0.1/Gy </li></ul><ul><li>Tpot = 2-25 days (5 day median) </li></ul><ul><li>30F X 2Gy/6 weeks (39 days) </li></ul><ul><li>Early Effects: </li></ul><ul><ul><li>(0.693/  )(t/Tpot) = (0.693/0.3)(39/5) = 18 Gy 10 </li></ul></ul><ul><li>Late Effects: </li></ul>Correction for Tumor Proliferation
    29. 31. Increasing Therapeutic Ratio <ul><li>Dose Distribution </li></ul><ul><ul><li>IMRT </li></ul></ul><ul><ul><li>RIT </li></ul></ul><ul><li>DNA Damage </li></ul><ul><ul><li>Halogenated Pyrimidines </li></ul></ul><ul><li>Repair </li></ul><ul><ul><li>High LET </li></ul></ul><ul><ul><li>Chemical Inhibitors </li></ul></ul><ul><li>Hypoxia </li></ul><ul><ul><li>Hypoxic Cell Sensitizers </li></ul></ul><ul><ul><li>Hyperbaric Oxygen </li></ul></ul><ul><ul><li>Transfusion </li></ul></ul><ul><li>Protection </li></ul><ul><ul><li>Aminothiols </li></ul></ul><ul><ul><li>Cytokines </li></ul></ul>
    30. 32. Halogenated Pyrimidines <ul><li>BrdUrd (bromodeoxyuridine) </li></ul><ul><li>IdUrd (iododeoxyuridine) </li></ul><ul><ul><li>Take advantage of higher cell proliferation in tumors </li></ul></ul><ul><ul><li>Replace normal nucleotide precursor </li></ul></ul><ul><ul><li>Substituted DNA is more easily broken </li></ul></ul><ul><ul><li>Sensitization is seen at low dose rates, therefore it has been used in conjunction with brachytherapy </li></ul></ul><ul><ul><ul><li>Drugs are rapidly dehalogenated in liver, therefore it is difficult to maintain high tumor levels for long times </li></ul></ul></ul><ul><ul><ul><li>Also sensitizes to UV as well, therefore skin damage may be limiting (BrdUrd more so than IdUrd) </li></ul></ul></ul>
    31. 33. Nitroimadazoles Short T½, less toxic Doesn’t cross blood-brain barrier (less neurotoxic). Not effective in RT trials Less effective than others, but much less toxic Promising results from H&N cancer RT trials Etanidazole Nimorazole Good SER (At 10 mM, eliminates effect of hypoxia on radiation sensitivity) Preferential cytotoxicity to hypoxic cells that is increased with hyperthermia Dose-limiting toxicity (peripheral neuropathy) Poor results with fractionation Misonidazole First compound studied Minimal effects (at 10 mM, SER is 1.6) Metronidazole
    32. 34. Hypoxic Cell Sensitzers <ul><li>Overall – tumor control increase by 4.6%; survival by 2.8%; complication by 0.6% </li></ul><ul><li>Most trials in head and neck </li></ul><ul><li>Also potentiate cytotoxicity of: </li></ul><ul><ul><ul><ul><li>Melphalan, Bleomycin, Cisplatin </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Cyclophosphamide, Nitrosourea </li></ul></ul></ul></ul><ul><li>Hypoxic Cell Radiosensitization </li></ul><ul><li>Tolerable doses of sensitizer are well below those needed for maximum radiosensitization </li></ul><ul><li>Fractionation reduces radiosensitization because of reoxygenation </li></ul><ul><li>Not all tumors in any one trial are hypoxic </li></ul>
    33. 35. Hypoxic Cell Cytoxins (Bioreductive Drugs) <ul><li>Selectively toxic to hypoxic cells </li></ul><ul><li>Metabolized to toxic products (usually radical ions) in absence of oxygen </li></ul><ul><li>In the presence of oxygen, the toxic intermediate is converted back to parent molecule </li></ul><ul><li>Nitroimidazoles </li></ul><ul><ul><li>Misonidazole </li></ul></ul><ul><ul><li>Etanidazole </li></ul></ul><ul><li>Quinones </li></ul><ul><ul><li>Mitomycin C </li></ul></ul><ul><ul><li>Pofiromycin </li></ul></ul><ul><li>Benzotriazine di-N-Oxides </li></ul><ul><ul><li>Tirapazamine </li></ul></ul>
    34. 36. Phosphorothioates <ul><li>WR compounds </li></ul><ul><li>Metabolized into active thiols by phosphatase enzymes </li></ul><ul><li>Effects parallel the oxygen effect </li></ul><ul><ul><li>Maximal for low LET </li></ul></ul><ul><ul><li>DRF range from 1-3 </li></ul></ul><ul><li>Requires RT immediately following drug treatment </li></ul><ul><li>Requires increasing overall dose </li></ul><ul><li>Not all tumors may respond similarly </li></ul><ul><li>Toxicity: not well tolerated </li></ul>