Therapeutic Ratio

1. Therapeutic Ratios
•Dose Response Relationships and
Therapeutic Ratio
•Normal Tissue Responses
–Alpha/Beta
–Overall Time Factor
–Tissue Organization
•Alternative Fractionation Schemes
–Predicting Responses
•Increasing Therapeutic Ratios

2. Dose-Response Relationships

3. Dose-Response Relationships

4. 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
TISSUE CLASIFICATIONS

5. TISSUE CLASIFICATIONS
TISSUE TYPE
•Highly Differentiated
Tissues
–Little or no mitotic activity
–Closed static population
•Self-renewing tissue
–Mitosis-Mediated Effects
–Rate of renewal (expression
time)
TOXICITY MECHANISM
•Cell Killing Mediated
–Inherent Radiosensitivity
–Response Related to Tissue
Growth Kinetics
–Tissue Organization Important
•Not Obviously Mediated
by Cell Killing
–Nausea/Vomiting
–Fatigue, Somnolence
–Acute Edema
–Erythema

6. Early Effects
•Early or acute effects occur within a few days of
irradiation
•Early or acute effects result from the death of
large numbers of cells
•Response is determined by a hierarchical cell
lineage composed of stem cells and their
differentiated offspring
•Time to onset correlates with the relatively short
lifespan of the mature functional cells
•The target cell is usually obvious
•Examples include skin epidermis, GI epithelium,
and hematopoietic system

7. Late Effects
•Late or chronic effects appear after a delay of
months
•Late effects occur predominately in slowly
proliferating tissues
•Late damage is usually not completely reversible
•Targets for late damage include vascular and
parenchymal cells
•Examples include lung, kidney, heart, liver and
CNS

8. Dose-Response Curves

9. Dose-Response Curves
Withers, 1982

10. Early and Late Effects

11. Four R’s of Radiotherapy
•Reoxygenation
•Reassortment of cells within the cell cycle
•Repair of Sublethal Damage
•Repopulation

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. Population Turnover Time
•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
Treatment protocols are never sufficiently long to include proliferation
of late-responding tissues

14. Accelerated Repopulation
28 Days
Withers: head and
neck cancers
Dashed line:
predicted from a
constant 2 month
clonogen doubling
rate

15. Summary:
Overall Time Effect
•Prolonged radiotherapy schedules:
–Spare acute reactions and tumors but not late
complications
•Shortened radiotherapy schedules:
–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

16. Functional Subunits in Tissues
•Can be structurally defined:
–Survival of unit depends on the survival of one or
more clonogenic cells within unit
–Small units more sensitive to radiation (smaller #s of
clonogens)
–Examples: Kidney nephron, Liver lobule
•Can have no clear anatomic demarcation
–Clonogenic cells can migrate from one unit to another
–Tissue-rescue units
–Examples: Bone marrow, Skin, Mucosa, Spinal cord

17. Volume Effect
•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.
•Serial arrangement
–Steep dose response
–Example: spinal cord
•Loss of one FSU leads to myelopathy
•No serial arrangement
–Less steep dose response
–More usual condition

19. Volume Effect
•Clinical tolerance depends strongly on
volume irradiated in:
–Spinal cord, Kidney, Lung
•Skin
–No well defined FSU but respond similar to
where FSUs are in parallel
•Severity is dose independent
•Larger area – potentially more problems
–Infection, prolonged healing time
–Not based on increased probability of injury

20. Increasing Therapeutic Ratio
•Changing Dose/Fraction
–Often leads to change in overall treatment
time
–With fast-growing tumors, overall time may be
more important than fraction number
–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).

21. Alternative Fractionation Schemes
•Hyperfractionation
•Accelerated Treatment
•Continuous Hyperfractionation with
Accelerated RT
•Accelerated Hyperfractionation RT while
Breathing Carbogen and with the Addition
of Nicotinamide
•Hypofractionation

22. Using Linear-Quadratic Concept
to Calculate Effective Doses
•Emphasizes differences between early and late
effects
•Never possible to match two different
fractionation regimens to be equivalent for both
•Useful guide but not a substitute for clinical
judgment and experience

24. Biologically Equivalent Doses (BED)
•BED is the quantity by which different
fractionation regimens are compared.
–Extrapolated tolerance dose
•Effect (e.g. cell kill) = n(ad + bd²)
•E/a = nd(1+ d/(a/b))
–(1+ d/(a/b)) is the relative effectiveness term
–E/a (biologically equivalent dose) is the dose in Gy
required to produce some given endpoint such as
tissue tolerance or complication rate of 5%

25. Predict the Effect of
Hyperfractionation
•Conventional Treatment: 30 fractions of
2-Gy given one fraction per day, 5 days
per week for an overall treatment time of 6
weeks.
–30F X 2Gy/6 weeks
•E/a = nd(1+ d/(a/b))

26. •Conventional Treatment:
–30F X 2Gy/6 weeks
–E/a = nd(1+ d/(a/b))
•Early effects:
–E/a = 60(1+ 2/(10)) = 72 Gy
10
•Late effects:
–E/a = 60(1+ 2/(3)) = 100 Gy
3

27. Predict the effect of hyperfractionation
•Hyperfractionation:
–70F X 1.15 Gy twice daily/7 weeks
–E/a = nd(1+ d/(a/b))
•Early effects:
–E/a = 80.5(1+ 1.15/(10)) = 89.8 Gy
10
•Late effects:
–E/a = 80.5(1+ 1.15/(3)) = 114 Gy
3

28. ([35F X 1.8 Gy] + [12F X 1.5 Gy])/6 weeks
•Early effects:
–E/a = 54(1+ 1.8/(10)) + 18(1+ 1.5/(10)) =
84.4 Gy
10
•Late effects:
–E/a = 54(1+ 1.8/(3)) + 18(1+ 1.5/(3))
113.4 Gy
10
Concomitant Boost:

29. •N = N
0
e
lt
N = number of clonogens at time t
–N
0
= initial number of clonogens
– l = constant related to Tpot
• l =log
e
²/Tpot = 0.693/Tpot
•E/a = nd(1+ d/(a/b)) – (0.693/a)(t/Tpot)
–(0.693/a)(t/Tpot) = log
e
²/a (# of cell doublings)
Correction for Tumor Proliferation

30. •Assume a = 0.3 ± 0.1/Gy
•Tpot = 2-25 days (5 day median)
•30F X 2Gy/6 weeks (39 days)
•Early Effects:
–(0.693/a)(t/Tpot) = (0.693/0.3)(39/5) = 18 Gy
10
•Late Effects:
Correction for Tumor Proliferation

31. Increasing Therapeutic Ratio
•Dose Distribution
–IMRT
–RIT
•DNA Damage
–Halogenated
Pyrimidines
•Repair
–High LET
–Chemical Inhibitors
•Hypoxia
–Hypoxic Cell
Sensitizers
–Hyperbaric Oxygen
–Transfusion
•Protection
–Aminothiols
–Cytokines

32. Halogenated Pyrimidines
•BrdUrd (bromodeoxyuridine)
•IdUrd (iododeoxyuridine)
–Take advantage of higher cell proliferation in tumors
–Replace normal nucleotide precursor
–Substituted DNA is more easily broken
–Sensitization is seen at low dose rates, therefore it has
been used in conjunction with brachytherapy
•Drugs are rapidly dehalogenated in liver, therefore it
is difficult to maintain high tumor levels for long
times
•Also sensitizes to UV as well, therefore skin
damage may be limiting (BrdUrd more so than IdUrd)

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

34. Hypoxic Cell Sensitzers
•Overall – tumor control increase by 4.6%; survival by
2.8%; complication by 0.6%
•Most trials in head and neck
•Also potentiate cytotoxicity of:
–Melphalan, Bleomycin, Cisplatin
–Cyclophosphamide, Nitrosourea
Hypoxic Cell Radiosensitization
Tolerable doses of sensitizer are well below those
needed for maximum radiosensitization
Fractionation reduces radiosensitization because of
reoxygenation
Not all tumors in any one trial are hypoxic

35. Hypoxic Cell Cytoxins
(Bioreductive Drugs)
•Selectively toxic to hypoxic cells
•Metabolized to toxic products (usually radical ions) in
absence of oxygen
•In the presence of oxygen, the toxic intermediate is
converted back to parent molecule
•Nitroimidazoles
–Misonidazole
–Etanidazole
•Quinones
–Mitomycin C
–Pofiromycin
•Benzotriazine di-N-Oxides
–Tirapazamine

36. Phosphorothioates
•WR compounds
•Metabolized into active thiols by phosphatase
enzymes
•Effects parallel the oxygen effect
–Maximal for low LET
–DRF range from 1-3
•Requires RT immediately following drug
treatment
•Requires increasing overall dose
•Not all tumors may respond similarly
•Toxicity: not well tolerated