1. The Radiobiology Behind Dose Fractionation Bill McBride Dept
The Radiobiology Behind Dose Fractionation Bill McBride Dept. Radiation Oncology David Geffen School Medicine UCLA, Los Angeles, Ca.
Radiation Biology is study of the effects of radiation on living things. For the most part, this course deals with the effects of radiation doses of the magnitude of those used in radiation therapy.

2. Objectives To understand the mathematical bases behind survival curves
Know the linear quadratic model formulation
Understand how the isoeffect curves for fractionated radiation vary with tissue and how to use the LQ model to change dose with dose per fraction
Understand the 4Rs of radiobiology as they relate to clinical fractionated regimens and the sources of heterogeneity that impact the concept of equal effect per fraction
Know the major clinical trials on altered fractionation and their outcome
Recognize the importance of dose heterogeneity in modern treatment planning

3. Relevance of Radiobiology to Clinical Fractionation Protocols
Conventional treatment:
Tumors are generally irradiated with 2Gy dose per fraction delivered daily to a more or less homogeneous field over a 6 week time period to a specified total dose
The purpose of convenntional dose fractionation is to increase dose to the tumor while PRESERVING NORMAL TISSUE FUNCTION
Deviating from conventional fractionation protocol impacts outcome
How do you know what dose to give; for example if you want to change dose per fraction or time? Radiobiological modeling provide the guidelines. It uses
Radiobiological principles derived from preclinical data
Radiobiological parameters derived from clinical altered fractionation protocols
hyperfractionation, accelerated fractionation, some hypofractionation schedules
The number of non-homogeneous treatment plans (IMRT) and extreme hypofractionated treatments are increasing. Do existing models cope?

4. In theory, knowing relevant radiobiological parameters one day may predict the response for
Dose given in a single or a small number of fractions
SBRT, SRS, SRT, HDR or LDR brachytherapy, protons, cyberknife, gammaknife
Non-uniform dose distributions optimized by IMRT
e.g. dose “painting” of radioresistant tumor subvolumes
Combination therapies with chemo- or biological agents
Different RT options when tailored by molecular and imaging theragnostics
If you know the molecular profile and tumor phenotype, can you predict the best delivery method?
Biologically optimized treatment planning

5. The First Radiation Dosimeter
prompted the use of dose fractionation

6. Modeling Radiation Responses
Assumes that ionizing ‘hits’ are random events in space
Which are fitted by a Poisson Distribution
P of x = e-m.mx/x!
where m = mean # hits, x is a hit
P survival
(when x = 0)
100 targets 100 hits m=1 e-1=0.368
100 targets 200 hits m=2 e-2=0.137
100 targets 300 hits m=3 e-3=0.05
N.B. Lethal hits in DNA are not really randomly distributed, e.g. condensed chromatin is more sensitive, but it is a reasonable approximation

7. How many logs of cells would be killed by 23 Gy if D0 = 1 Gy?
This Gives a Survival Curve Based on a Model where one hit will eliminate a single target
When there is single lethal hit per target S.F.= e-1 = 0.37
This is the mean lethal dose D0
D10 = 2.3 xD0
In general, S.F. = e-D/D0
or LnS.F. = -D/D0
or S.F. = e-aD , i.e. D0 = 1/a
Where a is the slope of the curve and D0 the reciprocal of the slope
1.0
0.1
0.01
0.001
0.37
S.F.
The mathematical bent of early radiobiologists led them to describe survival curves by the mean lethal dose (D37 or D0), which is the dose required to cause on average one lethal hit per cell and result in 37% survival. In practice D10, the dose that would reduce survival to by one log10, which is 2.3x D0 is easier to use. The slope of the curve is given by , where D0 is 1/. Bacterial killing and protein inactivation follow this log-linear curve, although the D0 values are high compared with mammalian cells. D0
How many logs of cells would be killed by 23 Gy if D0 = 1 Gy?
D10
DOSE Gy

8. Eukaryotic Survival Curves are Exponential, but have a ‘Shoulder’
Puck and Marcus, J.E.M.103, 563, 1956 First in vitro mammalian survival curve
Eukaryotic Survival Curves are Exponential, but have a ‘Shoulder’
1.0
0.1
0.01
0.001
Accumulation of
sub-lethal
damage
single
lethal
hits n
dose
Two component model
In 1956 Puck and Marcus published the first survival curve for mammalian cells and noted that the D0 was cGy. Furthermore, it had a shoulder region before the logarithmic decline. It is easiest to think of this as single-hit and multi-hit killing (another assumption!). At low doses, the rate of deposition of energy by a charged particle is inversely proportional to its energy, and as it loses energy through collisions and scattering the distribution of ionizing events become more dense and the probability of a lethal lesion being formed by a single track increases. At higher doses, accumulation of injury from other tracks (intertrack) becomes a more likely cause of a lethal lesion. Note that the nature of the chromosomal lesions will go from being predominantly deletions to more exchange-type (two-hit) lesions. Note that with doses of around 2Gy, the former will dominate.

9. Accumulation of sublethal
Two Component Model
Two Component Model
(or single target, single hit + multi-target (n), single hit)
S.F.=e-D/1D0[1-(1-e-D/nD0)n]
single
lethal
hits n
1.0
0.1
0.01
0.001
1D0 =
reciprocal
initial slope
nD0 =
final slope
S.F.
Extrapolation
Number
Single hit
Accumulated
damage
Accumulation of sublethal
damage
DOSE Gy

10. Mean Inactivation Dose (Do)
Virus D0 approx. = 1500 Gy
E. Coli D0 approx. = 100 Gy
Mammalian bone marrow cells D0 = 1 Gy
Generally, for mammalian cells D0 = Gy
Why the differences?

11. FOOD TYPE DOSE (Gy) EFFECT
Meat, Poultry, Fish,
Shellfish, some vegetables
20, ,000
Spices, etc.
8, ,000
Meat, Poultry, Fish
1, ,000
Delays spoilage.
Kills salmonella.
Strawberries and
some other fruits
1, ,000
Delays mold growth
Grain, Fruit, Vegetables
,000
Kills some insects
Bananas and other
non-citrus fruits
Delays ripening
Pork
Inactivates trichinae
Sterilization. Storage
at room temperature
Reduces micro-organisms
and insects
Potatoes, Onions, etc.,.
Inhibits sprouting

12. SBRT/SRS often aims at TISSUE ABLATION
In general, history has shown repeatedly that single high doses of radiation do not allow a therapeutic differential between tumor and critical normal tissues. Dose fractionation does.
SBRT/SRS often aims at TISSUE ABLATION

13. “Double Trouble” Does this Matter? Prescribed Dose:
25 fractions of 2Gy = 50Gy
Hot spot: 110%
Physical dose: 55Gy
Biological dose: 60.5Gy
“Double Trouble”

14. EARLY MODELS OF THE EFFECT OF FRACTIONATION
Strandquist plot
effect depended only on dose and time
D = const x T 1-p
Linear on log/log plot
1-p = slope = 0.22 from skin erythema
Fowler 1963 in pig skin - Number of Fx important
Ellis formula - nominal standard dose (NSD)
Number of fx important based on pig skin expts.
Dose = (NSD)T0.11.N0.24

15. Failed to account for differences between tissues.

16. Linear Quadratic Formula Biological effect is based on a linear term and a quadratic term
Lea and Catchside 1942
Radiation-induced chromosome aberrations in Tradescantia microspores
Kellerer and Rossi, 1972
Theory of dual radiation action based on microdosimetry

17. Linear Quadratic Model
Cell kill is the result of single lethal hits plus accumulated damage from 2 independent sublethal events
The generalized formula is E = aD + bD2
For a fractionated regimen E= nd(a + bd) = D (a + bd) Where d = dose per fraction and D = total dose
a/b is dose at which death due to single lethal lesions = death due to accumulation of sublethal lesions i.e.aD = bD2 and D = a/b in Gy
1.0
0.1
0.01
0.001 aD
S.F. = e-aD
Single lethal hits
bD2
S.F.
S.F. = e-(aD+bD2)
Single lethal hits plus accumulated damage
a/ in Gy
DOSE Gy

18. Over 90% of radiation oncologists use the LQ model:
it is simple and has a microdosimetric underpinning
a/b is large (> 6 Gy) when survival curve is almost exponential and small (1-4 Gy) when shoulder is wide
the a/b value quantifies the sensitivity of a tissue/tumor to fractionated radiation.
But:
Both a and b vary with the cell cycle. At high doses, S phase and hypoxic cells become more important.
The a/b ratio varies depending upon whether a cell is quiescent or proliferative
The LQ model best describes data in the range of 1 - 6Gy and should not be used outside this range

19. The Linear Quadratic Formulation
Does not work well at high dose/fx
Assumes equal effect per fraction

20. N.B. Survival curves may deviate from L.Q. at low and high dose!!!!
Certain cell lines, and tissues, are hypersensitive at low doses of Gy.
The survival curve then plateaus over Gy
Not seen for all cell lines or tissues, but has been reported in skin, kidney and lung
At high dose, the model probably does not fit data well because D2 dominates the equation
HT29 cells
An additional complication has been reported by Joiner et al, who have shown that certain cell lines show a hypersensitivity zone at Gy that flattens out over Gy, before showing the normal shape of survival curve. The basis for this is not well established but hypersensitivity is thought to be associated with increased apoptosis and lack of G2 arrest.
Lambin et al. Int J Radiat Biol 63:

21. The resultant slope is the effective D0 S.F. = e-D/eD024 20 16 12 8 4
.01 .1 1
Dose (Gy)
S.F.
Single dose
limiting slope/
low dose rate
3 fractions
5 fractions
Multi-fraction survival curves can be considered linear if sublethal damage is repaired between fractions
they have an extrapolation number (n) = 1.0
The resultant slope is the effective D0
eD0 is often Gy and eD Gy
S.F. = e-D/eD0
If S.F. after 2Gy = 0.5, eD0 = 2.9Gy; eD10 = 6.7Gy and 30 fractions of 2 Gy (60Gy) would reduce survival by (0.5)30 = almost 9 logs (or 60/6.7)
If a 1cm tumor had 109 clonogenic cells, there would be an average of 1 clonogen per tumor and cure rate would be about 37%

22. Thames et al Int J Radiat Oncol Biol Phys 8: 219, 1982.
The slope of an isoeffect curve changes with size of dose per fraction depending on tissue type
Acute responding tissues have flatter curves than do late responding tissues
 measures the sensitivity of tumor or tissue to fractionation i.e. it predicts how total dose for a given effect will change when you change the size of dose fraction
Reciprocal
total dose
for an isoeffect
Slope = 
Douglas and Fowler Rad Res 66:401, 1976
Showed and easy way to arrive at an  ratio
Intercept = 
Dose per fraction

23. Response to Fractionation Varies With Tissue
.01 .1 1 1
Acute Responding
Tissues a/b = 10Gy
Fractionated
Late Effects
S.F.
S.F. .1
Fractionated
Acute Effects
Late Responding
Tissues - a/b = 2Gy
Single Dose
Late Effects
a/b = 2Gy
Single Dose
Acute Effects
a/b = 10Gy
a/b is high (>6Gy) when survival curve is almost exponential and low (1-4Gy) when shoulder is wide
.01 4 8 12 16 4 8 12 16 20
Dose (Gy)
Dose (Gy)
Fractionation spares late responding tissues

24. 20 30 40 50 60 70 80
=3Gy; 1.5Gy/fx
=30Gy; 1.5Gy/fx
2.0Gy/fx
=30Gy; 4Gy/fx
D new
=3Gy; 4Gy/fx 80 70 60 50 40 30 20
D old
Note how badly late responding tissues respond to increased dose/fraction

25. Sensitivity of Tissue to Dose Fractionation can be estimated by the ratio

26. What are a/ ratios for human cancers?
In fact, for some tumors e.g. prostate, breast, melanoma, soft tissue sarcoma, and liposarcoma a/ ratios may be moderately low
Prostate
Brenner and Hall IJROBP 43:1095, 1999
comparing implants with EBRT
a/ ratio is 1.5 Gy [0.8, 2.2]
Lukka JCO 23: 6132, 2005
Phase III NCIC 66Gy 33F in 45days vs 52.5Gy 20F in 28 days
Compatible with a/ ratio of 1.12Gy ( )
Breast
Owen, J.R., et al. Lancet Oncol, 7: , 2006 and Dewar et al JCO, ASCO Proceedings Part I. Vol 25, No. 18S: LBA518, 2007.
UK START Trial
50Gy in 25Fx c.w. 39Gy in 13Fx; or 41.6Gy in 13Fx [or 40Gy in 15Fx (3 wks)]
Breast Cancer a/ = 4.0Gy ( )
Breast appearance a/ = 3.6Gy; induration a/ = 3.1Gy
Adenocarcinoma may be fractionation sensitive, like LRT
If fractionation sensitivity of a cancer is similar to dose-limiting healthy tissues, it may be possible to give fewer, larger fractions without compromising effectiveness or safety

27. What total dose (D) to give if the dose/fx (d) is changed
New Old
Dnew (dnew + ) = Dold (dold +)
So, for late responding tissue, what total dose in 1.5Gy
fractions is equivalent to 66Gy in 2Gy fractions?
Dnew (1.5+2) = 66 (2 + 2)
Dnew = 75.4Gy
NB: Small differences in  for late responding tissues can make a big difference in estimated D!

28. Biologically Effective Dose (BED)
S.F. = e-E = e-(aD+bD2)
E = nd(a + bd)
E/a = nd(1+d/a/b)
Biologically Effective Dose
Relative
Effectiveness
Total dose
Fractionation alpha nd beta
35 x 2Gy = B.E.D.of 84Gy10 and 117Gy3
NOTE: 3 x 15Gy = B.E.D.of 113Gy10 and 270Gy3
Normalized total dose2Gy
= BED/RE
= BED/1.2 for  of 10Gy
= BED/1.67 for of 3Gy
Equivalent to 162 Gy in 2Gy Fx -unrealistic!
(Fowler et al IJROBP 60: 1241, 2004)

29. Isoeffect Curves
D= NSD x N0.24
Withers et al Radiat Res 119:395, 1989

30. 4Rs OF DOSE FRACTIONATION
Redistribution
Repair
Repopulation
700R
1500R
Assessed by varying the time between 2 or more doses of radiation

31. 4Rs OF DOSE FRACTIONATION
These are radiobiological mechanisms that impact the response to a fractionated course of radiation therapy
Repair of sublethal damage
spares late responding normal tissue preferentially
Redistribution of cells in the cell cycle
increases acute and tumor damage, no effect on late responding normal tissue
Repopulation
spares acute responding normal tissue, no effect on late effects,
danger of tumor repopulation
Reoxygenation
increases tumor damage, no effect in normal tissues
Fractionation benefits

32. Repair
“Repair” between fractions should be complete - N.B. we are dealing with tissue recovery rather than DNA repair
Correction for incomplete repair is possible (Thames)
In general, time between fractions for most tissues should be >6 hours
Some tissues, such as CNS, recover slowly making b.i.d. treatment inadvisable
Bentzen - Radiother Oncol 53, 219, 1999
CHART analysis HNC showed that late morbidity was less than would be expected assuming complete recovery between fractions
Is the T1/2 for recovery for late responding normal tissues hrs?
Fractionation spare late tissues

33. Regeneration in Normal Tissues
The lag time to regeneration varies with the tissue
In acute responding tissues,
Regeneration has a considerable sparing effect
In human mucosa, regeneration starts days into a 2Gy Fx protocol and increases tissue tolerance by at least 1Gy/dy
Prolonging treatment time has a sparing effect
As treatment time is reduced, acute responding tissues become dose-limiting
In late responding tissues,
Prolonging overall treatment time beyond 6wks has little effect, but
prolonging time to retreatment may increase tissue tolerance

34. Repopulation in Tumor Tissue
Rat rhabdosarcoma
Human SCC head and neck
T2 T3 70 55 40
local control
Total
Dose
(2 Gy equiv.)
no local control
Fractionation and time prolongation
Treatment Duration
Hermens and Barendsen, EJC 5:173, 1969
4 weeks to start of accelerated repopulation.
Thereafter T1/2 of 4 days = loss of 0.6Gy per day
Withers, H.R., Taylor, J.M.G., and Maciejewski, B.
Acta Oncologica 27:131, 1988
Treatment breaks are often “bad”

35. Regeneration assumed to be exponential
S.F.regeneration = eT = e (ln2/Tp)T
Where T = overall treatment time; Tp = effective doubling time
i.e. S.F. = e-(D+D2)+ln2/Tp(T-Tk)
Where Tk is time of start of regeneration

36. Altered Fractionation or How to optimally distribute dose over time

37. Players Total dose (D) Dose per fraction (d)
Interval between fractions (t)
Overall treatment time (T)
Tumor type
Acute reacting normal tissues
Late reacting normal tissues

38. TCP or NTC TCP or NTC Dose Tumor control Late responding tissue
complications
Complication-free cure
TCP
or NTC
Hyperfractionation
Accelerated
Fractionation
TCP
or NTC
Dose

39. Other Sources of Heterogeneity
Biological Dose
Cell cycle
Hypoxia/reoxygenation
Clonogenic “stem cells” (G.F.)
Number
Intrinsic radiosensitivity
Proliferative potential
Differentiation status
Physical Dose
Need to know more about the importance of dose-volume constraints
Dose
oxic
hypoxic
S.F
Phillips, J Natl Cancer Inst 98:1777, 2006

40. TCP/NTCP and Heterogeneity
100
100 80 80
SF2
= 0.5
N=109
TCP (%)
N=109
TCP (%) 60
SF2=0.7 60
N=1010
SF2=0.6 40
SF2=0.5 40
N=1011
SF2=0.4
Average 20
SF2=0.3 20 10 20 30 40 50 60 70 80 90
100
110
120
130
140 10 20 30 40 50 60 70 80 90
DOSE (Gy)
DOSE (Gy)
Rafi Suwinski
In order to cure a tumor, the last surviving clonogen must be killed, which is a probability function of dose.
TCP = e-(m. SF) or e-m.e-(ad+bD2)
Where m is the initial number of clonogenic cells
TCP=37% when, on average, 1 cell survives
Slope of curve represents radiobiological heterogeneity
Alternative or supplemental indicator of treatment outcome

41. Heterogeneity within and between between tumors in dose-response characteristics, often resulting in large error bars for  values
In spite of this, the outcome of clinical studies of altered fractionation generally fit the models, within the constraints of the clinical doses used

42. Definitions Conventional fractionation Hyperfractionation
Daily doses (d) of 1.8 to 2 Gy
Dose per week of 9 to 10 Gy
Total dose (D) of 40 to 70 Gy
Hyperfractionation
The number of fractions (N) is increased
T is kept the same
Dose per fraction (d) less than 1.8 Gy
Two fractions per day (t)
Rationale: Spares late responding tissues
Conventional empirically developed Fletcher
Radiosensitive tumors can be controlled with low doses (seminoma and lymphoma), low incidence of normal tissue damage
GBM very radioresistant
Most tumors intermediate sensitivity SCC, adenoca
Tumor size also plays a role
Conformal radiotherapy: dose escalation with sparing of normal tissues but when done in a conventional way, lengthening OTT
Hyperfractionation: escalate dose, improve tumor control without increasing risk of late complications.

43. Definitions Accelerated fractionation Hypofractionation
Shorter overall treatment time
Dose per fraction of 1.8 to 2 Gy
More than 10 Gy per week
Rationale: Overcome accelerated tumor repopulation
Hypofractionation
Dose per fraction (d) higher than 2.2 Gy
Reduced total number of fractions (N)
Rationale: Tumor has low a/b ratio and there is no therapeutic advantage to be gained with respect to late complications
Exceptions of tumors with low a/b: melanoma, prostate, liposarcoma
Applied in the palliative setting, limited life expectancy, late side effects not an issue
Moderate hypofractionation used in some countries, total dose usually lower but OTT also shorter which may compensate for the expected reduction in local tumor control
A way to escalate dose in trials of CRT? SIB
Accelerated fractionation:early normal tissue reactions are expected to increase. If interval between fractions is long enough late normal tissue side effects should be the same or less if fractionsize is lower than 1.8 or 2 Gy and/or total dose is decreased

44. Very accelerated with reduction of dose
Conventional
70 Gy - 35 fx - 7 wks
Hyperfractionated
81.6 Gy - 68 fx - 7 wks
Very accelerated with reduction of dose
54 Gy - 36 fx - 12 days
Moderately accelerated
72 Gy - 42 fx - 6 wks

45. Hyperfractionated Barcelona (586), Brazil (112), RTOG 90-03 (1113), EORTC 22791 (356), Toronto (331)
Very accelerated CHART (918), Vancouver (82), TROG (350),GORTEC (268)
Moderately accelerated RTOG (1113), DAHANCA (1485), EORTC (512) CAIR (100), Warsaw (395)
Other EORTC (348), RTOG (210)
7623 patients in 18 randomized phase III trials !!
HNSCC only will be discussed

46. Scatter plot of selected altered fractionation schedules tested in randomised controlled trials according to the dose per fraction employed and the rate of dose accumulation. The Manchester schedule is included for comparison. The trial codes and the corresponding literature references are: 22791: European Organization for Research and Treatment of Cancer (EORTC) trial, 22851: EORTC trial, CHART, DAHANCA, Gliwice I and II : CAIR with 2.0 and 1.8 Gy/F, respectively, GORTEC 9402, Pinto: Radiation Therapy Oncology Group (RTOG) RTOG (HF: hyperfractionation, CB: concomitant boost, SC: accelerated split-course.
Bernier and Bentzen EJC 39:560, 2003

47. EORTC hyperfractionation trial in oropharynx cancer (N = 356)
Oropharyngeal Ca T2-3, N0-1
Horiot 1992
80.5 Gy - 70 fx - 7 wks control: 70 Gy fx wks
SURVIVAL
p = 0.08
LOCAL CONTROL
p = 0.02
Pooled grade 2 and 3 side effects
Increase of about 19 %in long term local tumor control
Interfraction interval 4 to 6 hours
Years
Years

48. Very Accelerated: CHART (N = 918)
Dische 1997
54 Gy - 36 fx - 12 days control: 66 Gy - 33 fx wks
Loco-regional control
Survival
12 consecutive days, 3 fractions per day, interval 6 hours, 1.5 Gy, total dose 54 Gy, total dose is lower to remain within tolerance of acutely responding tissues
918 patients
OTT reduced by 33 days, total dose is 12 Gy less but LC is the same.
conventional CHART
conventional CHART
Favourable outcome with CHART: well differentiated tumors larynx carcinomas

49. CHART: Morbidity
Dische 1997
54 Gy - 36 fx - 12 days control: 66 Gy - 33 fx wks
Moderate/severe subcutaneous fibrosis and oedema
P = 0.04
Mucosal ulceration and deep necrosis
P = 0.003
Moderate/severe dysphagia
P = 0.04
Laryngeal oedema
P = 0.009
Mucositis occured earlier but settled sooner as well, skin reactions were less severe.

50. Moderately Accelerated
Overgaard 2000
DAHANCA 6: only glottic, (N = 694) DAHANCA 7: all other sites, + nimorazole (N = 791)
66-68 Gy fx - 6 wks control: Gy fx - 7 wks
Actuarial 5-year rates
Local control DAHANCA 6 DAHANCA 7
Nodal control DAHANCA
Disease-specific survival DAHANCA 6 + 7
Overall survival
Late effects (edema, fibrosis)
5 fx/wk 6 fx/wk
73% 81% p=0.04
56% 68% p=0.009
87% 89% n.s.
65% 72% p=0.04
n.s.

51. Moderately Accelerated
CAIR: 7-day-continuous accelerated irradiation (N = 100)
Skladowski 2000
66-72 Gy fx - 5 wks control: Gy fx - 7 wks Gy fx wks control: Gy fx wks
OVERALL SURVIVAL
CONTROL
CAIR
log-rank p=
Follow-up (months)
Probability

52. Total dose (Gy) Treatment time (days)
CAIR: two schedules of continuous 7 days / week
with different dose per fraction
Total dose (Gy)
Maciejewski 1996, Skladowski 2000 80
excessive mucosal toxicity (2.0 Gy/day) 70
acceptable mucosal toxicity (1.8 Gy/day) 60 50 40
conventional 30 20 10 7 14 21 28 35 42 49
Treatment time (days)
Wygoda, A. IJROBP 2008

53. RTOG 90-03, Phase III comparison of fractionation schedules in Stage III and IV SCC of oral cavity, oropharynx, larynx, hypopharynx (N = 1113)
Fu 2000
Conventional
70 Gy - 35 fx - 7 wks
Hyperfractionated
81.6 Gy - 68 fx - 7 wks
Accelerated with split
67.2 Gy - 42 fx - 6 weeks (including 2-week split)
Accelerated with
Concomitant boost
72 Gy - 42 fx - 6 wks

54. RTOG 90-03, loco-regional control
Fu 2000

55. RTOG 90-03, survival
Fu 2000

56. RTOG 90-03, adverse effects Acute Late
Fu 2000
Acute
Maximum toxicity Conventional Hyperfract Concom Acc + per patient boost split
Grade % 4% 4% 7% Grade % 39% 36% 41% Grade % 54% % % Grade % 1% 1% 2%
Late
Maximum toxicity Conventional Hyperfract Concom Acc + per patient boost split
Grade % 8% 7% 16% Grade % 56% 44% 50% Grade % 19% 29% 20% Grade 4 8% 9% 8% 7% Grade 5 1% 0% 1% 1%

57. Acute effects in accelerated or hyperfractionated RT
Toxicity of RT in HNSCC
Acute effects in accelerated or hyperfractionated RT
Author Regimen Grade 3-4 mucositis
Cont Exp
Horiot (n=356) HF 49% 67%
Horiot (n=512) Acc fx + split 50% 67%
Dische (n=918) CHART 43% 73%
Fu (n=536) Acc fx(CB) 25% 46%
Fu (n=542) Acc fx + split 25% 41%
Fu (n=507) HF 25% 42%
Skladowski (n=99) Acc fx 26% 56%

58. Altered fractionation in head and neck cancer: meta-analysis
Bourhis, Lancet 2006
Randomized trials (no postop RT)
15 trials included (6515 patients)
Survival benefit: 3.4% (36% % at 5 years, p = 0.003) Loco-regional control benefit: 7% (46.5% % at 5 years, p < )

59. Conclusions for HNSCC
Hyperfractionation increases TCP and protects late responding tissues
Accelerated treatment increase TCP but also increases acute toxicity
What should be considered standard for patients treated with radiation only?
Hyperfractionated radiotherapy
Concomitant boost accelerated radiotherapy
Fractions of 1.8 Gy once daily when given alone, cannot be considered as an acceptable standard of care
TCP curves for SSC are frustratingly shallow … selection of tumors?

60. Conclusions for HNSCC
The benefit derived from altered fractionation is consistent with can be of benefit but should be used with care
In principle, tumors should be treated for an overall treatment time that is as short as possible consistent with acceptable acute morbidity, but with a dose per fraction that does not compromise late responding normal tissues, or total dose.
Avoid treatment breaks and treatment prolongation wherever possible – and consider playing “catch-up” if there are any
Start treatment on a Monday and finish on a Friday, and consider working Saturdays
Never change a winning horse!

61. Other Major Considerations
Not all tumors will respond to hyper or accelerated fractionation like HNSCC, especially if they have a low a/b ratio.
High single doses or a small number of high dose per fractions, as are commonly used in SBRT or SRS generally aim at tissue ablation. Extrapolating based on a linear quadratic equation to total dose is fraught with danger.
Addition of chemotherapy or biological therapies to RT always requires caution and preferably thoughtful pre-consideration!!!
Don’t be scared to get away from the homogeneous field concept, but plan it if you intend to do so.

62. Questions: The Radiobiology Behind Dose Fractionation

63. Random events occurring in cell nuclei
109. A basic assumption in modeling of radiation responses is that lethal ionizing events are
Random events occurring in cell nuclei
Random events in space as defined by the Poisson distribution
A Gaussian distribution
Logarithmic dose response curves
#2 – This mathematical assumption is the basis of the log linear survival curve

64. Is a measure of the shoulder of a survival curve
110. D0 is
Is a measure of the shoulder of a survival curve
Is the mean lethal dose for the linear portion of the dose-response curve
Represents the slope of the log linear survival curve
Is constant at all levels of radiation effect
#3 – It is the mean lethal dose which is also 1/slope.

65. The inverse of the terminal slope of the survival curve
111. Dq is
The inverse of the terminal slope of the survival curve
A measure of the inverse of the initial slope of the survival curve
A measure of the shoulder of the survival curve
A measure of the intercept of the terminal portion of the survival curve on the y axis
#3 – The terminal slope is extrapolated back to the x axis.

66. 112. If Dq for a survival curve is 2Gy, what dose is equivalent to a single dose of 6Gy given in 2 fractions, assuming complete repair and no repopulation between fractions.
4 Gy
6 Gy
8 Gy
10 Gy
#3 – When dose is fractionated Dq is repeated, so it is 6+2Gy.

67. 113. If hematopoietic bome marrow stem cells have a Do of 1Gy, and there is no shoulder on the survival curve, what fraction will survival a lethal dose of 6.9Gy?
0.0001
0.001
0.01
0.37
#2 – If Do is 1Gy, D10 is 2.3Gy i.e. 3xD10.

68. 114. If 90% of a tumor is removed by surgery, what does this likely represent in term of radiation dose given in 2 Gy fractions?
1-2 Gy
3-4 Gy
6-10 Gy
10-20 Gy
20-30 Gy
#2 – The eDo for fractionated radiation is around Gy and the eD10 will be 2.3 times this.

69. 115. What is true for the  ratio It is unitless
It is a measure of the shoulder of the survival curve
It measures the sensitivity of a tissue to changes in size of dose fractions
It is the ratio where the number of non-repairable lesions equals that for repairable lesions
#3 – Low  ratios reflect the sensitivity of late responding tissues to fractionation and high  ratios the lack of sensitivity of acute responding tissues.

70. Unrepairable DNA double strand breaks Lethal single track events
116. The alpha component in the linear quadratic formula for a survival curve can be thought of as representing
Unrepairable DNA double strand breaks
Lethal single track events
Multiply damaged sites in DNA
Damage that can not be altered by hypoxia
#2 – The beta component may be thought of as representing intertrack accumulated damage

71. The extrapolation number
117. Which parameter contributes most to cell killing in standard clinical fractionated regimens in RT
The  ratio Do
Alpha
Beta
The extrapolation number
#3 – Single lethal hits predominate at low doses (2Gy).

72. 118. If cells have a Do of 2 Gy, assuming no shoulder, what dose is required to kill 95% of the cells?
6 Gy
12 Gy
18 Gy
24 Gy
30 Gy
#1 – 3xDo or e-3 = 0.05

73. Dependent on the size of the dose per fraction
119. The extrapolation number N for a multi-fraction survival curve, allowing complete repair between fractions and no repopulation is 1
< 1
>1
Dependent on the size of the dose per fraction
#1 – It is a straight log-linear curve with the slope extrapolating to the x/y intersect at 1.0.

74. Dependent on the size of the dose per fraction
120. The extrapolation number N for a single dose neutron survival curve is 1
< 1
>1
Dependent on the size of the dose per fraction
#1 – It is a straight log-linear curve with the slope extrapolating to the x/y intersect at 1.0.

75. 121. The extrapolation number N for a low dose rate survival curve is
< 1
>1
Dependent on the size of the dose per fraction
#1 – It is a straight log-linear curve with the slope extrapolating to the x/y intersect at 1.0.

76. 122. The inverse of the slope of a multifraction survival curve (effDo) for x-rays is generally within the range Gy Gy Gy Gy
#3 – This obviously has a lot of assumption, but is not a bad ‘ball-park’ figure to remember.

77. 123. If the effDo for a multifraction survival curve is 3
123. If the effDo for a multifraction survival curve is 3.5 Gy, what dose would cure 37% of a series of 1cm diameter tumors (109 clonogens).
56 Gy
64 Gy
72 Gy
80 Gy
#3 – The eD10 would be about 8Gy (2.3x3.5Gy), so 72Gy would reduce survival to on average 1 surviving cell or e-1 and would give 37% cure. Or TCP= e-m.SF

78. 124. If the effDo for a multifraction survival curve is 3
124. If the effDo for a multifraction survival curve is 3.5 Gy, what dose would cure 87% of a series of 1cm diameter tumors (109 clonogens).
56 Gy
64 Gy
72 Gy
80 Gy
#3 – 2 more eDo doses would reduce survival from 1 to e-2 or cells/tumor. TCP = e = 87%

79. 125. If a tumor has an effective Do of 3. 5 Gy, what is the S. F
125. If a tumor has an effective Do of 3.5 Gy, what is the S.F. after 70 Gy?
2 x 10-11
2 x 10-9
2 x 10-7
2 x 10-5
2 x 10-3
#2 – The eD10 would be about 8Gy (2.3x3.5Gy), so 70Gy would reduce survival to about 2 x 10-9.

80. 126. If 16 x 2 Gy fractions reduce survival by 10-4, what dose would be needed to reduce survival to 10-10?
50 Gy
60 Gy
64 Gy
70 Gy
80 Gy
#5 – x 2Gy = 80Gy

81. 127. If 16 x 2 Gy fractions reduce survival by 10-4, what is the effective Do?
#4 – The eD10 would be about 8Gy, so eDo would be 3.5Gy.

82. 128. The  ratio for mucosal tissues is closest to 1 Gy 3 Gy 5 Gy
#4 – Acute responding tissues have a high  ratio.

83. 129. Which of the following human tumors has recently been thought to have an  ratio of 1-2 Gy
Oropharyngeal Ca
Prostate Ca
Glioblastoma
Colorectal Ca
#2 –Several studies have suggested this and therefore that hypofractionation may be of value.

84. 130. If tissue tolerance is 60Gy at 2 Gy/fraction and 40 Gy at 4Gy/fraction, what is its a/b ratio?
#2 – Dnew (dnew + ) = Dold (dold +)

85. 131. It is decided to treat a patient with hypofractionation at 3 Gy/fraction instead of the conventional schedule of 60 Gy in 2 Gy fractions. What total dose should be delivered in order for the risk of late normal‑tissue damage to remain unchanged assuming an a/b for late damage of 3 Gy?
40 Gy
48 Gy
50 Gy
55.4 Gy
75 Gy
#3 – Dnew (3 + 3) = 60 (2 +3) = 50Gy

86. 132. Hyperfractionation using a fraction size of 1
132. Hyperfractionation using a fraction size of 1.2 Gy is replacing a standard 70Gy in 2Gy fractions for HNSCC. Assume full repair of sublethal damage between fractions and an a/b of 3 Gy, what total dose should be used to maintain the same level of late complications?
42 Gy
58 Gy
70 Gy
83 Gy
117 Gy
#4 – Dnew ( ) = 70 (2 +3) = 83Gy

87. 133. A standard treatment of 70 Gy in 2 Gy/fraction is changed to 83Gy in 1.2 Gy. Assuming no proliferation and complete repair between fractions, an a/b of 3 Gy for late responding tissue and 12 Gy for tumor, what would be the therapeutic gain. 6%
12%
18%
24%
#2 – The response of the tumor is not going to change much, so you can guess 83/70 = 12%

88. 134. Which of the following sites is the least suitable for b. I. d
134. Which of the following sites is the least suitable for b.I.d. treatment
Head and neck
Brain
Lung
Prostate
#2 – The brain does not respond well to b.i.d. treatment

89. 135. The rationale behind accelerated fractionation is
To spare late responding normal tissue
To combat encourage tumor reoxygenation
To exploit redistribution in tumors
To combat accelerated repopulation in tumors
#4 – The idea is to get the dose in during the lag time before accelerated repopulation starts.

90. 136. The CHART regimen for HNSCC of 54Gy in 36 fractions over 12 days compared with 66 Gy in 33 fractions in 6.5 weeks, overall showed
Superior locoregional control, no increase in overall survival, increased late effects
Superior locoregional control that translated into an increase in overall survival, no change in late effects
No change in locoregional control and overall survival, decreased late effects
Superior locoregional control, no increase in overall survival, increased acute effects
#3 – The aim of this trial was not to increase response but to decrease normal tissue reactions, unlike a later NSCLC CHART trial

91. Was a hyperfractionation trial
137. DAHANCA 6 and 7 clinical trials with 66-68Gy given in 6 compared to 7 weeks
Was a hyperfractionation trial
Involved treating patients 6 days a week
Showed no increase in local control
Showed no increase in disease-specific survival
#2 – with better outcomes…

92. 138. RTOG compared hyperfractionation, accelerated fractionation with a split, and accelerated fractionation with a boost. It showed
Hyperfractionation to be superior in terms of loco-regional control and late effects
Accelerated fractionation with a split to be equivalent to hyperfractionation in terms of loco-regional control
There to be no advantage to altered fractionation
Accelerated fractionation to be superior to hyperfractionation
#1 – The lead investigator was K. Fu.