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**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.

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**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

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**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?

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**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

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**The First Radiation Dosimeter**

prompted the use of dose fractionation

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**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

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**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

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**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.

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**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

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**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?

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**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

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**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

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**“Double Trouble” Does this Matter? Prescribed Dose:**

25 fractions of 2Gy = 50Gy Hot spot: 110% Physical dose: 55Gy Biological dose: 60.5Gy “Double Trouble”

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**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

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**Failed to account for differences between tissues.**

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**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

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**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

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**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

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**The Linear Quadratic Formulation**

Does not work well at high dose/fx Assumes equal effect per fraction

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**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:

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**The resultant slope is the effective D0 S.F. = e-D/eD0**

24 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%

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**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

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**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

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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

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**Sensitivity of Tissue to Dose Fractionation can be estimated by the ratio**

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**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

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**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!

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**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)

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

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**4Rs OF DOSE FRACTIONATION**

Redistribution Repair Repopulation 700R 1500R Assessed by varying the time between 2 or more doses of radiation

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**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

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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

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**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

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**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”

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**Regeneration assumed to be exponential**

S.F.regeneration = eT = 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

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**Altered Fractionation or How to optimally distribute dose over time**

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**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

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**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

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**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

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**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

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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

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**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.

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**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

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**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

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**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

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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

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**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

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**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

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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.

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**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.

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**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

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**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

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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

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**RTOG 90-03, loco-regional control**

Fu 2000

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RTOG 90-03, survival Fu 2000

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**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%

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**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%

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**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 < )

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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?

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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!

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**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.

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**Questions: The Radiobiology Behind Dose Fractionation**

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**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

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**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.

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**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.

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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.

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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.

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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.

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**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.

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**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

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**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).

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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

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**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.

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**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.

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**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.

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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.

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**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

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**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%

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**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.

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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

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**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.

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**128. The ratio for mucosal tissues is closest to 1 Gy 3 Gy 5 Gy **

#4 – Acute responding tissues have a high ratio.

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**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.

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**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 +)

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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

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**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

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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%

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**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

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**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.

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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

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**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…

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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.

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