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www.radbiol.ucla.edu WMcB2009 The Radiobiology Behind Dose Fractionation Bill McBride Dept. Radiation Oncology David Geffen School Medicine UCLA, Los.

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2 WMcB2009 The Radiobiology Behind Dose Fractionation Bill McBride Dept. Radiation Oncology David Geffen School Medicine UCLA, Los Angeles, Ca.

3 WMcB2009 Objectives To understand the mathematical bases behind survival curvesTo understand the mathematical bases behind survival curves Know the linear quadratic model formulationKnow 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 fractionUnderstand 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 fractionUnderstand 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 outcomeKnow the major clinical trials on altered fractionation and their outcome Recognize the importance of dose heterogeneity in modern treatment planningRecognize the importance of dose heterogeneity in modern treatment planning

4 WMcB2009 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 outcomeDeviating 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 usesHow 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 scheduleshyperfractionation, accelerated fractionation, some hypofractionation schedules The number of non-homogeneous treatment plans (IMRT) and extreme hypofractionated treatments are increasing. Do existing models cope?

5 WMcB2009 In theory, knowing relevant radiobiological parameters one day may predict the response for Dose given in a single or a small number of fractions Dose given in a single or a small number of fractions SBRT, SRS, SRT, HDR or LDR brachytherapy, protons, cyberknife, gammaknife SBRT, SRS, SRT, HDR or LDR brachytherapy, protons, cyberknife, gammaknife Non-uniform dose distributions optimized by IMRT Non-uniform dose distributions optimized by IMRT e.g. dose “painting” of radioresistant tumor subvolumes e.g. dose “painting” of radioresistant tumor subvolumes Combination therapies with chemo- or biological agents Combination therapies with chemo- or biological agents Different RT options when tailored by molecular and imaging theragnostics 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? If you know the molecular profile and tumor phenotype, can you predict the best delivery method? Biologically optimized treatment planning Biologically optimized treatment planning

6 WMcB2009 The First Radiation Dosimeter prompted the use of dose fractionation

7 WMcB2009 Which are fitted by a Poisson Distribution P of x = e -m.m x /x! where m = mean # hits, x is a hit P survival (when x = 0) 100 targets 100 hits m=1 e -1 = targets 200 hits m=2 e -2 = targets 300 hits m=3 e -3 =0.05 Modeling Radiation Responses N.B. Lethal hits in DNA are not really randomly distributed, e.g. condensed chromatin is more sensitive, but it is a reasonable approximation Assumes that ionizing ‘hits’ are random events in space

8 WMcB2009 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 = 0.37When there is single lethal hit per target S.F.= e -1 = 0.37 This is the mean lethal dose D 0This is the mean lethal dose D 0 D 10 = 2.3 xD 0D 10 = 2.3 xD 0 In general, S.F. = e -D/D 0In general, S.F. = e -D/D 0 or LnS.F. = -D/D 0 or S.F. = e -  D, i.e. D 0 = 1/  Where  is the slope of the curve and D 0 the reciprocal of the slope DOSE Gy D0D0D0D0 S.F. D How many logs of cells would be killed by 23 Gy if D 0 = 1 Gy?

9 WMcB2009 Puck and Marcus, J.E.M.103, 563, 1956 First in vitro mammalian survival curve Accumulation of sub-lethaldamage singlelethalhits n dose Two component model Eukaryotic Survival Curves are Exponential, but have a ‘Shoulder’

10 WMcB2009 DOSE Gy 1 D 0 = reciprocal initial slope n D 0 = reciprocal final slope S.F. Two Component Model (or single target, single hit + multi-target (n), single hit) S.F.=e -D/ 1 D 0 [1-(1-e -D/ n D 0) n ] Single hit Accumulateddamage Accumulation of sublethal damage single lethal hits n ExtrapolationNumber

11 WMcB2009 Mean Inactivation Dose (Do) Virus D 0 approx. = 1500 Gy E. Coli D 0 approx. = 100 Gy Mammalian bone marrow cells D 0 = 1 Gy Generally, for mammalian cells D 0 = Gy Why the differences?

12 WMcB2009 Reduces micro-organisms and insects Potatoes, Onions, etc.,. 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 Inhibits sprouting

13 WMcB2009 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

14 WMcB2009 Prescribed Dose: 25 fractions of 2Gy = 50Gy Hot spot: 110% Physical dose: 55Gy Biological dose: 60.5Gy Does this Matter? “Double Trouble”

15 WMcB2009 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)T 0.11.N 0.24

16 WMcB2009 Failed to account for differences between tissues.Failed to account for differences between tissues.

17 WMcB2009 Lea and Catchside 1942 Radiation-induced chromosome aberrations in Tradescantia microspores Kellerer and Rossi, 1972 Theory of dual radiation action based on microdosimetry Linear Quadratic Formula Biological effect is based on a linear term and a quadratic term

18 WMcB2009 S.F. = e -  D Single lethal hits S.F. = e -(  D+  D 2 ) Single lethal hits plus accumulated damage Cell kill is the result of single lethal hits plus accumulated damage from 2 independent sublethal eventsCell kill is the result of single lethal hits plus accumulated damage from 2 independent sublethal events The generalized formula is E =  D +  D 2 For a fractionated regimen E= nd(  +  d) = D (  +  d) Where d = dose per fraction and D = total dose  /  is dose at which death due to single lethal lesions = death due to accumulation of sublethal lesions i.e.  D =  D 2 and D =  /  in Gy S.F DOSE Gy  in Gy DDDD D2D2D2D2 Linear Quadratic Model

19 WMcB2009 Over 90% of radiation oncologists use the LQ model:Over 90% of radiation oncologists use the LQ model: – –it is simple and has a microdosimetric underpinning – –  /  is large (> 6 Gy) when survival curve is almost exponential and small (1-4 Gy) when shoulder is wide – –the  value quantifies the sensitivity of a tissue/tumor to fractionated radiation. But:But: – –Both  and  vary with the cell cycle. At high doses, S phase and hypoxic cells become more important. – –The  /  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

20 WMcB2009 The Linear Quadratic Formulation Does not work well at high dose/fxDoes not work well at high dose/fx Assumes equal effect per fractionAssumes equal effect per fraction

21 WMcB2009 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.Certain cell lines, and tissues, are hypersensitive at low doses of Gy. The survival curve then plateaus over GyThe survival curve then plateaus over Gy Not seen for all cell lines or tissues, but has been reported in skin, kidney and lungNot 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 D 2 dominates the equationAt high dose, the model probably does not fit data well because D 2 dominates the equation HT29 cells Lambin et al. Int J Radiat Biol 63:

22 WMcB 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 D 0The resultant slope is the effective D 0 e D 0 is often Gy and e D Gy S.F. = e -D/ e D 0S.F. = e -D/ e D 0 If S.F. after 2Gy = 0.5, e D 0 = 2.9Gy; e D 10 = 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 10 9 clonogenic cells, there would be an average of 1 clonogen per tumor and cure rate would be about 37%

23 WMcB2009 Thames et al Int J Radiat Oncol Biol Phys 8: 219, The slope of an isoeffect curve changes with size of dose per fraction depending onThe 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 Acute responding tissues have flatter curves than do late responding tissues i.e. it predicts how total dose for a given effect will change when you change the size of dose fraction  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 Dose per fraction Intercept =  Slope =  Douglas and Fowler Rad Res 66:401, 1976 Showed and easy way to arrive at an  ratio

24 WMcB2009 Response to Fractionation Varies With Tissue Dose (Gy) S.F. Late Responding Tissues -  = 2Gy Acute Responding Tissues  = 10Gy  /  is high (>6Gy) when survival curve is almost exponential and low (1-4Gy) when shoulder is wide Dose (Gy) S.F. Single Dose Late Effects  = 2Gy Single Dose Acute Effects  = 10Gy Fractionated Late Effects Fractionated Acute Effects Fractionation spares late responding tissues

25 WMcB  =30Gy; 4Gy/fx  =3Gy; 4Gy/fx  =3Gy; 1.5Gy/fx  =30Gy; 1.5Gy/fx 2.0Gy/fx D old D new Note how badly late responding tissues respond to increased dose/fraction

26 WMcB2009 Sensitivity of Tissue to Dose Fractionation can be estimated by the  ratio

27 WMcB2009 What are  ratios for human cancers? In fact, for some tumors e.g. prostate, breast, melanoma, soft tissue sarcoma, and liposarcoma  ratios may be moderately low Prostate –Brenner and Hall IJROBP 43:1095, 1999 comparing implants with EBRTcomparing implants with EBRT  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 daysPhase III NCIC 66Gy 33F in 45days vs 52.5Gy 20F in 28 days Compatible with  ratio of 1.12Gy ( )Compatible with  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, UK START TrialUK START Trial –50Gy in 25Fx c.w. 39Gy in 13Fx; or 41.6Gy in 13Fx [or 40Gy in 15Fx (3 wks)] Breast Cancer  = 4.0Gy ( )Breast Cancer  = 4.0Gy ( ) Breast appearance  = 3.6Gy; induration  = 3.1GyBreast appearance  = 3.6Gy; induration  = 3.1Gy 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

28 WMcB2009 What total dose (D) to give if the dose/fx (d) is changed New Old New Old D new (d new +  ) = D old (d old +  ) So, for late responding tissue, what total dose in 1.5Gy fractions is equivalent to 66Gy in 2Gy fractions? D new (1.5+2) = 66 (2 + 2) D new = 75.4Gy NB: Small differences in  for late responding tissues can make a big difference in estimated D!

29 WMcB2009 Biologically Effective Dose (BED) Biologically Effective Dose Total dose RelativeEffectiveness S.F. = e -E = e -(  D+  D 2 ) E = nd(  +  d) E/  = nd(1+d/  ) 35 x 2Gy = B.E.D.of 84Gy 10 and 117Gy 3 NOTE: 3 x 15Gy = B.E.D.of 113Gy 10 and 270Gy 3 Normalized total dose 2Gy = 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)

30 WMcB2009 Isoeffect Curves Withers et al Radiat Res 119:395, 1989 D= NSD x N 0.24

31 WMcB2009 Redistribution Repair Repopulation 700R1500R 4Rs OF DOSE FRACTIONATION Assessed by varying the time between 2 or more doses of radiationAssessed by varying the time between 2 or more doses of radiation

32 WMcB2009 4Rs OF DOSE FRACTIONATION These are radiobiological mechanisms that impact the response to a fractionated course of radiation therapy Repair of sublethal damageRepair of sublethal damage –spares late responding normal tissue preferentially Redistribution of cells in the cell cycleRedistribution of cells in the cell cycle –increases acute and tumor damage, no effect on late responding normal tissue RepopulationRepopulation –spares acute responding normal tissue, no effect on late effects, –danger of tumor repopulation ReoxygenationReoxygenation –increases tumor damage, no effect in normal tissues

33 WMcB2009 Repair “Repair” between fractions should be complete - N.B. we are dealing with tissue recovery rather than DNA 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 hoursIn general, time between fractions for most tissues should be >6 hours Some tissues, such as CNS, recover slowly making b.i.d. treatment inadvisableSome tissues, such as CNS, recover slowly making b.i.d. treatment inadvisable Bentzen - Radiother Oncol 53, 219, 1999Bentzen - 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?

34 WMcB2009 Regeneration in Normal Tissues The lag time to regeneration varies with the tissueThe lag time to regeneration varies with the tissue In acute responding tissues,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/dyIn 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,In late responding tissues, –Prolonging overall treatment time beyond 6wks has little effect, but prolonging time to retreatment may increase tissue tolerance

35 WMcB2009 Human SCC head and neck 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 TotalDose (2 Gy equiv.) Treatment Duration local control no local control T2 T3 Repopulation in Tumor Tissue Hermens and Barendsen, EJC 5:173, 1969 Treatment breaks are often “bad” Rat rhabdosarcoma

36 WMcB2009 Regeneration assumed to be exponentialRegeneration assumed to be exponential S.F. regeneration = e  T = e (ln2/Tp)TS.F. regeneration = e  T = e (ln2/Tp)T –Where T = overall treatment time; Tp = effective doubling time i.e. S.F. = e -(  D+  D 2 )+ln2/Tp(T-Tk)i.e. S.F. = e -(  D+  D 2 )+ln2/Tp(T-Tk) –Where Tk is time of start of regeneration

37 WMcB2009 Altered Fractionation or How to optimally distribute dose over time

38 WMcB2009 Players Total dose (D)Total dose (D) Dose per fraction (d)Dose per fraction (d) Interval between fractions (t)Interval between fractions (t) Overall treatment time (T)Overall treatment time (T) Tumor typeTumor type Acute reacting normal tissuesAcute reacting normal tissues Late reacting normal tissuesLate reacting normal tissues

39 WMcB2009 TCP or NTC Dose Hyperfractionation Accelerated Fractionation Tumor control Late responding tissue complications Complication-free cure TCP or NTC

40 WMcB2009 Other Sources of Heterogeneity Biological DoseBiological Dose –Cell cycle –Hypoxia/reoxygenation –Clonogenic “stem cells” (G.F.) NumberNumber Intrinsic radiosensitivityIntrinsic radiosensitivity Proliferative potentialProliferative potential Differentiation statusDifferentiation status Physical DosePhysical 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

41 WMcB2009 DOSE (Gy) N=10 9 = 0.5 = 0.5 N=10 10 N=10 11 SF 2 TCP (%) Average 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-(  d+  D2) TCP = e -(m. SF) or e -m.e-(  d+  D2) Where m is the initial number of clonogenic cells Where m is the initial number of clonogenic cells TCP=37% when, on average, 1 cell survives TCP=37% when, on average, 1 cell survives Slope of curve represents radiobiological heterogeneity Slope of curve represents radiobiological heterogeneity DOSE (Gy) N=10 9 SF 2 =0.3 TCP (%) SF 2 =0.4 SF 2 =0.5 SF 2 =0.6 SF 2 =0.7 TCP/NTCP and Heterogeneity Rafi Suwinski

42 WMcB2009 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

43 WMcB2009 Definitions Conventional fractionationConventional fractionation –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 HyperfractionationHyperfractionation –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

44 WMcB2009 Definitions Accelerated fractionationAccelerated fractionation –Shorter overall treatment time –Dose per fraction of 1.8 to 2 Gy –More than 10 Gy per week Rationale: Overcome accelerated tumor repopulation HypofractionationHypofractionation –Dose per fraction (d) higher than 2.2 Gy –Reduced total number of fractions (N) Rationale: Tumor has low  ratio and there is no therapeutic advantage to be gained with respect to late complications

45 WMcB2009 Conventional 70 Gy - 35 fx - 7 wks Very accelerated with reduction of dose 54 Gy - 36 fx - 12 days Moderately accelerated 72 Gy - 42 fx - 6 wks Hyperfractionated 81.6 Gy - 68 fx - 7 wks

46 WMcB2009 Hyperfractionated Barcelona (586), Brazil (112), RTOG (1113), EORTC (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

47 WMcB2009 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

48 WMcB2009 Oropharyngeal Ca T2-3, N0-1 Years LOCAL CONTROL LOCAL CONTROL SURVIVAL SURVIVAL Years Horiot Gy - 70 fx - 7 wks control: 70 Gy fx wks p = 0.02 p = 0.02 p = 0.08 p = 0.08 EORTC hyperfractionation trial in oropharynx cancer (N = 356)

49 WMcB2009 Loco-regional control Survival conventional CHART 54 Gy - 36 fx - 12 days control: 66 Gy - 33 fx wks Dische 1997 Favourable outcome with CHART:well differentiated tumors larynx carcinomas Very Accelerated: CHART (N = 918)

50 WMcB Gy - 36 fx - 12 days control: 66 Gy - 33 fx wks CHART: Morbidity Dische 1997 Moderate/severe subcutaneous fibrosis and oedema P = 0.04 Moderate/severe dysphagia P = 0.04 Mucosal ulceration and deep necrosis P = Laryngeal oedema P = 0.009

51 WMcB2009 DAHANCA 6: only glottic, (N = 694) DAHANCA 7: all other sites, + nimorazole (N = 791) Overgaard 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 Overall survival Late effects (edema, fibrosis) Moderately Accelerated 5 fx/wk6 fx/wk 73%81% p= %68% p= %89% n.s. 65%72% p=0.04 n.s.n.s.

52 WMcB2009 Skladowski 2000 OVERALL SURVIVAL CONTROL CAIR log-rank p= Follow-up (months) Probability Gy fx - 5 wks control: Gy fx - 7 wks Gy fx wks control: Gy fx wks CAIR: 7-day-continuous accelerated irradiation (N = 100) Moderately Accelerated

53 WMcB2009 CAIR: two schedules of continuous 7 days / week with different dose per fraction Maciejewski 1996, Skladowski 2000 Treatment time (days) Total dose (Gy) excessive mucosal toxicity (2.0 Gy/day) acceptable mucosal toxicity (1.8 Gy/day) conventional Wygoda, A. IJROBP 2008

54 WMcB2009 Conventional Accelerated with split 70 Gy - 35 fx - 7 wks 67.2 Gy - 42 fx - 6 weeks (including 2-week split) 72 Gy - 42 fx - 6 wks Hyperfractionated 81.6 Gy - 68 fx - 7 wks Accelerated with Concomitant boost Fu 2000 RTOG 90-03, Phase III comparison of fractionation schedules in Stage III and IV SCC of oral cavity, oropharynx, larynx, hypopharynx (N = 1113)

55 WMcB2009 RTOG 90-03, loco-regional control Fu 2000

56 WMcB2009 RTOG 90-03, survival Fu 2000

57 WMcB2009 RTOG 90-03, adverse effects Maximum toxicityConventionalHyperfractConcomAcc + per patientboostsplit Grade 1 15%4%4%7% Grade 257%39%36% 41% Grade 3 35%54% 58% 49% Grade 4 0% 1% 1%2% Fu 2000 Acute Maximum toxicityConventionalHyperfractConcomAcc + per patientboostsplit Grade 111%8%7%16% Grade 250%56%44%50% Grade 319%19%29%20% Grade 48%9%8%7% Grade 51%0%1%1% Late

58 WMcB2009 Acute effects in accelerated or hyperfractionated RT AuthorRegimen Grade 3-4 mucositis ContExp Horiot (n=356)HF49%67% Horiot (n=512) Acc fx + split50%67% Dische (n=918)CHART43%73% Fu (n=536) Acc fx(CB)25%46% Fu (n=542) Acc fx + split25%41% Fu (n=507)HF25%42% Skladowski (n=99) Acc fx 26%56% Toxicity of RT in HNSCC

59 WMcB2009 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% 39% at 5 years, p = 0.003) Loco-regional control benefit: 7% (46.5% 53% at 5 years, p < )

60 WMcB2009 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?

61 WMcB2009 Conclusions for HNSCC The benefit derived from altered fractionation is consistent with can be of benefit but should be used with careThe 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.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 anyAvoid 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 SaturdaysStart treatment on a Monday and finish on a Friday, and consider working Saturdays Never change a winning horse!Never change a winning horse!

62 WMcB2009 Other Major Considerations Not all tumors will respond to hyper or accelerated fractionation like HNSCC, especially if they have a low  ratio.Not all tumors will respond to hyper or accelerated fractionation like HNSCC, especially if they have a low  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.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!!!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.Don’t be scared to get away from the homogeneous field concept, but plan it if you intend to do so.

63 WMcB2009 Questions: The Radiobiology Behind Dose Fractionation

64 WMcB 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

65 WMcB D 0 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.

66 WMcB 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.

67 WMcB 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.

68 WMcB 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? #2 – If Do is 1Gy, D 10 is 2.3Gy i.e. 3xD 10.

69 WMcB 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 eD 10 will be 2.3 times this.

70 WMcB 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.

71 WMcB 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

72 WMcB 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).

73 WMcB 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

74 WMcB 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.

75 WMcB 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.

76 WMcB The extrapolation number N for a low dose rate 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.

77 WMcB The inverse of the slope of a multifraction survival curve ( eff Do) 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.

78 WMcB If the eff Do for a multifraction survival curve is 3.5 Gy, what dose would cure 37% of a series of 1cm diameter tumors (10 9 clonogens). –56 Gy –64 Gy –72 Gy –80 Gy #3 – The eD 10 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

79 WMcB If the eff Do for a multifraction survival curve is 3.5 Gy, what dose would cure 87% of a series of 1cm diameter tumors (10 9 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%

80 WMcB If a tumor has an effective Do of 3.5 Gy, what is the S.F. after 70 Gy? – –2 x – –2 x – –2 x – –2 x – –2 x #2 – The eD 10 would be about 8Gy (2.3x3.5Gy), so 70Gy would reduce survival to about 2 x

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

82 WMcB If 16 x 2 Gy fractions reduce survival by 10 -4, what is the effective Do? – –2.0 Gy – –2.3 Gy – –3.0 Gy – –3.5 Gy – –3.8 Gy #4 – The eD 10 would be about 8Gy, so eDo would be 3.5Gy.

83 WMcB The  ratio for mucosal tissues is closest to –1 Gy –3 Gy –5 Gy –10 Gy #4 – Acute responding tissues have a high  ratio.

84 WMcB 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.

85 WMcB If tissue tolerance is 60Gy at 2 Gy/fraction and 40 Gy at 4Gy/fraction, what is its  ratio? – –1 Gy – –2 Gy – –4 Gy – –10 Gy – –20 Gy D new (d new +  ) = D old (d old +  ) #2 – D new (d new +  ) = D old (d old +  )

86 WMcB 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  for late damage of 3 Gy? – –40 Gy – –48 Gy – –50 Gy – –55.4 Gy – –75 Gy D new (3 + 3  ) = 60 (2 +  3  ) = 50Gy #3 – D new (3 + 3  ) = 60 (2 +  3  ) = 50Gy

87 WMcB 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  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 D new (  ) = 70 (2 +  3  ) = 83Gy #4 – D new (  ) = 70 (2 +  3  ) = 83Gy

88 WMcB 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  of 3 Gy for late responding tissue and 12 Gy for tumor, what would be the therapeutic gain. – 6% –12% –18% –24% The response of the tumor is not going to change much, so you can guess 83/70 = 12% #2 – The response of the tumor is not going to change much, so you can guess 83/70 = 12%

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

90 WMcB 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 The idea is to get the dose in during the lag time before accelerated repopulation starts. #4 – The idea is to get the dose in during the lag time before accelerated repopulation starts.

91 WMcB 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 The aim of this trial was not to increase response but to decrease normal tissue reactions, unlike a later NSCLC CHART trial #3 – The aim of this trial was not to increase response but to decrease normal tissue reactions, unlike a later NSCLC CHART trial

92 WMcB DAHANCA 6 and 7 clinical trials with Gy 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 with better outcomes… #2 – with better outcomes…

93 WMcB 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 The lead investigator was K. Fu. #1 – The lead investigator was K. Fu.


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