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Radiobiology behind dose fractionation

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  • 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.
  • 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.
  • In 1956 Puck and Marcus published the first survival curve for mammalian cells and noted that the D0 was 100-150cGy. 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.
  • Adenocarcinoma may be fractionation sensitive, like LRT
  • Fractionation alpha nd beta
  • An additional complication has been reported by Joiner et al, who have shown that certain cell lines show a hypersensitivity zone at 0.05-0.2 Gy that flattens out over 0.05-1 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.
  • Fractionation benefits
  • Fractionation spare late tissues
  • Fractionation and time prolongation
  • Alternative or supplemental indicator of treatment outcome
  • 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.
  • 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
  • Pooled grade 2 and 3 side effects
    Increase of about 19 %in long term local tumor control
    Interfraction interval 4 to 6 hours
  • 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.
  • Mucositis occured earlier but settled sooner as well, skin reactions were less severe.
  • Transcript

    • 1. The Radiobiology Behind Dose Fractionation Bill McBride Dept. Radiation Oncology David Geffen School Medicine UCLA, Los Angeles, Ca. wmcbride@mednet.ucla.edu WMcB2009 www.radbiol.ucla.edu
    • 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 WMcB2009 www.radbiol.ucla.edu
    • 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? WMcB2009 www.radbiol.ucla.edu
    • 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 WMcB2009 www.radbiol.ucla.edu
    • 5. The First Radiation Dosimeter prompted the use of dose fractionation WMcB2009 www.radbiol.ucla.edu
    • 6. 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 WMcB2009 www.radbiol.ucla.edu
    • 7. How to modify a treatment schedule WMcB2009 www.radbiol.ucla.edu
    • 8. 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 WMcB2009 www.radbiol.ucla.edu
    • 9. 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 1.0 • S.F.= e-1 = 0.37 This is the mean lethal dose D0 0.37 • D10 = 2.3 xD0 • In general, S.F. = e-D/D0 S.F. 0.1 or LnS.F. = -D/D0 0.01 0.001 or S.F. = e-αD , i.e. D0 = 1/α D0 D 10 DOSE Gy Where α is the slope of the curve and D0 the reciprocal of the slope How many logs of cells would be killed by 23 Gy if D0 = 1 Gy? WMcB2009 www.radbiol.ucla.edu
    • 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 = 1-1.5 Gy Why the differences? WMcB2009 www.radbiol.ucla.edu
    • 11. Puck and Marcus, J.E.M.103, 563, 1956 First in vitro mammalian survival curve Eukaryotic Survival Curves are Exponential, but have a ‘Shoulder’ Two component model single lethal hits n 1.0 0.1 0.01 Accumulation of sub-lethal damage 0.001 dose WMcB2009 www.radbiol.ucla.edu
    • 12. Two Component Model single lethal hits n 1.0 D0 = 1 reciprocal initial slope S.F. 0.1 • Two Component Model (or single target, single hit + multi-target (n), single hit) • S.F.=e-D/1D0[1-(1-e-D/nD0)n]Extrapolation Number Single hit 0.01 Accumulation of sublethal damage 0.001 Accumulate d damage D0 = n reciprocal final slope DOSE Gy WMcB2009 www.radbiol.ucla.edu
    • 13. 1 limiting slope/ low dose rate S.F. Multi-fraction survival curves can be considered linear if sublethal damage is repaired between fractions they have an extrapolation number (n) = 1.0 5 fractions •The resultant slope is the effective D0 •e D 0 is often 2.5 - 5.0Gy and e D 10 5.8 - 11.5Gy .1 •S.F. = e-D/eD0 3 fractions Single dose .01 0 4 8 12 16 Dose (Gy) 20 •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% 24 WMcB2009 www.radbiol.ucla.edu
    • 14. Linear Quadratic Model • 1.0 αD S.F. = e-αD Single lethal hits βD2 S.F. 0.1 Cell kill is the result of single lethal hits plus accumulated damage from 2 independent sublethal events S.F. = e-(αD+βD2) Single lethal hits plus accumulated damage 0.01 • The generalized formula is E = αD + βD2 • 0.001 α/β in Gy DOSE Gy For a fractionated regimen E= nd(α + βd) = D (α + βd) Where d = dose per fraction and D = total dose ∀ α/β is dose at which death due to single lethal lesions = death due to accumulation of sublethal lesions i.e. αD = βD2 and D = α/β in Gy WMcB2009 www.radbiol.ucla.edu
    • 15. • Over 90% of radiation oncologists use the LQ model: – it is simple and has a microdosimetric underpinning α/β is large (> 6 Gy) when survival curve is almost exponential and small (1-4 Gy) when shoulder is wide – the α/β value quantifies the sensitivity of a tissue/tumor to fractionated radiation. • But: – Both α and β vary with the cell cycle. At high doses, S phase and hypoxic cells become more important. – The α/β 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 WMcB2009 www.radbiol.ucla.edu
    • 16. 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 • α/β 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 Douglas and Fowler Rad Res 66:401, 1976 Showed and easy way to arrive at an α/β ratio Reciprocal total dose for an isoeffect Slope = β Intercept = α Dose per fraction WMcB2009 www.radbiol.ucla.edu
    • 17. Response to Fractionation Varies With Tissue 1 1 Acute Responding Acute Tissues α/β = 10Gy S.F. Late Responding Tissues - α/β = 2Gy 0 4 8 12 Dose (Gy) Fractionated Acute Effects Single Dose Late Effects α/β = 2Gy α/β is high (>6Gy) when survival curve is almost exponential and low (1-4Gy) when shoulder is wide .01 Fractionated Late Effects .1 .1 S.F. Single Dose Acute Effects α/β = 10Gy .01 16 0 4 8 12 16 Dose (Gy) 20 Fractionation spares late responding tissues WMcB2009 www.radbiol.ucla.edu
    • 18. Sensitivity Fractionation the of Tissue to Dose can be estimated by α/β ratio WMcB2009 www.radbiol.ucla.edu
    • 19. What are α/β ratios for human cancers? In fact, for some tumors e.g. prostate, breast, melanoma, soft tissue sarcoma, and liposarcoma α/β ratios may be moderately low Prostate – Brenner and Hall IJROBP 43:1095, 1999 • comparing implants with EBRT ∀ α/β 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 α/β ratio of 1.12Gy (-3.3-5.6) Breast – Owen, J.R., et al. Lancet Oncol, 7: 467-471, 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 α/β = 4.0Gy (1.0-7.8) • Breast appearance α/β = 3.6Gy; induration α/β If fractionation sensitivity of a cancer is similar to = 3.1Gy dose-limiting healthy tissues, it may be possible to give fewer, larger fractions without compromising effectiveness or safety WMcB2009 www.radbiol.ucla.edu
    • 20. What total dose (D) to give if the dose/fx (d) is changed New Dnew (dnew + α/β ) Old = Dold (dold + α/β ) 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 α/β for late responding tissues can make a big difference in estimated D! WMcB2009 www.radbiol.ucla.edu
    • 21. Biologically Effective Dose (BED) S.F. = e-E = e-(αD+βD2) E = nd(α + βd) E/α = nd(1+d/α/β) Biologically Effective Dose Total dose Relative Effectiveness 35 x 2Gy = B.E.D.of 84Gy10 and 117Gy3 NOTE: 3 x 15Gy = B.E.D.of 113Gy10 and 270Gy3 Equivalent to 162 Gy in 2Gy Fx -unrealistic! (Fowler et al IJROBP 60: 1241, 2004) Normalized total dose2Gy = BED/RE = BED/1.2 for α/β of 10Gy = BED/1.67 for α/β of 3Gy www.radbiol.ucla.edu WMcB2009
    • 22. α/β=3Gy; 1.5Gy/fx α/β=30Gy; 1.5Gy/fx 80 2.0Gy/fx 70 α/β=30Gy; 4Gy/fx 60 D new α/β=3Gy; 4Gy/fx 50 40 30 20 20 30 40 50 60 70 80 D old Note how badly late responding tissues respond to increased dose/fraction WMcB2009 www.radbiol.ucla.edu
    • 23. Does this Matter? Prescribed Dose: 25 fractions of 2Gy = 50Gy Hot spot: 110% Physical dose: 55Gy Biological dose: 60.5Gy “Double Trouble” www.radbiol.ucla.edu WMcB2009
    • 24. The Linear Quadratic Formulation • Does not work well at high dose/fx • Assumes equal effect per fraction WMcB2009 www.radbiol.ucla.edu
    • 25. HT29 cells 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 0.050.2Gy. • The survival curve then plateaus over 0.05-1Gy • 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 Lambin et al. Int J Radiat Biol 63:639 1993 www.radbiol.ucla.edu WMcB2009
    • 26. The Linear Quadratic Formulation • Does not work well at low or high dose/fx • Assumes equal effect per fraction WMcB2009 www.radbiol.ucla.edu
    • 27. 4Rs OF DOSE FRACTIONATION • Assessed by varying the time between 2 or more doses of radiation 700R 1500R Repopulation Redistribution Repair WMcB2009 www.radbiol.ucla.edu
    • 28. 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 WMcB2009 www.radbiol.ucla.edu
    • 29. 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 2.5-4.5hrs? WMcB2009 www.radbiol.ucla.edu
    • 30. 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 10-12 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 WMcB2009 www.radbiol.ucla.edu
    • 31. Repopulation in Tumor Tissue Rat rhabdosarcoma Human SCC head and neck T2 70 Total Dose (2 Gy equiv.) 55 T3 local control no local control 40 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 Treatment breaks are often “bad” Withers, H.R., Taylor, J.M.G., and Maciejewski, B. WMcB2009 www.radbiol.ucla.edu Acta Oncologica 27:131, 1988
    • 32. Other Sources of Heterogeneity • Biological Dose – Cell cycle – Hypoxia/reoxygenation – Clonogenic “stem cells” (G.F.) • • • • S.F hypoxic oxic Dose Number Intrinsic radiosensitivity Proliferative potential Differentiation status Phillips, J Natl Cancer Inst 98:1777, 2006 • Physical Dose – Need to know more about the importance of dose-volume constraints WMcB2009 www.radbiol.ucla.edu
    • 33. • Heterogeneity within and between between tumors in dose-response characteristics, often resulting in large error bars for α/β 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 WMcB2009 www.radbiol.ucla.edu
    • 34. Altered Fractionation or How to optimally distribute dose over time WMcB2009 www.radbiol.ucla.edu
    • 35. 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 WMcB2009 www.radbiol.ucla.edu
    • 36. Definitions • Conventional 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 • 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 WMcB2009 www.radbiol.ucla.edu
    • 37. Definitions • Accelerated 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 • Hypofractionation – Dose per fraction (d) higher than 2.2 Gy – Reduced total number of fractions (N) Rationale: Tumor has low α/β ratio and there is no therapeutic advantage to be gained with respect to late complications WMcB2009 www.radbiol.ucla.edu
    • 38. TCP or NTC Tumor control Late responding tissue complications Complication-free cure TCP or NTC Accelerated Fractionation Hyperfractionation Dose www.radbiol.ucla.edu WMcB2009
    • 39. 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 WMcB2009 www.radbiol.ucla.edu
    • 40. Hyperfractionated Barcelona (586), Brazil (112), RTOG 90-03 (1113), EORTC 22791 (356), Toronto (331) Very accelerated CHART (918), Vancouver (82), TROG 91-01 (350),GORTEC 94-02 (268) Moderately accelerated RTOG 90-03 (1113), DAHANCA (1485), EORTC 22851 (512) CAIR (100), Warsaw (395) Other EORTC 22811 (348), RTOG 79-13 (210) 7623 patients in 18 randomized phase III trials !! HNSCC only will be discussed WMcB2009 www.radbiol.ucla.edu
    • 41. EORTC hyperfractionation trial in oropharynx cancer (N = 356) Oropharyngeal Ca T2-3, N0-1 80.5 Gy - 70 fx - 7 wks LOCAL CONTROL Years Horiot 1992 control: 70 Gy - 35-40 fx - 7-8 wks p = 0.02 SURVIVAL p = 0.08 Years WMcB2009 www.radbiol.ucla.edu
    • 42. Very Accelerated: CHART (N = 918) Dische 1997 54 Gy - 36 fx - 12 days control: 66 Gy - 33 fx - 6.5 wks Loco-regional control conventional CHART Favourable outcome with CHART: www.radbiol.ucla.edu Survival conventional CHART well differentiated tumors larynx carcinomas WMcB2009
    • 43. CHART: Morbidity Dische 1997 54 Gy - 36 fx - 12 days control: 66 Gy - 33 fx - 6.5 wks P = 0.04 P = 0.003 Moderate/severe subcutaneous fibrosis and oedema Mucosal ulceration and deep necrosis P = 0.04 P = 0.009 Laryngeal oedema Moderate/severe dysphagia WMcB2009 www.radbiol.ucla.edu
    • 44. Moderately Accelerated Overgaard 2000 DAHANCA 6: only glottic, (N = 694) DAHANCA 7: all other sites, + nimorazole (N = 791) 66-68 Gy - 33-34 fx - 6 wks control: 66-68 Gy - 33-34 fx - 7 wks Actuarial 5-year rates Local control DAHANCA 6 DAHANCA 7 Nodal control DAHANCA 6 + 7 Disease-specific survival DAHANCA 6 + 7 5 fx/wk 6 fx/wk 73% 56% 81% p=0.04 68% p=0.009 Overall survival Late effects (edema, fibrosis) n.s. n.s. 87% 65% . 89% n.s. 72% p=0.04 WMcB2009 www.radbiol.ucla.edu
    • 45. Moderately Accelerated CAIR: 7-day-continuous accelerated irradiation (N = 100) Skladowski 2000 66-72 Gy - 33-36 fx - 5 wks 68.4-72 Gy - 38-40 fx - 5.5 wks control: 70-72 Gy - 35-36 fx - 7 wks control: 66.6-72 Gy - 37-40 fx - 7.5-8 wks OVERALL SURV IV AL Probability CAIR CONTROL log-rank p=0.00001 Follow-up (months) WMcB2009 www.radbiol.ucla.edu
    • 46. 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 WMcB2009 www.radbiol.ucla.edu
    • 47. RTOG 90-03, loco-regional control Fu 2000 WMcB2009 www.radbiol.ucla.edu
    • 48. RTOG 90-03, survival Fu 2000 WMcB2009 www.radbiol.ucla.edu
    • 49. RTOG 90-03, adverse effects Acute Fu 2000 Maximum toxicity Conventional Hyperfract Concom Acc + per patient boost split Grade 1 15% 4% 4% 7% Grade 2 57% 39% 36% 41% Grade 3 35% 54% 58% 49% Grade 4 0% 1% 1% 2% Late Maximum toxicity per patient Grade 1 Grade 2 Grade 3 Grade 4 Grade 5 Conventional 11% 50% 19% 8% 1% Hyperfract 8% 56% 19% 9% 0% Concom Acc + boost split 7% 16% 44% 50% 29% 20% 8% 7% 1% 1% WMcB2009 www.radbiol.ucla.edu
    • 50. 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% WMcB2009 www.radbiol.ucla.edu
    • 51. Altered fractionation in head and neck cancer: meta-analysis Randomized trials 1970-1998 (no postop RT) 15 trials included (6515 patients) Bourhis, Lancet 2006 Survival benefit: 3.4% (36% 39% at 5 years, p = 0.003) Loco-regional control benefit: 7% (46.5% 53% at 5 years, p < 0.0001) WMcB2009 www.radbiol.ucla.edu
    • 52. 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? WMcB2009 www.radbiol.ucla.edu
    • 53. 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! WMcB2009 www.radbiol.ucla.edu
    • 54. Other Major Considerations • Not all tumors will respond to hyper or accelerated fractionation like HNSCC, especially if they have a low α/β 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 preconsideration!!! • Don’t be scared to get away from the homogeneous field concept, but plan it if you intend to do so. WMcB2009 www.radbiol.ucla.edu
    • 55. Questions: The Radiobiology Behind Dose Fractionation WMcB2009 www.radbiol.ucla.edu
    • 56. Modeling of radiation responses are based on 1. Random events occurring in cell nuclei 2. Random events in space as defined by the Poisson distribution 3. A Gaussian distribution 4. Logarithmic dose response curves WMcB2009 www.radbiol.ucla.edu
    • 57. D0 is 1. Is a measure of the shoulder of a survival curve 2. Is the mean lethal dose of the linear portion of the dose-response curve 3. Represents the slope of the log linear survival curve 4. Is constant at all levels of radiation effect WMcB2009 www.radbiol.ucla.edu
    • 58. Dq is 1. A measure of the inverse of the terminal slope of the survival curve 2. A measure of the inverse of the initial slope of the survival curve 3. A measure of the shoulder of the survival curve 4. A measure of the intercept of the terminal portion of the survival curve on the y axis WMcB2009 www.radbiol.ucla.edu
    • 59. 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. 1. 4 Gy 2. 6 Gy 3. 8 Gy 4. 10 Gy WMcB2009 www.radbiol.ucla.edu
    • 60. A whole body dose of 7 Gy of x‑rays would produce severe, potentially lethal hematologic toxicity. Assuming that the Do of the hematopoietic stem cells is 1 Gy and that these cells have a negligible capacity to repair sublethal radiation damage, what is the surviving fraction of these stem cells after this dose of radiation? 1. 0.0001 2. 0.001 3. 0.025 4. 0.067 5. 0.1167 WMcB2009 www.radbiol.ucla.edu
    • 61. 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. 1-2 Gy 2. 3-4 Gy 3. 6-7 Gy 4. 9-12 Gy 5. 20-30 Gy WMcB2009 www.radbiol.ucla.edu
    • 62. What is true for the α/β ratio 1. It is unitless 2. It is a measure of the shoulder of the survival curve 3. It measures the sensitivity of a tissue to changes in size of dose fractions 4. It is the ratio where the number of nonrepairable lesions equals that for repairable lesions WMcB2009 www.radbiol.ucla.edu
    • 63. The alpha component in the linear quadratic formula for as radiation survival curve represents 1. Unrepairable DNA double strand breaks 2. Lethal single track events 3. Multiply damaged sites in DNA 4. Damage that can not be altered by hypoxia WMcB2009 www.radbiol.ucla.edu
    • 64. Which parameter is most relevant for standard clinical regimens in RT 1. The α/β ratio 2. Do 3. Alpha 4. Beta 5. The extrapolation number WMcB2009 www.radbiol.ucla.edu
    • 65. If cells have a Do of 2 Gy, assuming no shoulder, what dose is required to kill 95% of the cells? 1. 6 Gy 2. 12 Gy 3. 18 Gy 4. 24 Gy 5. 30 Gy WMcB2009 www.radbiol.ucla.edu
    • 66. The extrapolation number N for a multifraction survival curve, allowing complete repair between fractions and no repopulation is 1. 1 2. < 1 3. >1 4. Dependent on the size of the dose per fraction WMcB2009 www.radbiol.ucla.edu
    • 67. The extrapolation number N for a single dose neutron survival curve is 1. 1 2. < 1 3. >1 4. Dependent on the size of the dose per fraction WMcB2009 www.radbiol.ucla.edu
    • 68. The extrapolation number N for a low dose rate survival curve is 1. 1 2. < 1 3. >1 4. Dependent on the size of the dose per fraction WMcB2009 www.radbiol.ucla.edu
    • 69. The inverse of the slope of a multifraction survival curve (effDo) is generally within the range 1. 1.0-1.5 Gy 2. 1.5-2.5 Gy 3. 2.5-5.0 Gy 4. 5.0-10.0 Gy WMcB2009 www.radbiol.ucla.edu
    • 70. 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). 1. 56 Gy 2. 64 Gy 3. 72 Gy 4. 80 Gy WMcB2009 www.radbiol.ucla.edu
    • 71. If the effDo for a multifraction survival curve is 3.5 Gy, what dose would cure 69% of a series of 1cm diameter tumors (109 clonogens). 1. 56 Gy 2. 64 Gy 3. 72 Gy 4. 80 Gy WMcB2009 www.radbiol.ucla.edu
    • 72. If a tumor has an effective Do of 3.5 Gy,what is the S.F. after 70 Gy? 1. 2 x 10-11 2. 2 x 10-9 3. 2 x 10-7 4. 2 x 10-5 5. 2 x 10-3 WMcB2009 www.radbiol.ucla.edu
    • 73. If 16 x 2 Gy fractions reduce survival by 10-4, what dose would be needed to reduce survival to 10-10? 1. 50 Gy 2. 60 Gy 3. 64 Gy 4. 70 Gy 5. 80 Gy WMcB2009 www.radbiol.ucla.edu
    • 74. If 16 x 2 Gy fractions reduce survival by 10-4, what is the effective D0? 1. 2.0 Gy 2. 2.3 Gy 3. 3.0 Gy 4. 3.5 Gy 5. 3.8 Gy WMcB2009 www.radbiol.ucla.edu
    • 75. The α/β ratio for mucosal tissues is closest to 1. 2 Gy 2. 4 Gy 3. 6 Gy 4. 8 Gy 5. 10 Gy WMcB2009 www.radbiol.ucla.edu
    • 76. Which of the following human tumors Is thought to have an α/β ratio of 1-2 Gy 1. Oropharyngeal Ca 2. Prostate Ca 3. Glioblastoma 4. Colorectal Ca WMcB2009 www.radbiol.ucla.edu
    • 77. The TD5/5 for a certain tissue irradiated at 2 Gy/fraction is 60 Gy whereas at 4 Gy/fraction it is 40 Gy. Assuming that the linear quadratic equation, ‑lnSF= N (αD + βD2), accurately represents cell survival for this tissue, what is the value of α/β? 1. 1 Gy 2. 2 Gy 3. 4 Gy 4. 10 Gy 5. 20 Gy WMcB2009 www.radbiol.ucla.edu
    • 78. 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 according to the linear‑quadratic model with α/β for late damage = 3 Gy? 1. 40 Gy 2. 48 Gy 3. 50 Gy 4. 55.4 Gy 5. 75 Gy WMcB2009 www.radbiol.ucla.edu
    • 79. A standard treatment for HNSCC tumors is 70 Gy delivered at 2 Gy/fraction. Hyperfractionation is being attempted with a fraction size of 1.2 Gy. What total treatment dose should be used to maintain the same complication rate for the late responding normal tissues. Assume full repair of sublethal damage between fractions and an α/β of 3 Gy. 1. 42 Gy 2. 58 Gy 3. 70 Gy 4. 83 Gy 5. 117 Gy WMcB2009 www.radbiol.ucla.edu
    • 80. A standard treatment for HNSCC tumors is 70 Gy delivered at 2 Gy/fraction. Hyperfractionation is being attempted with a fraction size of 1.2 Gy. What total treatment dose should be used to maintain the same complication rate for the late responding normal tissues. Assuming no proliferation and complete repair between fractions, an α/β of 3 Gy for late responding tissue and 12 Gy for tumor, what would be the therapeutic gain. 1. 6% 2. 12% 3. 18% 4. 24% WMcB2009 www.radbiol.ucla.edu
    • 81. Which of the following sites is the least suitable for b.i.d. treatment 1. Head and neck 2. Brain 3. Lung 4. Prostate WMcB2009 www.radbiol.ucla.edu
    • 82. The rationale behind accelerated fractionation is 1. To spare late responding normal tissue 2. To combat encourage tumor reoxygenation 3. To exploit redistribution in tumors 4. To combat accelerated repopulation in tumors WMcB2009 www.radbiol.ucla.edu
    • 83. 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 1. Superior locoregional control, no increase in overall survival, increased late effects 2. Superior locoregional control that translated into an increase in overall survival, no change in late effects 3. No change in locoregional control and overall survival, decreased late effects 4. Superior locoregional control, no increase in overall survival, increased acute effects WMcB2009 www.radbiol.ucla.edu
    • 84. DAHANCA 6 and 7 clinical trials with 6668Gy given in 6 compared to 7 weeks 1. Was a hyperfractionation trial 2. Treated 6 days a week 3. Showed no increase in local control 4. Showed no increase in disease-specific survival WMcB2009 www.radbiol.ucla.edu
    • 85. RTOG 90-03, which compared hyperfractionation, accelerated fractionation with a split, and accelerated fractionation with a boost showed 1. Hyperfractionation to be superior in terms of loco-regional control and late effects 2. Accelerated fractionation with a split to be equivalent to hyperfractionation in terms of locoregional control 3. There to be no advantage to altered fractionation 4. Accelerated fractionation to be superior to hyperfractionation WMcB2009 www.radbiol.ucla.edu
    • 86. Answers 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. NA 2 2 4 1 5 2 4 2 4 4 3 2 1 3 2 1 2 3 3 1 3 1 2 5 1 3 1 3 3 WMcB2009 www.radbiol.ucla.edu