La ricerca e la terapia in adroterapia-2. R.Orecchia / P. Fossati

Transcription

1 La ricerca e la terapia in adroterapia-2 R.Orecchia / P. Fossati

2 Dose (Gy) = energy (joule) / mass (kg) One degree of fever (from 37.5 to 38.5 ) > 4000 Gy RT small dose big damage

3 Photons : Dose Resposne

4 A uniform dose of photons Makes comparisons easy Maybe is the optimal distribution (under given conditions)

5 If I deliver a uniform dose of photons RT I care about: Prescribed dose If I deliver a Non uniform dose of photons RT I care about: voxel by voxel dose I never care (at least as a first approximation) Number of fields ; IMRT vs. 3D-CRT ; 5 MeV vs. 18 MeV Target shape; Target depth; Flattening filter

6 Two quite separate problems 1 delivering a optimal dose distribution (prescribing) 2 understanding each other (reporting)

7 Which is the optimal dose distribution? Uniform? BTV and dose painting? Shrinking fields?

8 Optimal dose distribution High cure probability Low risk of toxicity

9 When is uniform dose the optimal choice? For the patient: when there is uniform carcinogenic cells distribution within the CTV and uniform distribution of factors determining dose response (e.g. hypoxia) For the population when there is total ignorance about clonogens an hypoxia distributions

10 SHRINKING FIELDS / DOSE PAINTING GIVE MORE DOSE WHERE IT IS NEEDED

11 BAD DOSE NON-UNIFORMITY TECHNICALLY DRIVEN: BRACHYTHERAPY CYBERKNIFE GAMMAKNIFE ISODOSE PRESCRIPTION

12 PROSTATE HDR

13 Cold spots in the target are bad Hot spots in hypoxic areas with high density of clonogens are good Hot spots at random may be acceptable if they do not involve critical structures

14 Which are acceptable hot spots? Microsocopic Brachytherapy with seed imoplantations or catheter based HDR Central Cyberknife Gammknife Gyncological brachytherapy

15 Inacceptable hot spot: 100 Gy to left prostate lobe 50 Gy to right prostate lobe No cure A lot of toxicity

16 High LET, High RBE

17 Carbonio Ions high LET?(only where you need it) high LET lowlet

18 But you have to calculate it

19 Carbon ion treatment is not high LET RT, not even in the target KeV/μm Dose averaged LET Dose fisica NIRS, physical dose and dose averaged LET for 1 field Courtesy of Dr. Matsufuji

20 Protons uniform physical dose Not different form photons

21 Carbon ions More biological effect Whichever endpoint you choose

22 What if we give a uniform physical dose of carbon ions

23 It would be like prescribing 57 Gy to the right prostate lobe and 99 to the left prostate lobe

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25 Beam line at Lanzhou, Institute of Modern Physics China

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27 > 100 patients!!!

28 Most people (including IMP colleagues) agree that a lower dose is needed in areas where there are mainly slow particles with high LET and a higer dose is needed where there are mainly fast particles with low LET

29 How much less? How much more?

30 Passive systems (NIRS, HYOGO, GUNMA and IMP) You only need a shape of SOBP Distal and proximal planes receive different radiation quality but there is no relevant change perpendicular to the beam axis

31 active systems (GSI, HIT, NIRS, CNAO) Weight must be assigned to single monocromatic beamlets, each beamlet contributes to dose in many voxels A radiobiolgical mathematical model must be embedded in the TPS

32 All system used in the clinics are based on a very simple concept Less dose where there is more LET

33 All models do not refer to a given endpoint (10% survival of HSG cell lines) but unfortunately to a GyE

34 The worst possible reference radiationis X-RAy Non linear Higly sensitive to almost anything

35 Short outline of Kanai Model LEM I model LEM IV model MKM model

36 KANAI Model

37 Human salivary gland cell lines Maybe not so critical a choice

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39 Measure several survival curves in several position along a monochromatic bragg peak Describe the single monochromatic braag peak and the mixed field as Linear quadratic Use Zaider Rossi formula Manufacture a less spiky ridge filter

40 From this point the story becomes complicated Why the red line? Why do we care about 80 KeV/μm?

41 Multiple endpoints vs singkle endpoint? HSG surviival or pig skin reddening or clinical toxicity 80 KeV/μm was the LET of fast neutron used at NIRS

42 More than 1000 patients from 1975 to 1984 Melanoma, NSCLC, H&N SCC, Gynecological cancer

43 1. Neutron at NIRS were used with RBE 3 2. Carbon with the same LET must have the same RBE 3. Pig skin reddening agrees with neutrons and not with HSG survival 4. you do not get curves out of pig skin reddening or clinicla experience Solution: Scale linearly the biological dose of HSG multipling by 1.5

44 We have measured that for HSG it is equivalent to 1.84 Gy but we Believe taht for the aptient it may be equivalent to 2.7 Gy

45 Even more complicated 1. Dose escalation trials have been carried out at NIRS escalating dose per fraction 2. SOBP shape has not been changed and RBE has been assumed to scale linearly

46 It is not straightforward to compare Kanai Model with anything else The dose distribution produce a uniform effect (at least for HSG cell lines) only if 2.7 GyE per fraction are prescribed

47 All clinical results from Japan (NIRS, Hyogo and Gunma) are based on Kanai Model

48 LEM I (Local Effect Model)

49 LEM I (Local Effect Model) The difference depends on microscopic pattern of dose deposition: Photons are like spanking, carbon like stabbing with a dagger

50 LEM IV (Local Effect Model)

51 Photons survival curves are used Survival means zero lethal events Probability of lethal events for a cell is derived from survival curves with Poisson statistics Lethal events are assumed uniformly spaced in the nucleus for photons

52 For carbon ions number of lethal events is integrated over the nucleus and local probability is derived from photons global curves Local dose is calculated based on the amorphous track There are some free parameters

53 The most critical free parameter is Transition dose from linear quadratic to linear Local doses can exceed 1000 Gy It is not possible to assume LQ relation between dose and survival, survival curves are linearized at a given dose

54 LEM model You can apply it to any mixed field of particles OK for spot scanning OK for inverse planning Predicts cell survival for complex beam arrangements You can change the reference cell line easily

55 All clinical results from Europe (GSI, HIT and CNAO) are based on LEM I Model with an idealized chordoma cell line as reference

56 LEM IV (Local Effect Model)

57 LEM I focuses on dose and survival to calculate local probability of lethal events LEM IV introduces a new concept : simple DSB vs. complex (clustered) DSB Better agreement with in vitro and in vivo study Never used with patients

58 Microdosimetric Kinetic Model (MKM)

59 The basic idea is not so much different from LEM Expected number of lethal event in a cell is obtained by summation of expected number of lethal events in a small domains Instead of integrating points over a volume a finite number of small domains is added. This allows to directly measure relvant radiation parameters down in the microscopic domain

60 MKM Once again a lot of dose clustered in a small volume is predict to create more damage Once again there is linear quadratic dependence The model is less of a black box respect to LEM as many of tis parameters can be derived form microdismetric measurments

61 Good fit of in vitro data Nasty mathematics

62 It is / will be used for NIRS spot scanning

63 Different way to prescribe carbon ion RT Everyone agree qualitatively but there is quantitative disagreement No one is right as there are many relevant endpoints and all are difficult to measure

64 BUT We risk not to understand each other Kanai vs. LEM one is a clinically relevant conversion The shape wil be different but we want to avoid systematic errors

65 10% difference is clinically relevant High dose (70.4 GyE jp ) 5yrs. 76.4% H&N Sarcoma at NIRS Low dose (64.0 or 57.6 GyE jp ) 5yrs. 21.4% LogRank p<0.0001

66 Can we compare physical dose? NO

67 Same model: comapre biological doses 2 fields big target 1 field big target 1 field, small target

68 Same DVH of RBE weighted dose Dosse GyE LEM

69 Different physical dose DVH

70 No easy way to compare carbon ion RT plans obtained with different models You cannot compare physical dose (not even with the same RBE model) You cannot compare RBE weigted dose

71 Possible solution: Compare physical dose after fixing reference conditions : 1. Same volumes 2. Same number of fields 3. Same field orientation

72 Water phantom 5 Cubic targets : (4, 6, 8, 10, 12 cm)

73 Same volumes in superficial position

74 Fields 1 single field 2 opposed fields 2 orthogonal fields

75 NIRS physical dose (4 GyE jp ) 6 cm SOBP

76 NIRS physical dose in 6 cm SOBP (4 GyE jp )

77 NIRS physical dose in 6 cm SOBP (4 GyE jp )

78 NIRS 4 GYE jp CNAO 4.05 GYE LEM

79 NIRS 4 GYE jp CNAO 4.05GYE LEM CNAO 4.2 GYE LEM

80 NIRS 4 GYE jp CNAO 4.3 GYE LEM

81 NIRS 4 GYE jp CNAO 4.4 GYE LEM

82 NIRS 4 GYE jp CNAO 4.5 GYE LEM

83 Physical dose in SOBP CNAO 4.5 GYE LEM CNAO 4.45 GYE LEM CNAO 4.05 GYE LEM NIRS 4 GYE jp

84 CNAO 4.45 GYE LEM Cost = Red area 2 Abs (red area) NIRS 4 GYE jp

85 Same size different prescriptrion doses 6 cm SOBP Cost (physical Gy) CNAO GyE LEM

86 Optimal dose is size dependant! NIRS 3.6 GyE JP Cost (physical Gy) CNAO GyE LEM

87 Sizes are weigthed according to real tumor size Number of pts. Number of pts. mm mm

88 Optimal dose depends on field arrangement 0,14 0,12 NIRS 3.6 GyE jp 0,1 Cost (physical Gy) 0,08 0,06 0,04 0,02 single field opposed fields 90 2 fields 0 4,1 4,15 4,2 4,25 4,3 4,35 4,4 CNAO GyE LEM

89 Cubes spheres or patients?

90 Tails of wasted SOBP were LEM is underdosing

91 Water phantom 5 spheric targets : (4, 6, 8, 10, 12 cm)

92 NIRS 3.6 GyE jp Cost (physical Gy) CNAO GyE LEM If we treat spheres we should give slightly lower doses

93 Final results

94 Head and neck NIRS 4 GyE x 16 frazioni = 64 GyE CNAO 4.45 GyE x 16 frazioni = 71,2 GyE Retroperitoneal sarcoma NIRS 4.4 GyE x 16 frazioni = 70,4 GyE CNAO 4.75 GyE x 16 frazioni = 76 GyE

95 Risultati finali

96 (2) Recalculating NIRS biological dose according to LEM We can recreate the same physical dose shape with CNAO spot scanning and then calculate the resulting biological dose, this would be the biological dose of NIRS plan calculated with LEM. Not possible with Syngo PT but with other non commercial softwares (MyLEM)

97 NIRS physical dose physical Gy mm

98 Monocromatic peaks (MyLEM) physical Gy mm

99 Fitted peaks to reproduce NIRS dose physical Gy mm

100 Recalculated biological dose of NIRS-fitted dose distribution according to LEM physical Gy GyE LEM mm

101 Perfect agreement between the two approaches? indication NIRS dose 1 field Min err quad Recalc biol dose Min err ab H&N 3,6 4,15 4, ,2 H&N 4 4, 45 4, ,5 ch ch skull base 3,8 4,35 4, ,4 ch ch spine 4,2 4,6 4, ,65 sarcoma body 4,4 4,75 4, ,8 sarcoma H&N 4,4 4,7 4, ,75

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105 Indipendent calculation similar results

106 CONCLUSION Treatment plans for carbon ions should include enough information on local physical quantitties to enable anybody to recalculate RBE weighted dose according to their own radiobilogical model