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Dosimetry in multi-cycle therapies with 90 Y microspheres

La Terapia Radiometabolica in Emilia Romagna e Marche Nuove terapie e protocolli in evoluzione: aspetti fisici, dosimetrici e radioprotezionistici. Macerata, 5 febbraio 2009. Dosimetry in multi-cycle therapies with 90 Y microspheres. Marta Cremonesi, Francesca Botta.

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Dosimetry in multi-cycle therapies with 90 Y microspheres

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  1. La Terapia Radiometabolica in Emilia Romagna e Marche Nuove terapie e protocolli in evoluzione: aspetti fisici, dosimetrici e radioprotezionistici Macerata, 5 febbraio 2009 Dosimetry in multi-cycle therapies with 90Y microspheres Marta Cremonesi, Francesca Botta francesca.botta@ieo.it

  2. Selective Internal Radiation Therapy Selective Internal Radiation Therapy: *locoregional treatment able to release high radiation doses to malignant hepatic lesions *administration of the radiopharmaceutical into the hepatic artery Rationale * liver mainly supplied from the portal vein * blood supply for tumours mainly provided by hepatic artery (80-100%) tumours are passively targeted

  3. Selective Internal Radiation Therapy • 1- Hepatic Angiography and Intervention * to assess liver vascular anatomy and embolise gastroduodenal artery, right gastric artery and possible artery branches * to guarantee only one artery feeding the whole liver, to be used for the therapeutical administration • 2- Scintigraphic examination after intra-artery administration of a tracer • amount / surrogate 99mTc-MAA • *to evaluate the radiopharmaceutical distribution and any possible shunt •  lungs: radiation pneumonitis •  liver: radiation induced hepatitis and ascites •  GI tract: gastroduodenal injury •  gallbladder, pancreas injury • * to evaluate if tumour uptake is appropriate (indication for therapy?) • * to help identifying the amount of therapeutical activity imaging and dosimetry have the purpose of detecting and avoiding risks

  4. SIRT: activity calculation There are several common factors to be considered when establishing the amount of injected activity (IA) in any clinical trial: liver involvement body surface area (BSA) tumour to non tumour ratio liver mass tumour masses radiation protection ...and... tolerance dose to healthy tissues...

  5. SIRT: activity calculation I. Empirical method of liver involvement 3, 2.5, 2 GBq for tumour / total liver:> 50%, 25-50%, < 25% SIRTEX® II. Empirical method of BSA A (GBq) = (BSA – 0.2) + tumour / total liver further restrictions in case of pulmonaryshunt III.MIRD method (partition model) -dose restrictions to normal organs normal liver: < 80 Gy (70 Gy if cirrhosis) SIRTEX user-guide recommends... lungs: < 25 Gy

  6. ATOT = ATUM + ANORMAL MNORMAL · ATOT ANORMAL = ATUM/MTUM (MTUM · T/NT)+ MNORMAL T/NT = ANORMAL/MNORMAL MNORMAL · Fract.ATOT Fract.ANORMAL = (MTUM · T/NT)+ MNORMAL Fract.ANORMAL N.D.NORMAL = λphysical [limit dose]NORMAL Administrable Activity = [dose/activity] NORMAL SIRT: activity calculation III.MIRD Method [partition model] In case of >1 lesion: weighted T/NT according to lesions’ extension ([# pixel lesion]/[Σ # pixel lesions]) Fract.ATOT = 1 –shunt fraction OLINDA: [dose/activity]NORMAL

  7. 15% to 35% ! 3.5 3.0 Surprisingly, the median values between dosimetry and BSA did not differ very much !? 2.5 IA (GBq) 2.0 1.5 1.0 ? 0.5 dosimetry [ III ] BSA [ II ] Iiver involvement [ I ] IA from different methods IA by dosimetry [ III: MIRD method] IA by empirical methods [ I, II ] vs. DISCREPANCIES: -30% to 35%

  8. IA (dosimetry) vs. IA (BSA) - 25 pts 2,4 However, IA dosimetry and IABSA do not correlate 2,2 2,0 IA (BSA) GBq 1,8 1,6 1,4 1,2 1,0 1,0 1,5 2,0 2,5 3,0 3,5 IA (dosimetry) - GBq IA from different methods: dosimetry vs. BSA IAdosim= 1.64 [0.94 – 3.36] GBq IABSA = 1.67 [1.27 – 2.19] GBq

  9. BSA vs Liver INVOLVEMENT % BSA vs Total Liver Mass 70% 4,5 60% 4,0 50% 3,5 R2 = 0,0107 40% 3,0 involvement% Liver mass (kg) 30% 2,5 20% 2,0 10% 1,5 0% 1,0 1 1,5 2 2,5 1 1,5 2 2,5 BSA (m2) BSA (m2) IA from different methods: BSA No correlation was found between the total liver mass or the tumour involvement and the BSA Consequently, the empiricalformula for IABSA offers an easy method to identify the activity to be injected, but BSA is not related to the individual tumour and liver masses

  10. Individual dosimetry with dose constraints to normal organs seemed the suitable rationale for treatment planning Phase I study - IEO At IEO - Milan, a phase I study started October 2005 [ liver metastases] It was considered that: Patients candidate to SIRT always received chemotherapy. The association of hepatotoxic therapies can turn out in unrestrained effects at doses lower than expected. Tolerability of healthy tissues, especially the liver, was the major concern.

  11. * If shunt: Lungs < 10 Gy; GI tract < 20 Gy * Tolerated dose for normal liver ? 40 Gy as reasonable and cautelative compromise 70 – 80 Gy, as acceptable 100 – 150 Gy, as tolerated 60  40 Gy, as loweredforcaution 30 Gy, as TD5/5 for EBRT The literature is controversial (empirical considerations, escalation studies; hystol. analysis) * Therapeutical dose to the tumour? > 100 Gy – reported as associated to efficacy Phase I study: dose constraints

  12. Phase I study: procedure • 1. CT • - liver and lesion masses • 2. Hepatic Angiography • - vascular anatomy • - embolisation of the artery branches • - unique artery feeding the liver for SIRT • 3. Scintigraphic evaluation • [99mTc-MAA, • Whole Body & SPECT] • - distribution: shunt (lungs, GI tract) • - appropriate tumour uptake (T / NT ) • - tumour, normal organ dosimetry - activity to be adminstered (IA) • 4. Therapy • - two weeks later, if the established • conditions are respected

  13. NON WELL IDENTIFIABLE LESIONS: • roi in not-uptaking area (NT) • isoroi above NT threshold • T/NT Phase I study: imaging to simulate therapy SPECT images: • WELL IDENTIFIABLE LESIONS: • roi on every lesion (T) • roi in not-uptaking area (NT) • T/NT evaluation for each lesion • weighted T/NT

  14. with 40Gy CONSTRAINT for normal liver… IA = 1.7 [0.9 – 3.2] GBq Tumour dose = 130 [65-235] Gy Phase I study: dosimetry results DOSIMETRY RESULTS: Normal liver: 24 [13 – 43] Gy/GBq Tumour: 65 [30 – 200] Gy/GBq

  15. “All 18 patients well tolerated the procedure… Side effects […] were not related to an early radiation effect but, principally, to the embolization procedure. No significant delayed liver and haematological toxicities were observed in our group of patients” Phase I study: toxicity with 40Gy CONSTRAINT for normal liver… [Radioembolisation with 90Y microspheres: dosimetric and radiobiological investigation for multi-cycle treatment M.Cremonesi et al., Eur J Nucl Med Mol Imaging (2008) 35:2088-2096]

  16. Phase I study: response FOLLOW UP patients were monitored with 18F-FDG PET/CT and CT: 6, 12 weeks +, >6 months whenever possible after radioembolisation • PARAMETERS • lesions identifiable in PET/CT, SPECT, CT were monitored: • maximum SUV body weighed • mPET - mass with pathological metabolism • mCT - mass extension EVALUATIONS the variations [∆%] of SUV, mPET and mCT vs. basal examinations were evaluated to establish the OVERALL RESPONSE to therapy and the LESION per LESION [LxL] RESPONSE, whenever possible

  17. Phase I study: response Complete-Response (CR), Partial-Response (PR), Stable-Disease (SD), and Progressive-Disease (PD) definition criteria: Non tumoral liver Isoroi identifying the functional mass (mPET) * RECIST criteria for CT ** Coldwell D, 2007 *** IEO massPET based on the reduction of the functional mass identified in PET by isorois with threshold uptake higher than non tumoral liver

  18. 21% 21% 0% 11% 26% CR CR CR PD 0% 42% 0% PD 56% PR PR 30% PR 33% SD SD 21% PR 21% SD PD 50% 50% PD 50% PR 32% 16% SD 0% 20% 0% 30% 30% 40% PD PR SD 30% Phase I study: response 22 lesions (16 pts) could be studied completely (dosimetry and response). The response evaluated at 12 weeks by CT and PET was the following: mPET SUV mCT L x L response Overall response

  19. 6w 12w 18w 6mo 1y 0 100% -20% 60% -40% 20% 6w 12w (%) SUV, mPET, mCT (%) SUV, mPET, mCT 0 -60% 6mo -20% -80% SUV -60% mPET -100% mCT -100% Phase I study: response PET was often able to anticipate the response as compared with CT, especially in case of progression, but also in case of response (variation of SUVmax, mPET, mCT). The PET acquisition seemed more appropriate after 12 weeks (pt #2), while PET at 6 weeks was often too early to be predictive of response. Pt # 1: response Pt # 2: progression Tumour absorbed dose: 140 Gy Tumourabsorbed dose: 55 Gy

  20. CR PR SD PD 100% 60% 2 2 R = 0.45 R = 0.90 Variation(%) of mPET and SUV 20% -20% -60% ▲% mPET % SUV -100% Phase I study: response Despite %mPET and %SUV are in good correlation among them, %mPET (for all the lesions) offers a better correlation with a PET qualitative evaluationof the objective responses [R2=0.90 vs 0.45]

  21. R 2 = 0,2762 Tumour doses vs. variation of SUV (%) Tumour doses vs. variation of mPET (%) 300% R2= 0,331 300% 250% mPET increment 250% SUV increment 200% 200% 150% 150% 100% %  mPET % SUV 100% 50% 50 0 100 150 200 50% 50 0% 0 100 150 200 0% -50% -50% -100% mPET decrease -100% SUV decrease Tumour doses Gy Tumour doses Gy Phase I study: response 22 lesions could be completely evaluated for dosimetry and responses. Correlation of tumour doses vs. %SUV, %mPET, or %mCT was NOT statistically significant However, the trend of curves indicates that tumour doses >80-100 Gy lower the PD rate

  22. A dose-effect & dose-toxicity study… “A radiobiological model to evaluate efficacy and toxicity of 90Y microspheres treatment of liver tumours” *55 patients [31 hepatocellular carcinoma HCC, 24 colorectal liver metastases CRC] * BSA method for activity calculation (1.63 [1.1 - 2] GBq) * Tumour & Normal liver dose calculation [voxel dosimetry] * Local response [complete and partial] & liver toxicity rate evaluation * Radiobiological models: TCP & NTCP to describe dose-response relationship: Normal Tissue Complication Probability Tumor Control Probability [L.Strigari et al., poster at EANM 2008] TCP=exp(- N surviving cells) from linear-quadratic model

  23. HCCCRC TCP 41.6% 86.6% 78 [43-171] Gy 97 [14-199] Gy NTCP 5% 28% 44 [9-77] Gy 34 [23-57] Gy “additional data on larger series are necessary to improve accuracy of model in outcome prediction” A dose-effect & dose-toxicity study… “A radiobiological model to evaluate efficacy and toxicity of 90Y microspheres treatment of liver tumours” [L.Strigari et al., poster at EANM 2008]

  24. to set new clinical protocols to evaluate possible improvements of the risk /benefit balance Further improvements ? DOSIMETRIC DATA can be reviewed from a RADIOBIOLOGICAL PERSPECTIVE to evaluate possible improvements of the risk /benefit balance Some radiobiological considerations

  25. Biological Effective Dose (BED) BED = n· d· [1+d/(α/β)] Tolerance biological dose BED5,5 : 54 – 63 – 90 Gy [3/3, 2/3, 1/3 irradiation] T1/2 rep BED = d + d2 (T1/2 rep+T1/2 eff)·α/β Tolerance dose D5,5 for SIRT di :  : T1/2 rep : T1/2eff : dose / cycle 2.5 Gy liver; 10 Gy tumour 2.5 h liver 1.5 h tumour [ln2/μ] T1/2 Y-90 =64.2 h [ln2/λeff] ..to derive Liver Tolerance Dose from EBRT data Tolerance dose TD5,5 from EBRT: 30 – 35 – 50 Gy [3/3, 2/3, 1/3 irradiation]

  26. doseEBRT to BEDEBRT 100 60 80 BED - TD 5/5 50 BED - TD 50/5 72 83 101 60 BED (TD) [Gy] 40 45 55 40 40 TD [Gy] 30 54 63 90 30 35 50 20 20 TD 5/5 10 TD 50/5 0 0 tot liver 2/3 liver 1/3 liver tot liver 2/3 liver 1/3 liver ..to derive Liver Tolerance Dose from EBRT data

  27. BEDSIRT to doseSIRT BED - TD 5/5 BED - TD 50/5 60 50 100 40 D [Gy] 44 48 55 30 80 20 36 40 51 72 83 101 60 BED (TD) [Gy] 10 40 54 63 90 0 tot liver 2/3 liver 1/3 liver 20 BEDEBRT = BEDSIRT 0 • These doses in SIRT • corresponding to TDEBRT – • should be “safe” tot liver 2/3 liver 1/3 liver SIRT dose corresp. to TD5/5 SIRT dose corresp. to TD50/5 ..to derive Liver Tolerance Dose from EBRT data

  28. alfa/beta = 10 alfa/beta = 3 1,E+00 1,E+00 0 1 2 3 4 5 6 7 8 9 10 0 1 2 3 4 5 6 7 8 9 10 1,E-01 1,E-01 1,E-02 1,E-02 1,E-03 1,E-03 1,E-04 1,E-04 1,E-05 1,E-05 1,E-06 1,E-06 D(Gy) D(Gy) Rationale for a multi-cycle approach Fractionation advantage in EBRT: differential increase in repair of radiation damage in LATE-RESPONDING NORMAL TISSUES compared with TUMORS growing dose-rate …as fractionation spares the dose-limiting normal tissue, keeping normal liver dose FIXED it enables an INCREASE in the total administered activity

  29. 40 Gy to normal liver (constraint)  IA x 1 cycle correspondent BED value ? NEW constraint for a multiple cycle SIRT cumulativeACTIVITY recalculated variation of IA, tumour dose, tumour BED Rationale for a multi-cycle approach In case of SIRT… what’s the amount of the possible INCREASE in TUMOUR DAMAGE with FRACTIONATION? ?

  30. +23 +14 +42 +24 +0.8 183 +0.5 76 139 +14 2.6 +8 45 BED [Gy] dose [Gy] dose [Gy] BED[Gy] IA[GBq] 1 2 3 1 2 3 2 3 2 3 1 1 BED concept as a rationale: multi-cycle approach activity normal tissue tumour 2 WITHOUT taking into account TUMOUR REPOPULATION between cycles [Radioembolisation with 90Y microspheres: dosimetric and radiobiological investigation for multi-cycle treatment M.Cremonesi et al., Eur J Nucl Med Mol Imaging (2008) 35:2088-2096]

  31. T ln(2) - · Tav α T1/2 rep BED = d + d2 ·  (T1/2 rep+T1/2 eff)·α/β d = ∫ do·exp(-λefft)dt 0 ln(2) T BED = dT·RET - · Tav · α T dT = ∫ do·exp(-λefft)dt 0 · RET = Relative Effectiveness = RET(d0, μ, λeff, α/β, T) “The application of the linear-quadratic dose-effect equation to fractionated and Protracted radiotherapy”, DALE R.G. et al., Br. J. Radiol. 58 (1985):515-528 BED concept as a rationale: multi-cycle approach TUMOUR REPOPULATION: reduces treatment biological effectiveness Tav : tumour cells doubling time *Without repopulation – 1 cycle: *With repopulation – 1 cycle: BED as a function of T:

  32. 120 100 80 BED (Gy) 60 40 20 0 0 500 1000 1500 2000 time (h) …strictly related to the trend of NS/N0 (fraction of surviving clonogenic cells) as a function of time, too: 0 500 1000 1500 2000 1.E+00 NS/N0 = exp(- α· BED) 1.E-02 1.E-04 1.E-06 NS/No 1.E-08 1.E-10 1.E-12 1.E-14 1.E-16 time (h) BED concept as a rationale: multi-cycle approach BED as a function of time…

  33. 120 100 80 BED (Gy) 60 40 20 0 0 500 1000 1500 2000 time (h) Tc = Critical Time, beyond which delivered dose is considered to be “wasted” and treatment is considered to be ineffective, giving no contribution to tumour cure 0 500 1000 1500 2000 1.E+00 1.E-02 1.E-04 TC 1.E-06 NS/No TC ln(2) Tc TC · 1.E-08 BED = dTc·RETc - dTc = ∫ do·exp(-λefft)dt 1.E-10 · Tav α 1.E-12 0 1.E-14 1.E-16 time (h) BED concept as a rationale: multi-cycle approach

  34. (T1/2 rep+T1/2 eff)·α/β TC,i ln(2) TC,i · BED =ΣidTc,i·RETc,i - dTc,i = ∫ do·exp(-λefft)dt · Tav α ·  0 di = ∫ do,i·exp(-λefft)dt 0 Multi-cycle approach: open questions… *Without repopulation – multiple cycles: T1/2 rep BED =i di + di2 *With repopulation – multiple cycles: Or… …take into account not only the effect of every single cycle, but also repopulation between two following cycles …get a better understanding of the role of timing between fractions …which value for radiobiological parameter Tav? ?

  35. Multi-cycle approach: open questions… However… *SIRT multi-cycle treatments were not performed in our centre – with the exception of 2 patients – in absence of necessity of port-a-cath for other concomitant therapies *PRRTwith other therapies clinical data support the validity of the model, at least as regards organs at risk [kidneys]

  36. Thank you!!

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