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DOSIMETRY IN RADIOIODINE THERAPY OF METASTATIC DIFFERENTIATED THYROID CANCER

DOSIMETRY IN RADIOIODINE THERAPY OF METASTATIC DIFFERENTIATED THYROID CANCER. Chiesa 1 C., Castellani 1 M.R., Botta 2 F., Azzeroni 2 R., Seregni 1 E., Bombardieri 1 E. National Tumour Institute – Milan - Italy Post graduate Health physics school – Milan - Italy. Table of content.

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DOSIMETRY IN RADIOIODINE THERAPY OF METASTATIC DIFFERENTIATED THYROID CANCER

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  1. DOSIMETRY IN RADIOIODINE THERAPY OF METASTATIC DIFFERENTIATED THYROID CANCER Chiesa1 C., Castellani1 M.R., Botta2 F., Azzeroni2 R., Seregni1 E., Bombardieri1 E. National Tumour Institute – Milan - Italy Post graduate Health physics school – Milan - Italy

  2. Table of content • The history of dosimetry: • Benua (healthy organ dosimetry - toxicity) • Maxon (lesion dosimetry - efficacy) • The present development of dosimetry • EANM SOP for blood and marrow dosimetry • The Italian Internal Dosimetry Group • The experience at INT • The future development - SPET/CT + Montecarlo aplications • Conclusions

  3. PAST

  4. History of dosimetry in DTC: Benua - hematological and lung toxicity Poor statistics !

  5. History of dosimetry in DTC: Benua - hematological and lung toxicity • Blood as surrogate of red marrow • “Serious complications were also more frequent when the blood total irradiation exceeded 200 rads = 2 Gy” • Doses were calculated with old “S factors” • The translation in nowdays terms is (Benua blood dose):

  6. Benua’s safety prescriptions (hematological and lung toxicity) • Blood dose < 2 Gy • At 48 h, ATB < 120 mCi (4.4 GBq) • At 48 h, ATB < 80 mCi (3.0 GBq) in presence of functioning diffuse lung metastases • This is not a dose limit. It is a dose rate limit !! (See Song et J Nucl Med 2006; 47:1985–1994) • This approach is a maximization of injectable activity. • No data were published about increased efficacy (Why ?) • We are trying to optimize therapy ! (Dorn et al J Nucl Med 2003; 44:451–456)

  7. Pre-treatment = post-treatment ?

  8. Lesion Dosimetry: Maxon NEMJ 1983 (review Maxon H.R. Quantitative radioiodine therapy in the treatment of differentiated thyroid cancer – Q J Nucl Med 1999;43:313-23) • Planar imaging • Dual head gammacamera – conjugate view technique • Fast scan for total body clearance (2, 24, 48, 72 h) • Patient prone and supine for lesion imaging in anterior head • Attenuation correction: Blank and transimission scan with 131I standard source • Standard source in the FOV at each scintigram • Scan for background correction

  9. Maxon: lesion mass D = E / m • Remnant mass: area on scintigram x 2 mm thickness (assumption !) • “If a lesion is too small to permit a determination of mass, then a default value of 0.15 g is used” (assumption !) • Metastases mass: “same method, assuming spherical shape. Whenever possible, US, CT, MRI” • Crucial mass determination was not optimal

  10. Lesion Dosimetry: Maxon (review Maxon H.R. Quantitative radioiodine therapy in the treatment of differentiated thyroid cancer – Q J Nucl Med 1999;43_313-23 Maxon et al, NEJM 1983 Remnant Dose D < 300 Gy D >300 Gy Succesful Ablation 3/7 22/23 (96%) Dose to metsD < 80 Gy D > 80 Gy Successful treatment of mets 12/19 (63%) 46/47 (98%) Maxon et al J Nucl Med 1992;33:1132-1136 D > 300 Gy 142 remnants 86% successful Activity mean [range] 86.8 [25.8 – 246.3]. A < 50 mCi in 50% of cases

  11. PRESENT

  12. Metastases dosimetryrhTSH + 7.4 GBq 131-Ide Keizer et al, EJNM (2003) 30:367-373 • Median tumor dose : 26.3 [ 1.3 – 368 ] Gy • Median tumor halflife : 2.7 [ 0.5 - 6.5 ] dd • Tumor dose > 80 Gy only in 5/25 tumors

  13. Main open questions about dosimetry in DTC: pre - post treatment ? • Pre – post treatment biokinetics are identical? • Benua blood and total body dose: no. • Canzi et al, benignant nodule: no • Med. Phys. 33(8) August 2006 2860-2867 • Koral et al 131-I mIBG liver dose: no • Eur J Nucl Med Mol Imaging (2008) 35:2105–2112 • Therapy uptake was always 10% 12% less than predicted

  14. Main open questions about dosimetry in DTC: pre - post treatment ? Pre treatment • Hypothyroidism therapy: • which time schedule for tracer administration ? • Low activity (Low gammacamera sensitivity) • “High” activity (stunning) • rhTSH Therapy: • Tracer administration must be performed under identical rhTSH administration Post treatment • No treatment planning • OK for verification • OK for red marrow dosimetry of the next treatment

  15. Main open questions about dosimetry in DTC: Toxicity or efficacy oriented ? • Ideally both side should be approached • Red marrow dosimetry: easy. • Only probe and blood samples • Lesion dosimetry: not so easy. • Problem of heterogeinity of lesion dose

  16. NUCLEAR MEDICINE THERAPY OF THEMETASTATIC DIFFERENTIATIED THYROID CANCER RED MARROW DOSE CALCULATIONPeriodico AIFM Feb 2007 C. Chiesa, S. C. Medicina Nucleare, Istituto Nazionale Tumori, MilanoA. De Agostini, S. C. Fisica Sanitaria, A O Spedali Civili, BresciaM. Ferrari, Servizio di Fisica Sanitaria, Istituto Europeo di Oncologia, MilanoG. Pedroli, S. C. Fisica Sanitaria, A O ” Niguarda Cà Granda”, MilanoA. Savi, Istituto Scientifico Ospedale S.Raffaele, MilanoA.C. Traino, U.O. Fisica Sanitaria, A O -Universitaria Pisana, Pisa Other coworkers: L. Bianchi, S. C. Fisica Sanitaria, A O “Ospedale di Circolo”, Busto Arsizio F. Botta, Scuola di Specializzazione in Fisica Sanitaria, Università degli Studi MilanoI. Butti, Servizio di Fisica Sanitaria, A O “Ospedale di Lecco”, LeccoC. Carbonini, S. C. Fisica Sanitaria, A O ” Niguarda Cà Granda”, MilanoL. Indovina, U. O. di Fisica Sanitaria, U.C.S.C., Policlinico “A. Gemelli”, Roma C. Pettinato, S. C. Fisica Sanitaria, A O Policlinico S. Orsola – Malpighi Bologna D. Zanni, S. C. Fisica Sanitaria, A O ” Niguarda Cà Granda”, Milano And all members of the work group AIFM- AIMN “Dosimetry in methabolic therapy”

  17. EANM Blood-based Dosimetry EANM Dosimetry Committee Series on Standard Operational Procedures for Pre-Therapeutic Dosimetry I. Blood and Bone Marrow Dosimetry in Differentiated Thyroid Cancer Therapy M Lassmann, H Hänscheid, C Chiesa, C Hindorf, G Flux, M Luster Eur J Nucl Med Mol Imaging (2008) 35:1233-1235 Very detailed and practical methodology

  18. EANM Blood-based Dosimetry: Methods

  19. EANM Blood-based Dosimetry: Calculation FIA(t): Fraction of the administered activity A0 as a function of time t; An objective criterion for the goodness of the fit such as the minimization of 2 should be used. The residence times for the whole body and activity concentration in blood, ttotal body [h] and tml of blood [h], are calculated by integrating the respective retention functions FIA(t) = A(t) / A0 from 0 to infinity:

  20. EANM Blood-based Dosimetry: ASSUMPTIONS Sblooddistant blood  STBTB Sblood remainder  STBTB Italian Internal Dosimetry Group contribution: red marrow dose. RMBLR = 1

  21. Same input data: TB , blood1 mL Benua-EANM almost identical Blood-Red marrow good agreement. Blood dose is 39% higher Blood vs red marrow dose

  22. Italian Internal Dosimetry Group Multicentrical dosimetric protocol DOSIMETRY IN METASTATIC DTC Chiesa C, Indovina L, Traino C, Sarti G, Savi A, Amato E, De Agostini A, Pedroli G Azzeroni R, Bianchi L, Botta F, Canzi C, Carbonini C, Cremonesi M, Strigari L, Fabbri C, Fioroni F, Giostra A, Grassi E, Pettinato C, Poli G, Rodella C, Spiccia P, Zanni D http://www.fisicamedica.org/aifm/ris/01_documenti_r/2008_10_06_PROTOCOLLO_DOSIMETRICO_CDT.pdf

  23. Italian Internal Dosimetry Group Multicentrical dosimetric protocol • 1st STEP: within fixed dose approach, to see what happens • Blood and red marrow: external probe and blood sampling • Lesions post treatment dosimetry • Planar and/or SPET/CT • CT MRI mass determination • Dead time correction with standard source • Rigorously uniform methodology • Data acquisition up to > 96 h, > 4 imaging scan • 2nd STEP: dosimetry based high activity administrations

  24. Italian Internal Dosimetry Group Multicentrical dosimetric protocol • Additional red marrow formula: non linear scaling of S value vs patient weight • Traino AC, Ferrari M, Cremonesi M, Stabin M “Influence of total-body mass on scaling of S-factors for patient-specific, blood-based red-marrow dosimetry” Phys Med Biol 52 (2007) 5231-5248

  25. X = water level INT contributionquantification methodChiesa et al Cancer Biother & Radiopharm 22(1) 2007 • Attenuation correction based on pre injection transmission scan with flood 57Co eff(57Co; water)=0.101/cm • Absolute gammacamera calibration with sphere in water, providing also eff(131I; water)=0.096/cm (pseudoextrapolation number MIRD16) • Check of the accuracy with same sphere in water without background: -10% +4% depending on the position • Very optimistic estimate without bkg, uniform medium, regular shapes

  26. INT dead time correction method • WB multstep (GE Infinia), • Different dead time count losses in different FOVS • Continuity hypothesys: counts in adjacent rows must change without jumps • A MATLAB code was developed • It locates discontinuities • It calculates the ratio between two summed row counts at the interface • Feet FOV is assumed dead time free • It calculates the ratio, used as correction factor Cn, • Cn=ROI(n-1)/ROI(n)) • Algorithm stars from feet, and it is applied in sequence upwards • A dead time corrected image is generated ROI(n) ROI(n-1)

  27. Approximated dead time correctionA0 = 321 mCi; scan @ 24 h Difference in tumour dose: a factor of 3

  28. INT:Dead time presence (grey cells)

  29. Results: Blood & red marrow dose 1 Gy to red marrow (blood) was overcome only in 3/8 (4/8)patients Red marrow (blood) dosimetry allows to increase the administered activity

  30. Results: dose to lesions † Dead † Lung lobe surgical resection Further biopsy and surgical operation Objective response (TC): volume reduction BUT Thyreoglobulin increases Patient under observation External beam radiotherapy Problem: Heterogeneity of lesion dose within the same patient !

  31. Heterogeneity of dose to different lesions • In patient MD, the lesion with high dose was absent in the previous treatment. So it was a new lesion with high uptake • The other lesion (pretreated) shows now very low uptake and dose • A single shoot, high activity treatment could have been more effective • Heterogeneity of lesion dose supports maximization of injected activity (Benua approach)

  32. 26 Gy 48 Gy 71 Gy 59 Gy 2nd treatment 260 mCi Sept ‘07 DOSIMETRY Diagnostic march ‘08 Patient UAM 1st treatment 200 mCi Feb ‘07 NO DOSIMETRY Diagnostic Sept ’08

  33. DISCUSSION:INT planar post treatment dosimetry • Radiation protection hazards are limited by a small number of patients • Major difficulties were: • Dead time correction • Lacking of recent morphological 3D imaging in electronic format • Difficult volume determination • Cooperation between physician and physicist • Limited quantification accuracy • Advantages • Strongest point: it gave the true absorbed dose during therapy • Simple red marrow (blood) dosimetry is a reliable pre treatment dosimetry for subsequent treatments • Lesion dosimetry, especially in low dose cases, can lead to immediate choices towards other therapeutic options

  34. FUTURE

  35. O’Donoghue Implications of Nonuniform Tumor Doses for radioimmunotherapy: Equivalent Uniform DoseJNM 1999 40:1337-1341 • BED  • ds()=[p() d]exp(-) • S= p() d exp(-) • EUD = -1/ ln(S) • Is the BED which gives the same effect if the distribution was uniform • EUD <= BED

  36. Non uniformity worsen efficacy • EUD <= mean BED • More heterogeneity is bad • The effect is relatively worse for • higher mean value (almost no advantage injecting more) • Higher radiosensitive tumours

  37. Application in the real world ? • BED concept have been applied • 3D dosimetry is required to apply EUD • SPET/CT system, now available can open the way • PET/CT with long lived isotopes (124I) begin to be applied • Siemens scanner include the spurious photons correction within scatter correction

  38. SPET/CT + MONTECARLO METHOD JNM 2006

  39. SPET/CT + MONTECARLO METHOD JNM 2007

  40. Conclusions • Many open questions – Large space for research. • Dosimetry alone is not sufficient but it is necessary for the optimization of radioiodine DCT treatment • Red marrow dosimetry and general absence of toxicity indicate that we can individually increase injected activity on a dosimetric base. • Ideally, pre treatment dosimetry is the best and necessary approach, but the correlation between pre – post treatment dosimetry must be deeply investigated. It is not free from problems (stunning, logistical problems). Post treatment dosimetry still has a role. • It gives the true biokinetics during therapy • It could be a first historical step towards a systematic optimization of radioiodine DTC therapy • It probably provides the informations for the Benua approach in subsequent treatments • It gives important clinical indications about the choices of therapeutic strategy • The future use of BED and EUD technology (industries investments) together with SPET/CT or PET/CT with 124-I will sharpen our weapons

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