( ) Outline. Internal Dosimetry for Targeted Radionuclide Therapy. Glenn Flux. Initial uses of TRT: I-131 NaI therapy for Ca Thyroid

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1 Outlne Internal Dosmetry for Targeted Radonuclde Therapy Glenn Flux Royal Marsden Hosptal & Insttute of Cancer Research Surrey, UK Background to targeted radonuclde therapy (TRT) MIRD methodology Whole-body dosmetry Tumour dosmetry Developments Mayneord Phlps summer school 29 Intal uses of TRT: I-3 NaI therapy for Ca Thyrod (Almost) standard admnstratons: P-32 to treat Leukaema, Berkeley Metabolc studes of bone tumours wth Sr-89, Berkeley P-32 for treatment of polycythema vera, Chcago 95 - I-3 for dagnoss and treatment of Graves dsease and ca thyrod (from 4 MBq to 3 MBq), Brookhaven 3 MBq ablaton followng surgery 55 MBq for further therapes Hgh actvty admnstratons of 9 MBq Good success rate. Dosmetry generally not requred. Ths set the standard for future therapes. MIRD methodology: Source and target organs Source organ Target organ MIRD Formalsm Eo φ( x, E )= E E ( ) Φ( x, E )= φ x,e dm x E dv Absorbed fracton, dmensonless Fracton of emtted energy deposted n target

2 Absorbed dose defnton Volume generalsaton D = E dm = φ ( x, E ) E dm Source h Target k D = Φ( x,e ) E D ( k h) = E = φ( k h) E m k m k = Φ( k h) E Dose n Gy (J/kg) D mean dose over target volume Non-penetratng radaton Radonuclde generalsaton () Source h Target k If a radonuclde emts: one type of partcle one energy E D& ( k h) = Ah E Φ( k h) φ φ ( k h) = f k h ( k h) = f k = h Depends on: organ sze partcle range D ( k k) = φ( k k) E = E m k D ( k h) = m k D& ( k h) s the mean dose rate (Gy/s) n target k from source h at tme t Radonuclde generalsaton (2) In fact, most radonucldes emt several partcle types and energes Let represent one partcle type then E s the partcle energy n s the number of partcles (photons or electrons) of type emtted per nuclear transton Then s the mean energy of type radaton emtted per nuclear transton Radonuclde generalsaton (3) The dose rate s the sum of all contrbutons (all type radaton) D& ( k h) k Ah ne Φ ( k h) = = k n E (k:converson factor) It s possble to smplfy: And s the total energy emtted per transton: = = k n E D& ( k h) = Ah Φ( k h) 2

3 Integraton over the tme nterval of nterest Integraton over the tme nterval of nterest (2) In fact, t s necessary to take nto account the tme durng whch rradaton takes place... t2 D ( k h) = D& ( k h) dt t Ah(t) Therefore: D t 2 ( k h ) = Ah Φ ( k h) t D ( k h) s the mean dose (Gy) n target k from source h dt A h = A h (t)dt Tme t Cumulated actvty (Bq.s or µc.h) tme ntegral of the actvty Cumulated actvty A h = A h (t)dt à h represents the total number of nuclear transtons occurrng n source h Usually: lower lmt: upper lmt: A h = A h (t)dt à h s calculated from bologcal data: pharmacoknetcs estmated graphcally, numercally, The MIRD S value D ~ = ( k h) k Ah ne Φ( k h) For a gven problem: k, n, E radonuclde data Φ Ã h ( k h) geometry and radonuclde data radopharmaceutcal knetcs It s possble to regroup all terms ndependent of tme: S( k h) = k n E Φ( k h) Ah(t) Ah(t) Ah(t) D ( k h) = A h S ( k h) Tme t Tme t Tme t MIRD smplfed equaton MIRD phantoms Crsty-Eckermann models Adult equaton- based model (MIRD/ICRP - 975) Equaton-based models of chldren and adults 987 3

4 The pregnant woman NURBS Sketches of the woman at varous stages of gestaton Geometrcal model for the 3 month pregnant woman (Stabn et al. 995) Rchard C. Ward RADAR dose factors Calculated dose factors for >8 radonucldes for: Adult Male 5-year-old -year-old 5-year-old -year-old Newborn Unt Densty Sphere Model Adult Female 3 month pregnant female 6 month pregnant female 9 month pregnant female MIRD Head and Bran Model Prostate Gland Model Pertoneal Cavty Model Get the data free, by electronc download, at the RADAR ste. Publcaton: Health Physcs, 85(3):294-3, 23. MIRD Concluson The MIRD scheme: mpressve collecton of data Can be used smply BUT... A number of assumptons & approxmatons Method developed n the 96 s for radaton protecton S values are for a standard patent, - a model rather than YOUR patent Therapy s not covered explctly (tumours?) Personal dosmetry reles on quanttatve magng (Ã) Now movng towards patent-specfc dosmetry Problems & Issues. Defnton of target organs anatomcal vs functonal volumes. 2. Assumpton that actvty s unformly dstrbuted 3. Image quantfcaton methods vary from centre to centre - varous correctons to be made attenuaton & scatter, partal volume 4. Treatment plannng? Optmsaton of dose to the target volume whlst mnmsng dose to normal tssue. Target volume defned as for EBRT, although organs at rsk vary. Crtcal organ toxcty Myelotoxcty s the greatest problem wth most therapes. Often exacerbated by marrow nvolvement. Platelets Fall n platelets followng I-3 mibg therapy for neuroblastoma 4

5 Red marrow dosmetry Whole-body dosmetry Possbly the most dffcult dosmetry to perform accurately Drect samplng? Imagng? Evaluaton from blood doses? Whole-body dosmetry? External countng Easy to perform Imagng not necessary Ward staff, carers can take measurements Tracer & therapy actvty-tme curves I-3 mibg for neuroblastoma - predcton of whole-body doses from tracer studes Actvty remanng (MBq) Tracer Therapy Tme post admn (h) WB dose gven (Gy) WB dose predcted from tracer study (Gy) I-3 mibg therapy for neuroblastoma Buckley et al (J Nucl Med n press) I-3 mibg for neuroblastoma Absorbed dose to whole-body absorbed whole-body dose (Gy) % fall n platelet count Prevous therapy Tracer Weght-based Fxed actvty Correlaton of absorbed whole-body dose (Gy) wth percentage fall n platelet count, Spearman rank correlaton, p <.5 5

6 I-3 mibg for neuroblastoma I-3 mibg for neuroblastoma Trombodrop versus WB dose WB dose Trombodrop n % per day Correlaton of neutrophl toxcty wth WB dose p=.5 Monseurs et al Eur J Nucl Med 29, (22) I-3 mibg for neuroblastoma I-3 mibg for neuroblastoma Study: Feasblty of Dosmetry-Based Hgh-Dose 3 I-Meta Iodobenzylguandne wth Topotecan as a Radosenstzer n Chldren wth Metastatc Neuroblastoma Am: To delver 4 Gy whole-body dose n two treatments Treatment 444 MBq / kg n treatment Treatment 2 Actvty based on that delvered for treatment to make up a total of 4 Gy WB dose Gaze et al CBR 2 (2) (25) Results (8 patents): Mean total dose of 4.2 Gy (range Gy) Range of admnstered actvtes: GBq 25 GBq Gaze et al CBR 2 (2) (25) Frst admnstraton based on pre-therapy dosmetry Posttherapeutc scan after 3 I-mIBG cycle 2 Somewhat lower bone marrow actvty n comparson to cycle. Note the rght paravertebral focus (arrow), probably n the remanng rght adrenal gland Pre-therapeutc scan Post-therapeutc scan after 3 I-mIBG cycle Becherer et al Venna chldren s hosptal 6

7 23 I-mIBG scan 7 mo after 3 I-mIBG therapy Normal mibg scan asde from a slghtly asymmetrc uptake n the thyrod bed (arrow) Example of tumour dosmetry Dosmetry study for thyrod ablaton: 3 MBq I-3 NaI 23 patents (7 papllary, 6 follcular) Dosmetry: SPECT (3-4 scans) Trple energy wndow scatter correcton Chang attenuaton correcton Separate calbraton phantom maged Also, blood, PBI s, whole-body radaton doses calculated Delneaton of volume outlne Maxmum voxel uptake Thyrod remnant (24 hours post admn) Thyrod remnant (24 hours post admn) Sequental scans Tme actvty curve Actvty (MBq) Scan (7 mns) h Scan 2 (2 mns) 5.5 h p.a. Scan 3 (25 mns) 66.8h p.a. Actvty remanng (MBq) Tme post admnstraton (h) 7

8 Absorbed dose maps Absorbed dose + CT Radaton Dose (Gy) 22 Transaxal Coronal Sagttal Maxmum voxel radaton dose Absorbed dose to blood.35 Maxmum voxel dose (Gy) Non-responders Responders Blood self-absorbed dose (Gy) Faled ablaton (mean.23 Gy) Successful ablaton (mean.6 Gy) Sgnfcant correlaton (p=.3) Range of doses:.6.29 Gy t-test: p =.43 Absorbed dose to blood Results absorbed blood dose (Gy) % fall n platelet count Correlaton of absorbed blood dose (Gy) wth percentage fall n platelet count Spearman rank correlaton, p <. Mean dose +/- SD (Gy) Responders Range of doses (Gy) Non-responders Mean dose +/- SD (Gy) Range of doses (Gy) p value Remnants Blood Red marrow Wholebody X Flux et al (Eur J Nucl Med n press) 8

9 6 day - day PBI Correlaton tumor response vs dose (measured wth PET and CT-scan) at end of treatment 9 Y-SMT-487 tral (n = 32) 6 day - Day PBI (%dose/l) % tumor reducton Non-responders Responders Gy p =.74 (Mann Whtney) Stephan Walrand, Brussels UCL Brussels Polymer gels for TRT Calbraton Calbraton curve for dfferent gel batches rradated wth I3 Batch Batch 2 3. Batch 3 Batch 4 ml P-32 9 ml MAGIC Mx castor ol R 2 (s - ) ft to data ponts Dose (Gy) afte r ~ 6 Hrs Jon Gear, RMH Polymer gels for TRT Polymer gels for TRT 9

10 Polymer gels for TRT Polymer gels for TRT Patent stuaton Create phantom of MAGIC gel smulatng patent SPECT Perform conventonal dosmetry Measure dose usng MRI CT Compare doses MRI optmse dosmetry protocol determne accuracy of dosmetry for patent I-3 NaI for thyrod treatment TRACER 8 MBq THERAPY 893 MBq Developments SPECT The dstrbuton of uptake (& absorbed dose) s not always unform Lung metastases from ca thyrod dose maps CT & I-23 SPECT (neuroblastoma) I-3 mibg for neuroblastoma I-3 mibg for neuroblastoma I-3 SPECT Absorbed dose Dose (rendered) R S L CT + sodose contours I

11 Treatment plannng: Combned modalty radotherapy Dose (Gy) 45 TRT dose map Physcal Dose Maps Radonuclde dose Max 45 Gy Dose (Gy) 45 Dose (Gy) 6 External Beam dose 6 Gy to socentre Parallel opposed par Dose (Gy) 6 Parallel opposed par Rachel Bodey IMRT + TRT dose map Combned Modalty Radotherapy? CMRT Dose volume hstogram Dose (Gy) 6 Dose(Gy) 4 2 Dose-Volume Hstogram Percentage Volume Dose (Gy) Rachel Bodey, ICR External Beam CTV External Beam left kdney Combned therapy CTV Combned therapy left kdney Concluson Rules and regs. Targeted therapy s ncreasng n range and numbers of therapes. It s lkely that ths wll be developed wthn radotherapy (NCRI support). 2. The current state of dosmetry for TRT s probably some decades behnd that of EBT. But there are sgnfcant dfferences as well as smlartes and problems to be solved. 3. Dosmetry has been developed to the extent that t s clncally benefcal. The new challenge s treatment plannng.

12 Cumulated actvty (2) Fundamental equaton of the MIRD scheme Ah(t) If A h (t) can be approxmated by a sum of exponentals: Then: Where: And: Tme t A h (t) = ( ) eff A h = A j (λ + λ j ) =.443 A j T j j j = ( T j ) eff T + T j ( T j ) eff =.693 (λ + λ j ) j A j e ( λ+λ j )t (T j ) eff s the effectve half-lfe of the j-th exponental component D Source h ~ = ( k h) k Ah ne Φ ( k h) Target k Summary: Mean absorbed dose (Gy) Source h Target k à h nuclear transtons n source h (Bq.s) Range of radaton doses thyrod ablaton Range of radaton doses Dorn et al (JNM 23): GBq to gve a 3 Gy marrow dose. Sgouros (JNM 24): Mean doses of.2 54 Gy (usng I- 24 NaI) RMH (unpublshed): Maxmum voxel doses - 6 Gy n 23 patents (more later) Matthay et al (JNM 22) I-3 mibg for neuroblastoma Admnstered actvty: 555 MBq/kg I-3 mibg Tumour absorbed doses: 3-35 Gy Wseman et al (Cancer 22) Zevaln (Y-9) Admnstered actvty: 5 MBq/kg Absorbed doses: Red marrow.3.2 Gy Absorbed tumour dose Gy 2