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. D = E / m Maxon: lesion mass
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 mets D < 80 Gy D > 80 Gy
Successful treatment
of mets 12/19 (63%) 46/47 (98%)
Maxon et al J Nucl Med 1992;33:
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 dosimetry rhTSH + 7
Metastases dosimetry rhTSH GBq 131-I de Keizer et al, EJNM (2003) 30:
Median tumor dose : [ 1.3 – 368 ] Gy
Median tumor halflife : 2.7 [ ] 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
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 THE METASTATIC DIFFERENTIATIED THYROID CANCER RED MARROW DOSE CALCULATION Periodico AIFM Feb 2007
C. Chiesa, S. C. Medicina Nucleare, Istituto Nazionale Tumori, Milano A. De Agostini, S. C. Fisica Sanitaria, A O Spedali Civili, Brescia M. Ferrari, Servizio di Fisica Sanitaria, Istituto Europeo di Oncologia, Milano G. Pedroli, S. C. Fisica Sanitaria, A O ” Niguarda Cà Granda”, Milano A. Savi, Istituto Scientifico Ospedale S.Raffaele, Milano A.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 Milano I. Butti, Servizio di Fisica Sanitaria, A O “Ospedale di Lecco”, Lecco C. Carbonini, S. C. Fisica Sanitaria, A O ” Niguarda Cà Granda”, Milano L. 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:
Very detailed and practical methodology

18. EANM Blood-based Dosimetry: Methods
Time
Task
Quality control,
preparation of 131I standard and tracer activity,
micturition (just before administration)
Administration of 131I tracer activity
Avoid micturition or defecation
10 min (i.v. admin.)
2 h (oral admin)
Measurement of whole body activity, blood sampling (2 ml)
6 h
Micturition (just before whole body measurements),
measurement of whole body activity, blood sampling (2 ml)
24 h
measurement of whole body activity, blood sampling (2 ml)
96 h
144 h
blood sampling (2 ml)
optional: measurement of whole body activity
Evaluation of blood absorbed dose and therapeutic activity

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:
Dose to the blood is the sum of the blood self-dose plus the contribution of the whole body.

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. Blood vs red marrow dose
Same input data: TB , blood 1 mL
Benua-EANM almost identical
Blood-Red marrow good agreement. Blood dose is 39% higher

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

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)

25. INT contribution quantification method Chiesa 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
X = water level

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 correction A0 = 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. Patient UAM Diagnostic march ‘08 2nd treatment 260 mCi Sept ‘07
DOSIMETRY
26 Gy
71 Gy
59 Gy
48 Gy
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 Dose JNM :
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