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.

DOSIMETRY IN RADIOIODINE THERAPY OF METASTATIC DIFFERENTIATED

THYROID CANCER

Chiesa1 C., Castellani1 M.R.,

Botta2 F., Azzeroni2 R.,Seregni1 E., Bombardieri1 E.

1) National Tumour Institute – Milan - Italy2) Post graduate Health physics school – Milan -

Italy

Table of content1. The history of dosimetry:

– Benua (healthy organ dosimetry - toxicity)– Maxon (lesion dosimetry - efficacy)

2. The present development of dosimetry– EANM SOP for blood and marrow dosimetry– The Italian Internal Dosimetry Group– The experience at INT

3. The future development- SPET/CT + Montecarlo aplications

4. Conclusions

PAST

History of dosimetry in DTC: Benua - hematological and lung toxicity

Poor statistics !

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):

)/(112)()(

092.0)/( 1 mLhh

kgmGBqGyd mL

BLtotalbodyp

RM

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)

Pre-treatment = post-treatment ?

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

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

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 GySuccesful Ablation 3/7 22/23 (96%)

Dose to mets D < 80 Gy D > 80 GySuccessful 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

PRESENT

Metastases dosimetry

rhTSH + 7.4 GBq 131-I

de 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

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

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

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

NUCLEAR MEDICINE THERAPY OF THEMETASTATIC DIFFERENTIATIED THYROID CANCER

RED MARROW DOSE CALCULATION

Periodico AIFM Feb 2007C. 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”

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

Time Task

Quality control, preparation of 131I standard and tracer activity, micturition (just before administration)

0 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 Micturition (just before whole body measurements),measurement of whole body activity, blood sampling (2 ml)

96 h Micturition (just before whole body measurements),measurement of whole body activity, blood sampling (2 ml)

144 h blood sampling (2 ml)optional: measurement of whole body activity

Evaluation of blood absorbed dose and therapeutic activity

EANM Blood-based Dosimetry: Methods

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, total body [h] and ml of blood [h], are calculated by integrating the

respective retention functions FIA(t) = A(t) / A0 from 0 to infinity:

EANM Blood-based Dosimetry: Calculation

)exp()exp()( btBatAtFIA

bBaAdt FIA(t) 0

//

EANM Blood-based Dosimetry: ASSUMPTIONS

)/(108)()(

0188,0)/(

3/2mLhh

kgmMBqGyd mL

bloodTB

p

Bl

Sblood distant blood STBTB

Sblood remainder STBTB

)/(61)()(

106.0)/( 1 mLhh

kgmGBqGyd mL

BLtotalbodyp

RM

Italian Internal Dosimetry Group contribution: red marrow dose.

RMBLR = 1

Blood vs red marrow dosePost therapy dosimetry

0.0

0.5

1.0

1.5

2.0

2.5

Patient

D (Gy)

Red Marrow

EANM blood

BENUA blood

• Same input data: TB , blood 1 mL

• Benua-EANM almost identical

• Blood-Red marrow good agreement. Blood dose is 39% higher

Red marrow - blood dose correlation

y = 1.39x - 0.04

R2 = 1.00

0.0

0.5

1.0

1.5

2.0

2.5

0.0 0.5 1.0 1.5 2.0 2.5

Red marrow dose (Gy)

EA

NM

Blo

od

do

se (

Gy)

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 GAzzeroni 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

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

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

948.1331.1

1

026.01

1683.4698.0)/(2.15)(

)()/(588.5)/(

pp

pmL

BLtotalbody

pmL

BLRM

mmmmLhh

kgmmLhGBqGyd

INT contributionquantification 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

Calibration factor including attenuation correction

y = 4.7887e-0.0480x

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

4.5

5.0

0.0 5.0 10.0 15.0 20.0 25.0

Water thickness X (cm) [Source at half thickness]

Se

ns

itiv

ity

(c

pm

/kB

q)

X = water level

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-1)

ROI(n)

Difference in tumour dose: a factor of 3

Lung lesion

0

0.0005

0.001

0.0015

0.002

0 24 48 72 96 120 144 168 192 216

h

FIA

WITHOUT dead timecorrection

WITH dead timecorrection

Approximated dead time correctionA0 = 321 mCi; scan @ 24 h

INT:Dead time presence (grey cells)

Pt ID DL FI PAM MN DTL FA MD UAM median min max

Sex m f f f m m m f

Weight 77 70 77 60 88 70 90.5 70

Adm activity (MBq) 5869 9477 6620 10000 7621 6944 11882 9574.3 8549 5869 11882

Adm activity (mCi) 159 256 179 270 206 188 321 259 231 159 321

Time of 1^ scan (h) 23 31 53 22 23 23 28

Time of 2^ scan (h) 72 53 70 53 71 56 54

Time of 3^ scan (h) 94 70 95 70 71 71

Time of 4^ scan (h) 93 190 94

Time of 5^ scan (h) 0 189

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

Maximum Red marrow (Blood) Dose = 1.4 (1.9) GyPLT (x 1000/uL)

0

20

40

60

80

100

120

140

160

180

0 7 14 21 28 35 42 49 56 63(d)

PL

T x

10

00

Pz ID DL FI PAM MN DTL FA MD UAM median min MAXAdm activity (MBq) 5869 9477 6620 10000 7621 6944 11882 9574 8549 5869 11882

Absorbed Dose per unit activity (Gy/GBq)RED MARROW 0.04 0.06 0.05 0.12 0.04 0.12 0.12 0.11 0.09 0.04 0.12BLOOD 0.05 0.10 0.08 0.18 0.06 0.16 0.16 0.17 0.13 0.05 0.18

Absorbed Dose (Gy)RED MARROW 0.3 0.6 0.4 1.2 0.3 0.8 1.4 1.1 0.70 0.25 1.44BLOOD 0.3 0.9 0.5 1.8 0.4 1.1 1.9 1.6 1.03 0.26 1.92

Results: dose to lesions

Lung lobe surgical resection

Further biopsy and surgical operation

External beam radiotherapyObjective response (TC): volume reduction

BUT Thyreoglobulin increases

Patient under observation

Pz ID DL FI PAM MN DTL FA MD UAMno

Lesion mass measurement n/a RX lesion n/a SPET SPET CT NMR

Lesion mass (g) 4 25 1195 0.7 2.41.7 2.6

0.62.2

ABSORBED DOSE (Gy) 12.2 0.5 7.2 288 482 26

5971

Problem: Heterogeneity of lesion dose within the same patient !

† Dead †

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)

Patient UAM

1st treatment

200 mCi Feb ‘07

NO DOSIMETRY

2nd treatment

260 mCi Sept ‘07

DOSIMETRY

26 Gy

71 Gy

59 Gy

48 Gy

Diagnostic march ‘08 Diagnostic Sept ’08

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

FUTURE

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

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

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

SPET/CT + MONTECARLO METHOD

JNM 2006

SPET/CT + MONTECARLO METHOD

JNM 2007

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