DOSIMETRY IN RADIOIODINE THERAPY OF METASTATIC DIFFERENTIATED THYROID CANCER

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
Benuas safety prescriptions (hematological and
lung toxicity)

• Blood dose lt 2 Gy
• At 48 h, ATB lt 120 mCi (4.4 GBq)
• At 48 h, ATB lt 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 4719851994)
• 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 44451456)

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 199943313-23)

• 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
199943_313-23
Maxon et al, NEJM 1983 Remnant Dose D lt 300
Gy D gt 300 Gy Succesful Ablation 3/7 22/23
(96) Dose to mets D lt 80 Gy D gt 80
Gy Successful treatment of mets 12/19
(63) 46/47 (98) Maxon et al J Nucl Med
1992331132-1136 D gt 300 Gy 142 remnants 86
successful Activity mean range 86.8 25.8
246.3. A lt 50 mCi in 50 of cases
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PRESENT
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Metastases dosimetry rhTSH 7.4 GBq 131-I de
Keizer et al, EJNM (2003) 30367-373

• Median tumor dose 26.3 1.3 368 Gy
• Median tumor halflife 2.7 0.5 - 6.5 dd
• Tumor dose gt 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) 3521052112
• 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

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NUCLEAR MEDICINE THERAPY OF THEMETASTATIC
DIFFERENTIATIED THYROID CANCER RED MARROW DOSE
CALCULATION Periodico 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

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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)
351233-1235 Very detailed and practical
methodology
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EANM Blood-based Dosimetry Methods
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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
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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
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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

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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

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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 gt 96 h, gt 4 imaging scan
• 2nd STEP dosimetry based high activity
  administrations

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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

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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

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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,
• CnROI(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)
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Approximated dead time correctionA0 321 mCi
scan _at_ 24 h
Difference in tumour dose a factor of 3
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INTDead time presence (grey cells)
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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
1st treatment 200 mCi Feb 07 NO DOSIMETRY
Diagnostic Sept 08
33
DISCUSSIONINT 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

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FUTURE
35
ODonoghue Implications of Nonuniform Tumor
Doses for radioimmunotherapy Equivalent Uniform
DoseJNM 1999 401337-1341

• 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 lt BED

36
Non uniformity worsen efficacy

• EUD lt 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