�radiometabolic therapy: history and evolution Dott. Diana Salvo

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�radiometabolic therapy: history and evolution Dott. Diana Salvo Powered By Docstoc
					“radiometabolic therapy: history and evolution
                     Dott. Diana Salvo

La Terapia Radiometabolica in Emilia Romagna e Marche.
         Nuove terapie e protocolli in evoluzione:
       Aspetti fisici, dosimetrici e radioprotezionistici
                   Macerata 5 febbraio 2009
       In principio………………

…….erat iodium

1945: first treatment with 131I-radioiodine
           Why it is a success

• Availability post bellum of radionuclides
• Excellent metabolic carrier-free tracer
• His use helped to know metabolic
  mechanisms of the body and thyroid function,
  developing methods to describe kinetic
  phenomenon and his K and to calculate
  the dose to subministrate
• Favourable emission for therapy, but also for
               Dosimetry - 1

• Is born from necessity to define the
  irradiation received by target and internal
  organs from used radiopharmaceutical: the
  dose is calculated by dosimetric approach
  and depends on the objective (function
  decrease? tissue destruction?).
                Dosimetry - 2

• All the methods of calculation are
  influenced by the impossibility to define
  exactly all the complex metabolic
  mechanisms implicated in this therapy
  and are therefore invalidated by a non
  definible factor of inaccuracy.
                  Dosimetry - 3

• In the first decades of metabolic therapy, the
  limitation of technical devices available to
  determinate kinetic and dimensions of the thyroid
  conditioned heavily the dosimetric calculation.
                   Dosimetry - 4

• In the Marinelli‟s historic formula (1948), there is
  no mention of thyroid size:

                    Db=73.8 C0EbT
                Dosimetry - 5

After a few of years, the gland volume and weight
were inserted: the value was absolutely
approximate, extracted by bidimensional maps,
built with values taken point to point by a manual
probe, subsequently placed on a mechanical arm
that moved above the neck.
             DMQ = 0.185A0Teff x U
Thyroid Cancer - 1970
Scintigraphic scan with gammacamera - 1975
                Tracers theory

• With these devices (a lot of enthusiasm and a
  pinch of unconsciousness ), the tracers theory
  was constructed; it is indispensable for who
  wishes to know the reason of some biological
  behaviours of our radiopharmaceutical.
• The introduction of gamma camera, US-scan,
  more sensitive probes and new
  radiopharmaceutical helps the task of the
  medical physicist evaluations
 Internal dosimetry: a challenge to win
         (Bestagno - Notiziario AIMN n° 4 2008)

• Not simple for some problems
  • Scientific
  • Logistic
  • Operative
• The D.Lgs 187/2000 requires the optimization of
  the doses, a “process” in which is included the
  dosimetry “which cannot be ignored”, even if
  sometimes it is more simple and equally efficient
  to use standard procedures.
    Internal and external dosimetry

Both calculate the absorbed dose as a quantity of
energy emitted by a source and deposited in a
region/mass unit
but the difficulty of a correct calculation of dose in
internal dosimetry is due to physiopathological
processes in the human body that determines the
radiopharmaceutical concentration in the target
and control the absorption and elimination

• We must accept in the preliminary step
  an approximation to verify, afterwards,
  the accuracy of our calculations and to
  produce, if possible, the suitable
        “Old” Radiometabolic Therapy

131I   iodine
   • Hyperthyroidism (doses up to 600 MBq):
      • about il 52% of therapeutic activity in Italy
      • usually outpatient or DH
      • safe treatment: no radiation damage, no
        increase % of other tumours or leukemia,
        no genetic damage or fertility decrease
   Old” Radiometabolic Therapy

• Differentiated thyroid
   • Ablation of remnant and adjuvant treatment of
      • Criteria for the dose definition
          • size of remnant
          • histology
          • N status and risk of metastasis
      • Fixed dose with rhTSH
   • Treatment of metastasis
Low risk – 1850 MBq
High risk – 5550 MBq
N+ - 5550 MBq
Post therapy WB
with linear scanner
             Post therapy WB
             with linear scanner
124I   WB: metastatic spread
     Old” Radiometabolic Therapy


  In polycythemia resistent to chemotherapy
  age > 70 yrs
  High risk (15%) of acute leukemia
    Radiometabolic Therapy “Now”

Palliative treatment of metastatic bone pain
• Pain resistent to usual treatment
• Without complications metastases
• Bone scan positive in the site of x-ray lesions
• No visceral disease
• Acceptable hemochrome, renal and hepatic
• No recent chemotherapy and radiotherapy
• Life expectation > 6 m
 Radiometabolic Therapy “Now”

Palliative treatment of metastatic bone pain
• 153Sm-EDTMP - b e g emitter; weight-related dose
• 89Sr-cloruro - b emitter; fixed dose (148 MBq)
• 186Re-HEDP - b e g emitter
Feasible dosimetry with g emitter
Matched treatments : chemo + radiometabolic
  (+ Cisplatino - Sciuto)
    Radiometabolic Therapy “Now”

Radiosinoviortesis (0.4% of treatments)
•   90Y-citrate  (big joint: knee)
•   186Re-solphide (middle joint: elbow)

•   169Er-citrate (little joint: finger)

    It isn‟t a metabolic therapy, but a
    radioactive drug distribution into a closed
      Radiometabolic Therapy “Now”

• NeuroEndocrine Tumor (NET) therapy
  •    131I-mIBG

      with complete or incomplete responses = 20%
• Ab monoclonale therapy in NHD follicular
  lymphoma CD20+, relapsed or resistent to
  •   90Y-ibritumomab   tiuxetan (Zevalin®)
• Therapy in hepatocellular carcinoma
  •   131I-Lipiodol

      tumor regression up to 80% of patients;
      improuvement of life quality
          What is necessary
for radiometabolic therapy evolution?
• New radionuclides with optimal peculiarities
  for therapy (b e a emitters) that make easier
  the patient management (DH or outpatient?)
• New molecules, specific for single target
• Feasibility of imaging to control specificity and
  localization of radioactive drug
• Association with other treatments (chemo or
• Dosimetry feasibility                   Pace 2008
                New radionuclides

a emitters:
  • LET: high, ideal for therapy.
  • Irradiation risk very low for the staff
    Dangerous internal contamination
     •   211At, 213Bi, 223Ra
          Radionuclides a- emitters
                for therapy

Nuclide    Half-life     Emission             Emission
                       Therap.   MeV    Diagn.     KeV
 213Bi      45 m         a       5.85     g        293
                       (and b)
 211At     7.2 h         a       5.8      g        687
223Ra      11.4 d        a       5.7      g      144 - 154
              New radionuclides

b emitters:
  • suitable for therapy; LET < a emitters
  • high risk of hands irradiation for the workers
    during the manipulation and injection operations;
    contamination risk
               New radionuclides

b emitters:
   • sometimes further emission, usable for diagnostic
     imaging or, subsequently, for dose distribution
   • used often to label di- and tetraphosphonate and
      • 177Lu, 186Re, 188Re, 166Ho, 153Sm
      • 64Cu
          Radionuclides b- emitters
                for therapy
Nuclide   Half-life      Emission         Emission
                      Therap.   MeV   Diagn.     KeV
 213Bi     45 m       a e b-   1.4      g       293
177Lu      6.7 d        b-     0.5     g      113-208
186Re     90.6 h        b-     1.1     g        137
188Re     16.9 h        b-     2.1     g        155
166Ho     26.8 h        b-     1.9     g        184
153Sm     12.7 h        b-     0.6     g        127
 64Cu     46.7 h        b-     0.6     b+       0.7
 From now on,
all the treatments
are experimental
    New very specific molecules
         for single target
• Receptor tracers
  • Analogous to Somatostatine (SMS):      90Y
    • DOTATOC    labeled by                177Lu

    • DOTATATE                             213Bi


                                           for therapy
                      b+ emitter for PET
              Receptorial therapy
        with labeled analogous of STS
• Each radionuclide has some little differences
  in kinetics compared with other labeled
• 111In and 90Y have similar half-life and, using
  the same analogous DOTA…., dosimetric
  calculation by 111In to evaluate the
  therapeutic effect of 90Y is reasonable; 68Ga-
  DOTA… can be used in diagnostic step.
111In-DOTATOC   Dosimetry

                     An example of ROI
                     creation window
           Receptorial therapy
     with labeled analogous of STS

• In NETs
                   Intestinal NETs

111In-Octreoscan                     68Ga-Dotatoc
              Intestinal NETs
               68Ga-DOTATOC   PET/CT

Pre-therapy                                Post-therapy
R.A. male, 59 yrs - Liver metastases from intestinal NET
Partial response to 90Y-DOTATOC Treatment
                            Lung NET
                         68Ga-DOTATOC   PET/CT

             Pre-therapy                             Post-therapy
R.I. male, 76 y - Liver, bone and lymph node metastases from lung
neuroendocrine carcinoma.
Progression disease after 90Y-DOTATOC treatment
           Receptorial therapy
     with labeled analogous of STS

• in other tumours with SMS receptors:
  • Microcitoma
  • Thyroidy Differentiated Carcinoma with no
    131I uptake

  • Some glioblastomas
  • Some breast tumours
        Differentiated Thyroid Cancer

                        68Ga-DOTATOC   PET/CT

B.M. male, 75 yrs: Diffuse lung metastases (+ bone and lymph node mts)
        Differentiated Thyroid Cancer

WB 131I may „03

                         BS february „05

PET 18F-FDG august „04                     PET 68Ga DOTATOC: september „07
    Hepatocellular carcinoma therapy

•   188Re-Lipiodol

       • For radioembolization of afferent vessels
         of hepatic well perfused lesions
  Hepatocellular carcinoma therapy

……. but radioembolization also by
• 90Y- glass microspheres (Therasfere-1)
• 90Y- SIR-spheres (2)
    Both are devices; 90Y is integrated in non
    biodegradable glass (1) and syntetic resin
    ( 2)

Intraoperative Avidination for Radionuclide
  Therapy in breast cancer
• 1st step: avidine introduction in surgical site
• 2st step: after 2 days, 90Y- o 177Lu-biotine
  injection i.v.; this radiopharmaceutical
  binds quickly to avidine and sterilizes the
  surgical bed

Bladder Intraoperative Avidination for Radionuclide
  Therapy (preliminary study)
  in the bladder cancer:
   • 1° step: avidine injection into the bladder
   • 2° step: 111In-biotine introduction; diagnostic
     control of radiopharmaceutical concentration
     in cancer
         …….and tomorrow?

• Theoretically, it is possible to label all
  molecules or particles of oncological
• It is indispensable to simplify bureaucratic
  procedures and regulations to test new
  radiopharmaceutical, warranting the
  maximum of safety to the patient.
                Final questions 1

• Can we really have a correct calculation of
  the dose to administrate?
• No. The error percentage (up to 40-50%) is
  too high now
• Solution: it is important to know as well as its
  possible the physiopathologic problems, but a
  part of phenomena shall remain always
                   Final questions 2

• Is preliminary dosimetry useful to physician?
• Yes, in some situations:
  • When he studies a new radiopharmaceutical
  • In non oncologic treatments
  • In oncologic treatments
     • to define the maximum of dose to kill the tumour
       without damage to patient (organ at risk evaluation)
     • to define the radiation dose of a lesion; when there is a
       metastatic spread, dosimetric calculation is impossible
                Final questions 3

• Is the time employed in the dosimetric
  evaluations correct for the patient and
• Yes, absolutely necessary if the dosimetric
  calculations give important information to the
  physician; if the data are useless, ineffective
  or inaccurate, we must look for other
        Last question
   (only for italian people)

Terapia Radiometabolica
   Terapia molecolare
Terapia Medico Nucleare?

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