TIME (sec)

Yu Wen Chen ( 陳毓雯)M.D.

Department of Nuclear Medicine, Kaohsiung Medical University

Hospital; Department of Medicine, School of Medicine,

Kaohsiung Medical University, Kaohsiung, Taiwan

 Introduction of radiopharmaceutics –

 Concept of radiation biology- alpha emitter

 History of radiopharmeceutics in Tx of prostate cancer with bone metas.

 Concept of bone metastasis- prostate cancer

 The phase III clinic trial of Ra 223- NEJM

 Comparison with bone seeking

radiopharmaceutics- Sr89, Sm153

 Most a combination of

 (A) a radioactive molecule, a radionuclide

(放射核種),

providing radiation eg. diagnosis (gamma

and X ray) and therapy ( betta and alpha).

(B) a biologically active molecule or drug providing a carrier and determining localization and

biodistribution (生物分佈).

Some radioactive atoms themselves confer the desired

localization properties, eg iodine, gallium, radium etc.

Antoine Henri Becquerel

The Nobel Prize in Physics 1903

• The becquerel (symbol Bq)

(pronounced: 'be-kə-rel) is the SI derived unit of radioactivity.

• 1 Bq is defined as the activity of a quantity of radioactive material in which one nucleus decays per

second.

• The becquerel succeeded the curie (Ci), an older, non-SI unit of

radioactivity based on the activity of 1 gram of radium-226.

1 Ci = 3.7×10

¹⁰

Bq = 37 GBq 1 μCi = 37,000 Bq = 37 kBq

1 Bq = 2.7×10

⁻¹¹

Ci = 2.7×10

⁻⁵

µCi

It is impossible to know at what time a certain radioactive nucleus will decay. It is, however possible to determine the probability l of decay in a certain time. In a sample of N nuclei the number of decays per unit time is then:

Rt = -dNt/ dt;

radioactivity: No. of disintegration of a sample of nuclei (atoms) per unit of time

Rt = λ Nt; λ: decay constant

ln 2= 0.693







2 T ln

e N

= N(t)

dt N dN

2 / 1

t - 0













 Alpha 

 Beta 

 Gamma 

 X-ray X

 Neutron n

E =MC ²

Linear Energy Transfer

LET

8



α radiation consists of helium (

⁴

He) nuclei and is stopped by a sheet of paper or skin



β radiation, consisting of electrons, is halted by an aluminum plate or plastic



γ radiation, consisting of energetic photons, is

attenuated by dense material

Paper

or Skin Aluminum Lead or

Concrete Water or Polyethylene

α β γ

1. Kassis AI. Semin Nucl Med. 2008;38(5):358-366. 2. Brechbiel MW. Dalton Trans. 2007;43:4918- 4928. 3. Nilsson S, et al. Poster 2385 presented at: American Society for Radiation Oncology Annual

Meeting; October 31-November 4, 2010; San Diego, CA.

10^-6 10^-12

10^-9 10^-15

10^-3

1 second

1 hour 1 day 1 year

100 years 1 ms

10⁰

10⁹ 10⁶ 10³

Energy deposition Excitation/ionization Initial particle tracks

Radical formation

PHYSICAL INTERACTIONS

PHYSICO-CHEMICAL INTERACTIONS

BIOLOGICAL RESPONSE

MEDICAL EFFECTS

Diffusion, chemical reactions Initial DNA damage

DNA breaks / base damage

Repair processes Damage fixation Cell killing

Promotion/completion

Teratogenesis Cancer

Hereditary defects

Proliferation of "damaged" cells Mutations/transformations/aberrations

TIME (sec)

Timing of events leading to  radiation effects

Absorbed energy per mass unit

1 Gy (gray) 戈雷=1 J/kg

Harold Gray 1905-1965

H _e = w _r * D

D: absorbed dose (Gy), w

_r

: radiation weighting factor (1-20)

H _eff =w _T *H _e

H

_e

: equivalent dose (Sv), w

_T

: tissue weighting factor (0.05-0.20)

Unit: 1 Sv (sievert) 西弗

E w _T H

T

   T

Rolf Sievert (1896-1966)

Radiation types Quality factors

Camma rays and X-rays 1

Electrons, beta particles 1

Neurtons 5-20

Protons 5

Alpha particles 20



Double-strand break(DSB) yield and repair



Traversal required for cell kill (LET)



Cell survival curve



Oxygen effect



Dose rate



Oncogenesis



Bystander effect, and bystander effect in vivo



Fractionation



Radiomodulation

DIRECT ACTION

DIRECT ACTION INDIRECT ACTION INDIRECT ACTION

Relative biological effectiveness

(RBE)

5.78 MeV

6.88 MeV

7.53 MeV

0.45 MeV

6.68 MeV

0.01MeV

0.49 MeV

Of the total decay energy¹ 93.5% emitted as - particles

< 4% emitted as - particles

< 2% emitted as γ- or x-rays

Measured on standard dose calibrators

PA-27

Role of the osteoclast in bone pathology

Growth factors

Osteoclast activity

Osteolysis Direct bone destruction

Bone Bone secondaries Primary

Local factors Systemic factors

Tumour cells

Bony complications

C

Activated

osteoclast

PA-28

C

Osteolytic bone disease Osteoblastic bone disease

Osteoclast

Osteoblast Unknown

GFs TGF-

Numerous bone metastases in 67-year-old man with prostate cancer.

A–D, Bone scintigraphy (A) and 18F-NaF PET/CT (B–D) images show more lesions in skull and ribs

than do whole body-bone MR images (E–G).

Range of alpha-particle

Radium-223

Bone surface

Mechanism of action for the targeting of osseous metastases by 223Ra.

Reprinted with permission from Algeta ASA, from 2012 ASCO GU Symposium

presentation.

Fig. 2

. Microautoradiography from a dog injected with an a-emitting bone seeker. Distribution of a-particle tracks in normal spongious bone (A, left) and an osteoblastic zone (B, right).

34

1. After intravenous injection, radium-223 is rapidly cleared from the blood and is distributed primarily into bone or is excreted into intestine.

2. The after injection of remaining blood radioactivity as 15 minutes, about 20%; 4 hours, about 4% and less than 1% at 24 hours.

3. At 10 minutes post-injection, radioactivity was observed in bone and in intestine. At 4 hours post-injection, the percentage of the radioactive dose present in bone and intestine was approximately 61% and 49%, respectively.

4. No significant uptake was seen in other organs such as heart, liver, kidneys, urinary bladder, and spleen at 4 hours post-injection.

FDA Package i

The whole body measurements indicated that approximately 63% of the administered radioactivity was excreted from the body within 7 days after injection (after correcting for decay). Fecal excretion is the major route of elimination from the body. At 48 hours after injection, the cumulative fecal

excretion was 13% (range 0 - 34%), and the cumulative urine excretion was 2%

(range 1 - 5%). There was no evidence of hepato-biliary excretion based on

imaging data.

FDA Package 36

 Purpose 223Ra-Dichloride (223Ra) is a novel bone-seeking alpha-emitter that prolongs survival in patients with castration resistant metastatic prostate cancer. We conducted a study to better profile the pharmacokinetics, pharmacodynamics, and biodistribution of this agent. Methods Ten patients received either 50, 100, or 200 kBq of 223Ra per kilogram of body weight. Subsequently, six of these ten patients received a second dose of 50 kBq/kg. Pharmaco-kinetics and biodistribution were

assessed by serial blood sampling, planar imaging, and whole-body counting. Pharmacodynamic assessment was based on measurements of prostate-specific antigen, bone alkaline phosphatase, and serum N-telopeptide. Safety was also assessed. Results Pharmacokinetic studies showed rapid

clearance of 223Ra from the vasculature, with a median of 14 % (range 9– 34 %), 2 % (range 1.6–3.9

%), and 0.5 % (range 0.4–1.0 %) remaining in plasma at the end of infusion, after 4 h, and after 24 h, respectively. Biodistribution studies showed early passage into the small bowel and subsequent fecal excretion with a median of 52 % of administered 223Ra in the bowel at 24 h. Urinary excretion was relatively minor (median of 4 % of administered 223Ra). Bone retention was prolonged. No

doselimiting toxicity was observed. Pharmacodynamic effects were observed (alkaline phosphatase and serum N-telopeptides) in a significant fraction of patients. Conclusion 223Ra cleared rapidly from plasma and rapidly transited into small bowel, with fecal excretion the major route of

elimination. Administered activities up to 200 kBq/kg were associated with few side effects and appeared to induce a decline in serum indicators of bone turnover.

Serial dynamic images of anterior abdomen/pelvis obtained after intravenous administration of 7,585 kBq (0.205 mCi) of 223Ra-dichloride (patient 4). The images show prompt uptake throughout small bowel with mild uptake in liver and no gallbladder

visualization. The uptake in small bowel, although showing some changes, persists for 232 min. The activity moves intraluminally into ascending and transverse colon (1 day), then into descending colon (2 days), and there is significant clearing from bowel by 6 days.

The volume-rendered contrast CT shows bowel loops that

correspond to the early 223Rachloride images. A 99mTc-MDP

bone scan is available for reference. There is prompt uptake in the bone metastasis that persists and improves in contrast over time. Small amount of liver uptake is noted in the early dynamic images, but resolves in the later images

0-10 m 20-30 m 40-50 m

232 min post 1 d 2 d

6 d Volume rendered CT Bone scan –D13

Whole-body bone scan in left panel shows multiple metastatic disease to bone.

223Ra whole-body bone scan in right panel was taken 1 day after injection. Although 223Ra images have lower counts and are noisier than the bone scan, they clearly show focal

accumulation in the most obvious bone metastasis, e.g., left distal femur, right femur, left proximal humerus. In addition, excretion into the ascending and transverse colon is noted.

Tc-99m MDP Ra-223

anterior posterior anterior posterior

Representative biodistribution images. Serial posterior images

following injection of 4,366 kBq (0.118 mCi) of 223Ra-dichloride show initial accumulation in bone metastasis and normal bone that persists over time, compared to posterior 99mTc-MDP bone scan spot image of the same region. Early images will often show some mild uptake in the kidneys that decreases rapidly and is barely seen at 4 h and not seen beyond 1 day.

0-1 h 4 h

1 day Post-bone scan

50



Single-use vial at a concentration of 1,000 kBq/mL (27 microcurie/mL) at the

reference date with a total radioactivity of 6,000 kBq/vial (162 microcurie/vial) at the reference date (Day 0)



Half life: 11.4 days

52

• Ready to use

¹

• Long shelf life     (28 days)

• Ready to use

¹

• Long shelf life     (28 days)

• One visit per dose

• IV injection

• Outpatient treatment

²

• One visit per dose

• IV injection

• Outpatient treatment

²

1. Nilsson et al. Presented at: American Society for Radiation Oncology annual meeting 2010; poster 2385. 

2. Biggin. Eur J Nucl Med Mol Imag. 2007;34:S391 Abstract P646.

53

• Ready to use

¹

• Long shelf life (28 days)

• Easy to handle

²

• Ready to use

¹

• Long shelf life (28 days)

• Easy to handle

²

• One visit per dose

• IV injection

• Outpatient treatment

²

• One visit per dose

• IV injection

• Outpatient treatment

²

Phase III Dose: 50

kBq/kg × 4 injections at 4-week intervals³

Half-life is 11.4 days⁴, which allows for sufficient time for preparation, distribution (including long-distance shipment), and administration⁵

Radium-223 that is not rapidly taken up in bone is rapidly excreted into the small bowel^6,7 Requires no additional

specialized detection equipment⁵

The ultra short penetration of α particles is easily

blocked (even by paper), allowing Radium-223 to be simply handled

without the requirement for complex shielding during shipping and administration²

Virtually no restrictions on patients after they leave the clinic²

Product is isotonic with physiological pH and is supplied as single-dose glass vials with

radioactivity

concentration of 1,000 kBq/mL (0.3 mCi/mL) at the reference date⁸

1. Nilsson S, et al. Poster 2385 presented at: American Society for Radiation Oncology Annual Meeting; October 31-November 4, 2010; San Diego, CA. 2. Biggin. C Eur J Nucl Med Mol Imag. 2007;34:S391. Abstract P646. 3. Parker C, et al. J Clin Oncol. 2012;30(Suppl). Abstract LBA4512. 4. McDevitt MR, et al. Eur J Nucl Med. 1998;25(9):1341-1351. 5. Nilsson S, et al. Clin Can Res. 2005;11(12):4451-4459. 6.

Lewington V, et al. Presented at: ASCO Genitourinary Cancers Symposium 2010: Poster 216. 7. Morris MJ, et al. Presented at: ASCO Genitourinary Cancers Symposium 2010: Poster 211. 8. Data on file, Algeta ASA.

1. Primary end point was overall survival.

2. Secondary efficacy end points included time to the first symptomatic

skeletal event and various Biochemical end points.

E =MC ²