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Francesco GIAMMARILE « Aut tace aut loquere meliora silentio »

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1 Francesco GIAMMARILE « Aut tace aut loquere meliora silentio »

2 Bone scan and F-Choline Radionuclide treatment Presentation Outline Introduction NO CONFLICT OF INTEREST

3 General aspects Introdiction In prostate cancer, bone is the second common site of metastases (after LN) Bone metastases have poorer prognosis and significant higher morbidity & mortality -osteoblastic (80 %) -osteolytic (15 %) -mixed osteoblastic/osteolytic (5 %)

4 Biphosphonates (bone uptake) Labelled with 99mTc  99m Tc-DP Bone scintigraphy What is bone scan?  SPECT-CT

5 18 Fluorine  18 F-NaF Bone PET What is bone scan? ++ PET-CT ‘historical’ agent (1960) 18 F-NaF 18 F-FCholine

6 SPECT or PET ? What is bone scan? CharacteristicsSPECTPET Image Quality+++++ Availability++++/++ Cost+++ Irradiation== PET-CT has a better spatial resolution than SPECT-CT Bone peripheral reaction is more evident in FNa imaging  better detection and analysis of small lesion in FNa

7 Superiority of PET? What is bone scan?  CT add sensitivity (lytic lesion with no osteoblastic reaction) and specificity (equivocal bone uptake) to functional imaging

8 Uptake mechanisms What is the use of bone scan? Bone uptake related to osteoblastic hyperactivity  very sensitive  no uptake (FN) in bone marrow, pure lytic lesions!  poor uptake in or old sclerotic lesions providing a sufficient blood supply and capillary permeability  poor uptake in case of bone edema

9 Indications Infection Orthopedics Oncology Primary bone tumors Metastatic diseases CAVEAT No therapeutic follow-up! (flare-up phenomenon) What is the use of bone scan? 18 F-FDG

10 FCH vs FLUORIDE PET/CT Bone scan in metastatic prostate cancer FNa and Tc-HMDPFCH PET/SPECTCTPETCT BenignTrauma++-+ Arthrosis++-+ Bone Metastase Sclerotic++-+ Mixed++/-+ Indolent++-+ Bone marrow --+- Pure Lytic-+++

11 FCH vs FLUORIDE PET/CT Bone scan in metastatic prostate cancer FCH PET/CTTrueFalseTotal Positive Negative Estimated value sensitivity 74 % specificity 99 % (p < 0.01) accuracy 85 % NaF PET/CTTrueFalseTotal Positive Negative Estimated value sensitivity 81 % ns specificity 93 % accuracy 86 % Beheshti et al, EJNMMI 2008

12 FCH vs FLUORIDE PET/CT Bone scan in metastatic prostate cancer L2 S L4 FCH L2 S L4 Metastases in L2 and S  FCH, FLUORIDE, BONE TP Degenerative lesion in L4  FCH TN, FLUORIDE, BONE FP FLUORIDE L2 L4 S BONE

13 FCH vs FLUORIDE PET/CT Bone scan in metastatic prostate cancer FCHO TN NaF FP CT: degenerative lesion

14 FCH vs FLUORIDE PET/CT Bone scan in metastatic prostate cancer FCHO - NaF + CT: densely sclerotic lesion

15 Patterns of bone metastases: phase 1 Bone scan in metastatic prostate cancer CT - CHOLINE + CT + CHOLINE + FLUORIDE + CT + CHOLINE - FLUORIDE + CT + CHOLINE - FLUORIDE – phase 1 phase 2 phase 3 phase 4 FLUORIDE - (adapted from Werner LANGSTEGER) bone marrow metastases

16 Patterns of bone metastases: phase 1 Bone scan in metastatic prostate cancer PSA 13,3 PSA 3,8 FCH + FCH - phase 0 (no BM mets) phase 1 (3 month later)

17 Patterns of bone metastases: phase 2 Bone scan in metastatic prostate cancer CT - CHOLINE + phase 1 phase 3 phase 4 FLUORIDE - phase 2 CT + CHOLINE - FLUORIDE + CT + CHOLINE - FLUORIDE – CHOLINE + CT + FLUORIDE + mixed osteoblastic/osteolytic lesions bone marrow metastases

18 Patterns of bone metastases: phase 2 Bone scan in metastatic prostate cancer HU 680 FCH + FLUORIDE + sclerotic lesion

19 Patterns of bone metastases: phase 2 Bone scan in metastatic prostate cancer lytic lesion FCH + FLUORIDE +

20 Patterns of bone metastases: phase 3 Bone scan in metastatic prostate cancer CT - CHOLINE + phase 1 phase 4 FLUORIDE - phase 2 CT + CHOLINE - FLUORIDE – CHOLINE + CT + FLUORIDE + phase 3 CT + FLUORIDE + CHOLINE - diagnostic problem! dense sclerotic lesion (HU >825) mixed osteoblastic/osteolytic lesions bone marrow metastases

21 Patterns of bone metastases: phase 3 Bone scan in metastatic prostate cancer HU 1350 HU 550 FLUORIDE + FCH - with increasing HU – FCH becomes NEGATIVE

22 Phase 3: clinical explications Bone scan in metastatic prostate cancer True negative: non viable sclerosis apoptosis therapy response True negative: non viable sclerosis apoptosis therapy response False negative: reduced sensitivity tumor density / perfusion  in dense sclerosis (HU >825) False negative: reduced sensitivity tumor density / perfusion  in dense sclerosis (HU >825) HU 3070 FCH - FLUORIDE + HU 1250 FCH - Beheshti et al, EJNMMI 2008

23 Patterns of bone metastases: phase 4 Bone scan in metastatic prostate cancer CT - CHOLINE + phase 1 FLUORIDE - phase 2 CHOLINE + CT + FLUORIDE + phase 3 CT + FLUORIDE + CHOLINE - phase 4 CT + CHOLINE - FLUORIDE - highly dense sclerotic lesion (HU >1000) dense sclerotic lesion (HU >825) mixed osteoblastic/osteolytic lesions bone marrow metastases

24 Patterns of bone metastases: phase 4 Bone scan in metastatic prostate cancer HU 2400 FLUORIDE - FCH -

25 Severe pain Pathological fractures Spinal-cord compression Hypercalcemia Bone marrow infiltration Mobility restriction Sleep reduction → Worsening patient’s quality of life. Bone metastases: major complications Treatment in metastatic prostate cancer

26 RadiopharmaceuticalT ½ (d) E  (keV) Range (mm) E  (keV) Dose (cGy/MBq) NuclideLabelledMaxAveMaxAveLesionBone 32 PPhosphate SrChloride SmEDTMP HoDOTMP NA81NA 186 ReHEDP ReHEDP NA 85 SrChloride6415 (e - Auger)10 nm m SnDTPA14150 (e - Auger)30 nm RaChloride (  ) 50 µm154NA Bone seeking radiopharmaceuticals Treatment in metastatic prostate cancer

27 Antitumoral effect Antalgic effect Possible effects of the radiometabolic treatment Treatment in metastatic prostate cancer

28 Contra-indications Treatment in metastatic prostate cancer Low blood cell count: – Hb <90 g/l – WBC <3.5×10 9 /l – PLT <100×10 9 /l Bone marrow involvement Poor renal function: if GFR <50 ml/min: halve the dose if GFR 180 μmol/l): exclude “Chronic” spinal cord compression Corticosteroids Life expectancy < 4 weeks  This is the limit, but BSR are more beneficial in patients with relatively long life expectancy !

29 Procedure: patient preparation Treatment in metastatic prostate cancer Bone pain – limiting normal activities – not easily controlled by analgesics Recent bone scan (<4 weeks) Exclude: – neurogenic pain – pathological fractures Wait: – ≥3 mo after wide-field RT – ≥ 4 weeks after chemo Recent full haematological and biochemical profile (<7 days) – clotting tests if DIC suspected

30 RadiopharmaceuticalT ½ (d) E  (keV) Range (mm) E  (keV) Dose (cGy/MBq) NuclideLabelledMaxAveMaxAveLesionBone 32 PPhosphate SrChloride SmEDTMP HoDOTMP NA81NA 186 ReHEDP ReHEDP NA 85 SrChloride6415 (e - Auger)10 nm m SnDTPA14150 (e - Auger)30 nm RaChloride (  ) 50 µm154NA Bone pain palliation Treatment in metastatic prostate cancer Lewington VJ, et al. Eur J Cancer 1991;27:954-8 Sartor O, et al. Urology 2004;63:940-5

31 Bone pain palliation Treatment in metastatic prostate cancer Analgesics Bisphosphonates Chemotherapy Hormonal therapy External beam radiotherapy Surgery BONE SEEKING RADIOPHARMACEUTICALS -Simultaneous treatment of multiple sites -Concentrate at sites of increased bone turnover (selectively sparring healthy bone and associated bone marrow) ) -Control metastatic bone pain and improve quality of life as an effective alternative treatment to conventional therapies (analgesics, external beam radiotherapy) -Repeatability -Potential integration with the other treatments

32 Slow intravenous infusion, followed by saline flush, of – 89 Sr-chloride: = 150 MBq – 153 Sm-lexidronam = 37 MBq/kg, – 186 Re-etidronate = 1,295 MBq Bone pain palliation Treatment in metastatic prostate cancer Recommended activities The amount of activity to be administered should be checked with an isotope calibrator (  emission)

33 Improved pain control and reduction of analgesic consumption – Unlikely immediately after therapy – More probable 2 weeks after therapy – Delayed even to 4 weeks, especially with 89 Sr-chloride Duration of response – Prolonged: up to 12 months with 89 Sr-chloride – Shorter duration: up to 5-9 months with 153 Sm-lexidronam and 186 Re-etidronate Bone pain palliation Treatment in metastatic prostate cancer Efficacy Modified from Lewington V. J Nucl Med 2005

34 “Flare” phenomena, usually within 72 hrs, in 10% of pts Myelotoxicity: decrease in PLT and WBC – 3-5 weeks nadir for 153 Sm-lexidronam or 186 Re-etidronate – weeks nadir for 89 Sr-chloride – bone marrow reserve Bone pain palliation Treatment in metastatic prostate cancer Side effects In responding patients when pain recurs Quality of response may decrease Haematological parameters must be recovered: – 8 weeks for 153 Sm-lexidronam – 6-8 weeks for 186 Re-etidronate – 12 weeks for 89 Sr-chloride Retreatment

35 Loberg, R. D. J Clin Oncol; 23: Ricci, S. Eur J Nucl Med; 34: Combined treatment Treatment in metastatic prostate cancer

36 Stabilization and reduction of tumour markers Delayed occurrence of new painful sites and new metastases Better response in patients with few metastases Bone pain palliation Treatment in metastatic prostate cancer Advantages The exposure of surrounding tissues to β-emissions can be associated with toxicity (relatively long range of the radiation) The consequent myelosuppression limits the dosages that can be given and the use of repeated therapy Beta-emitters produce low LET radiation which has a low probability for inducing double strand DNA breaks Prejudices: myelosuppression, high costs The late use is associated with an unlikely benefit Neither drug confers a survival advantage Disadvantages Finlay IG, et al. Lancet Oncology 2005;6: Nilsson S, et al. Clinical Cancer Research 2005;11:

37 RadiopharmaceuticalT ½ (d) E  (keV) Range (mm) E  (keV) Dose (cGy/MBq) NuclideLabelledMaxAveMaxAveLesionBone 32 PPhosphate SrChloride SmEDTMP HoDOTMP NA81NA 186 ReHEDP ReHEDP NA 85 SrChloride6415 (e - Auger)10 nm m SnDTPA14150 (e - Auger)30 nm RaChloride (  ) 50 µm154NA Alpha treatment Treatment in metastatic prostate cancer

38 38 Differences between alpha emitters and beta emitters Alpha emittersBeta emitters Example emittersRadium 223Strontium 89, Samarium 153 Particle, size, and bubble chamber images showing ionization tracks He nucleusElectron Relative particle mass70001 Initial energy (MeV)5–90.05–2.3 Range in tissue (μm)40–10050–12,000 Linear energy transfer (KeV/μm) 60–3000.1–1.0 Ion pairs/μm2000–70005–20 DNA hits to kill cell1–4>1000 DNA damageIrrepairableRepairable Brechbiel MW. Dalton Trans 2007;43:4918–28; Kassis A. Semin Nucl Med 2008;38:358–66; Nilsson S et al. ASTRO 2010 poster presentation 2385; Sgouros G. (accessed August 2013)www.molecularimagingcenter.org/index.cfm?PageID=8892

39 39 Radium-223-chloride (Xofigo)

40 40 Radium Ra 223 Dichloride: Majority α-Decay, Minimal  - and γ-Decay Of the total decay energy % emitted as  -particles ( KeV) 3.6 % emitted as  -particles ( KeV) 1.1 % emitted as γ- or x-rays ( KeV) Measured on standard dose calibrators Decays via a series of α-, β-, and γ-emitting daughters 223 Ra d 219 Rn 3.96 s α α α α β− α 215 Po 1.78 ms 211 Pb 36.1 min 207 TI 4.77 min 211 Bi 2.17 min 211 Po 516 ms 207 Pb stable (0.28%) (99.72%) Radium 223 decay chain 2 1. Bruland Ø, et al. Clin Cancer Res. 2006;12:6250s-6257s. 2. Henriksen G, et al. Cancer Res. 2002;62:

41 41 Tc Ra Radium-223-chloride acts as a calcium mimic – hence it is incorporated into the bony matrix and directly targets new bone formation in and around bone metastases Radium Ra 223 Dichloride: γ-Decay appearance

42 42 Short Range of α-Emitters Reduces Bone Marrow Exposure 1 Marrow Bone Range of α-particle: (short range – 2 to 10 cell diameters 2 ) Radium Ra 223 dichloride Range of β-particle: (long range – 10 to 1000 cell diameters 2 ) Bone β-emitter Marrow 1. Henriksen G, et al. Cancer Res. 2002;62:3120– Brechbiel MW. Dalton Trans. 2007;43:

43 43 Radium 223 Dichloride: Bruland et al. Clin Cancer Res 2006;12:6250s Targets newly formed bone, eg bone metastases Bone marrow Tumour cells Osteoclast Osteoblast Alpha particle irradiates adjacent tumour cells leading to highly localized tumour cell killing Calcium analogue (eg Radium 223) Attached to phosphate

44 44 The updated analysis confirmed the 30% reduction in risk of death (HR = 0.70) for patients in the radium-223 group compared with placebo. ALSYMPCA Updated Analysis: Radium-223 Significantly Improved Overall Survival — Radium — Placebo CI, confidence interval; HR, hazard ratio; OS, overall survival. SOURCE: Parker C, et al. N Engl J Med. 2013;369(3): MEDIAN OS (months) — Radium-223: 14.9 — Placebo:11.3 HR (95% CI): 0.70 (0.58–0.83) P < Survival, % Months Since Randomization

45 45 Poster ASCO 2013

46 46 Dose protocol The patient dose is specific for each patient: 50 kBq per kg of body weight Volume to inject (mL) = Body weight (kg) × 50 kBq/kg body weight DK × 1000 kBq/mL The treatment is repeated 6 times Complete treatment = 6 injections at 4-week intervals

47 47 Administered at a licensed facility No shielding required Note: Before and after injection, the cannula is flushed with saline Patient comes in for injection and can leave right afterwards—no shielding or monitoring of the patient required No restrictions with regards to contact with other people Radium Ra 223 Dichloride Is Administered as a Simple IV Injection in an Outpatient Setting IV, intravenous.

48 Take home messages: diagnosis Conclusions What is bone scan?  Radionuclide imaging of bone activity with 99mTc-DP or, better, 18F-NaF What is the use of bone scan?  Detection of bone lesions with high sensitivity and poor specificity Bone scan in prostate cancer  Detection of osteoblastic activity around metastasis  Particularly useful in case of choline negative and highly dense sclerotic lesions

49 Take home messages: treatment Conclusions Systemic radionuclide therapy represents a feasible, safe, effective, well tolerated and cost-effective palliative treatment in patients with refractory bone pain  Only patients with a reasonably good general condition should be candidate for this treatment (radioprotection rules)  Patients at an early stage of metastatic disease benefit the most from treatment However,  the evaluation of the pain relief is difficult (subjectivity, placebo), the dosimetric calculations are not implemented yet  the competition with chemotherapy/bisphosphonates is strong Radium-223 dichloride (novel alpha emitting radiopharmaceutical) showed a significant prolonged OS in CRPC patients with bone metastases  Xofigo may provide a new standard of care

50 Radioactivity to Cure Cancer


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