Nuclear Medicine procedures in prostate cancer: from diagnosis to treatment - PowerPoint Presentation

1. Nuclear Medicine procedures in prostate cancer: from diagnosis to treatment Francesco GIAMMARILE« Aut tace aut loquere meliora silentio »

2. Bone scan and F-Choline Radionuclide treatment Presentation OutlineIntroductionNO CONFLICT OF INTEREST

3. General aspectsIntrodictionIn 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 99mTc-DPBone scintigraphyWhat is bone scan?SPECT-CT

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

6. SPECT or PET ?What is bone scan?CharacteristicsSPECTPETImage Quality+++++Availability++++/++Cost+++Irradiation==PET-CT has a better spatial resolution than SPECT-CTBone 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 mechanismsWhat is the use of bone scan?Bone uptakerelated to osteoblastic hyperactivityvery sensitiveno uptake (FN) in bone marrow, pure lytic lesions!poor uptake in or old sclerotic lesionsproviding a sufficient blood supply and capillary permeability poor uptake in case of bone edema

9. IndicationsInfectionOrthopedicsOncologyPrimary bone tumorsMetastatic diseasesCAVEATNo therapeutic follow-up!(flare-up phenomenon)What is the use of bone scan?18F-FDG

10. FCH vs FLUORIDE PET/CT Bone scan in metastatic prostate cancer FNa and Tc-HMDPFCHPET/SPECTCTPETCTBenignTrauma++-+Arthrosis++-+Bone MetastaseSclerotic++-+Mixed++/-++/-Indolent++-+Bone marrow --+-Pure Lytic-+++

11. FCH vs FLUORIDE PET/CT Bone scan in metastatic prostate cancerFCH PET/CTTrueFalseTotalPositive97198Negative9534129Estimated valuesensitivity 74 %specificity 99 % (p < 0.01)accuracy 85 %NaF PET/CTTrueFalseTotalPositive1087115Negative8926115Estimated valuesensitivity 81 % ns specificity 93 %accuracy 86 %Beheshti et al, EJNMMI 2008

12. FCH vs FLUORIDE PET/CT Bone scan in metastatic prostate cancerL2 S L4 FCHL2 S L4 Metastases in L2 and S  FCH, FLUORIDE, BONE TP Degenerative lesion in L4  FCH TN , FLUORIDE, BONE FPFLUORIDEL2 L4 S BONE

13. FCH vs FLUORIDE PET/CT Bone scan in metastatic prostate cancerFCHO TNNaF FPCT: degenerative lesion

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

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

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

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

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

19. Patterns of bone metastases: phase 2Bone scan in metastatic prostate cancerlytic lesionFCH +FLUORIDE +

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

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

22. Phase 3: clinical explicationsBone scan in metastatic prostate cancerTrue negative: non viable sclerosisapoptosis therapy responseFalse negative: reduced sensitivitytumor density / perfusion in dense sclerosis (HU >825) HU 3070FCH -FLUORIDE +HU 1250FCH -Beheshti et al, EJNMMI 2008

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

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

25. Severe painPathological fracturesSpinal-cord compressionHypercalcemiaBone marrow infiltrationMobility restrictionSleep reduction→ Worsening patient’s quality of life.Bone metastases: major complicationsTreatment in metastatic prostate cancer

26. RadiopharmaceuticalT½ (d)E (keV)Range (mm)E  (keV)Dose (cGy/MBq)NuclideLabelledMaxAveMaxAveLesionBone32PPhosphate14.317106957.91.85-50.689SrChloride50.514905836.71.75-231153SmEDTMP1.958102243.40.531036715166HoDOTMP1.118406659NA81NANA186ReHEDP3.7710803294.70.9213720.1188ReHEDP0.71212079510.82.43155NANA85SrChloride6415 (e- Auger)10 nm5148.21.4117mSnDTPA14150 (e- Auger)30 nm1595.4-80.1-0.2223RaChloride11.45.8 ()50 µm154NANABone seeking radiopharmaceuticalsTreatment in metastatic prostate cancer

27. Antitumoral effectAntalgic effectPossible effects of the radiometabolic treatmentTreatment in metastatic prostate cancer

28. Contra-indicationsTreatment in metastatic prostate cancerLow blood cell count:Hb <90 g/lWBC <3.5×109/lPLT <100×109/lBone marrow involvementPoor renal function:if GFR <50 ml/min: halve the dose if GFR <30 ml/min (creatinine >180 μmol/l): exclude“Chronic” spinal cord compressionCorticosteroidsLife expectancy < 4 weeks This is the limit, but BSR are more beneficial in patients with relatively long life expectancy !

29. Procedure: patient preparationTreatment in metastatic prostate cancerBone painlimiting normal activitiesnot easily controlled by analgesicsRecent bone scan (<4 weeks)Exclude:neurogenic painpathological fracturesWait:≥3 mo after wide-field RT≥ 4 weeks after chemoRecent full haematological and biochemical profile (<7 days)clotting tests if DIC suspected

30. RadiopharmaceuticalT½ (d)E (keV)Range (mm)E  (keV)Dose (cGy/MBq)NuclideLabelledMaxAveMaxAveLesionBone32PPhosphate14.317106957.91.85-50.689SrChloride50.514905836.71.75-231153SmEDTMP1.958102243.40.531036715166HoDOTMP1.118406659NA81NANA186ReHEDP3.7710803294.70.9213720.1188ReHEDP0.71212079510.82.43155NANA85SrChloride6415 (e- Auger)10 nm5148.21.4117mSnDTPA14150 (e- Auger)30 nm1595.4-80.1-0.2223RaChloride11.45.8 ()50 µm154NANABone pain palliationTreatment in metastatic prostate cancerLewington VJ, et al. Eur J Cancer 1991;27:954-8Sartor O, et al. Urology 2004;63:940-5

31. Bone pain palliationTreatment in metastatic prostate cancerAnalgesicsBisphosphonatesChemotherapyHormonal therapyExternal beam radiotherapySurgeryBONE SEEKING RADIOPHARMACEUTICALSSimultaneous 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)RepeatabilityPotential integration with the other treatments

32. Slow intravenous infusion, followed by saline flush, of89Sr-chloride: = 150 MBq153Sm-lexidronam = 37 MBq/kg,186Re-etidronate = 1,295 MBqBone pain palliationTreatment in metastatic prostate cancerRecommended activitiesThe 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 therapyDelayed even to 4 weeks, especially with 89Sr-chlorideDuration of response Prolonged: up to 12 months with 89Sr-chlorideShorter duration: up to 5-9 months with 153Sm-lexidronam and 186Re-etidronateBone pain palliationTreatment in metastatic prostate cancerEfficacyModified from Lewington V. J Nucl Med 2005

34. “Flare” phenomena, usually within 72 hrs, in 10% of ptsMyelotoxicity: decrease in PLT and WBC3-5 weeks nadir for 153Sm-lexidronam or 186Re-etidronate12-16 weeks nadir for 89Sr-chloridebone marrow reserveBone pain palliationTreatment in metastatic prostate cancerSide effectsIn responding patients when pain recursQuality of response may decreaseHaematological parameters must be recovered:8 weeks for 153Sm-lexidronam6-8 weeks for 186Re-etidronate12 weeks for 89Sr-chlorideRetreatment

35. Loberg, R. D. J Clin Oncol; 23:8232-8241 2005Ricci, S. Eur J Nucl Med; 34:1023-30 2007Combined treatmentTreatment in metastatic prostate cancer

36. Stabilization and reduction of tumour markersDelayed occurrence of new painful sites and new metastasesBetter response in patients with few metastasesBone pain palliationTreatment in metastatic prostate cancerAdvantagesThe 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 therapyBeta-emitters produce low LET radiation which has a low probability for inducing double strand DNA breaksPrejudices: myelosuppression, high costsThe late use is associated with an unlikely benefitNeither drug confers a survival advantageDisadvantagesFinlay IG, et al. Lancet Oncology 2005;6:392-400Nilsson S, et al. Clinical Cancer Research 2005;11:4451-4459

37. RadiopharmaceuticalT½ (d)E (keV)Range (mm)E  (keV)Dose (cGy/MBq)NuclideLabelledMaxAveMaxAveLesionBone32PPhosphate14.317106957.91.85-50.689SrChloride50.514905836.71.75-231153SmEDTMP1.958102243.40.531036715166HoDOTMP1.118406659NA81NANA186ReHEDP3.7710803294.70.9213720.1188ReHEDP0.71212079510.82.43155NANA85SrChloride6415 (e- Auger)10 nm5148.21.4117mSnDTPA14150 (e- Auger)30 nm1595.4-80.1-0.2223RaChloride11.45.8 ()50 µm154NANAAlpha treatmentTreatment in metastatic prostate cancer

38. Differences between alpha emitters and beta emittersAlpha emittersBeta emittersExample emittersRadium 223Strontium 89, Samarium 153Particle, size, and bubble chamber images showing ionization tracksHe 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 damageIrrepairableRepairableBrechbiel 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. www.molecularimagingcenter.org/index.cfm?PageID=8892 (accessed August 2013)

39. Radium-223-chloride (Xofigo)

40. Radium Ra 223 Dichloride:Majority α-Decay, Minimal - and γ-DecayOf the total decay energy195.3% emitted as -particles (500-750 KeV)3.6 % emitted as -particles (445-492 KeV)1.1 % emitted as γ- or x-rays (10-1270 KeV)Measured on standard dose calibratorsDecays via a series of α-, β-,and γ-emitting daughters223Ra11.43 d219Rn3.96 sααααβ−β−β−α215Po1.78 ms211Pb36.1 min207TI4.77 min211Bi2.17 min211Po516 ms207Pbstable(0.28%)(99.72%)Radium 223 decay chain21. Bruland Ø, et al. Clin Cancer Res. 2006;12:6250s-6257s. 2. Henriksen G, et al. Cancer Res. 2002;62:3120-3125.

41. TcRaRadium-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 metastasesRadium Ra 223 Dichloride:γ-Decay appearance

42. Short Range of α-Emitters Reduces Bone Marrow Exposure1MarrowBoneRange of α-particle:(short range – 2 to 10 cell diameters2)Radium Ra 223dichlorideRange of β-particle:(long range – 10 to 1000 cell diameters2)Boneβ-emitterMarrow1. Henriksen G, et al. Cancer Res. 2002;62:3120–3125. 2. Brechbiel MW. Dalton Trans. 2007;43:4918-4928.

43. Radium 223 Dichloride:Bruland et al. Clin Cancer Res 2006;12:6250sTargets newly formed bone, eg bone metastasesBone marrowTumourcellsOsteoclastOsteoblastAlpha particle irradiates adjacent tumour cells leading to highly localized tumour cell killingCalcium analogue (eg Radium 223)Attached to phosphate

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-2236145785043692741781056041187100— Placebo3072882281571036739241474210CI, confidence interval; HR, hazard ratio; OS, overall survival.SOURCE: Parker C, et al. N Engl J Med. 2013;369(3):213-23. IncreaseOS∆=3.6mosMEDIAN OS (months)— Radium-223: 14.9— Placebo: 11.3HR (95% CI): 0.70 (0.58–0.83)P <0.001200406080100Survival, %Months Since Randomization091524303936332721181263

45. Poster ASCO 2013

46. Dose protocolThe patient dose is specific for each patient: 50 kBq per kg of body weightVolume to inject (mL) =Body weight (kg) × 50 kBq/kg body weightDK × 1000 kBq/mLThe treatment is repeated 6 timesComplete treatment = 6 injections at 4-week intervals

47. Administered at alicensed facilityNo shielding requiredNote: Before and after injection, the cannula is flushed with salinePatient comes in for injection and can leave right afterwards—no shielding or monitoring of the patient requiredNo restrictions with regards to contact with other peopleRadium Ra 223 Dichloride Is Administered as a Simple IV Injection in an Outpatient SettingIV, intravenous.

48. Take home messages: diagnosisConclusions What is bone scan? Radionuclide imaging of bone activity with 99mTc-DP or, better, 18F-NaFWhat is the use of bone scan? Detection of bone lesions with high sensitivity and poor specificityBone scan in prostate cancerDetection of osteoblastic activity around metastasisParticularly useful in case of choline negative and highly dense sclerotic lesions

49. Take home messages: treatmentConclusions Systemic radionuclide therapy represents a feasible, safe, effective, well tolerated and cost-effective palliative treatment in patients with refractory bone painOnly 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 treatmentHowever, the evaluation of the pain relief is difficult (subjectivity, placebo), the dosimetric calculations are not implemented yet the competition with chemotherapy/bisphosphonates is strongRadium-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