Bone targeted radionuclide therapy. Val Lewington Royal Marsden Hospital, London

Transcription

1 Bone targeted radionuclide therapy Val Lewington Royal Marsden Hospital, London

2 Bone malignancy Primary bone tumours

3 Bone malignancy Primary bone tumours - chemotherapy, surgery & external beam radiotherapy

4 Bone malignancy Primary bone tumours Secondary tumours: Skeleton common metastatic site 80% of malignancies metastasise to bone

5 Bone physiology Re-modelling: resorption : formation

6 Bone metabolism Re-modelling: resorption : formation Metastasis: Bone formation - sclerosis

7 Bone metabolism Re-modelling: resorption : formation Metastasis: Bone destruction - lysis

8 carrier label

9 carrier label Bone mineral turnover Ca 2+ analogue phosphate complex

10 Half life Radionuclide selection

11 Radionuclide selection Half life - Physical t 1/2 vs biological t 1/2 - Dose rate

12 Radionuclide selection Half life - Physical t 1/2 vs biological t 1/2 - Dose rate Particle range

13 Radiolabels - Therapy 223 Ra short/med range long range 188 Re Sm, 186 Re Y, 89 Sr,

14 Radiolabels - Therapy 223 Ra short/med range long range 188 Re Sm, 186 Re Y, 89 Sr,

15 89 SrCl 2 Calcium analogue t 1/2 50 d max 1.46 MeV range ~ 50 cell diameters

16 99m Tc MDP 85 Sr

17

18 153 Sm t 1/2 phys max 2 d 0.81 MeV 153 Sm EDTMP t 1/2 bio 7-12h

19 t1/2 ph t1/2 bio 89 SrCl 2 50 d >90d 153 Sm EDTMP 2 d 12 h

20

21 Metastatic bone pain Primary tumour control - tumouricidal

22 Metastatic bone pain Primary tumour control Pain palliation - Analgesics - Local RT

23 Metastatic bone pain Primary tumour control Pain palliation - analgesics - Local RT - Wide field RT - bisphosphonates

24 Metastatic bone pain Primary tumour control Pain palliation - analgesics - Local RT - Wide field RT - bisphosphonates

25 Targeted Radionuclide Therapy Systemic Tumour specific

26 Patient Selection Refractory bone pain +ve bone scan

27 Patient Selection Refractory bone pain +ve bone scan Pain map

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29 Patient Selection Refractory bone pain +ve bone scan Stable haematology Platelet > 100 x10 9 /l

30 Patient Selection Refractory bone pain +ve bone scan Stable haematology Stable renal function GFR > 40 ml/min

31 Patient Selection Refractory bone pain +ve bone scan Stable haematology Stable renal function

32 Administration Outpatient i.v. bolus Continue analgesics

33 Response Symptom benefit Pain severity/frequency No.of pain sites Analgesic intake Performance status Quality of life

34 Efficacy % benefit 25 % pain free Multi-site palliation Response ~ tumour extent Laing 1989

35 t 1/2 Response Duration time 153 Sm 2d 2 7 d 2 4 m 89 Sr 50d 2 4 w 3 6 m

36 Systemic effect Equal efficacy with EBRT Delays new pain Quilty Radiother Oncol 1994 Porter Int J Radiat Oncol Biol Phys 1993

37 Systemic TRT delays new pain

38 Toxicity

39 Toxicity Temporary myelosuppression ~ 30% platelet fall at 4-6 w Recovery over 8 12 w Recovery reflects marrow reserve

40 Recovery vs marrow reserve

41 Toxicity t 1/2 Myelosuppression 89 Sr 50d Sm 2 d +

42 Mechanism of action Radiation effect active Rx v placebo

43 Mechanism of action Radiation effect active Rx v placebo EBRT 8Gy single fraction effective

44 Mechanism of action Radiation effect active Rx v placebo EBRT 8Gy single fraction effective Pain palliation not dependent on cell kill

45 Mechanism of action Radiation effect active Rx v placebo EBRT 8Gy single fraction effective EBRT Efficacy independent of primary tumour histology Hoskin PJ Clin Oncol 1989

46 Mechanism of action Radiation effect active Rx v placebo EBRT 8Gy single fraction effective EBRT Efficacy independent of primary tumour histology Hoskin PJ Clin Oncol 1989 Tumour:normal bone interface target

47 Myelotoxicity t 1/2 Myelosuppression 89 Sr 50d Sm 2 d + Cumulative myelotoxicity - radiation absorbed dose - advancing underlying disease

48 The future 1. Integrated therapy - chemotherapy + isotope

49 Chemo/isotope combination 89 Sr + low dose cisplatin Sciuto J Nucl Med 2002 doxorubicin /estramustine/vinblastine + 89 Sr estramustine + vinblastine + 89 Sr Tu Lancet 2001 Ackerley Cancer 2002 docetaxel Sm Massard Abs. 227 ASCO 2007 Combined Rx superior to isotope or chemo alone

50 The future 1. Integrated therapy - chemotherapy + isotope - bisphosphonate + isotope

51 The future 1. Integrated therapy - chemotherapy + isotope - bisphosphonate + isotope - EBRT + isotope Porter Int J Radiat Oncol Biol Phys 1993 Smeland Int J Radiat Oncol Biol Phys 2003

52 The future 1. Integrated therapy 2. Isotope combination short t ½ + long t ½

53 The future 1. Integrated therapy 2. Isotope combination eg short t ½ + long t ½ 3. Activity escalation

54 The future 1. Integrated therapy 2. Isotope combination eg short t ½ + long t ½ 3. Activity escalation 153 Sm EDTMP Collins J Nucl Med Re HEDP [+ PBSC] O Sullivan Br J Cancer 2002

55 The future 1. Integrated therapy 2. Isotope combination eg short t ½ + long t ½ 3. Activity escalation 4. New radiopharmaceuticals eg 223 RaCl 2

56 223 Ra Ca 2+ analogue t 1/2 11 d emitter

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58 Why use alpha emitters? Alpha Beta Range in tissue m m Linear Energy Transfer DNA hits to kill a cell kev/ m kev/ m Relative particle mass

59 Canine Model Micro-autoradiography Normal bone Bone metastasis

60 223 Ra Ca 2+ analogue t 1/2 11 d emitter Short range i.e. Low toxicity Phase I & II trials - dose limiting toxicity not reached Repeated Rx for sustained response

61 Conclusions Simple, safe, effective palliative Rx Well tolerated Best response in early disease Integrated, multi modality regimen 223 Ra in clinical trials