Radionuclide Treatment in Osseous Metastases. Dimitris J. Apostolopoulos Prof. of Nuclear Medicine University of Patras, Greece

Size: px

Start display at page:

Download "Radionuclide Treatment in Osseous Metastases. Dimitris J. Apostolopoulos Prof. of Nuclear Medicine University of Patras, Greece"

Bridget Stevens
5 years ago
Views:

1 Radionuclide Treatment in Osseous Metastases Dimitris J. Apostolopoulos Prof. of Nuclear Medicine University of Patras, Greece

2 The presenter declares no conflict of interest

3 Management of Metastatic Bone Pain The appropriate management of painful skeletal metastases is complicated, expensive, and should be carried out by a multidisciplinary approach. Among other physicians a pain specialist is required. Methods for pain palliation It is understood that no single method is capable of offering adequate pain control in the individual patient and that usually a combination of the systemic and local treatment is necessary. Systemic analgesics, opioids Hormones (for breast and prostate Ca), Biphosphonates Chemotherapeutic agents, Steroids, External beam radiation, Radiofrequency ablation, Local surgery, and Radiopharmaceuticals Paes FM, Serafini AN. Semin Nucl Med. 2010;40:

Radionuclide Treatment in Osseous Metastases History Charles Pecher was the first to administer 89 Srlactate to a patient with osteoblastic metastases (8 mci in three doses) in 1939.

4 Radionuclide Treatment in Osseous Metastases History Charles Pecher was the first to administer 89 Srlactate to a patient with osteoblastic metastases (8 mci in three doses) in The patient s pain disappeared and his general condition improved. Unfortunately Charles Pecher was recalled for military duty in Belgium and sadly on his way home he committed suicide. His wife thought that he did this because he was despondent at coming so close to discovering a cure for cancer and being stopped by the war. Pecher C. Biological investigations with radioactive calcium and strontium. Proc Soc Exp Biol Med 1941;46:86-91.

5 Radionuclide Treatment in Osseous Metastasis History FDA 1993 FDA P-PO Sr-Cl Sm-EDTM Re-HEDP Pioneers Friedell HL, Storaasli JP. The use of radioactive phosphorus in the treatment of carcinoma of the breast with widespread metastases to bone. Am J Roentgenol Radium Ther 1950;64: Firusian N, Mellin P, Schmidt CG. Results of 89strontium therapy in patients with carcinoma of the prostate and incurable pain from bone metastases: a preliminary report. J Urol 1976;116: A Turner JH, Claringbold PG, Hetherington EL, et al. A phase I study of samarium-153 ethylenediaminetetramethylene phosphonate therapy for disseminated skeletal metastases. J Clin Oncol 1989;7: Maxon HR 3rd, Schroder LE, Thomas SR, et al. Re-186(Sn) HEDP for treatment of painful osseous metastases: initial clinical experience in 20 patients with hormone-resistant prostate cancer. Radiology 1990;176: FDA alpha-emitting radium-223 in the treatment of skeletal metastases. Clin Cancer Res 2005;11: Ra-Cl 2 Nilsson S, Larsen RH, Fosså SD, et al. First clinical experience with

6 Radionuclide Treatment in Osseous Metastasis History 117m Sn-DTPA 166 Ho-DOTMP 188 Re-HEDP 177 Lu-EDTMP 90 Y-EDTMP 90 Y-DOTA-HBP 170 Tm-EDTMP Pioneers Atkins HL, Mausner LF, Srivastava SC, et al. Tin-117m(4+)-DTPA for palliation of pain from osseous metastases: a pilot study. J Nucl Med 1995;36: Louw WK, Dormehl IC, van Rensburg AJ, et al. Evaluation of samarium- 153 and holmium-166-edtmp in the normal baboon model. Nucl Med Biol 1996;23: Maxon HR 3rd, Schroder LE, Washburn LC, et al. Rhenium-188(Sn)HEDP for treatment of osseous metastases. J Nucl Med 1998;39: Ando A, Ando I, Tonami N, et al. 177Lu-EDTMP: a potential therapeutic bone agent. Nucl Med Commun 1998;19: Khalid M, Bokhari TH, et al. Evaluation of carrier added and no carrier added 90Y-EDTMP as bone seeking therapeutic radiopharmaceutical. Pak J Pharm Sci 2014;27: Ogawa K, Kawashima H, Shiba K, et al. Development of [(90)Y]DOTAconjugated bisphosphonate for treatment of painful bone metastases. Nucl Med Biol 2009;36: Das T, Chakraborty S, Sarma HD, et al. (170)Tm-EDTMP: a potential costeffective alternative to (89)SrCl(2) for bone pain palliation. Nucl Med Biol 2009;36:561-8.

Mechanisms of metastatic bone pain Bone-targeting radiopharmaceuticals: Mechanisms of action Mechanisms of bone pain Indirect stimulation of sensory nerve endings through release of cytokines,

7 Mechanisms of metastatic bone pain Bone-targeting radiopharmaceuticals: Mechanisms of action Mechanisms of bone pain Indirect stimulation of sensory nerve endings through release of cytokines, histamine, prostaglandins etc. Stimulation of periosteal nerve endings due to direct neoplastic involvement Infiltration of the bone trabeculae and matrix by tumor Increased intramedullary pressure Collapse of bone structure fracture Radicular compression (spine) Radionuclides Target Krishnamurthy GT, Krishnamurthy S. J Nucl Med. 2000;41:688-9.

8 Radionuclide Treatment in Osseous Metastasis Patient Selection Contraindications Clinical and Imaging Laboratory Contraindications Positive bone scintigraphy within 8 weeks Positive correlation between osteoblastic lesions and painful sites Severe pain despite analgesics or analgesic side effects Not a candidate for local control with radiotherapy No chemotherapy or large field XRT in the past 4-12 wk Incontinence: place urinary catheter Life expectancy more than 4-12 wk Signed informed consent Hemoglobin >9.0 mg/dl Absolute WBC >3500/dL Absolute Neutrophil >1500/dL PLT >100,000/dL Glomerular filtration rate >50 ml/min Pregnancy: obtain pregnancy test the day of injection Breastfeeding: stop permanently GFR <30 ml/min or dialysis Spinal cord compression: needs XRT Extensive bone marrow involvement: low blood counts or superscan Paes FM, Serafini AN. Semin Nucl Med. 2010;40:

9 Radionuclides for pain palliation Physical characteristics T 1/2 (days) Emission Type Emax (MeV) Eγ (MeV) (%) Tissue penetration max (mm) 89 Sr 50.5 β (0.1) Sm 1.93 β (28) Re 3.8 β (9) Ra 11.4 α (5.6) 0.1 Guerra Liberal FD, et al. Appl Radiat Isot Apr;110:87-99

10 Radionuclide efficacy for pain palliation in prostate cancer patients with bone metastases Comparison of radiopharmaceuticals No of Studies dose EFFICACY FOR PAIN PALLIATION Mean (range) WBC GRADE 3/4 Mean (range) PLT GRADE 3/4 Mean (range) 89 Sr-Cl MBq 63.2% (35-92%) 0.6% ( %) 1.8% ( %) 153 Sm-EDTMP 7 37 MBq/Kg 67.2% (38-85%) 5.3% ( %) 1.9% ( %) 18 Re- HEDP MBq 70.1% (42-79%) 1.4% ( %) 2.6% (0.0-21%) 223 Ra-Cl kbq/kg 60.5% (56-65%) - (0.0% aftrer 3 doses) - (2.6% after 3 doses) Efficacy is higher in pure osteoblastic than mixed-type metastases Bone-seeking agents and biphosphonates they may be used concomitantly. Jong JM, et al. Eur Urol [Epub ahead of print]

11 89 Sr-Cl 2 vs. 186 Re-HDTP Randomized study in Breast Cancer patients Onset of response Time to PLT recovery Duration of response Time to WBC recovery Sciuto R, et al. Breast Cancer Res Treat. 2001;66:101-9.

12 Castration-Resistant Prostate Cancer (CRPR) 89 Sr-chlodide, 153 Sm-lexidronam, 186 Re-editronate Any benefit apart from pain palliation?

Castration-Resistant Prostate Cancer (CRPR) Bone-targeted therapy for advanced androgen-independent carcinoma of the prostate: a randomised phase II trial nothing Dox+Sr89 Dox alone 103 patients with

13 Castration-Resistant Prostate Cancer (CRPR) Bone-targeted therapy for advanced androgen-independent carcinoma of the prostate: a randomised phase II trial nothing Dox+Sr89 Dox alone 103 patients with CRPC received induction chemotherapy, consisting of ketoconazole and doxorubicin alternating with estramustine and vinblastine. After two or three cycles of induction chemotherapy, we randomly assigned 72 patients who were clinically stable or responders to receive doxorubicin with or without strontium-89 (Sr-89) every week for 6 weeks. Bone-targeted consolidation therapy consisting of one dose of Sr-89 plus doxorubicin once a week for 6 weeks, when given to patients with stable or responding advanced androgen-independent carcinoma of the prostate after induction chemotherapy, improved overall survival. Tu SM, et al. Lancet. 2001;357:

Castration-Resistant Prostate Cancer (CRPR) Phase II Trial of Consolidation Docetaxel and Samarium- 153 in Patients With Bone Metastases From Castration- Resistant Prostate Cancer Median PSA-PFS = 6.

14 Castration-Resistant Prostate Cancer (CRPR) Phase II Trial of Consolidation Docetaxel and Samarium- 153 in Patients With Bone Metastases From Castration- Resistant Prostate Cancer Median PSA-PFS = 6.4 months Median OS=29 months 43 patients with bone metastases from CRPC who achieved a response or stabilization after four cycles of docetaxel and estramustine were given consolidation docetaxel 20 mg/m 2 /wk for 6 weeks and samarium- 153-EDTMP (37 MBq/kg) during week 1. There was no febrile neutropenia, and only 2 episodes (5%) of rapidly reversible grade 3 thrombocytopenia occurred. Although a serum PSA relapse eventually occurred in all patient cases, this regimen resulted in pain control in the long-term. Combining docetaxel and samarium-153 EDTMP in patients with bone metastases from CRPC is well tolerated, and it yields major pain relief that persists long after treatment. Overall survival compares favorably with that expected in this population of patients, most of whom exhibit symptoms. Fizazi K, et al. J Clin Oncol. 2009;27:

15 Castration-Resistant Prostate Cancer (CRPR) Results of a double blind study of 89-strontium therapy of skeletal metastases of prostatic carcinoma 49 patients were treated with either 3 x 75 MBq 89 Sr at monthly intervals or saline as placebo. Analysis of results 1 to 3 years after therapy revealed the ineffectiveness of 89 Sr to relieve pain from metastases. Unexpectedly, a higher survival rate was found after 89 Sr application (46% vs 4% after 2 years). Covariate analysis underlines the effect of 89 Sr therapy on life expectation. Buchali K, et al. Eur J Nucl Med. 1988;14:

$Castration-Resistant Prostate Cancer (CRPR) Palliation and Survival After Repeated 188 Re-HEDP Therapy of Hormone-Refractory Bone Metastases of Prostate Cancer: A Retrospective Analysis Group A$

16 Castration-Resistant Prostate Cancer (CRPR) Palliation and Survival After Repeated 188 Re-HEDP Therapy of Hormone-Refractory Bone Metastases of Prostate Cancer: A Retrospective Analysis Group A (n=19) Group B (n=19) Group C (n=19) 1 dose 2 doses 3 doses Biersack H-J, et al. J Nucl Med. 2011;52: Post-treatment overall survival could be improved from 4.50 to mo by multipleinjection bone-targeted therapy with 188 Re- HEDP, when compared with a single injection.

17 Castration-Resistant Prostate Cancer (CRPR) 223 Ra-Cl 2 for the treatment of bone metastases

18 Alpha Emitter Radium-223 and Survival in Metastatic Prostate Cancer The ALSYMCA Trial (ALSYMCA = Alpharadin in Symptomatic Prostate Cancer Patients) Randomized, double-blind, placebo-controlled study, randomly assigning 921 patients who had received, were not eligible to receive, or declined docetaxel, in a 2:1 ratio, to receive six injections of radium-223 (at a dose of 50 kbq/kg) or matching placebo. Parker C et al. N Engl J Med. 2013;369:

hematologic adverse event was considered to be possibly related to the study drug:

19 Alpha Emitter Radium-223 and Survival in Metastatic Prostate Cancer The ALSYMCA Trial (ALSYMCA = Alpharadin in Symptomatic Prostate Cancer Patients) Only one grade 5 hematologic adverse event was considered to be possibly related to the study drug: thrombocytopenia in one patient in the radium-223 group. Parker C et al. N Engl J Med. 2013;369:

phase 3 ALSYMPCA trial Radium-223 is effective and well tolerated in patients with castration-resistant prostate cancer

20 Efficacy and safety of radium-223 dichloride in patients with castration-resistant prostate cancer and symptomatic bone metastases, with or without previous docetaxel use: a prespecified subgroup analysis from the randomised, double-blind, phase 3 ALSYMPCA trial Radium-223 is effective and well tolerated in patients with castration-resistant prostate cancer and symptomatic bone metastases, irrespective of previous docetaxel use. Hoskin P, et al. Lancet Oncol. 2014;15:

21 Bone-targeted Radionuclide Treatment in Osseous Metastases Patient Selection, Treatment Goals, Cost Cancer type Setting Life expectancy Treatment goal Cost in Greece ( ) 89 Sr-Cl 2 Prostate, Breast, Lung Multiple pain sites, (+) scan > 4-12 weeks Pain palliation Sm- EDTMP Prostate, Breast, Lung and Osteosarcoma Multiple pain sites, (+) scan > 4-12 weeks Pain palliation Ra-Cl 2 Prostate (CRPR) Symptomatic 2 (+) bone scan sites, no splachnic meta, LN meta <3 cm > 6-12 months Overall Survival improvement, Pain palliation, QoL improvement 4800 (per dose), (for 6 cycles) Modified from Finlay IG, Mason MD, Shelley M. Lancet Oncol 2015;6:

Castration-Resistant Prostate Cancer (CRPR) Available therapies for OS improvement Agent Docetaxel (2004) Cabazitaxel (2010) Sipuleucel-T (2010) Abiraterone (2011) Enzalutamide (2012)

22 Castration-Resistant Prostate Cancer (CRPR) Available therapies for OS improvement Agent Docetaxel (2004) Cabazitaxel (2010) Sipuleucel-T (2010) Abiraterone (2011) Enzalutamide (2012) Radium-223 (2013) Target microtubules microtubules immune system androgen synthesis androgen receptors tumor cells, osteoblasts, osteoclasts, etc. Body JJ, et al. Nat. Rev. Urol. 2015; 12:

Castration-Resistant Prostate Cancer (CRPR) Available therapies for OS improvement Survival benefit 1.4-2.

23 Castration-Resistant Prostate Cancer (CRPR) Available therapies for OS improvement Survival benefit mo 2.4 mo 4.1 mo mo 4.6 mo 5.2 mo 3.6 mo Modified from Ryan CJ, et al. Oncologist. 2014;19:

Castration-Resistant Prostate Cancer (CRPR) Sequencing of agents in castration-resistant prostate cancer Data from small retrospective series suggest the possibility of cross-resistance between

24 Castration-Resistant Prostate Cancer (CRPR) Sequencing of agents in castration-resistant prostate cancer Data from small retrospective series suggest the possibility of cross-resistance between abiraterone acetate, enzalutamide, and docetaxel, and reduced activity when agents are used in sequence. 89 Sr or 153 Sm for pain palliation if 223 Ra is not indicated Lorente D, et al. Lancet Oncology 2015;16:e

177 Lu-PSMA-617) PSMA is over-expressed in 90-100% of local lesions, as well as in cancerous lymph

25 Radionuclide Treatment in CRPC The future Beyond bone-seeking agents Prostate Specific Membrane Antigen (PSMA) Gastrin Releasing Peptide Receptors (GRPr) Anti-PSMA Mab ( 177 Lu-j591) PSMA-ligand ( 177 Lu-PSMA-617) PSMA is over-expressed in % of local lesions, as well as in cancerous lymph node and bone. Bombesin derivatives ( 177 Lu-AMBA) Maffioli L, et al. Q J Nucl Med Mol Imaging 2015;59:420-38

26 Radionuclide Treatment in CRPC The future Beyond bone-seeking agents Theranostics 68 Ga-PSMA 177 Lu-PSMA Kratochwil C, et al. Eur J Nucl Med Mol Imaging.2015;42:987-8.

27 Thank you for your attention Patras, Greece. The bridge.

Alpha-emitting Radionuclides: Ra-223

Alpha-emitting Radionuclides: Ra-223 prof. dr. K. Goffin Nuclear Medicine and Molecular Imaging Department of Imaging & Pathology UZ Leuven KU Leuven Belgium International Course on Theranostics and Molecular