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Metastatic Bone Tumor Therapy
Pushpender Gupta, MBBS
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KEY FACTS

  • Terminology

    • Preprocedure

      • Procedure

        • Post Procedure

          TERMINOLOGY

          • Definitions

            • Bone pain is cardinal symptom of bone metastases
              • Initially intermittent pain of variable intensity; progresses to chronic pain with breakthrough acute episodes
              • Major impact on quality of life
              • Mechanical allodynia (normal, nonpainful activities become painful, e.g., coughing)
            • Metastatic bone tumor therapy
              • Radiopharmaceutical treatment of metastatic bone pain refractory to analgesics
                • Alpha emitter: Ra-223 (trade name Xofigo; formerly known as Alpharadin)
                  • ALSYMPCA (ALpharadin in SYMptomatic Prostate CAncer) trial showed survival benefit of Ra-223 treatment in castration-resistant prostate cancer (CRPC) patients
                  • Median survival advantage of 3.6 months as compared to placebo
                  • 30% ↓ in risk of death compared to placebo
                  • Monthly IV administration of Ra-223 for 6 months
                  • Usually effective by 3rd Ra-223 administration (3 months)
                  • Approved for prostate cancer
                • Beta emitters: Sm-153, Sr-89
                  • Considered palliative to reduce pain
                  • One-time IV therapy, but can be repeated
                  • Usually effective within 1-2 weeks after administration
                  • Approved for multiple tumors that metastasize to bone
          • Alpha Emitter

            • Ra-223
              • 1st α-particle therapy approved in United States
              • 1st radiopharmaceutical therapy that extends survival in patients with bone metastases
              • Bone-seeking α emitter mimicking calcium, 4 α-particles generated for each decay
              • Produced from Ra-223 extraction generator (parent isotopes Ac-227 and Th-227)
              • t1/2: 11.43 days
              • Alpha emission (95.3%; energy range: 5-7.5 MeV), beta emission (3.6%; average energies: 0.445 MeV and 0.492 MeV), gamma emission (1.1%; energy range: 0.01-1.27 MeV)
              • Greater biologic effectiveness due to high linear energy transfer
              • Less hematologic toxicity due to shorter path length (60-100 µm) of α-particles
              • Rapid blood clearance (< 1% blood activity at 24 hours), no significant redistribution
              • Decreases bone specific alkaline phosphatase (ALP), marker for tumor response in CRPC
              • Excretion: Gastrointestinal (52% activity in bowel at 24 hours), minimal urinary excretion (< 5%)
              • Mechanism of action
                • Increased uptake and complex formation with hydroxyapatite at sites of increased bone turnover
                • α-particle-induced double-stranded DNA breaks
              • Benefits
                • Survival benefit in symptomatic and progressive metastatic CRPC (≥ 2 skeletal metastases, no visceral metastases) regardless of disease extent, previous treatment with docetaxel and current treatment with bisphosphonates (ALSYMPCA trial)
                  • 16% of patients showed ≥ 30% drop in PSA at 12 weeks
                  • Delayed onset of first symptomatic skeletal event (symptomatic pathologic bone fracture)
                  • Pain relief
                  • Improved quality of life
                  • Delayed increase in ALP and PSA
          • Beta Emitters

            • Sm-153 (Lexidronam/Quadramet)
              • t1/2: 1.9 days
              • Dose: 1 mCi (37 MBq)/kg maximum
              • Mixed beta and gamma emitter
              • 640, 710, and 810 keV beta emissions (mean: 0.23 MeV); average path length: 0.6 mm
              • Can image 103 keV gamma emissions (28% abundance)
              • Labeled to bisphosphonate ethylenediamine tetramethylene phosphate (EDTMP) (↑ bone-seeking properties)
              • Urinary excretion: Complete ~ 6 hours after administration
              • < 1% activity in blood 5 hours after injection
            • Sr-89 (Metastron)
              • t1/2: 50.5 days
              • Dose 40-60 uCi (1-1.6 MBq)/kg up to 4 mCi (148 MBq); dose can be repeated after 3-4 months
              • Pure beta emitter (1.49 MeV maximum energy; mean: 0.58 MeV), maximum path length: 8 mm; average path length: 2.4 mm
              • Bremsstrahlung imaging possible, but not practical
              • Physiologic distribution mimics calcium
              • Excretion: Mainly urinary (80%), partially fecal (20%)
              • Used in patients with moderate pain, reasonable life expectancy (> 3 months) due to long response duration
            • P-32
              • First tracer used for metastatic bone pain palliation
              • Not widely used for bone pain palliation since 1980s; now abandoned
              • t1/2: 14.3 days
              • Pure beta emitter
              • Bremsstrahlung imaging possible, but not practical
              • Major drawback: Normal marrow receives high radiation dose relative to metastatic deposits (→ myelosuppression)
              • Also used to treat hematologic disease, primarily polycythemia vera
            • Rhenium 186 (Re-186)
              • t1/2: 90 hours
              • Not approved in United States
              • Similar to technetium, labeled to bisphosphonate
              • Gamma emission (187 keV) suitable for imaging
              • High radiation dose to normal bone
            • Tin 117m (Sn-117m), lutetium 177 (Lu-177)
              • Primarily investigational
              • Not currently in clinical use
            • Mechanism of action
              • Not well understood
              • Localized radiation to metastatic sites
              • May ↓ tumor volume
              • Likely ↓ in circulating cytokine, humoral factors that sensitize and stimulate nerve endings

          PREPROCEDURE

          • Indications

            • Contraindications

              • Getting Started

                PROCEDURE

                • Procedure Steps

                  • Alternative Procedures/Therapies

                    POST PROCEDURE

                    • Expected Outcome

                      OUTCOMES

                      • Problems

                        • Complications

                          Selected References

                          1. Den RB et al: Ra-223 treatment for bone metastases in castrate-resistant prostate cancer: Practical management issues for patient selection. Am J Clin Oncol. 42(4):399-406, 2019
                          2. Abi-Ghanem AS et al: Radionuclide therapy for osseous metastases in prostate cancer. Semin Nucl Med. 45(1):66-80, 2015
                          3. Shore ND: Radium-223 dichloride for metastatic castration-resistant prostate cancer: The urologist's perspective. Urology. 85(4):717-24, 2015
                          4. Pandit-Taskar N et al: Bone-seeking radiopharmaceuticals for treatment of osseous metastases, Part 1: α therapy with 223Ra-dichloride. J Nucl Med. 55(2):268-74, 2014
                          5. Wadas TJ et al: Molecular targeted α-particle therapy for oncologic applications. AJR Am J Roentgenol. 203(2):253-60, 2014
                          6. Wieder HA et al: Clinical use of bone-targeting radiopharmaceuticals with focus on alpha-emitters. World J Radiol. 6(7):480-5, 2014
                          7. Parker C et al: Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med. 369(3):213-23, 2013
                          8. Chiacchio S et al: Radionuclide therapy and integrated protocols for bone metastases. Q J Nucl Med Mol Imaging. 55(4):431-47, 2011
                          9. Bauman G et al: Radiopharmaceuticals for the palliation of painful bone metastasis-a systemic review. Radiother Oncol. 75(3):258-70, 2005
                          10. Damerla V et al: Recent developments in nuclear medicine in the management of bone metastases: a review and perspective. Am J Clin Oncol. 28(5):513-20, 2005
                          11. Lewington VJ: Bone-seeking radionuclides for therapy. J Nucl Med. 46 Suppl 1:38S-47S, 2005
                          12. Liepe K et al: Systemic radionuclide therapy in pain palliation. Am J Hosp Palliat Care. 22(6):457-64, 2005
                          13. Liepe K et al: The benefit of bone-seeking radiopharmaceuticals in the treatment of metastatic bone pain. J Cancer Res Clin Oncol. 131(1):60-6, 2005
                          14. Pinski J et al: Prostate cancer metastases to bone: pathophysiology, pain management, and the promise of targeted therapy. Eur J Cancer. 41(6):932-40, 2005
                          15. Reisfield GM et al: Radiopharmaceuticals for the palliation of painful bone metastases. Am J Hosp Palliat Care. 22(1):41-6, 2005
                          16. Lam MG et al: 186Re-HEDP for metastatic bone pain in breast cancer patients. Eur J Nucl Med Mol Imaging. 31 Suppl 1:S162-70, 2004
                          17. Maini CL et al: 153Sm-EDTMP for bone pain palliation in skeletal metastases. Eur J Nucl Med Mol Imaging. 31 Suppl 1:S171-8, 2004
                          18. Pandit-Taskar N et al: Radiopharmaceutical therapy for palliation of bone pain from osseous metastases. J Nucl Med. 45(8):1358-65, 2004
                          19. Sapienza MT et al: Retrospective evaluation of bone pain palliation after samarium-153-EDTMP therapy. Rev Hosp Clin Fac Med Sao Paulo. 59(6):321-8, 2004
                          20. Sartor O et al: Samarium-153-Lexidronam complex for treatment of painful bone metastases in hormone-refractory prostate cancer. Urology. 63(5):940-5, 2004
                          21. Ashayeri E et al: Strontium 89 in the treatment of pain due to diffuse osseous metastases: a university hospital experience. J Natl Med Assoc. 94(8):706-11, 2002
                          22. Lewington VJ: A practical guide to targeted therapy for bone pain palliation. Nucl Med Commun. 23(9):833-6, 2002
                          23. Giammarile F et al: Bone pain palliation with strontium-89 in cancer patients with bone metastases. Q J Nucl Med. 45(1):78-83, 2001
                          24. Hamdy NA et al: The palliative management of skeletal metastases in prostate cancer: use of bone-seeking radionuclides and bisphosphonates. Semin Nucl Med. 31(1):62-8, 2001
                          25. Han SH et al: 186Re-etidronate. Efficacy of palliative radionuclide therapy for painful bone metastases. Q J Nucl Med. 45(1):84-90, 2001
                          Related Anatomy
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                          Related Differential Diagnoses
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                          References
                          Tables

                          Tables

                          KEY FACTS

                          • Terminology

                            • Preprocedure

                              • Procedure

                                • Post Procedure

                                  TERMINOLOGY

                                  • Definitions

                                    • Bone pain is cardinal symptom of bone metastases
                                      • Initially intermittent pain of variable intensity; progresses to chronic pain with breakthrough acute episodes
                                      • Major impact on quality of life
                                      • Mechanical allodynia (normal, nonpainful activities become painful, e.g., coughing)
                                    • Metastatic bone tumor therapy
                                      • Radiopharmaceutical treatment of metastatic bone pain refractory to analgesics
                                        • Alpha emitter: Ra-223 (trade name Xofigo; formerly known as Alpharadin)
                                          • ALSYMPCA (ALpharadin in SYMptomatic Prostate CAncer) trial showed survival benefit of Ra-223 treatment in castration-resistant prostate cancer (CRPC) patients
                                          • Median survival advantage of 3.6 months as compared to placebo
                                          • 30% ↓ in risk of death compared to placebo
                                          • Monthly IV administration of Ra-223 for 6 months
                                          • Usually effective by 3rd Ra-223 administration (3 months)
                                          • Approved for prostate cancer
                                        • Beta emitters: Sm-153, Sr-89
                                          • Considered palliative to reduce pain
                                          • One-time IV therapy, but can be repeated
                                          • Usually effective within 1-2 weeks after administration
                                          • Approved for multiple tumors that metastasize to bone
                                  • Alpha Emitter

                                    • Ra-223
                                      • 1st α-particle therapy approved in United States
                                      • 1st radiopharmaceutical therapy that extends survival in patients with bone metastases
                                      • Bone-seeking α emitter mimicking calcium, 4 α-particles generated for each decay
                                      • Produced from Ra-223 extraction generator (parent isotopes Ac-227 and Th-227)
                                      • t1/2: 11.43 days
                                      • Alpha emission (95.3%; energy range: 5-7.5 MeV), beta emission (3.6%; average energies: 0.445 MeV and 0.492 MeV), gamma emission (1.1%; energy range: 0.01-1.27 MeV)
                                      • Greater biologic effectiveness due to high linear energy transfer
                                      • Less hematologic toxicity due to shorter path length (60-100 µm) of α-particles
                                      • Rapid blood clearance (< 1% blood activity at 24 hours), no significant redistribution
                                      • Decreases bone specific alkaline phosphatase (ALP), marker for tumor response in CRPC
                                      • Excretion: Gastrointestinal (52% activity in bowel at 24 hours), minimal urinary excretion (< 5%)
                                      • Mechanism of action
                                        • Increased uptake and complex formation with hydroxyapatite at sites of increased bone turnover
                                        • α-particle-induced double-stranded DNA breaks
                                      • Benefits
                                        • Survival benefit in symptomatic and progressive metastatic CRPC (≥ 2 skeletal metastases, no visceral metastases) regardless of disease extent, previous treatment with docetaxel and current treatment with bisphosphonates (ALSYMPCA trial)
                                          • 16% of patients showed ≥ 30% drop in PSA at 12 weeks
                                          • Delayed onset of first symptomatic skeletal event (symptomatic pathologic bone fracture)
                                          • Pain relief
                                          • Improved quality of life
                                          • Delayed increase in ALP and PSA
                                  • Beta Emitters

                                    • Sm-153 (Lexidronam/Quadramet)
                                      • t1/2: 1.9 days
                                      • Dose: 1 mCi (37 MBq)/kg maximum
                                      • Mixed beta and gamma emitter
                                      • 640, 710, and 810 keV beta emissions (mean: 0.23 MeV); average path length: 0.6 mm
                                      • Can image 103 keV gamma emissions (28% abundance)
                                      • Labeled to bisphosphonate ethylenediamine tetramethylene phosphate (EDTMP) (↑ bone-seeking properties)
                                      • Urinary excretion: Complete ~ 6 hours after administration
                                      • < 1% activity in blood 5 hours after injection
                                    • Sr-89 (Metastron)
                                      • t1/2: 50.5 days
                                      • Dose 40-60 uCi (1-1.6 MBq)/kg up to 4 mCi (148 MBq); dose can be repeated after 3-4 months
                                      • Pure beta emitter (1.49 MeV maximum energy; mean: 0.58 MeV), maximum path length: 8 mm; average path length: 2.4 mm
                                      • Bremsstrahlung imaging possible, but not practical
                                      • Physiologic distribution mimics calcium
                                      • Excretion: Mainly urinary (80%), partially fecal (20%)
                                      • Used in patients with moderate pain, reasonable life expectancy (> 3 months) due to long response duration
                                    • P-32
                                      • First tracer used for metastatic bone pain palliation
                                      • Not widely used for bone pain palliation since 1980s; now abandoned
                                      • t1/2: 14.3 days
                                      • Pure beta emitter
                                      • Bremsstrahlung imaging possible, but not practical
                                      • Major drawback: Normal marrow receives high radiation dose relative to metastatic deposits (→ myelosuppression)
                                      • Also used to treat hematologic disease, primarily polycythemia vera
                                    • Rhenium 186 (Re-186)
                                      • t1/2: 90 hours
                                      • Not approved in United States
                                      • Similar to technetium, labeled to bisphosphonate
                                      • Gamma emission (187 keV) suitable for imaging
                                      • High radiation dose to normal bone
                                    • Tin 117m (Sn-117m), lutetium 177 (Lu-177)
                                      • Primarily investigational
                                      • Not currently in clinical use
                                    • Mechanism of action
                                      • Not well understood
                                      • Localized radiation to metastatic sites
                                      • May ↓ tumor volume
                                      • Likely ↓ in circulating cytokine, humoral factors that sensitize and stimulate nerve endings

                                  PREPROCEDURE

                                  • Indications

                                    • Contraindications

                                      • Getting Started

                                        PROCEDURE

                                        • Procedure Steps

                                          • Alternative Procedures/Therapies

                                            POST PROCEDURE

                                            • Expected Outcome

                                              OUTCOMES

                                              • Problems

                                                • Complications

                                                  Selected References

                                                  1. Den RB et al: Ra-223 treatment for bone metastases in castrate-resistant prostate cancer: Practical management issues for patient selection. Am J Clin Oncol. 42(4):399-406, 2019
                                                  2. Abi-Ghanem AS et al: Radionuclide therapy for osseous metastases in prostate cancer. Semin Nucl Med. 45(1):66-80, 2015
                                                  3. Shore ND: Radium-223 dichloride for metastatic castration-resistant prostate cancer: The urologist's perspective. Urology. 85(4):717-24, 2015
                                                  4. Pandit-Taskar N et al: Bone-seeking radiopharmaceuticals for treatment of osseous metastases, Part 1: α therapy with 223Ra-dichloride. J Nucl Med. 55(2):268-74, 2014
                                                  5. Wadas TJ et al: Molecular targeted α-particle therapy for oncologic applications. AJR Am J Roentgenol. 203(2):253-60, 2014
                                                  6. Wieder HA et al: Clinical use of bone-targeting radiopharmaceuticals with focus on alpha-emitters. World J Radiol. 6(7):480-5, 2014
                                                  7. Parker C et al: Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med. 369(3):213-23, 2013
                                                  8. Chiacchio S et al: Radionuclide therapy and integrated protocols for bone metastases. Q J Nucl Med Mol Imaging. 55(4):431-47, 2011
                                                  9. Bauman G et al: Radiopharmaceuticals for the palliation of painful bone metastasis-a systemic review. Radiother Oncol. 75(3):258-70, 2005
                                                  10. Damerla V et al: Recent developments in nuclear medicine in the management of bone metastases: a review and perspective. Am J Clin Oncol. 28(5):513-20, 2005
                                                  11. Lewington VJ: Bone-seeking radionuclides for therapy. J Nucl Med. 46 Suppl 1:38S-47S, 2005
                                                  12. Liepe K et al: Systemic radionuclide therapy in pain palliation. Am J Hosp Palliat Care. 22(6):457-64, 2005
                                                  13. Liepe K et al: The benefit of bone-seeking radiopharmaceuticals in the treatment of metastatic bone pain. J Cancer Res Clin Oncol. 131(1):60-6, 2005
                                                  14. Pinski J et al: Prostate cancer metastases to bone: pathophysiology, pain management, and the promise of targeted therapy. Eur J Cancer. 41(6):932-40, 2005
                                                  15. Reisfield GM et al: Radiopharmaceuticals for the palliation of painful bone metastases. Am J Hosp Palliat Care. 22(1):41-6, 2005
                                                  16. Lam MG et al: 186Re-HEDP for metastatic bone pain in breast cancer patients. Eur J Nucl Med Mol Imaging. 31 Suppl 1:S162-70, 2004
                                                  17. Maini CL et al: 153Sm-EDTMP for bone pain palliation in skeletal metastases. Eur J Nucl Med Mol Imaging. 31 Suppl 1:S171-8, 2004
                                                  18. Pandit-Taskar N et al: Radiopharmaceutical therapy for palliation of bone pain from osseous metastases. J Nucl Med. 45(8):1358-65, 2004
                                                  19. Sapienza MT et al: Retrospective evaluation of bone pain palliation after samarium-153-EDTMP therapy. Rev Hosp Clin Fac Med Sao Paulo. 59(6):321-8, 2004
                                                  20. Sartor O et al: Samarium-153-Lexidronam complex for treatment of painful bone metastases in hormone-refractory prostate cancer. Urology. 63(5):940-5, 2004
                                                  21. Ashayeri E et al: Strontium 89 in the treatment of pain due to diffuse osseous metastases: a university hospital experience. J Natl Med Assoc. 94(8):706-11, 2002
                                                  22. Lewington VJ: A practical guide to targeted therapy for bone pain palliation. Nucl Med Commun. 23(9):833-6, 2002
                                                  23. Giammarile F et al: Bone pain palliation with strontium-89 in cancer patients with bone metastases. Q J Nucl Med. 45(1):78-83, 2001
                                                  24. Hamdy NA et al: The palliative management of skeletal metastases in prostate cancer: use of bone-seeking radionuclides and bisphosphonates. Semin Nucl Med. 31(1):62-8, 2001
                                                  25. Han SH et al: 186Re-etidronate. Efficacy of palliative radionuclide therapy for painful bone metastases. Q J Nucl Med. 45(1):84-90, 2001