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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 a 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: Radium-223 (Ra-223) (trade name Xofigo; formerly known as Alpharadin)
                  • ALSYMPCA (ALpharadin in SYMptomatic Prostate CAncer patients) 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
                • Beta emitters: Samarium-153, strontium-89
                  • Considered palliative: Usually do not affect survival
          • Alpha Emitter

            • Radium-223 (Xofigo)
              • 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 biological effectiveness due to high linear energy transfer
              • Less hematological 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 or more 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 pathological 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 phospate (EDTMP) (↑ bone-seeking properties)
              • Urinary excretion: Complete ~ 6 hrs after administration
              • < 1% activity in blood 5 hrs 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
              • T½ 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)
              • T½ 90 hours
              • Not approved in United States
              • Similar to technetium, labeled to a 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. Abi-Ghanem AS et al: Radionuclide therapy for osseous metastases in prostate cancer. Semin Nucl Med. 45(1):66-80, 2015
                          2. Shore ND: Radium-223 Dichloride for Metastatic Castration-resistant Prostate Cancer: The Urologist's Perspective. Urology. 85(4):717-724, 2015
                          3. 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
                          4. Wadas TJ et al: Molecular targeted α-particle therapy for oncologic applications. AJR Am J Roentgenol. 203(2):253-60, 2014
                          5. Wieder HA et al: Clinical use of bone-targeting radiopharmaceuticals with focus on alpha-emitters. World J Radiol. 6(7):480-5, 2014
                          6. Parker C et al: Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med. 369(3):213-23, 2013
                          7. Chiacchio S et al: Radionuclide therapy and integrated protocols for bone metastases. Q J Nucl Med Mol Imaging. 55(4):431-47, 2011
                          8. Bauman G et al: Radiopharmaceuticals for the palliation of painful bone metastasis-a systemic review. Radiother Oncol. 75(3):258-70, 2005
                          9. 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
                          10. Lewington VJ: Bone-seeking radionuclides for therapy. J Nucl Med. 46 Suppl 1:38S-47S, 2005
                          11. Liepe K et al: Systemic radionuclide therapy in pain palliation. Am J Hosp Palliat Care. 22(6):457-64, 2005
                          12. 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
                          13. 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
                          14. Reisfield GM et al: Radiopharmaceuticals for the palliation of painful bone metastases. Am J Hosp Palliat Care. 22(1):41-6, 2005
                          15. 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
                          16. 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
                          17. Pandit-Taskar N et al: Radiopharmaceutical therapy for palliation of bone pain from osseous metastases. J Nucl Med. 45(8):1358-65, 2004
                          18. 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
                          19. 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
                          20. 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
                          21. Lewington VJ: A practical guide to targeted therapy for bone pain palliation. Nucl Med Commun. 23(9):833-6, 2002
                          22. 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
                          23. 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
                          24. 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 a 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: Radium-223 (Ra-223) (trade name Xofigo; formerly known as Alpharadin)
                                          • ALSYMPCA (ALpharadin in SYMptomatic Prostate CAncer patients) 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
                                        • Beta emitters: Samarium-153, strontium-89
                                          • Considered palliative: Usually do not affect survival
                                  • Alpha Emitter

                                    • Radium-223 (Xofigo)
                                      • 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 biological effectiveness due to high linear energy transfer
                                      • Less hematological 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 or more 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 pathological 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 phospate (EDTMP) (↑ bone-seeking properties)
                                      • Urinary excretion: Complete ~ 6 hrs after administration
                                      • < 1% activity in blood 5 hrs 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
                                      • T½ 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)
                                      • T½ 90 hours
                                      • Not approved in United States
                                      • Similar to technetium, labeled to a 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. Abi-Ghanem AS et al: Radionuclide therapy for osseous metastases in prostate cancer. Semin Nucl Med. 45(1):66-80, 2015
                                                  2. Shore ND: Radium-223 Dichloride for Metastatic Castration-resistant Prostate Cancer: The Urologist's Perspective. Urology. 85(4):717-724, 2015
                                                  3. 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
                                                  4. Wadas TJ et al: Molecular targeted α-particle therapy for oncologic applications. AJR Am J Roentgenol. 203(2):253-60, 2014
                                                  5. Wieder HA et al: Clinical use of bone-targeting radiopharmaceuticals with focus on alpha-emitters. World J Radiol. 6(7):480-5, 2014
                                                  6. Parker C et al: Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med. 369(3):213-23, 2013
                                                  7. Chiacchio S et al: Radionuclide therapy and integrated protocols for bone metastases. Q J Nucl Med Mol Imaging. 55(4):431-47, 2011
                                                  8. Bauman G et al: Radiopharmaceuticals for the palliation of painful bone metastasis-a systemic review. Radiother Oncol. 75(3):258-70, 2005
                                                  9. 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
                                                  10. Lewington VJ: Bone-seeking radionuclides for therapy. J Nucl Med. 46 Suppl 1:38S-47S, 2005
                                                  11. Liepe K et al: Systemic radionuclide therapy in pain palliation. Am J Hosp Palliat Care. 22(6):457-64, 2005
                                                  12. 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
                                                  13. 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
                                                  14. Reisfield GM et al: Radiopharmaceuticals for the palliation of painful bone metastases. Am J Hosp Palliat Care. 22(1):41-6, 2005
                                                  15. 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
                                                  16. 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
                                                  17. Pandit-Taskar N et al: Radiopharmaceutical therapy for palliation of bone pain from osseous metastases. J Nucl Med. 45(8):1358-65, 2004
                                                  18. 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
                                                  19. 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
                                                  20. 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
                                                  21. Lewington VJ: A practical guide to targeted therapy for bone pain palliation. Nucl Med Commun. 23(9):833-6, 2002
                                                  22. 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
                                                  23. 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
                                                  24. Han SH et al: 186Re-etidronate. Efficacy of palliative radionuclide therapy for painful bone metastases. Q J Nucl Med. 45(1):84-90, 2001