Bone Metastases of Bone Metastases


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Bone Metastases of Bone Metastases

  1. 1. Radionuclide Therapy of Bone Metastases Presented by EKKASIT SRITHAMMASIT, MD. H. Palmedo
  2. 2. <ul><li>Radionuclide therapy of bone metastases </li></ul><ul><li>: a systemic therapy with IV administration of open radioactive agents. </li></ul><ul><li>Aim </li></ul><ul><li>: maximal dose to the target. </li></ul><ul><li>: minimal dose to the rest of the body. </li></ul>Introduction
  3. 3. <ul><li>Bone metastases </li></ul><ul><ul><li>Breast cancer (60%) </li></ul></ul><ul><ul><li>Prostate cancer (50%) </li></ul></ul><ul><ul><li>Lung cancer(30%) </li></ul></ul>Introduction
  4. 4. <ul><li>Once bone metastases are diagnosed, the disease must be classified as incurable . </li></ul>Introduction
  5. 5. <ul><li>At this stage, quality of life and prolongation of survival are the important parameters that form the basis for further medical decision making. </li></ul>Introduction
  6. 6. <ul><li>Although bone metastases are rarely the cause of cancer-related death, they lead to serious complications : </li></ul><ul><ul><li>Pain symptoms of varying intensity. </li></ul></ul><ul><ul><li>Fractures resulting in considerable morbidity </li></ul></ul><ul><ul><li>Hypercalcemic syndrome due to increased bone resorption of osteolytic metastases - paraneoplastic syndrome . </li></ul></ul><ul><ul><li>Destroyed and clinically relevant alterations of the blood counts . </li></ul></ul>Introduction
  7. 7. <ul><li>Chronic pain syndrome is the most important complication of bone metastases and has a negative impact on quality of life and the social environment of the patient. </li></ul><ul><li>“ These patients represent the main indication for radionuclide therapy” </li></ul>Introduction
  8. 8. <ul><li>“ Radionuclide therapy is useful in nociceptor pain patients </li></ul><ul><li>but not for neuropathy pain ” </li></ul><ul><li>Nociceptor pain : patient as being of a stinging, gnawing or dull character gnawing or dull character. </li></ul><ul><li>Neuropathic pain : burning and appearing suddenly. </li></ul>Introduction
  9. 9. <ul><li>Bone metastases can generate pain by </li></ul><ul><ul><li>A strong mechanical impact to the nociceptor. </li></ul></ul><ul><ul><li>An osteoblastic (and osteoclastic) induced excretion of pain mediators that result in sensitization of the nociceptor. </li></ul></ul>Introduction [ prostaglandin E, bradykinin, histamine, and interleukin ]
  10. 10. Table of content <ul><li>Radiopharmaceuticals </li></ul><ul><li>Methodology </li></ul><ul><ul><li>Dosimetry </li></ul></ul><ul><ul><li>Pain Documentation </li></ul></ul><ul><li>Clinical Indications </li></ul><ul><li>Pain Palliation </li></ul><ul><li>Progression Free Interval and Survival </li></ul><ul><li>Side Effects </li></ul><ul><li>New Treatment Strategies </li></ul>
  11. 11. <ul><li>Radionuclide therapy of bone metastases was started decades ago with the administration of phosphorus-32 . </li></ul><ul><li>This inappropriate ratio and the frequently observed strong myelosuppression were the reasons for abandoning phosphorus-32. </li></ul>Radiopharmaceuticals
  12. 12. <ul><li>Since that time a variety of β -emitters have been investigated for therapy of bone metastases. </li></ul>Radiopharmaceuticals
  13. 13. <ul><li>Principally, the radiation dose can be applied over a very short period, necessitating a high dose rate, or over a longer time period administering a radionuclide with a low dose rate. </li></ul>Radiopharmaceuticals
  14. 14. <ul><li>Strontium-89 </li></ul><ul><ul><li>Excreted renally to 70–90% </li></ul></ul><ul><ul><li>Eliminated from the vascular compartment within the first few hours. </li></ul></ul><ul><ul><li>Except for the bone uptake and the excretion via the urinary system, there is no accumulation in any organ system. </li></ul></ul><ul><ul><li>The tracer uptake in the skeletal system ranges between 12% and 90% of the administered activity. </li></ul></ul><ul><ul><li>The accumulation of strontium-89 chloride in metastatic lesions is 5–20 times as high as the accumulation in normal bone tissue. </li></ul></ul><ul><ul><li>The effective half-life = over 50 days and thus strontium-89 chloride delivers a low dose rate radiation. </li></ul></ul>Radiopharmaceuticals
  15. 15. <ul><li>A different radiopharmaceutical option is to label radionuclides to phosphonates that are known to have a high osteoaffinity . </li></ul><ul><ul><li>Sm-153 EDTMP: </li></ul></ul><ul><ul><li>samarium-153 ethylenediaminetetramethylenephosphonate </li></ul></ul><ul><ul><li>Re-186 HEDP: </li></ul></ul><ul><ul><li>rhenium-186 hydroxyethylidenediphosphonate </li></ul></ul>Radiopharmaceuticals
  16. 16. <ul><li>Sm-153 EDTMP and Re-186 HEDP </li></ul><ul><ul><li>Excreted mainly by the kidneys and they disappear rapidly from the vascular compartment. </li></ul></ul><ul><ul><li>The uptake in the skeleton ranges between 20–30% and 30–50% of the injected dose for Re-186 HEDP and Sm-153 EDTMP, respectively. </li></ul></ul><ul><ul><li>The accumulation in the metastatic lesions is between 3 and 20 times as high as normal bone. </li></ul></ul><ul><ul><li>The effective half-life of Re-186 HEDP and Sm-153 EDTMP lies in the range of 2–3 days. </li></ul></ul>Radiopharmaceuticals
  17. 17. Radiopharmaceuticals
  18. 18. Table of content <ul><li>Radiopharmaceuticals </li></ul><ul><li>Methodology </li></ul><ul><ul><li>Dosimetry </li></ul></ul><ul><ul><li>Pain Documentation </li></ul></ul><ul><li>Clinical Indications </li></ul><ul><li>Pain Palliation </li></ul><ul><li>Progression Free Interval and Survival </li></ul><ul><li>Side Effects </li></ul><ul><li>New Treatment Strategies </li></ul>
  19. 19. Methodology Dosimetry <ul><li>The accumulation of radiopharmaceuticals is much higher in osteoblastic than in osteolytic metastases , with ratios of 1:15 and 1:3, respectively. </li></ul><ul><li>The uptake of the radionuclide determines the therapeutic dose in the bone metastases. </li></ul><ul><li>The predictive value of bone scintigraphy previous to treatment is indispensable even if osseous metastases have already been diagnosed by other imaging modalities. </li></ul>
  20. 20. Methodology Dosimetry <ul><li>To calculate the radiation dose to apply to tumor tissue and organs, different methods are used, showing a deviation of the calculated to the real dose of up to 50%. </li></ul><ul><li>Generally, a time-activity curve is generated over the region of interest by ROI analysis of multiple whole-body scintigrams. </li></ul><ul><li>The area under the curve represents the accumulated activity and must be multiplied by the S-value . </li></ul><ul><li>The S-value contains nuclide and tissue specific parameters . </li></ul>
  21. 21. Methodology Dosimetry <ul><li>The radiation dose to bone metastases </li></ul><ul><li>4 mCi Sr-89 chloride : 8 and 90 Gy. </li></ul><ul><li>70 mCi Sm-153 EDTMP : 10 and 70 Gy. </li></ul><ul><li>35 mCi Re-186 HEDP : 14 and 140 Gy. </li></ul>Normal bone tissue receives a dose between 1 and 2.5 Gy that below of metastatic lesions
  22. 22. Methodology Dosimetry <ul><li>The organ doses demonstrating that kidneys and bladder receive uncritical doses. </li></ul><ul><li>Obviously, the critical organ is the bone marrow, which is exposed to doses between 1 and 1.5 Gy. </li></ul><ul><li>At this level, the first alterations of blood counts can be expected . </li></ul>
  23. 23. Methodology Pain Documentation <ul><li>Documentation of pain is difficult because large inter and intra individual variations exist for the parameter “pain”. </li></ul><ul><li>It is recommended to use standardized questionnaires for pain documentation to evaluate the success of the treatment. </li></ul><ul><li>For the daily routine, such a questionnaire must be short but comprehensive enough to include the fields “ pain ,” “ activity of patient ” and “ consumption of analgesics .” </li></ul>
  24. 24. Methodology Pain Documentation <ul><li>There are a variety of different pain scores and questionnaires that supply these items of information adequately. </li></ul><ul><li>The reader’s attention is drawn to the well evaluated and widely used visual analog scale(VAS) and the scoring of analgesic consumption using Foley’s score . </li></ul>
  25. 25. Table of content <ul><li>Radiopharmaceuticals </li></ul><ul><li>Methodology </li></ul><ul><ul><li>Dosimetry </li></ul></ul><ul><ul><li>Pain Documentation </li></ul></ul><ul><li>Clinical Indications </li></ul><ul><ul><li>Pain Palliation </li></ul></ul><ul><ul><li>Progression Free Interval and survival </li></ul></ul><ul><ul><li>Side Effects </li></ul></ul><ul><ul><li>New Treatment Strategies </li></ul></ul>
  26. 26. Clinical Indications Pain Palliation <ul><li>The application of radionuclides for treatment of painful bone metastases has been investigated for several decades. </li></ul><ul><li>Beginning in the 1960s, the first nuclide administered for pain therapy of multiple osseous metastases was phosphorus-32. </li></ul><ul><li>Since that time many different radiopharmaceuticals such as strontium-89 chloride , yttrium-90 citrate, rhenium-186 HEDP , samarium-153 EDTMP , tin-177m DTPA, and rhenium-188 HEDP have been investigated. </li></ul><ul><li>This list is not complete and therefore this chapter can only concern itself with the most important agents. </li></ul>
  27. 27. Clinical Indications Pain Palliation <ul><li>Strontium-89 chloride </li></ul><ul><li>Laing et al. (1991) : </li></ul><ul><ul><li>A total of 75% of the prostate cancer with painful metastatic patients demonstrated a marked improvement of the pain status and every 5 patient was almost completely painfree. </li></ul></ul><ul><ul><li>The effect of Sr-89 treatment began 10–20 days postinjection and reached a maximum after 6 weeks. </li></ul></ul><ul><ul><li>Recommended dose of 150 MBq or 4 mCi of Sr-89 . ( standard dosage since that time.) </li></ul></ul><ul><li>Lewington et al. (1991) : </li></ul><ul><ul><li>The patients treated with Sr-89 showed a significantly better pain reduction than the patients in the placebo group. </li></ul></ul>
  28. 28. Clinical Indications Pain Palliation <ul><li>In the group of new radiopharmaceuticals, Sm-153 EDTMP and Re-186 HEDP are the best studied and also commercially available agents. </li></ul><ul><li>Serafini et al. (1998) : double blind and placebo-controlled study </li></ul><ul><ul><li>The response rate of the Sm-153 group was significantly better than that of the placebo group, which showed response rates of 40% and 2% after 4 weeks and 4 months, respectively. </li></ul></ul><ul><ul><li>Furthermore, the study delivered evidence that a dose of 1.0 mCi/kg body weight results more frequently and for a longer period in pain reduction than a dose of 0.5 mCi/kg body weight. </li></ul></ul>
  29. 29. Clinical Indications Pain Palliation <ul><li>Tian et al. (1999): </li></ul><ul><ul><li>were not able to confirm in their multicenter trial that the two different dose groups of Sm-153 have a different effect on pain palliation. </li></ul></ul>
  30. 30. Clinical Indications Pain Palliation <ul><li>Maxon et al. (1988): </li></ul><ul><ul><li>demonstrated in a group of 20 patients that a significant improvement of pain can be achieved in 80% of the cases after a single injection of Re-186. </li></ul></ul>
  31. 31. Clinical Indications Pain Palliation <ul><li>Palmedo 1996 : </li></ul><ul><ul><li>a response rate of 70% and an average time of 4 weeks for pain relief beginning 1 week after injection of Re-186 . </li></ul></ul>
  32. 32. Clinical Indications Pain Palliation <ul><li>Han et al. (1999): </li></ul><ul><ul><li>The total response of patients treated with Re-186 was statistically significantly better than that of the placebo group. </li></ul></ul><ul><ul><li>Also the rate of patients requesting additional radiotherapy was lower in the Re-186 group at 44% than in the placebo group at 67%. </li></ul></ul><ul><ul><li>Amazingly, the overall response rate of Re-186 was only 30% on average. </li></ul></ul><ul><ul><li>In summary, there is sufficient evidence-based data that confirm the benefit of radionuclide therapy as an effective treatment modality of painful osseous metastases in hormone-refractory prostate cancer patients. </li></ul></ul>
  33. 33. Clinical Indications Pain Palliation <ul><li>Robinson (1993): </li></ul><ul><ul><li>A responded rate 81% in breast cancer patients with multiple bone metastases after injection of Sr-89. </li></ul></ul><ul><li>Baziotis et al. (1998): 64 breast cancer patients by a single injection with 2 MBq/kg body weight of Sr-89. </li></ul><ul><ul><li>They found an improvement of the pain situation in 80% of the cases including 35% of patients demonstrating almost complete pain relief. </li></ul></ul><ul><ul><li>The average time of response was 3 months. </li></ul></ul>
  34. 34. Clinical Indications Pain Palliation <ul><li>Serafini et al. and Tian et al.: Sm-153 EDTMP for breast cancer patients. </li></ul><ul><ul><li>They reported effective pain therapy in 72–85% of metastatic bone disease with a mean duration of 1–2 months. </li></ul></ul><ul><ul><li>After 4 months, the response rate was still at the level of 43%. </li></ul></ul>
  35. 35. Clinical Indications Pain Palliation <ul><li>Hauswirth et al. (1998): prospectively 17 breast cancer patients receiving 35 mCi Re-186 </li></ul><ul><ul><li>a response rate of 60% and a mean duration of response of 5 weeks. </li></ul></ul><ul><li>Palmedo et al. 1999: confirmed these data . </li></ul><ul><li>Han et al. (1999): </li></ul><ul><ul><li>They also found a response rate of 60% and a mean duration of 1 month. </li></ul></ul>
  36. 36. Clinical Indications Pain Palliation <ul><ul><li>In summary , also in breast cancer patients, there is evidence that radionuclide therapy is effective in palliating painful bone metastases. </li></ul></ul>
  37. 37. Clinical Indications Progression Free Interval and Survival <ul><li>Porter et al. (1993): </li></ul><ul><ul><li>Efficacy of Sr-89 treatment for hormone-refractory prostate cancer patients as an adjunct to radiation therapy. </li></ul></ul><ul><ul><li>Three months after radiation therapy, the rates of new osseous metastases were 66% and 41% in the placebo group and the Sr-89 group, respectively . </li></ul></ul><ul><ul><li>This difference was statistically significant. </li></ul></ul><ul><ul><li>More patients in the Sr-89 group demonstrated a reduction of serum PSA and alkaline phosphatase over 50% within the first 4 months after treatment. </li></ul></ul>
  38. 38. Clinical Indications Progression Free Interval and Survival <ul><li>Quilty et al. (1993): </li></ul><ul><ul><li>284 prostate cancer patients with bone metastasis. ( Radiotherapy VS Sr-89) </li></ul></ul><ul><ul><li>Pain reduction was equivalent. </li></ul></ul><ul><ul><li>However, new pain foci were significantly less frequent in the Sr-89 group, even when compared to irradiation group . </li></ul></ul>
  39. 39. Clinical Indications Progression Free Interval and Survival <ul><li>Both studies cited give evidence that radionuclide therapy with Sr-89 is more than pure pain palliation and certainly has a tumoricidal effect . </li></ul>
  40. 40. Clinical Indications Side Effects
  41. 41. Clinical Indications Side Effects Blood cell counts can change if a dose of 1 Gy or more is applied.
  42. 42. Clinical Indications Side Effects <ul><li>the most relevant side effect of radionuclide therapy of bone metastases is a thrombo- and leukopenia. </li></ul>
  43. 43. Clinical Indications Side Effects <ul><li>Laing et al.(1991) : Sr 89 </li></ul><ul><ul><li>the main side effect was a thrombocytopenia with an average decrease of 25% and a nadir at week 6. </li></ul></ul><ul><ul><li>No patient showed a toxicity of more than grade II. </li></ul></ul>
  44. 44. Clinical Indications Side Effects <ul><li>Quilty et al. (1993) </li></ul><ul><ul><li>leuko- and thrombocyte counts demonstrate an average decrease of 30–40% compared to baseline values after the injection of Sr-89 200 MBq. </li></ul></ul><ul><ul><li>Nadir of thrombo- and leukocytes was 6 weeks. </li></ul></ul><ul><ul><li>Significant toxicity (WHO grade III and IV) of blood counts was observed in only 7% of patients. </li></ul></ul><ul><ul><li>Hemoglobin levels were not altered by radionuclide therapy. </li></ul></ul><ul><ul><li>Hemibody irradiation necessitated twice as many blood transfusions. Also nausea, vomiting and diarrhea were observed four times more frequently after hemibody irradiation. </li></ul></ul>
  45. 45. Clinical Indications Side Effects <ul><li>Sm-153 EDTMP and Re-186 HEDP </li></ul><ul><li>Lead to a mild hematotoxicity if a dose of 1.0 mCi/kg body weight and of 35 mCi are administered, respectively. </li></ul><ul><li>The nadir of the 20–30% decrease of thrombo- and leukocytes was found to be at week 4–5. </li></ul><ul><li>If higher doses of Sm-153 EDTMP (>2.0 mCi/kg BW) and Re-186 HEDP (>70 mCi) are used, grade III or higher toxicity can occur. </li></ul>
  46. 46. Clinical Indications Side Effects <ul><li>The patient must be informed that pain syndromes might be aggravating for some days ( flare-effect ) and go back to the initial level afterwards. </li></ul><ul><li>Rarely is it necessary to increase the pain medication in this situation. </li></ul>
  47. 47. Clinical Indications Side Effects <ul><li>There are some case reports in the literature describing temporary paresis and paresthesia for Re-186 HEDP in patients with extensive metastatic disease of the skull base and of the vertebral column. </li></ul><ul><li>However, this might also be caused by progressive bone metastases. </li></ul><ul><li>After more than 400 treatments with rhenium-188 HEDP, we were unable to observe any patient who had developed temporary paresis and paresthesia due to radionuclide therapy. </li></ul><ul><li>Conversely, one patient with pretherapeutic, unilateral hypoglossus paresis showed significant improvement of tongue movement after Re-188 HEDP treatment. </li></ul><ul><li>Eight weeks after radionuclide therapy, paresis had completely disappeared. </li></ul>
  48. 48. Clinical Indications Side Effects <ul><li>Bone marrow suppression </li></ul><ul><li>Flare effect </li></ul>
  49. 49. Clinical Indications New Treatment Strategies <ul><li>To enhance the effect of radionuclide therapy on the cancer cells, the following new strategies have been recently investigated: </li></ul><ul><ul><li>combined radionuclide and chemotherapy. </li></ul></ul><ul><ul><li>high dose radionuclide therapy. </li></ul></ul><ul><ul><li>repeated radionuclide therapy. </li></ul></ul>
  50. 50. Clinical Indications New Treatment Strategies <ul><li>Combined radionuclide and chemotherapy </li></ul><ul><li>Exponentially increased cell killing => higher tumoricidal effect. </li></ul><ul><li>Reduced-dosage protocol for chemotherapy => decrease side effects of chemotherapy. </li></ul>
  51. 51. Clinical Indications New Treatment Strategies <ul><li>Mertens et al 1992: </li></ul><ul><ul><li>18 hormone-refractory prostate cancer patients who received a combination of 4 mCi Sr-89 and a low-dose cisplatin infusion (35 mg/m2). </li></ul></ul><ul><ul><li>They observed good pain palliation and an improvement in hemoglobin, tumor markers and bone scans in some patients. </li></ul></ul>
  52. 52. Clinical Indications New Treatment Strategies <ul><li>Tu et al. (2001): </li></ul><ul><ul><li>103 patients with advanced, hormone-refractory prostate cancer. </li></ul></ul><ul><ul><li>Overall survival can be improved by combined chemo- and radionuclide therapy. </li></ul></ul><ul><ul><li>The median survival of patients also increased from 16.8 months (chemotherapy alone) to 27.7months after additional injection of Sr-89. </li></ul></ul>
  53. 53. Clinical Indications New Treatment Strategies <ul><li>Sciuto et al. (2002): </li></ul><ul><ul><li>70 patients with painful bone metastases either to a group A receiving 148 MBq Sr-89 and 50 mg/m 2 cisplatin or to a group B receiving 148 MBq Sr-89 plus placebo. </li></ul></ul>64% 27% progression of bone disease 2 mo 4 mo The median survival without new painful sites 30% 14% New painful sites on previously asymptomatic bone metastases 63% 91% Overall pain relief Arm B Arm A  
  54. 54. Clinical Indications New Treatment Strategies <ul><li>Sciuto et al. (2002): </li></ul><ul><ul><li>Between both arms of the cited study, there was no significant difference with regard to side effects. </li></ul></ul>64% 27% progression of bone disease 2 mo 4 mo The median survival without new painful sites 30% 14% New painful sites on previously asymptomatic bone metastases 63% 91% Overall pain relief Arm B Arm A  
  55. 55. Clinical Indications New Treatment Strategies <ul><li>Akerley et al. (2002) : </li></ul><ul><ul><li>Hormone-refractory prostate cancer patients using estramustine and vinblastine combined with Sr-89 </li></ul></ul><ul><ul><li>The addition of Sr-89 to chemotherapy and its repeated administration is safe and effective . </li></ul></ul><ul><ul><li>Repeated injections of radionuclides seem to enhance the treatment efficacy. </li></ul></ul><ul><ul><li>However, clinicians are often concerned about hematological toxicity when radionuclide therapy is repeated or administered simultaneously with chemotherapy. </li></ul></ul>
  56. 56. Clinical Indications New Treatment Strategies <ul><li>Another new approach to enhancing efficacy of radionuclide therapy is to repeat the injection , aiming at a higher radiation dose. </li></ul>
  57. 57. Clinical Indications New Treatment Strategies <ul><li>Palmedo et al. 2003 : </li></ul><ul><ul><li>Group A received a single injection of Re-188 HEDP, and patients of group B received two injections </li></ul></ul><ul><ul><li>In both groups, toxicity was low with moderate thrombo- and leukopenia. </li></ul></ul>12.7 mo 7 mo Median overall survivals 39% 7% PSA decrease B A  
  58. 58. Clinical Indications New Treatment Strategies <ul><li>A third new approach is the application of high dose radionuclide therapy necessitating bone marrow support. </li></ul>
  59. 59. Clinical Indications New Treatment Strategies <ul><li>Anderson et al. (2002): </li></ul><ul><ul><li>Administered different doses of Sm-153 EDTMP in 30 patients with locally recurrent or metastatic osteosarcoma or skeletal metastases. </li></ul></ul><ul><ul><li>High dose irradiation (39–241 Gy) by bone-targeted therapy with Sm-153 EDTMP is feasible and that non-hematologic side effects are minimal. </li></ul></ul>
  60. 60. The end….