
<b>Radioisotope Use In Cancer Metastatic to Bone
Radiosensitization
Strontium-89
Samarium-153
Rhenium-186
Phosphorus-32
Comparisons of RadioIsotopes</b>


<b>Radioisotope Use In Cancer Metastatic to Bone</b>
        Bone pain is a common symptom in disseminated malignancy and may be difficult to manage effectively.  Pain caused by multiple bone metastases is treated by non-steroidal anti-inflammatory drugs and opioid-containing analgesics, and possibly by bisphosphonates.<b> Radiation is also of proven benefit for palliation of painful bony tumors.  There is growing interest in the therapeutic potential of bone-seeking radiopharmaceuticals that selectively irradiate the bone metastases while sparing healthy surrounding tissue. The radioisotope would be present in a higher concentration for a longer period of time at the tumor.   The response rate is roughly 70 to 80% of the patients treated. Pain relief may last for between 1 and 6 months, with the option of multiple treatments.  Response to additional treatments may not be as good as initial response. The prognosis of the disease is, however, usually not affected.</b>[25,26] Patients with a positive bone scan using technetium 99m methylene diphosphonate (Tc-99-MDP) are eligible for treatment.  Although we can predict nonresponders, we cannot predict responders; however, patients with a better performance scale may have a better chance of pain relief. [120]

For patients with symptomatic widespread bone metastases, options include bisphosphonates or radiotherapy.  There are two forms of systemic radiotherapy available: hemibody irradiation and intravenous injection of radionuclides. <b>Studies have shown the combination of either focal irradiation and hemibody irradiation or focal irradiation and the injection of strontium (89) prolongs the pain-free duration of the patients.</b> [125]
               

<b>Phosphorus-32, strontium-89, samarium-153 EDTMP, rhenium-186 HEDP and tin-117m DTPA have all been used effectively for bone pain palliation. </b>[15,20,21,25,53,120] Each of these agents and/or radionuclides has specific advantages and disadvantages; however, the ideal agent for bone pain palliation has not yet been identified. [20,38,120] 

<b>Systemic radionuclide therapy has two major advantages: 
(i)  It addresses all sites of involvement; and  
(ii) Selective absorption limits normal tissue dose. As a result, toxicity is reduced and the therapeutic ratio increased.</b> 

It is also particularly useful when external beam therapy options have been exhausted, and normal tissue tolerance has been reached.  Prophylactic administration of systemic radionuclides for clinically occult metastases might delay their appearance [prostate cancer]. Often the isotope works better with a radiosensitizer [e.g. low dose cisplatin],  allowing for longer effectiveness, decreased growth and/or slowed progression of disease. <b> When the effect of the radioisotope wears off, and pain returns, repeat injections can be given, with repeat response [but it may not be so effective as initial response.]</b>  Radioisotopes can also be used as part of a multi-modality approach, with significant chemotherapy.  Research is also indicated to compare treatment with radioisotopes and bisphosphonates, and to see whether they might work well together.  [9,51]

Pain palliation with bone-seeking radiopharmaceuticals is an effective and cost-effective management tool in patients with advanced cancer metastatic to bone. Strontium-89 (Metastron) and samarium-153-EDTMP (Lexidronam) are licensed for use in patients in the United States. Patients with a positive bone scan using technetium 99m methylene diphosphonate (Tc-99-MDP) are eligible for treatment, and indications and contraindications for use are now well defined. Evidence now suggests that the radiopharmaceuticals can reduce pain and analgesic requirements, improve quality of life, reduce lifetime radiotherapy requirements and management costs, and may slow the progression of painful metastatic lesions. Retreatment is possible and effective. 

<b>Although sarcomas are relatively radioresistant, the total focal dose may be VERY high IF the tumor preferentially takes up the radioisotope. A very high dose might delay local progression or even achieve permanent local tumor control in patients with surgically inaccessible primary or relapsing osteoblastic tumors.</b> [4,6,49]  

<b>However, also because of their uptake in bone, treatment or repeated treatment of bone tumors by radioisotopes often results in myelodysplasia.  The bone marrow is exposed to radiation in higher doses and for longer periods by bone seeking radioisotopes.  A very high local dose can also cause bone marrow damage, so patients with extensive bone marrow invasion of tumor should be watched carefully as they are at high risk.</b> [126]

<b>Use of radioisotope treatment repeatedly, or concomitantly with, or additionally to chemotherapy or radiation puts patients at high risk of bone marrow failure.</b>  Stem Cell Harvesting and Autologous Re-Transfusion is a process that should be considered prior to instituting treatment in this case. [6] Other than myelodysplasia, the early side effect profile is negligible.[4]   <b>Late effects [long term permanent damage] are not completely known, but are probably related to bone marrow damage and new primary cancers.  Skeletal doses of this order of magnitude are also known to be osteosarcomogenic [49,107] and probably leukemogenic [121] in humans when given as Strontium-90 injections. </b> 

Generally, toxicity, the flare phenomenon, and myelosuppression, especially white cells and platelets--treatments should not be given to patients with suspected disseminated intravascular coagulation [can cause severe, life-threatening platelet loss]. [15,20,23,50, 120]   The Society of Nuclear Medicine's bone pain treatment procedure guideline states that patients referred for bone palliation should be screened for disseminated intravascular coagulation before therapy. [PMID: 10551466] 

<b>Without Stem Cell conservation and re-transfusion, radioisotope treatment of LMS bone lesions might result in myelodysplasia after only one treatment, because of previous chemotherapy having been given in the usual very high dosage range that LMS requires.   Therefore, it might also  limit further chemotherapy.  </b>

<b>Surgery remains the treatment of choice.</b> When surgery is not possible, then irradiation of the tumor, and possibly radioisotope treatment, might be used for palliation.  However, Stem Cell Harvesting and Autologous Retransfusion should be considered if radioisotope treatment of bone lesions is adopted. [3,4,6]  Radioisotopes seem to work best in prostate and breast cancer secondaries.  Although there is sometimes a response from other, lytic, cancers, the best responses come from these groups.  [117]
              
Radioisotope treatment is palliative, not curative, and might limit future chemotherapy treatments.

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About Radiosensitization</b>

Intravenous outpatient radiopharmaceuticals have proven effective in treating pain associated with multiple osteoblastic bony metastasis from prostate or breast cancer. Radiosensitizers such as idoxyuridine incorporate into the DNA and increase the susceptibility of the cancer cell to radiation damage. Hypoxic cell sensitizers (such as metronidazole, misonidazole, SR 2508, and Ro-038799) increase oxygen to the cancer hypoxic cells and promote damage of the DNA, thus preventing cell repair. Otto SE. J Intraven Nurs 1998 Nov-Dec;21(6):335-7. 
&&url PMID: 10392098 
              
This study reports on two preliminary experiences with low-dose platinum compounds, carboplatin and cisplatin, as radiosensitizers in Strontium-89 therapy.  No clinically significant adverse effects or myelosuppression by platinum compounds were observed. In carboplatin study a pain response was observed in 74% of the evaluable patients. The pain response in the patients treated with 89Sr and carboplatin was clearly and significantly superior to that seen in the patients treated with 89Sr alone, whereas survival was only marginally better in the combined treatment group.  In the cisplatin study a pain response was observed in 83% of the evaluable patients. 
CONCLUSIONS: Low-dose platinum compounds seem to enhance the effects of 89Sr radioisotope therapy on pain from bone metastases without relevant hematological toxicity.  
Sciuto R, Festa A, et. al., Clin Ter 1998 Jan-Feb;149(921):43, 
&&url PMID: 9621488 

        
<b>About Strontium-89</b>
To date, the best studied and most commonly used radionuclide is strontium-89. Its efficacy as first line therapy or as adjuvant to external beam radiotherapy has been documented.  

        <b>"Strontium-89 is a pure beta-emitting radioisotope, a chemical analogue of calcium, and it is therefore avidly concentrated by areas of high osteoblastic activity. Selective uptake and prolonged retention at sites of increased bone mineral turnover provide precise bone lesions targeting. 89Sr chloride (commercialised as Metastron) is typically administered in a single 150 MBq parenteral dose. Its radioactive  emission poses very little radioprotection concerns. Overall, studies show pain relief in up to 80% of patients, of whom 10 to 40% became effectively pain free. The mean duration of palliation was 3-4 months. </b> The mechanism of pain relief is controversial; it is probably, but not only, related to the absorbed dose in the tumor and bone. There is no clear dose-response relationship. The only reported toxicity is temporary myelosuppression. WBC and platelets should be monitored at least on a weekly basis until they return to baseline. It seems that only patients with a reasonably good general condition stand to benefit from this treatment. In conclusion, systemic radionuclide therapy using 89Sr represents a feasible, safe, effective, well tolerated and cost-effective palliative treatment in patients with refractory bone pain." [118]

<b>Because Sr-89 is a beta-emitting radionuclide with a long physical half-life (50.5 days), precautions should be taken by the caretaker(s) against Sr-89 contamination from the patient's blood or excretions, particularly if the patient is incontinent.</b> 
&&url PMID: 7545083

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<b>About Samarium-153</b>
"Samarium-153-EDTMP is a 1:1 complex of radioactive Samarium-153 and a Tetraphosphonate [ethylenediamine-tetramethylene phosphonic acid (EDTMP)]. Samarium Sm-153-EDTMP has a high affinity for skeletal tissue and concentrates by chemiabsorption in areas of enhanced metabolic activity, where it associates with the hydroxyapatite crystal. Samarium-153 Lexidronam [Quadramet (R)] has been approved for routine use by the FDA. This agent offers several advantages over other agents used for palliating bone pain. Due to its half-life of 46 hours and its beta emissions, a high dose rate can be delivered to regions adjacent to enhanced osteoblastic activity over a short period of time with little residual long term activity being left in the bone marrow. ... In addition, because it also emits a 103 keV gamma ray which makes it suitable for imaging and assessment of biodistribution, dosimetric applications are possible in the future."[11]
       
Samarium-153 ethylene diamine tetramethylene phosphonate [Samarium-153-EDTMP] is a beta particle and gamma ray emitting, bone-seeking radiopharmaceutical, and can provide therapeutic irradiation to osteoblastic [not osteoclastic or lytic] bone metastases [Osteoblasts are the bone cells that makes new bone]. It has been useful as an adjunct when treating some bony tumors with irradiation and polychemotherapy.  By itself, it is useful as a palliative agent for bone pain, and sometimes might slow development of metastases or slow tumor growth.  When the effect wears off, retreatment is possible. [3,4,6,37,39,47,49,56,59,60]

Benefit of Samarium-153 treatment in LMS is unknown, and unlikely to be more than palliative.  [3,4,6,37] Liver function tests were abnormal in some patients. [33]  
   
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<b>About Rhenium-186      </b>
In connection with our work on the development of 186Re-tetra-phosphonates with optimum properties for use in bone pain palliation, a novel cyclic tetraphosphonate derivative has been synthesized, complexed with 186Re and evaluated with promising results. The ligand consists of a cyclic array of tetra-aminomethylphosphonate groups. Biodistribution studies of the complex were performed. The results suggest the suitability of the complex for further evaluation in higher animals for bone pain palliation. [124]

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<b>About Phosphorus-32</b>
Can palliate pain and decrease tumor osteoblastic activity. It is given intravenously, and can be given repeatedly.  White count and platelet suppression can occur. [108]

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<b>Some Comparisons</b>

<b>Strontium-89 and external beam hemibody and local radiotherapy</b>
There was no significant difference in median survival.  All treatments provided effective pain relief; improvement was sustained to 3 months in 63.6% after hemibody radiotherapy compared with 66.1% after strontium-89, and in 61% after local radiotherapy compared with 65.9% in the strontium-89 group. Fewer patients reported new pain sites after strontium-89 than after local or hemibody radiotherapy (p < 0.05).   Radiotherapy to a new site was required by 12 patients in the local radiotherapy group compared with 2 after strontium-89 (p < 0.01), although there was no significant difference between hemibody radiotherapy (6 patients) and strontium-89 (9 patients) in this respect.  Platelets and leukocytes fell by an average 30-40% after strontium-89.[122]

89Sr appears as effective a treatment option as HBI. Response is most likely with either approach when patients have a good performance status and a limited extent of disease. [123]

<b>Strontium-89 and Samarium-153 </b>
There is probably no difference in response rates between samarium-153 and strontium-89 radioisotopes as measured by the effect on pain or in the time to progression. [26]

<b>Strontium-89, Radiation, and Bisphosphonate</b>
Local radiotherapy completely prevents the incidence of secondary bone mets in PROSTATE cancer, (89)Sr leads to an important decrease in this complication and olpadronate induces a significant, albeit smaller decrease in the incidence of SCC. [109]      
            

<b>Strontium-89 and Rhenium-186-HEDP</b>
"Retreatments showed significantly P<0.01) worse responses (48% levels 3+4), in comparison to first RTBM."
"Duration of palliation was 5.0+/-3.5 months, and was longer in cases of excellent response, in first RTBM, in patients with limited metastases and when 89Sr was used. Better responses were found in cases of limited skeletal disease, under good clinical conditions, when life expectancy exceeded 3 months, and in radiologically osteoblastic or mixed bone         lesions. The only statistically significant predictive factor was life expectancy (P<0.001). Flare phenomenon (14.1% of cases) did not correlate with the response. Haematological toxicity (mild to moderate in most cases) mainly affected platelets, and was observed in 25.5% of cases overall and in 38.9% of retreatments. RTBM did not seem to prolong life, though in some cases scintigraphic regression of bone metastases was observed. The two radiopharmaceuticals did not show any statistically significant differences in palliative efficacy and toxicity, either in first RTBM or in retreatments."   [109]
       
"The global response rate was 84% for 89Sr and 92% for 186Re-HEDP. The onset of pain palliation appeared  significantly earlier in Rhenium group. The duration of pain relief ranged from two months to 14 months (mean of 125 days with a median value of 120 days) in Group A and from one month to 12 months (mean of 107 days with a median value of 60 days) in Group B (p = 0.39).  A moderate hematological toxicity was apparent in both groups. Platelet and white blood cell counts returned to baseline levels within 12 weeks after 89Sr administration and 6 weeks after 186Re-HEDP administration [significant]. CONCLUSIONS: Both 89Sr and 186Re-HEDP are effective and safe in bone pain palliation in breast cancer with the latter showing a significantly faster onset of pain relief." [110]


<b>Strontium-89, Rhenium-188, and Rhenium-186-HEDP</b> 
All three radiopharmaceuticals were effective in pain palliation. The various radionuclides had no significant difference in the pain relief or bone marrow impairment. [119]


<b>Samarium-153 and Rhenium-186</b>
The level of the long-lived radioisotope impurity burden in 153Samarium appears low enough not to pose a problem, and was almost two orders of magnitude lower than that of 186Rhenium [Samarium-153 one hundredth of the long-lived radioactive impurity load carried by Rhenium-186].  This is a notable overall advantage of 153Sm over the use of 186Rhenium. [5]


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