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Bone: Embolization and Radiation
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Embolization

Embolization requires snaking a catheter [a long narrow tube] into the arteries feeding a tumor, and then injecting particles into that artery. The particles clog up the arteries, and clots form. This robs the tumor of its blood supply, so it dies. Embolization could also be used to cut off possible areas of bleeding if used preoperatively in hypervascular tumors. Operating on very vascular tumors usually means there is heavy bleeding. So embolization can either directly attack a tumor so that it dies back, and stops eroding bone, or it can be used to decrease blood flow to the area, allowing cleaner removal of tumor with less blood loss.

''The technique of selective embolization has been in use for years in the treatment of vascular anomalies, severe hemorrhage and benign or malignant tumors, notably renal cell cancer vertebral metastases. Because this technique is relatively easy to perform and can offer immediate relief of symptoms, it is an attractive option for patients with hypervascular vertebral metastases with signs of spinal cord compression. Selective catheterization of the arteries feeding the metastases is performed, followed by infusion of polyvinyl alcohol particles. Embolization results in rapid resolution of neurological symptoms, sometimes within hours. The therapeutic effect lasts from months to years. Embolization of hypervascular vertebral metastases is a palliative therapeutic option that may offer rapid relief of symptoms.''[44]

Embolization can also stop tumors from bleeding spontaneously. "Embolization therapy is reported in three patients bleeding from metastatic carcinoma of the breast. Two had life threatening hemorrhage from sternal erosion;.... The third patient had intermittent bleeding of extensive fungating axillary and anterior chest wall metastases. Autologous clot alone was used in the first case with immediate cessation of bleeding and transient neurological symptoms secondary to back flow of thrombus into the vertebral artery were noted. The second and third patients received Oxycel-Ivalon and Gel-foam respectively; bleeding ceased and no complications were noted." [15]

Embolization alone can often reduce metastatic spinal cord compression, so surgical decompression is either not necessary or can be postponed. [7,11, 12]

Massive perioperative hemorrhage is often associated with surgery for vertebral metastases. Preoperative embolization reduces operative blood loss so that hypervascular tumors may be removed safely after embolization. The resulting devascularization allows for an aggressive resection of pathologic tissue [4,5,6,8,18,57,72,87]

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Chemoembolization

Chemoembolization [also called transcatheter arterial embolization] consists of embolization, as described above, with specific catheterization of the artery or arteries supplying the tumor. But the embolization is with gelatin sponge particles, which are impregnated with chemotherapy agents. Thus the chemo agents remain in contact with the tumor at higher concentrations than would be possible systemically. Doxorubicin is one of the agents frequently used this way. This modality can be combined with RFA hyperthermia, and/or radiotherapy. [22]

For more information:
about chemoembolization and transcatheter arterial embolization [T.A.E.] see the section under Liver Metastases.

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Radioisotope Embolization
Theraspheres and Sirspheres

This would be a technique whereby the selective catheterization of tumor-supplying arteries would result in embolization of the arteries with either glass beads or resin impregnated with Yttrium-90. This would result in the radiation being discharged locally in the tumor. Currently this technique is only under investigation for treatment of liver metastases, not bone metastases. However, it would seem to lend itself to treatment of bone metastases.

Whether the presence of the glass or resin will prevent subsequent RFA treatment of the area, or the presence of the Yttrium-90 prevent use of other agents subsequently is not known.

For more information, see the Discussion of Radioisotope Embolization, Liver Page
Radioisotopes

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



Radioisotope Use In Cancer Metastatic to Bone
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. 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.[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. 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. [125]


Phosphorus-32, strontium-89, samarium-153 EDTMP, rhenium-186 HEDP and tin-117m DTPA have all been used effectively for bone pain palliation. [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]

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.


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. 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.] 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.

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. [4,6,49]

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. [126]

Use of radioisotope treatment repeatedly, or concomitantly with, or additionally to chemotherapy or radiation puts patients at high risk of bone marrow failure. 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] 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.

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]

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.

Surgery remains the treatment of choice. 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


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.
Fetch 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,
Fetch PMID: 9621488


About Strontium-89
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.

"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. 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]

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.
Fetch PMID: 7545083

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About Samarium-153
"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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About Rhenium-186
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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About Phosphorus-32
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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Some Comparisons

Strontium-89 and external beam hemibody and local radiotherapy
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]

Strontium-89 and Samarium-153
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]

Strontium-89, Radiation, and Bisphosphonate
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]


Strontium-89 and Rhenium-186-HEDP
"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]


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


Samarium-153 and Rhenium-186
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]


References
Radiotherapy

"Local radiotherapy plays an important and responsible role in the management of bone metastases according to the different treatment objectives in the sense of pain relief, remineralization and cord decompression. Radiotherapy schedules, aimed at the relief of pain, need to take into consideration life expectancy. Patients with a reduced life expectancy could have a good high chance of achieving pain relief with a single dose of 8 Gy. Patients with a solitary metastasis, patients with a longer life expectancy and patients with a pathological fracture should be treated with 'curative' irradiation doses, aimed at killing the maximum number of tumor cells. [134]

In addition to pain relief, remineralization is also an important treatment goal. Conventional radiotherapy with doses of 40-50 Gy resulted in pain relief in 70-100% and in remineralization in 60-80% of the patients. Remineralization could not be accelerated by short-course fractionation courses, but resulted in faster pain relief. Short-course fractionation schedules are not indicated as a 'standard' treatment in the vertebral column. Surgery is the treatment of choice for immediate cord decompression and stabilization of a pathological vertebral fracture. Radiotherapy alone could decrease neurological impairment and is suitable for patients with gradual onset and progression of symptoms, no spinal instability and lesions of the cauda equina." [134]

Intensity and severity of radiation-induced nausea and emesis depend on a number of factors including irradiation site, irradiation dose, treatment field (width and length), and age of the patients. Although less intensive than that induced by chemotherapy, during protracted courses of fractionated radiotherapy discomfort can be substantial. As early as 1953, Court-Brown [2] described characteristic symptoms after single-fraction radiotherapy as "acute irradiation syndrome": irradiation was followed by asymptomatic period of 40-90 minutes, after that the patient experienced an acute episode of emesis, usually without preceding nausea. After a period of relative stabilization, additional episodes of emesis occurred for six hours after irradiation, decreasing its intensity with time. Danjoux et al. [5] noted a higher incidence of radiation-induced emesis after the upper half-body irradiation (UHBI) than after the lower half-body irradiation (LHBI), lack of efficacy of antiemetics administered, and similar response to emesis after the lower or the upper half-body irradiation. These results suggested that critical area was the upper abdomen. [117]

Targeting of radiotherapy can be based on improving physical dose distribution of radiation delivered or on utilization of specific biological processes for targeting. Tools for physical targeting include Brach therapy, hadron therapy, conformal radiotherapy, stereotactic radiotherapy, stereotactically guided conformal fractionated radiotherapy, and intensity-modulated radiotherapy. Biological targeting can be based on specific metabolic pathways such as uptake of iodine-131 by thyroid cancer cells, difference in substrate uptake between cancer cells and normal cells (e.g. boronophenylalanine in boron neutron capture therapy), targeting of radioactive isotopes by specific carrier molecules (radioimmunotherapy, labeled hormone derivatives or bone-seeking phosphonates), or on the distribution of elements in the body (therapy of bone metastases with a calcium analog strontium-89 or phosphorus-32). [29]

Painful bone metastases are common in oncologic practice. The role of surgery should be limited to patients with neurologic compression or severe mechanical instability. [102] Ninety percent of patients with symptomatic bone metastases obtain some pain relief with a low dose, brief course of palliative radiotherapy. One half of the responding patients may experience complete pain relief. A single dose of 800 cGy in the setting of painful bone metastasis may provide pain control comparable to more protracted treatment at a higher dose of radiation. [80] There seem to be no significant differences in pain relief between the different fractionation schedules. A palliation is ensured in 75% of all cases with a partial response of 42% and complete response of 33%. With regard to pain response these results do not justify a recommendation for a standard fractionation schedule. Current fractionation schedules such as 10 x 3 Gy for 2 weeks or 5 x 4 Gy for 1 week should probably be used.[53] In one study, two short courses of radiation for bone pain were compared: 20 Gy in one week (daily dose 4 Gy), and 30 Gy in 3 weeks (daily dose 2 Gy). There was a light trend favoring 30 Gy in frequency of pain relief and recalcification. [78] However, it is not known whether these short radiation schedules are adequate for patients with longer prognoses, or what the optimal fractionation schedule is for maintaining the structural integrity of the bone.

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. 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. [80,100,125] HBI is a powerful palliative treatment in patients with multiple symptomatic bone metastases. Analysis of one study of 78 procedures on 71 patients, treated with 6 Gy (upper half-body) or 8 Gy (lower half-body) HBI in single fraction: Complete (37.5%) or partial responses were observed in 72/78 (92.3%) procedures, 80% appearing during the first 72 hours. A mean response duration of 101 days over a mean overall survival of 141 days implies coverage of 70% of patient's life span. [72]

A slower development of motor deficits before beginning of radiotherapy means a better therapeutic effect and a more favorable functional outcome after treatment. The prognosis is extraordinarily poor if severe deterioration of motor function occurs within 48 hours before radiotherapy. [54]

A meta-analysis of the literature on Radiotherapy for Skeletal Metastases was done in 1996. It was based on 171 scientific articles involving over 13,000 patients, and states: "Radiotherapy has been well documented as a method for alleviating pain, but the mechanisms underlying this effect are largely unknown. When used for pain palliation, radiotherapy achieves freedom from pain, or substantial alleviation of pain in nearly all cases, with few side effects. Half-body irradiation is effective in treating multiple metastatic sites and should be considered for use more frequently. However, this increases the requirements on equipment, dosimetry, and hospital beds. Systemic radiotherapy with radionuclides may be indicated for generalized skeletal pain. The role of radiotherapy in preventing or healing fractures is not fully evaluated. Optimum dose levels and fractionation schedules have not been established. Early radiotherapy for spinal cord compression may prevent symptoms from worsening, but the effects on existing paralysis are modest." [55]

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References for This Section


compiled/written by doctordee
with thanks to Lynette and Laura
June 2002
updated December 2003


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