Optimal timing of bisphosphonate administration in combination with samarium-153 oxabifore in the treatment of painful metastatic bone disease.

While bisphosphonates are indicated for prevention of skeletal-related events, radionuclide therapy is widely used for treatment of painful bone metastases. Combined radionuclide therapy with bisphosphonates has demonstrated improved effectiveness in achieving bone pain palliation in comparison to mono therapy with radionuclides or bisphosphonates alone. However, there are conflicting reports as to whether bisphosphonates adversely influence skeletal uptake of the bone-seeking radiotracers used for therapy. Recent studies analyzing influence of Zoledronic acid on total bone uptake of Samarium-153 EDTMP (Sm-153 EDTMP) by measuring cumulative urinary activity of Sm-153 on baseline study, as well as in combination with bisphosphonates (administrated 48 hours prior to Sm-153) did not provide any statistically significant difference in urinary excretion of Sm-153 between the two groups. It may be noted that the exact temporal sequence of bisphosphonate administration vis a vis radionuclide therapy has not yet been studied. One of the side effects of bisphosphonates is transient flare effect on bone pain. Radionuclide therapy may also have similar side effect. Keeping in view the above the current study was designed with the main objective of determining the exact timing of bisphosphonate administration in patients receiving combined therapy so as to achieve optimal efficacy of bone pain palliation. Ninety-three patients suffering from metastatic bone pain who received combination therapy with Sm-153 oxabifore (an analog of Sm-153 EDTMP) and Zoledronic acid were divided into three groups according to the timing of Zoledronic acid administration: Group I: 39 patients who received Zoledronic acid 7 or more days prior to Sm-153 oxabifore treatment; Group II: 32 patients who received Zoledronic acid 48-72 hours prior to Sm-153 oxabifore treatment and Group III: 22 patients who received Zoledronic acid 7 days after Sm-153 oxabifore treatment. Sm-153 oxabifore was administered to all patients at the standard bone palliation dose of 37 MBq/kg body weight. All patients received Zoledronic acid before and after treatment in standard dosage of 4 mg every 28 days. WB bone scan, CT, and MRI were performed before treatment in all patients to exclude cord compression and vertebral fractures. Pain scores and quality of life (QOL) measurements were recorded meticulously in all patients. In groups I, II, and III, pain relief occurred in 10.4 ± 3.1 (Range = 5-15); 3.1 ± 1.1 (Range = 1-5) and 22 ± 5.1 (Range = 15-35) days, respectively, following radionuclide therapy. There was statistically significant difference between pain score in all groups before and after treatment as well as statistically significant difference in time to pain relief onset between Group II and other groups of patients (P < 0.0001). Based on our results we concluded that administration of Zoledronic acid 48-72 hours prior to Sm-153 oxabifore treatment helps in achieving better pain relief, as well as at the shortest time interval from the start of therapy.

Effectiveness of bone metastases treatment by sm-153 oxabifore in combination with monoclonal antibody denosumab (xgeva): first experience.

Breast and prostate cancer have a propensity to metastasize to bones and cause osteolysis and abnormal new bone formation. Metastases locally disrupt normal bone remodeling. Although metastases from prostate cancer have been classified as osteoblastic based on the radiographic appearance of the lesion, data gleaned from a rapid autopsy program indicate that the same prostate cancer patient may have evidence of both osteolytic and osteoblastic disease as shown by histologic examinations. Thus, bone metastases are heterogeneous, requiring combined treatment targeting on both osteolytic and osteoblastic lesions. While Samarium-153 (Sm-153) oxabifore treatment is widely used for the relief of pain in patients with osteoblastic metastatic bone lesions, Xgeva (Denosumab) is indicated for the prevention of skeletal-related events in patients with bone metastases from solid tumors. It is a fully human monoclonal antibody that has been designed to target receptor activator of nuclear factor-kB ligand (RANKL), a protein that acts as the primary signal to promote bone removal. In many bone loss conditions, RANKL overwhelms the body's natural defense against bone destruction. The main objectives of the current pilot study were to estimate the effectiveness of bone metastases treatment by a combination of Sm-153 oxabifore and Xgeva (Denosumab). Five patients (four female and one male, aged 35-64, mean age 50.8) with multiple skeletal metastases from prostatic carcinoma (1) and breast carcinoma (4) were studied. Their mean objective pain score according to visual analog scoring system on a 1-10 scoring system was 7.8 ± 0.5 (range 6-9). Sm-153 oxabifore was administered at the standard bone palliation dose of 37 MBq/kg body weight. Xgeva (Denosumab) was administered at a dosage of 120 mg every 4 weeks, with the monitoring of calcium level and administration of calcium, magnesium, and vitamin D. Whole body (WB) bone scan was performed before and 3 months after treatment in all patients. After Sm-153 oxabifore administration, pain relief occurred within 4.4 ± 1.25 days (range 2-9 days) and the objective pain score decreased to 0.2 ± 0.2 (range 0-1). There was statistically significant difference found, according to the pain score system, before and after treatment (P < 0.0001). WB bone scan showed that in one patient, there was significant reduction in the number and intensity of bone metastases, and in four patients, there was no evidence of bone metastases found. Based on our first experience, combined treatment of bone metastases with Sm-153 oxabifore and Denosumab is effective and safe.

Clinical significance of myocardial perfusion abnormalities in patients with varying degree of coronary artery stenosis.

OBJECTIVES: (1) To identify myocardial perfusion abnormalities in a cohort of patients having coronary artery disease (CAD) risk factors, with either suspected or clinical evidence of ischaemic heart disease (IHD), and with varying degree of coronary artery stenosis. (2) To evaluate the clinical significance of the extent and severity of perfusion abnormalities assessed by myocardial perfusion scintigraphy (MPS) in relation to the anatomical location of coronary stenosis demonstrated by five-vessel selective coronary angiography (SCA). METHODS: One hundred and thirty-eight patients (106 male, 32 female) with suspected or clinical evidence of IHD underwent diagnostic evaluation at the Central Hospital of Nicosia, between November 2002 and August 2003. The diagnostic work-up included clinical examination, exercise tolerance test, SCA and myocardial perfusion scintigraphy (MPS) using either Tl chloride or Tc-tetrofosmin. RESULTS: Based on the results of SCA, patients were divided into five groups on the basis of stenosis as cross-sectional area of coronary artery lumen and its haemodynamic significance, ranging from group 1=less than 50% coronary stenosis to group 5=100% stenosis (occlusion). Nine of 11 (40.9%) patients with angiographically normal coronary arteries (group 1) had moderate inducible reversible ischaemia on MPS and 9/47 (19.1%) patients with insignificant coronary stenosis (less than 75% stenosis=group 2) had fixed perfusion defects, compatible with previous myocardial infarction. The extent of perfusion abnormalities in post-stress MPS patients from group 2 was not found to be statistically significant (P>0.05) when compared to patients belonging to groups 3, 4 and 5. However, the extent of perfusion abnormalities between patients from group 2, when compared to groups 3, 4 and 5 demonstrated significant statistical difference (P<0.05) on post-rest MPS studies. Furthermore, there was no significant statistical correlation between anatomical location of coronary stenosis and severity of perfusion abnormalities in the corresponding myocardial segments. CONCLUSION: Patients with CAD risk factors, and coronary arteries with insignificant stenosis on angiography, may demonstrate inducible reversible myocardial ischaemia. This is suggestive of coronary endothelial dysfunction. Patients with insignificant coronary artery stenosis and no previous history of adverse coronary events may demonstrate features of previous myocardial infarction on MPS. The severity of perfusion defects demonstrated by MPS may be independent of the anatomical location of coronary artery stenosis.