WITHDRAWN: Radioisotopes for metastatic bone pain.

BACKGROUND: This is an update of the review published in Issue 4, 2003. Bone metastasis cause severe pain as well as pathological fractures, hypercalcaemia and spinal cord compression. Treatment strategies currently available to relieve pain from bone metastases include analgesia, radiotherapy, surgery, chemotherapy, hormone therapy, radioisotopes and bisphosphonates. OBJECTIVES: To determine efficacy and safety of radioisotopes in patients with bone metastases to improve metastatic pain, decrease number of complications due to bone metastases and improve patient survival. SEARCH METHODS: We sought randomised controlled trials (RCTs) in MEDLINE, EMBASE, CENTRAL, and the PaPaS Trials Register up to October 2010. SELECTION CRITERIA: Studies selected had metastatic bone pain as a major outcome after treatment with a radioisotope, compared with placebo or another radioisotope. DATA COLLECTION AND ANALYSIS: We assessed the risk of bias of included studies by their sequence generation, allocation concealment, blinding of study participants, researchers and outcome assessors, and incomplete outcome data. Two review authors extracted data. We performed statistical analysis as an "available case" analysis, and calculated global estimates of effect using a random-effects model. We also performed an intention-to-treat (ITT) sensitivity analysis. MAIN RESULTS: This update includes 15 studies (1146 analyzed participants): four (325 participants) already included and 11 new (821 participants). Only three studies had a low risk of bias. We observed a small benefit of radioisotopes for complete relief (risk ratio (RR) 2.10, 95% CI 1.32 to 3.35; Number needed to treat to benefit (NNT) = 5) and complete/partial relief (RR 1.72, 95% CI 1.13 to 2.63; NNT = 4) in the short and medium term (eight studies, 499 participants). There is no conclusive evidence to demonstrate that radioisotopes modify the use of analgesia with respect to placebo. Leucocytopenia and thrombocytopenia are secondary effects significantly associated with the administration of radioisotopes (RR 5.03; 95% CI 1.35 to 18.70; Number needed to treat to harm (NNH) = 13). Pain flares were not higher in the radioisotopes group (RR 0.74; 95% CI 0.27 to 2.06). There are scarce data of moderate quality when comparing Strontium-89 (89Sr) with Samarium-153 (153Sm), Rhenium-186 (186Re) and Phosphorus-32 (32P). We observed no significant differences between treatments. Similarly, we observed no differences when we compared different doses of 153Sm (0.5 versus 1.0 mCi). AUTHORS' CONCLUSIONS: This update adds new evidence on efficacy of radioisotopes versus placebo, 89Sr compared with other radioisotopes, and dose-comparisons of 153Sm and 188Re. There is some evidence indicating that radioisotopes may provide complete reduction in pain over one to six months with no increase in analgesic use, but severe adverse effects (leucocytopenia and thrombocytopenia) are frequent.

Reversal of Severe and Refractory Humoral Hypercalcemia With 177Lu-Octreotate Peptide Receptor Radionuclide Therapy for Neuroendocrine Tumor of the Pancreas.

A 48-year-old Caucasian male patient with newly diagnosed neuroendocrine tumor of the pancreas with multiple liver metastases developed severe and refractory hypercalcemia. Complementary investigations were compatible with humoral hypercalcemia with high parathyroid hormone-related peptide (PTHrP) levels. Hypercalcemia was refractory to medical treatments for more than 2 years. Serum calcium returned to normal values only after 4 cycles of peptide receptor radionuclide therapy with Lu-octreotate, with concomitant reduction of PTHrP level and tumor regression. The use of radionuclide therapy could be an option for the management of severe humoral hypercalcemia in patients with inoperable metastatic pancreatic neuroendocrine tumor.

Zoledronic acid and radiation: toxicity, syergy or radiosensitization?

INTRODUCTION: Zoledronic acid (Z) is a bisphosphonate used in hypercalcaemia-related cancer, in complications for bone metastasis and in postmenopausal osteoporosis and it has been related to osteoradionecrosis, especially when associated with radiation to the head and neck structures.OBJECTIVES: To determine the radiosensitization capacity of zoledronic acid in the combined treatment with ionizing radiation (IR) by evaluating its genotoxic and cytotoxic capacities in non-tumoral cells. MATERIALS AND METHODS: The genotoxic effect of Z was studied by means of the micronucleus test in cytokinesis-blocked cells of human lymphocytes irradiated before and after a 2 Gy irradiation, while the cytotoxic effect was studied by a cell viability test in the PNT2 cell line before and after exposure to different X-ray doses (0-20 Gy) in four groups (Z alone, radiation alone, Z + IR and IR + Z). RESULTS: A dose-dependent and time-dependent cytotoxic effect of Z and IR on PNT2 cells in vitro (p > 0.001) was demonstrated. With the concentrations recommended for humans, the combined treatment had a more pronounced effect than individual treatments (p < 0.001). The effect was synergic (CI < 1), increasing the Z enhancement ratio (2.6) and sensitization factor (56 %); the effect of Z was always greater after IR exposure. In the genotoxic effect, only the administration of Z after irradiation (IR + Z) increased chromosome damage (p < 0.001) and the sensibilization factor (35.7 %). CONCLUSION: High concentrations of Z are toxic, but the concentrations recommended for clinical practice in humans give it the characteristics of a radiosensitization agent, whose effect is even greater when administered after IR (AU)

Radioisotopes for metastatic bone pain.

BACKGROUND: This is an update of the review published in Issue 4, 2003. Bone metastasis cause severe pain as well as pathological fractures, hypercalcaemia and spinal cord compression. Treatment strategies currently available to relieve pain from bone metastases include analgesia, radiotherapy, surgery, chemotherapy, hormone therapy, radioisotopes and bisphosphonates. OBJECTIVES: To determine efficacy and safety of radioisotopes in patients with bone metastases to improve metastatic pain, decrease number of complications due to bone metastases and improve patient survival. SEARCH STRATEGY: We sought randomised controlled trials (RCTs) in MEDLINE, EMBASE, CENTRAL, and the PaPaS Trials Register up to October 2010. SELECTION CRITERIA: Studies selected had metastatic bone pain as a major outcome after treatment with a radioisotope, compared with placebo or another radioisotope. DATA COLLECTION AND ANALYSIS: We assessed the risk of bias of included studies by their sequence generation, allocation concealment, blinding of study participants, researchers and outcome assessors, and incomplete outcome data. Two review authors extracted data. We performed statistical analysis as an "available case" analysis, and calculated global estimates of effect using a random-effects model. We also performed an intention-to-treat (ITT) sensitivity analysis. MAIN RESULTS: This update includes 15 studies (1146 analyzed participants): four (325 participants) already included and 11 new (821 participants). Only three studies had a low risk of bias. We observed a small benefit of radioisotopes for complete relief (risk ratio (RR) 2.10, 95% CI 1.32 to 3.35; Number needed to treat to benefit (NNT) = 5) and complete/partial relief (RR 1.72, 95% CI 1.13 to 2.63; NNT = 4) in the short and medium term (eight studies, 499 participants). There is no conclusive evidence to demonstrate that radioisotopes modify the use of analgesia with respect to placebo. Leucocytopenia and thrombocytopenia are secondary effects significantly associated with the administration of radioisotopes (RR 5.03; 95% CI 1.35 to 18.70; Number needed to treat to harm (NNH) = 13). Pain flares were not higher in the radioisotopes group (RR 0.74; 95% CI 0.27 to 2.06). There are scarce data of moderate quality when comparing Strontium-89 ((89)Sr) with Samarium-153 ((153)Sm), Rhenium-186 ((186)Re) and Phosphorus-32 ((32)P). We observed no significant differences between treatments. Similarly, we observed no differences when we compared different doses of (153)Sm (0.5 versus 1.0 mCi). AUTHORS' CONCLUSIONS: This update adds new evidence on efficacy of radioisotopes versus placebo, (89)Sr compared with other radioisotopes, and dose-comparisons of (153)Sm and (188)Re. There is some evidence indicating that radioisotopes may provide complete reduction in pain over one to six months with no increase in analgesic use, but severe adverse effects (leucocytopenia and thrombocytopenia) are frequent.

Radioisotopes for metastatic bone pain.

BACKGROUND: Bone metastases manifest through pain, which can arise even before the injury is radiologically detected. Pain occurs as a result of bone destruction and, as more destruction ensues, more pain can be experienced. Radiculopathies, plexopathies and shrinkage of spinal nerves due to tumour growth and fractures are very frequent in these patients. Relief of pain from bone metastasis can be achieved by treating the cancer itself; radiotherapy; conventional analgesics; and specific drugs that work on the bone tumour-induced alteration: biphosphonates, calcitonin or radioactive agents. OBJECTIVES: To determine the efficacy of radioisotopes to control metastatic pain in patients with bone metastases and complications due to bone metastases (hypercalcaemia, bone fracture and spinal cord compression) as well as its efficacy in terms of patient survival and adverse effects. SEARCH STRATEGY: Randomised and controlled clinical trials related to this review were retrieved electronically using MEDLINE (1966-2003), EMBASE (1974-2003) and Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 1 2003). general strategies to identify RCTs were combined with specific commands to identify trials of radioisotopes and metastatic bone pain. SELECTION CRITERIA: The inclusion criteria were: randomised trials of patients with metastatic bone pain that compared treatment with radioisotopes and placebo, and where the major outcome was either pain or complications of bone metastases (eg, hypercalcaemia, bone fracture, spinal cord compression) assessed at least four weeks after treatment. DATA COLLECTION AND ANALYSIS: The quality of included studies was assessed using the Jadad scale and the Oxford Pain Validity Score. Two independent reviewers extracted the data and completed a standard form designed for that purpose. An intention-to-treat analysis was performed, and global estimates of effect were calculated using a random effects model. MAIN RESULTS: Four trials (325 patients) provided data that suggest a small effect of radioisotopes on pain control both at short and medium term (one to six months). No evidence was available to assess long-term effects (12 months). Only one study provided data on analgesia use and concluded that patients given either radioisotopes or placebo showed similar levels of analgesic use when compared to baseline use. Leukocytopenia and thrombocytopenia are secondary effects associated with the administration of radioisotopes. The incidence of leukocytopenia is significantly greater in patients treated with radioisotopes (RR=4.56, 95% CI (1.22,17.08)). There were also a greater number of thrombocytopenia events in the treatment group, without reaching statistical significance. REVIEWER'S CONCLUSIONS: The efficacy of radioisotopes has been assessed in clinical trials with small sample sizes and short-term evaluations of the outcomes. There is some evidence indicating that radioisotopes may give complete reduction in pain over one to six months with no increase in analgesic use, but adverse effects, specifically leukocytopenia and thrombocytopenia, have also been experienced.

Half body irradiation (HBI) in metastatic carcinomas.

One hundred and twenty-nine patients with distressing pain due to widespread bony metastases have been treated by systemic radiation therapy. The response rate is very high (76%) and the relief of pain occurs dramatically within 24-48 h. Sixty-five per cent of all responders remained free from pain for the remainder of their liver (3-10 months). This treatment has also proved effective in reducing large tumour masses for a limited period of time (5-20 weeks). Effective control of resistant hypercalcaemia was also observed within 24 h in five patients out of nine. The treatment is well tolerated and is haematologically safe. The main limiting factor is pulmonary damage. Various corrective measure have been employed to reduce acute radiation toxicity. This report presents an up to date analysis of the response to, and toxicity of, systemic radiation therapy and speculates on its potential uses.