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      Comparative efficacy, tolerability, and survival outcomes of various radiopharmaceuticals in castration-resistant prostate cancer with bone metastasis: a meta-analysis of randomized controlled trials

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          A meta-analysis was conducted to assess the impact of radiopharmaceuticals (RPs) in castration-resistant prostate cancer (CRPC) on pain control, symptomatic skeletal events (SSEs), toxicity profile, quality of life (QoL), and overall survival (OS).

          Materials and methods

          The PubMed/MEDLINE, CANCERLIT, EMBASE, Cochrane Library database, and other search engines were searched to identify randomized controlled trials (RCTs) comparing RPs with control (placebo or radiation therapy) in metastatic CRPC. Data were extracted and assessed for the risk of bias (Cochrane’s risk of bias tool). Pooled data were expressed as odds ratio (OR), with 95% confidence intervals (CIs; Mantel–Haenszel fixed-effects model).


          Eight RCTs with a total patient population of 1,877 patients were identified. The use of RP was associated with significant reduction in pain intensity and SSE (OR: 0.63, 95% CI: 0.51–0.78, I 2=27%, P,0.0001), improved QoL (OR: 0.71, 95% CI: 0.55–0.91, I 2=65%, three trials, 1,178 patients, P=0.006), and a minimal improved OS (OR: 0.84, 95% CI: 0.64–1.04, I 2=47%, seven trials, 1,845 patients, P=0.11). A subgroup analysis suggested an improved OS with radium-223 (OR: 0.68, 95% CI: 0.51–0.90, one trial, 921 patients) and strontium-89 (OR: 0.21, 95% CI: 0.05–0.91, one trial, 49 patients). Strontium-89 (five trials) was associated with increased rates of grade 3 and 4 thrombocytopenia (OR: 4.26, 95% CI: 2.22–8.18, P=0.01), leucopenia (OR: 7.98, 95% CI: 1.82–34.95, P=0.02), pain flare (OR: 6.82, 95% CI: 3.42–13.55, P=0.04), and emesis (OR: 3.61, 95% CI: 1.76–7.40, P=0.02).


          The use of RPs was associated with significant reduction in SSEs and improved QoL, while the radium-223-related OS benefit warrants further large, RCTs in docetaxel naive metastatic CRPC patients.

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          Most cited references 22

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          Radioisotopes for the palliation of metastatic bone cancer: a systematic review.

          Strontium-89 and samarium-153 are radioisotopes that are approved in the USA and Europe for the palliation of pain from metastatic bone cancer, whereas rhenium-186 and rhenium-188 are investigational. Radioisotopes are effective in providing pain relief with response rates of between 40% and 95%. Pain relief starts 1-4 weeks after the initiation of treatment, continues for up to 18 months, and is associated with a reduction in analgesic use in many patients. Thrombocytopenia and neutropenia are the most common toxic effects, but they are generally mild and reversible. Repeat doses are effective in providing pain relief in many patients. The effectiveness of radioisotopes can be greater when they are combined with chemotherapeutic agents such as cisplatin. Some studies with 89Sr and 153Sm indicate a reduction of hot spots on bone scans in up to 70% of patients, and suggest a possible tumoricidal action. Further studies are needed to address the questions of which isotope to use, what dose and schedule to use, and which patients will respond.
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            Samarium-153-Lexidronam complex for treatment of painful bone metastases in hormone-refractory prostate cancer.

            A Phase III randomized trial was designed to assess the effectiveness of samarium-153 (153Sm)-lexidronam for palliation of bone pain in patients with hormone-refractory prostate cancer. A total of 152 men with hormone-refractory prostate cancer and painful bone metastases were enrolled in a prospective, randomized, double-blind trial comparing radioactive (153Sm) versus nonradioactive (152Sm) lexidronam complexes. Patients were randomized (2:1) to the radioactive (153Sm) agent. Patient diaries recording daily pain and analgesic use were completed during a planned 16-week evaluation period. Nonresponders were informed of the treatment received after 4 weeks of treatment and, if initially treated with placebo, were allowed to receive 153Sm-lexidronam in an open-label fashion. Pain was measured using validated patient-derived visual analog scales and pain descriptor scales. 153Sm-lexidronam had positive effects on measures of pain relief compared with placebo within 1 to 2 weeks. Reductions in opioid use were recorded at weeks 3 and 4. Because nonresponders were unblinded at week 4, statistical comparisons between the arms beyond week 4 were not possible. Mild, transient bone marrow suppression was the only adverse event associated with 153Sm-lexidronam administration. The mean nadir white blood cell and platelet count (3 to 4 weeks after treatment) was 3800/microL and 127,000/microL, respectively. Counts recovered to baseline after approximately 8 weeks. No grade 4 decreases in either platelets or white bloods cells were documented. These findings demonstrate that 1 mCi/kg 153Sm-lexidronam is both safe and effective for the palliation of painful bone metastases in patients with hormone-refractory prostate cancer.
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              A comparative study of 188Re-HEDP, 186Re-HEDP, 153Sm-EDTMP and 89Sr in the treatment of painful skeletal metastases.

              The surface bone-seeking radiopharmaceuticals 188Re-HEDP, 186Re-HEDP and 153Sm-EDTMP, and the volume seeker 89Sr were investigated to determine the efficacy and toxicity in pain palliation of bone metastases. The effect of treatment with 188Re-HEDP, 186Re-HEDP, 153Sm-EDTMP and 89Sr on pain symptoms, quality of life, and bone marrow function were studied. In total, 79 patients (18 with breast cancer and 61 with prostate cancer) were treated (31 patients with 188Re-HEDP, 15 patients each with 186Re-HEDP and 153Sm-EDTMP, and 18 patients with 89Sr). All patients were interviewed using standardized sets of questions before and after therapy weekly for 12 weeks. Blood counts were taken weekly for 6 weeks and after 12 weeks. In total, 73% of patients reported pain relief (77% after 188Re-HEDP, 67% after 186Re-HEDP 73% after 153Sm-EDTMP, and 72% after 89Sr). Fifteen percent of patients could discontinue their analgesics and were pain-free. Pain showed a decrease from 3.6+/-1.7 to a maximum of 2.2+/-1.8 at visual analogue scale in 10 steps (P<0.01). Patients described an improvement on the Karnofsky performance scale from 70+/-10% to 78+/-14% 12 weeks after treatment (P=0.15). There were eight patients with a thrombocytopenia grade I, two patients with grade II and one with grade III. The maximum nadir of platelet and leukocyte counts were observed between the 2nd to 5th week after treatment and was reversible within 12 weeks. There were no significant differences in pain palliation, Karnofsky performance status (KPS) and bone marrow toxicity between the different radionuclides (P=0.087-0.449). All radiopharmaceuticals were effective in pain palliation, without induction of severe side effects or significant differences in therapeutic efficacy or toxicity.

                Author and article information

                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Drug Design, Development and Therapy
                Dove Medical Press
                21 September 2015
                : 9
                : 5291-5299
                [1 ]Radiation Oncology, Comprehensive Cancer Center, King Fahad Medical City, Riyadh, Saudi Arabia
                [2 ]Radiation Oncology, National Cancer Institute, Cairo University, Cairo, Egypt
                Author notes
                Correspondence: Mutahir Tunio, Radiation Oncology, Comprehensive Cancer Center, King Fahad Medical City, Khurais Road, Riyadh 5046, Saudi Arabia, Tel +966 11 288 9999, Fax +966 11 461 4006, Email mkhairuddin@ 123456kfmc.med.sa
                © 2015 Tunio et al. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License

                The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

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