Oral Extramedullary Plasmacytoma Treatment Using a Combination of Marginal Excision and Strontium-90 Therapy in Five Dogs.

Extramedullary plasmacytoma (EMP) is a benign round cell tumor that is most commonly found in cutaneous locations in dogs and occurs less frequently in the oral cavity. They are highly radiosensitive, are distinct from systemic multiple myeloma syndrome and wide surgical excision is typically curative. This report describes five cases of non-invasive oral EMP in dogs treated with a combination of marginal excision and strontium-90 plesiotherapy. All five cases had narrow or incomplete margins on histopathologic evaluation but experienced no recurrence after combination therapy. Plesiotherapy radiation may offer a potential adjunct treatment for non-invasive oral EMP by providing a superficial dose of radiation that complements a less invasive surgical removal. The combination of plesiotherapy and marginal excision may offer an alternative to wide surgical excision for non-invasive oral EMPs.

Strontium-90 brachytherapy following intralesional triamcinolone and 5-fluorouracil injections for keloid treatment: A randomized controlled trial.

BACKGROUND: Keloid disease is hard to fully eradicate. Recurrence and other unsatisfactory results were found in many patients. No current therapeutic modality has been determined to be most effective for treating keloid scars. Intralesional corticosteroid injections is most commonly recommended for primary management of small and young keloids as well as hypertrophic scars. However, it's difficult for patients to adhere to long-term triamcinolone acetonide injection therapy because of the pain, inconvenience or complications including hormonal imbalance or irregular menstruation. OBJECTIVE: We aimed to determine whether and how Strontium-90 brachytherapy as an adjuvant radiation could affect keloid recurrence after intralesional triamcinolone and 5-fluorouracil injections. METHODS: We included keloid patients from March 2019 to September 2019 and randomly allocated them to two groups after 3 intralesional triamcinolone and 5-fluorouracil injections at 3 weeks interval. The experimental group received Strontium-90 brachytherapy at a total dose of 15-20Gy, while the control group didn't receive any adjuvant treatment. We performed both Vancouver Scar Scale scoring and Color Doppler ultrasound examination to monitor and evaluate lesions regularly. A one-year follow-up was completed for each patient. RESULTS: 31 patients who had 42 keloids in total were recruited. We found intralesional triamcinolone and 5-fluorouracil injections could effectively reduce the thickness and modify the hardness of small and young keloids. Strontium-90 brachytherapy reduced the one-year recurrence rate from 85.7 percent to 44.4 percent after 3 intralesional triamcinolone and 5-fluorouracil injections. The lesions' thickness or elasticity was not affected by Strontium-90 brachytherapy. CONCLUSION: Strontium-90 brachytherapy as an adjuvant radiation could effectively reduce small sized keloids recurrence after intralesional triamcinolone and 5-fluorouracil injections. It worked by enhancing the lesions' stability post-injection. TRIAL REGISTRATION: The clinical trial registration number: ChiCTR2000030141. Name of trial registry: Chinese Clinical Trial Registry (http://www.chictr.org.cn/).

Added value of hybrid SPECT with CT imaging for predicting poor therapeutic efficacy of 89Sr in patients with bone metastasis.

To utilize single-photon emission computed tomography/computed tomography (SPECT/CT) scanning to investigate the usefulness of nerve root compression (NRC) and radioactive cold zone lesions (RCZLs) for predicting poor therapeutic efficacy of strontium-89 chloride (Sr-89) in patients with bone metastasis. Patients with bone metastatic neoplasms who had undergone baseline bone SPECT/CT scanning before Sr-89 therapy (148 MBq Sr-89 chloride by an intravenous injection for each patient) between July 2011 and July 2018 were included. Bone SPECT/CT images were assessed by two readers independently. Associations between imaging features and therapeutic efficacy were obtained via multivariate logistic regression analysis. Of 231 patients analyzed, 50 (21.6%) had NRC at baseline. Of 31 patients who experienced poor therapeutic efficacy, 29 (93.5%) had NRC. In multivariate logistic regression analysis baseline NRC independently predicted poor therapeutic efficacy. The sensitivity of NRC for predicting poor therapeutic efficacy was 93.5%, specificity was 89.5%, positive predictive value was 58.0%, and negative predictive value was 98.9%. RCZLs were detected in17 patients (7.4%), of whom 14 experienced poor Sr-89 therapeutic efficacy. The sensitivity of the presence of RCZLs for predicting poor therapeutic efficacy was 45.2%, specificity was 98.5%, positive predictive value was 82.4%, and negative predictive value was 92.1%. After adjusting for age, bone metabolism and lesion type, the significant independent predictors of poor Sr-89 therapeutic efficacy were presence of NRC (p < 0.001) and RCZL (p = 0.001). NRC and RCZL on baseline bone SPECT/CT are reliable independent predictors of poor Sr-89 therapeutic efficacy in patients with bone metastasis. These associations may facilitate the administration of more effective therapeutic interventions.

Evaluation of Month-24 Efficacy and Safety of Epimacular Brachytherapy for Previously Treated Neovascular Age-Related Macular Degeneration: The MERLOT Randomized Clinical Trial.

Importance: Although anti-vascular endothelial growth factor (VEGF) treatment offers better outcomes than the natural history of neovascular age-related macular degeneration (ARMD), a less burdensome, less expensive, and more durable treatment is needed. Objective: To assess the efficacy and safety of epimacular brachytherapy (EMB) for chronic, active, neovascular ARMD. Design, Setting, and Participants: The Macular Epiretinal Brachytherapy vs Ranibizumab (Lucentis) Only Treatment (MERLOT) pivotal device trial was conducted at 24 National Health Service hospitals across the UK. Patients who had neovascular ARMD and received intravitreal ranibizumab were enrolled between November 10, 2009, and January 30, 2012. Eligible patients were randomized 2:1 and were stratified by lens status and angiographic lesion type to receive either EMB plus as-needed ranibizumab or as-needed ranibizumab monotherapy. Participants were followed up monthly for 24 months and then assessed at a final visit at month 36. Masking of participants and clinicians was not possible, but best-corrected visual acuity (BCVA) and imaging were analyzed by masked assessors. Analysis followed the intent-to-treat approach. Interventions: Pars plana vitrectomy with 24 Gy EMB plus as-needed ranibizumab vs as-needed ranibizumab monotherapy. Main Outcomes and Measures: Coprimary outcomes were the number of as-needed ranibizumab injections and the mean change in Early Treatment Diabetic Retinopathy Study (ETDRS) BCVA with a noninferiority margin of -5 ETDRS letters. Secondary outcomes were the percentage of participants losing fewer than 15 ETDRS letters and gaining 0 or more or 15 or more ETDRS letters and the mean change in angiographic total lesion size, choroidal neovascularization size, and foveal thickness on optical coherence tomography. Results: Of 363 participants, 329 (90.6%) completed 24 months of follow-up (222 participants in the EMB group and 107 in the ranibizumab group). The mean (SD) age of the combined groups was 76.5 (7.4) years. The mean (SD) number of ranibizumab injections was 9.3 (6.7) in the EMB group and 8.3 (4.5) in the ranibizumab group, with a difference of 1.0 injection (95% CI, -0.3 to 2.3; P = .13). The mean (SD) BCVA change was -11.2 (15.7) ETDRS letters in the EMB group and -1.4 (10.9) ETDRS letters in the ranibizumab group, with a difference of 9.8 ETDRS letters (95% CI, -6.7 to -12.9). In the EMB group, 65.6% of participants (160 of 244) lost fewer than 15 ETDRS letters vs 86.6% (103 of 119) in the ranibizumab group, with a difference of 21% (95% CI, 12.4%-29.5%; P < .001). Microvascular abnormalities occurred in 20 of 207 eyes (9.7%) in the EMB group and 1 of 97 eyes (1.0%) in the ranibizumab group. These abnormalities occurred outside the foveal center, and there were no unexpected safety concerns. Conclusions and Relevance: The MERLOT trial found that despite the acceptable safety of EMB, it did not reduce the number of ranibizumab injections and was associated with worse visual acuity than anti-VEGF treatment alone; these results do not support EMB use as an adjunct treatment for chronic, active neovascular ARMD. Trial Registration: ClinicalTrials.gov Identifier: NCT01006538.

Monitoring and Handing of 89Sr Injection Site Extravasation in a Patient With Breast Cancer.

Extravasation of various imaging tracers during administration was not a rare complication during nuclear medicine practice. However, the occurrence of extravasation of therapeutic radiopharmaceutical was rarely reported. Here we reported a 60-year-old woman with breast cancer and diffuse painful bone metastases who received strontium chloride (SrCl2) therapy to palliate her bone pain. Accidental subcutaneous extravasation in the injection site occurred. The extravasated Sr was absorbed rapidly by arm elevation, squeezing a stress ball, local warming, and gently massaging. Follow-up results showed the patient's bone pain significantly relieved and her right arm remained normal.

Treatment of Exuberant Granulation Tissue in an Umbrella Cockatoo (Cacatua alba) with Strontium Radiation.

A 26-year-old female umbrella cockatoo (Cacatua alba) was presented for reoccurrence of a soft tissue mass extending from a fractured area of the rhinotheca. The mass was originally observed 12 years before, after unknown trauma. Histopathology after initial removal was consistent with inflammatory granulation tissue. The mass reoccurred 3 additional times in the same location despite surgical removal and cryogenic therapy. On the fourth surgical resection, strontium-90 radiotherapy was applied to the site immediately after the surgical procedure. No recurrence of the tissue mass from this location has been observed for almost 2 years. This case demonstrates the novel use of strontium radiotherapy to treat exuberant granulation tissue in a bird.

The efficacy and safety of zoledronic acid and strontium-89 in treating non-small cell lung cancer: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Zoledronic acid (ZA) and strontium-89 have been widely used to treat lung cancer with bone metastases. The authors perform this meta-analysis to better evaluate the clinical outcome of ZA and strontium-89 for non-small cell lung cancer (NSCLC) patients. METHODS: We carried out standard meta-analysis and network meta-analysis based on a comprehensive data retrieval of EMBASE, PubMed, and Cochrane Library databases (up to March 2019). Random and fixed effects models were used where indicated and between-study heterogeneity was assessed. The primary endpoints were overall survival (OS) and skeletal-related events (SREs). The second endpoints were progression-free survival (PFS) and overall response rate (ORR). RESULTS: Seven randomized clinical trials, including 1426 NSCLC patients with seven studies of zoledronic acid and two studies of strontium-89, met the inclusion criteria. Compared with the control group, ZA is associated with a OS benefit (1-year survival rate: RR = 1.76, 95% CI 1.36-2.27; and 24-month survival rate: RR = 2.38, 95% CI 1.35-4.19) and a reduction of SREs (RR = 0.57, 95% CI 0.40-0.84) for the patients with bone metastases. No statistical differences were found in PFS and ORR. Network meta-analysis for the patients with bone metastases showed that ZA + strontium-89 and ZA harbored significantly clinical benefits than strontium-89 and placebo in terms of 1-year survival rate and SREs. Both head-to-head study and network meta-analysis showed that strontium-89 had no statistical impact on OS and SREs compared with placebo. CONCLUSION: Our analysis demonstrates that ZA +strontium-89 can be considered a priority for NSCLC patients with bone metastases, followed by ZA.

[Effectiveness of Strontium-89 for Neuropathic Pain Caused by Bone Metastases from Breast Cancer: A Case Report].

The patient was a 47-year-old female with stage IV breast cancer and multiple bone metastases. She received various systemic therapies (hormone therapy and chemotherapy) and underwent mastectomy between 2013 and 2018; in the beginning of 2018, she started experiencing bone metastatic pain in the right hip joint and neural pain on the dorsal side of the left thigh. These symptoms worsened gradually, and nonsteroidal anti-inflammatory analgesics or narcotic analgesics were not effective for treating this pain. Strontium-89 (89Sr) treatment was administered in April 2018. The pain was relieved immediately after 89Sr treatment. The patient's quality of life improved markedly. She spent her remaining life without using analgesic drugs, until she died in October 2018 due to exacerbation of the original disease. Although radiotherapy is believed to be less effective for neuropathic pain than for bone metastatic pain, it should be considered as a treatment option in patients with neuropathic pain.

[Efficacy of 89Sr as Pain Relief for Gastric Cancer Bone Metastasis].

We experienced 2 cases in which strontium chloride was used for pain associated with gastric cancer bone metastasis. Case 1 was of a 69-year-old woman. In 2015, she underwent surgery for advanced gastric cancer followed by adjuvant chemotherapy with S-1 for 1 year. Multiple bone metastases were confirmed 2 years and 3 months after surgery. Obvious pain relief was obtained after 89Sr was administered, and SOX therapy was started. Case 2 was of a 62-year-old man. In 2016, he underwent curative surgery for stomach cancer. Chemotherapy with S-1 was performed for approximately 6 months, but 9 months after surgery multiple LN metastases, liver metastasis, and multiple bone metastases were observed . In case 2, 89Sr was administered, but good pain control was not obtained. The use of 89Sr for pain relief against multiple bone metastases should be based on the previous literature.

Radium-223 for the treatment of bone metastases in castration-resistant prostate cancer: when and why.

Radium-223 dichloride (223Ra) is the first, recently approved, α-particle-emitting radiopharmaceutical for the treatment of patients with bone metastases in castration-resistant prostate cancer (CRPC) and no evidence of visceral metastases. We explored MEDLINE, relevant congresses, and websites for data on 223Ra and prostate cancer therapies, focusing on therapeutic strategies and timing, bone metastases, and diagnostic assessment. 223Ra represents the only bone-targeting agent that has significantly extended patients' overall survival while reducing pain and symptomatic skeletal events. Unlike other radiopharmaceuticals, such as strontium-89 and samarium-153 EDTMP, 223Ra (11.4-days half-life) has shown a high biological efficiency mainly due to its short penetration range. These features potentially allow reduced bone marrow toxicity and limit undue exposure. 223Ra has been validated under the product name Xofigo® by the US Food and Drug Administration and the European Medicines Agency. Patient selection, management, and treatment sequencing is recommended to be discussed in the context of a multidisciplinary environment, including oncology, urology, nuclear medicine, and radiation therapy physicians. No consensus has been achieved regarding the optimal timing and its administration as single agent or in combination with zoledronic acid or chemotherapy, so far. This review aims to provide a rationale for the use of 223Ra in treating metastases from CRPC, highlighting the crucial role of a multidisciplinary approach, the disputed inclusion and exclusion criteria on the basis of agencies regulations, and the value of diagnostics for therapy assessment.

Response, disease-free interval and overall survival of cats with nasal planum squamous cell carcinoma treated with a fractionated vs a single-dose protocol of strontium plesiotherapy.

OBJECTIVES: The main aim of the study was to establish response, disease-free interval (DFI) and overall survival of cats with nasal planum squamous cell carcinoma (SCC) treated with Sr90 plesiotherapy. A secondary aim was to determine whether a fractionated protocol is more effective than a single-dose protocol in terms of response, DFI and overall survival. The third aim was to evaluate whether we can identify prognostic factors that influence overall survival. METHODS: This was a retrospective study that included cats with a diagnosis of nasal planum SCC treated with Sr90 plesiotherapy at a single institution. RESULTS: Seventy-four cats were included in the study. Thirty-two were treated with a fractionated protocol and 42 with a single-dose treatment. Sr90 plesiotherapy was able to induce complete response in 74% of cats with nasal planum SCC. The median DFI was 780 days (95% confidence interval [CI] 383-1177), with 17% of cats experiencing local recurrence. The overall survival for all cats was 1039 days (95% CI 55-1528). The DFI of cats treated with the fractionated Sr90 was significantly longer compared with the single-dose treatment, whereas response and overall survival were not statistically different. Other prognostic factors that influenced the overall survival were early-stage disease, absence of concurrent problems and complete response to the treatment. Acute and long-term toxicity associated with the treatment were minimal and the aesthetic outcome was pleasing in almost all cases. CONCLUSIONS AND RELEVANCE: Strontium plesiotherapy is a safe and effective treatment of nasal planum SCC in cats.

Bone-targeted therapies to reduce skeletal morbidity in prostate cancer.

Bone metastases are the main driver of morbidity and mortality in advanced prostate cancer. Targeting the bone microenvironment, a key player in the pathogenesis of bone metastasis, has become one of the mainstays of therapy in men with advanced prostate cancer. This review will evaluate the data supporting the use of bone-targeted therapy, including (1) bisphosphonates such as zoledronic acid, which directly target osteoclasts, (2) denosumab, a receptor activator of nuclear factor-kappa B (RANK) ligand inhibitor, which targets a key component of bone stromal interaction, and (3) radium-223, an alpha-emitting calcium mimetic, which hones to the metabolically active areas of osteoblastic metastasis and induces double-strand breaks in the DNA. Denosumab has shown enhanced delay in skeletal-related events compared to zoledronic acid in patients with metastatic castration-resistant prostate cancer (mCRPC). Data are mixed with regard to pain control as a primary measure of efficacy. New data call into question dosing frequency, with quarterly dosing strategy potentially achieving similar effect compared to monthly dosing for zoledronic acid. In the case of radium-223, there are data for both pain palliation and improved overall survival in mCRPC. Further studies are needed to optimize timing and combination strategies for bone-targeted therapies. Ongoing studies will explore the impact of combining bone-targeted therapy with investigational therapeutic agents such as immunotherapy, for advanced prostate cancer. Future studies should strive to develop biomarkers of response, in order to improve efficacy and cost-effectiveness of these agents.

Tumoricidal effect and pain relief after concurrent therapy by strontium-89 chloride and zoledronic acid for bone metastases.

OBJECTIVE: The purpose of this study was to investigate the palliative and tumoricidal effects of concurrent therapy of strontium-89 chloride (89SrCl2) and zoledronic acid (ZA) for painful bone metastases. SUBJECTS AND METHODS: Fifty-one patients with painful bone metastases prostate cancer (n=17), lung cancer (n=13), breast cancer (n=12), other cancers (n=9) were treated. Bone metastases was confirmed in all patients by technetium-99m hydroxymethylene diphosphonate (99mTc-HMDP) bone scintigraphy. The numeric rating scale (NRS) and performance status (PS) were used to assess the degree of pain and patients' physical condition. The extent of bone metastases was assessed with imaging modalities including CT, MRI and/or 99mTc bone scintigraphy before treatment and 2 or 3 months after. RESULTS: The pain relief response of 89SrCl2 with ZA for bone metastases was 94% (48/51) from 1 to 3 months after treatment. The tumoricidal effect of concurrent therapy by 89SrCl2 with ZA for painful bone metastases was 8/22 as shown by imaging modalities and the rate of non-progressive disease (non-PD) was 19/22. Pain due to bone metastases assessed with the NRS was significantly improved (P<0.001) in many types of primary cancer, including prostate, breast and lung cancers. CONCLUSION: Concurrent therapy of 89SrCl2 with ZA may offer not only pain relief, but also a tumoricidal effect for painful bone metastases.

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.

A novel conformal superficial high-dose-rate brachytherapy device for the treatment of nonmelanoma skin cancer and keloids.

PURPOSE: To develop a novel conformal superficial brachytherapy (CSBT) device as a treatment option for the patient-specific radiation therapy of conditions including superficial lesions, postsurgical positive margins, Dupuytren's contractures, keloid scars, and complex anatomic sites (eyelids, nose, ears, etc.). METHODS AND MATERIALS: A preliminary CSBT device prototype was designed, built, and tested using readily available radioactive seeds. Iodine-125 (125I) seeds were independently guided to the treatment surface to conform to the target. Treatment planning was performed via BrachyVision Planning System (BPS) and dose distributions measured with Gafchromic EBT3 film. Percent depth dose curves and profiles for Praseodymium-142 (142Pr), and Strontium-90/Yttrium-90 (90Sr-90Y) were also investigated as potential sources. Results achieved with 90Sr-90Y and electron external beam radiation therapy were compared and Monte Carlo N-Particle eXtended 2.6 simulations of 142Pr seeds were validated. RESULTS: BPS was able to predict clinical dose distributions for a multiple seeds matrix. Calculated and measured doses for the 125I seed matrix were 500 cGy and 473.5 cGy at 5 mm depth, and 171.0 cGy and 201.0 cGy at 10 mm depth, respectively. Results of 90Sr-90Y tests demonstrate a more conformal dose than electron EBRT (1.6 mm compared to 4.3 mm penumbra). Measured 142Pr doses were 500 cGy at surface and 17.4 cGy at 5 mm depth. CONCLUSIONS: The CSBT device provides a highly conformal dose to small surface areas. Commercially available BPS can be used for treatment planning, and Monte Carlo simulation can be used for plans using beta-emitting sources and complex anatomies. Various radionuclides may be used in this device to suit prescription depths and treatment areas.

TRAPEZE: a randomised controlled trial of the clinical effectiveness and cost-effectiveness of chemotherapy with zoledronic acid, strontium-89, or both, in men with bony metastatic castration-refractory prostate cancer.

BACKGROUND: Bony metastatic castration-refractory prostate cancer is associated with a poor prognosis and high morbidity. TRAPEZE was a two-by-two factorial randomised controlled trial of zoledronic acid (ZA) and strontium-89 (Sr-89), each combined with docetaxel. All have palliative benefits, are used to control bone symptoms and are used with docetaxel to prolong survival. ZA, approved on the basis of reducing skeletal-related events (SREs), is commonly combined with docetaxel in practice, although evidence of efficacy and cost-effectiveness is lacking. Sr-89, approved for controlling metastatic pain and reducing need for subsequent bone treatments, is generally palliatively used in patients unfit for chemotherapy. Phase II analysis confirmed the safety and feasibility of combining these agents. TRAPEZE aimed to determine the clinical effectiveness and cost-effectiveness of each agent. METHODS: Patients were randomised to receive six cycles of docetaxel plus prednisolone: alone, with ZA, with a single Sr-89 dose after cycle 6, or with both. Primary outcomes were clinical progression-free survival (CPFS: time to pain progression, SRE or death) and cost-effectiveness. Secondary outcomes were SRE-free interval (SREFI), total SREs, overall survival (OS) and quality of life (QoL). Log-rank test and Cox regression modelling were used to determine clinical effectiveness. Cost-effectiveness was assessed from the NHS perspective and expressed as cost per additional quality-adjusted life-year (QALY). An additional analysis was carried out for ZA to reflect the availability of generic ZA. PATIENTS: 757 randomised (median age 68.7 years; Eastern Cooperative Oncology Group scale score 0, 40%; 1, 52%; 2, 8%; prior radiotherapy, 45%); median prostate-specific antigen 143.78 ng/ml (interquartile range 50.8-353.9 ng/ml). Stratified log-rank analysis of CPFS was statistically non-significant for either agent (Sr-89, p = 0.11; ZA, p = 0.45). Cox regression analysis adjusted for stratification variables showed CPFS benefit for Sr-89 [hazard ratio (HR) 0.845, 95% confidence interval (CI) 0.72 to 0.99; p = 0.036] and confirmed no effect of ZA (p = 0.46). ZA showed a significant SREFI effect (HR 0.76; 95% CI 0.63 to 0.93; p = 0.008). Neither agent affected OS (Sr-89, p = 0.74; ZA, p = 0.91), but both increased total cost (vs. no ZA and no Sr-89, respectively); decreased post-trial therapies partly offset costs [net difference: Sr-89 £1341; proprietary ZA (Zometa(®), East Hanover, NJ, USA) £1319; generic ZA £251]. QoL was maintained in all trial arms; Sr-89 (0.08 additional QALYs) and ZA (0.03 additional QALYs) showed slight improvements. The resulting incremental cost-effectiveness ratio (ICER) for Sr-89 was £16,590, with £42,047 per QALY for Zometa and £8005 per QALY for generic ZA. CONCLUSION: Strontium-89 improved CPFS, but not OS. ZA did not improve CPFS or OS but significantly improved SREFI, mostly post progression, suggesting a role as post-chemotherapy maintenance therapy. QoL was well maintained in all treatment arms, with differing patterns of care resulting from the effects of Sr-89 on time to progression and ZA on SREFI and total SREs. The addition of Sr-89 resulted in additional cost and a small positive increase in QALYs, with an ICER below the £20,000 ceiling per QALY. The additional costs and small positive QALY changes in favour of ZA resulted in ICERs of £42,047 (Zometa) and £8005 for the generic alternative; thus, generic ZA represents a cost-effective option. Additional analyses on the basis of data from the Hospital Episode Statistics data set would allow corroborating the findings of this study. Further research into the use of ZA (and other bone-targeting therapies) with newer prostate cancer therapies would be desirable. STUDY REGISTRATION: Current Controlled Trials ISRCTN12808747. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 20, No. 53. See the NIHR Journals Library website for further project information.

Epimacular Brachytherapy for Previously Treated Neovascular Age-Related Macular Degeneration (MERLOT): A Phase 3 Randomized Controlled Trial.

PURPOSE: To assess the safety and efficacy of epimacular brachytherapy (EMB) for patients with chronic, active, neovascular age-related macular degeneration (AMD). DESIGN: Phase 3 randomized controlled trial. PARTICIPANTS: Patients (n = 363) with neovascular AMD already receiving intravitreal ranibizumab injections. INTERVENTION: Either pars plana vitrectomy with 24-gray EMB and ongoing pro re nata (PRN) ranibizumab (n = 224) or ongoing PRN ranibizumab monotherapy (n = 119). MAIN OUTCOME MEASURES: The coprimary outcomes, at 12 months, were the number of PRN ranibizumab injections and Early Treatment of Diabetic Retinopathy Study (ETDRS) best-corrected visual acuity (VA). Secondary outcomes included the proportion of participants losing fewer than 15 ETDRS letters, angiographic total lesion size, choroidal neovascularization (CNV) size, and optical coherence tomography (OCT) foveal thickness. A predefined subgroup analysis tested the influence of baseline ocular characteristics on the response to EMB. RESULTS: The mean number of PRN ranibizumab injections was 4.8 in the EMB arm and 4.1 in the ranibizumab monotherapy arm (P = 0.068). The mean VA change was -4.8 letters in the EMB arm and -0.9 letters in the ranibizumab arm (95% confidence interval of difference between groups, -6.6 to -1.8 letters). The proportion of participants losing fewer than 15 letters was 84% in the EMB arm and 92% in the ranibizumab arm (P = 0.007). In the EMB arm, the mean total lesion size increased by 1.2 mm(2) versus 0.4 mm(2) in the ranibizumab arm (P = 0.27). The CNV size decreased by 0.5 mm(2) in the EMB arm and by 1.3 mm(2) in the ranibizumab arm (P = 0.27). The OCT foveal thickness decreased by 1.0 µm in the EMB arm and by 15.7 µm in the ranibizumab arm (P = 0.43). Most subgroups favored ranibizumab monotherapy, some significantly so. One participant showed retinal vascular abnormality attributed to radiation, but otherwise safety was acceptable. CONCLUSIONS: These results do not support the use of EMB for chronic, active, neovascular AMD. Safety is acceptable out to 12 months, but radiation retinopathy can occur later, so further follow-up is planned.

Palliative treatment of metastatic bone pain with radiopharmaceuticals: A perspective beyond Strontium-89 and Samarium-153.

PURPOSE: The present review article aims to provide an overview of the available radionuclides for palliative treatment of bone metastases beyond (89)Sr and (153)Sm. In addition, it aims to review and summarize the clinical outcomes associated with the palliative treatment of bone metastases using different radiopharmaceuticals. MATERIALS AND METHODS: A literature search was conducted on Science Direct and PubMed databases (1990 - 2015). The following search terms were combined in order to obtain relevant results: "bone", "metastases", "palliative", "care", "therapy", "treatment", "radiotherapy", "review", "radiopharmaceutical", "phosphorus-32", "strontium-89", "yttrium-90", "tin-117m", "samarium-153", "holmium-166", "thulium-170", "lutetium-177", "rhenium-186", "rhenium-188" and "radium-223". Studies were included if they provided information regarding the clinical outcomes. RESULTS AND CONCLUSIONS: A comparative analysis of the measured therapeutic response of different radiopharmaceuticals, based on previously published data, suggests that there is a lack of substantial differences in palliative efficacy among radiopharmaceuticals. However, when the comparative analysis adds factors such as patient's life expectancy, radionuclides' physical characteristics (e.g. tissue penetration range and half-life) and health economics to guide the rational selection of a radiopharmaceutical for palliative treatment of bone metastases, (177)Lu and (188)Re-labeled radiopharmaceuticals appear to be the most suitable radiopharmaceuticals for treatment of small and medium/large size bone lesions, respectively.

Radiopharmaceuticals for Palliation of Bone Pain in Patients with Castration-resistant Prostate Cancer Metastatic to Bone: A Systematic Review.

CONTEXT: The majority of patients with castration-resistant prostate cancer develop bone metastatic disease. It is often challenging to optimally palliate malignant bone pain. In case of multifocal pain due to diffuse osteoblastic metastases, treatment with bone-seeking radiopharmaceuticals can be considered. OBJECTIVE: This systematic review evaluates the efficacy of different bone-seeking radiopharmaceuticals for palliation of malignant bone pain from prostate cancer. EVIDENCE ACQUISITION: The PubMed (Medline) and Embase databases were searched for publications on 89-strontium-chloride ((89)Sr), 153-samarium-EDTMP ((153)Sm), 186-rhenium-HEDP ((186)Re), 188-rhenium-HEDP ((188)Re), and 223-radium-chloride ((223)Ra). Randomised controlled trials and prospective cohort studies were included. Metastatic bone pain had to be registered as outcome measure for prostate cancer patients separately. EVIDENCE SYNTHESIS: This review included 36 articles of which 13 randomised trials and 23 prospective studies. Of all trials, 10 studies used (89)Sr, 7 (153)Sm, 12 (186)Re, 2 (188)Re, and 2 (223)Ra; three reported on a combination of different radionuclides. Only a few trials contained a blinding procedure and several studies contained incomplete follow-up or lack of intention-to-treat analysis. It was not possible to calculate a pooled estimate of pain response to treatment with any of the radionuclides because different definitions of pain response were used. CONCLUSIONS: Overall, pain response percentages greater than 50-60% were seen with each radionuclide. Haematological toxicity was reported in 26 of the 36 studies and more than half of these trials stated no grade 3/4 leukopenia or thrombocytopenia occurred. PATIENT SUMMARY: In this report we reviewed the efficacy of bone-seeking radionuclides for treating bone pain from metastatic prostate cancer. Overall, treatment with bone-seeking radionuclides resulted in pain responses greater than 50-60%.

Concurrent use of strontium-89 with external beam radiotherapy for multiple bone metastases: early experience.

OBJECTIVE: The aim of the present study was to consider the safety and efficacy of concurrent use of strontium-89 (Sr-89) with external beam radiotherapy (EBRT) for multiple bone metastases, including lesions that require urgent therapy. METHODS: A retrospective review was performed of a consecutive series of patients who received Sr-89 for multiple bone metastases. Forty-five patients with multiple bone metastases received Sr-89 injection. Since 17 of the 45 patients had osteolytic bone lesions requiring emergent EBRT, they underwent concurrent use of Sr-89 with EBRT (concurrent group). The remaining 28 patients, none of whom had osteolytic lesions requiring urgent EBRT, were given Sr-89 injection only (singularity group). The injection of Sr-89 was to be given during EBRT, or on the day before the first day of EBRT. The dose of EBRT was 30 Gy in 10 fractions or 40 Gy in 20 fractions. Adverse events were evaluated according to hematological toxicity as measured by the Common Terminology Criteria for Adverse Events (V4.0). To assess efficacy, we checked changes in the pain scale and analgesic drug dosages, and the presence or absence of serious complications from bone metastases. RESULTS: Fifteen of 17 patients (88.2%) in the concurrent group and 17 of 28 patients (60.7%) in the singularity group reported bone pain relief. A statistically significant difference was found between the two groups, and severe complications (spinal cord compression and pathological fracture) from bone metastases could be prevented in all patients in the concurrent group. Severe hematological toxicity (grade 3 or higher) was not observed in the two groups. There was no statistical difference between the two groups. No one required additional intervention. The adverse events were tolerable. CONCLUSIONS: The results of our study suggest that concurrent use of Sr-89 with EBRT for multiple bone metastases can be performed safely if it is carried out with care, and that it may be an effective therapy in cases requiring emergency treatment.