Treatment Of Skeletal Metastases Research Articles

A Survey to Determine the Zone of Equipoise for the Proximal FEmur Resection or Internal Fixation fOR Metastases (PERFORM) Randomized Controlled Trial.

The objective of this study was to establish a zone of clinical equipoise for the Proximal FEmur Resection or Internal Fixation fOR Metastases (PERFORM) randomized controlled trial, which will compare resection and endoprosthetic reconstruction to internal fixation for skeletal metastases of the proximal femur. A survey was developed, piloted, and distributed to self-declared interested stakeholders in the PERFORM trial. The survey targeted orthopaedic oncologists and was designed to assess patient and bone lesion characteristics that drive surgical decision making in the treatment of skeletal metastases in the proximal femur. An Ethics Waiver was obtained at the lead academic institution and data was collected in the REDCap survey database. Responses were complete from 76 surgeons across North America, South America, Europe, Asia and Africa. Responses indicate that a study population for which either resection and endoprosthetic reconstruction or internal fixation are acceptable options include: (1) life expectancy at least 6 months, (2) bone loss of no more than 75% and no less than 25%, and (3) minimal to moderate risk for perioperative complications. Ninety-three percent of respondents indicated that they would be interested in participating in the PERFORM trial. A preliminary zone of equipoise for the PERFORM trial includes patients with 25-75% bone loss, low to moderate risk of operative complications, and life expectancy of at least 6 months. Further stakeholder discussions will finalize the PERFORM trial protocol prior to study initiation.

Targeted Radium Alpha Therapy in the Era of Nanomedicine: In Vivo Results.

Targeted alpha-particle therapy using radionuclides with alpha emission is a rapidly developing area in modern cancer treatment. To selectively deliver alpha-emitting isotopes to tumors, targeting vectors, including monoclonal antibodies, peptides, small molecule inhibitors, or other biomolecules, are attached to them, which ensures specific binding to tumor-related antigens and cell surface receptors. Although earlier studies have already demonstrated the anti-tumor potential of alpha-emitting radium (Ra) isotopes-Radium-223 and Radium-224 (223/224Ra)-in the treatment of skeletal metastases, their inability to complex with target-specific moieties hindered application beyond bone targeting. To exploit the therapeutic gains of Ra across a wider spectrum of cancers, nanoparticles have recently been embraced as carriers to ensure the linkage of 223/224Ra to target-affine vectors. Exemplified by prior findings, Ra was successfully bound to several nano/microparticles, including lanthanum phosphate, nanozeolites, barium sulfate, hydroxyapatite, calcium carbonate, gypsum, celestine, or liposomes. Despite the lengthened tumor retention and the related improvement in the radiotherapeutic effect of 223/224Ra coupled to nanoparticles, the in vivo assessment of the radiolabeled nanoprobes is a prerequisite prior to clinical usage. For this purpose, experimental xenotransplant models of different cancers provide a well-suited scenario. Herein, we summarize the latest achievements with 223/224Ra-doped nanoparticles and related advances in targeted alpha radiotherapy.

Surgical treatment of skeletal metastases in proximal tibia: a multicenter case series of 74 patients

Background and purpose — The proximal tibia is a rare site for metastatic bone disease and is a challenging anatomical site to manage due to the proximity to the knee joint and poor soft tissue envelope. We investigated implant survival and complications of different surgical strategies in the treatment of proximal tibia pathological fractures. Patients and methods — The study comprised a 4 medical center, retrospective analysis of 74 patients surgically treated for metastases of the proximal tibia. Patient records were reviewed to identify outcome, incidence, and type of complications as well as contributing factors. Results — Reconstruction techniques comprised cement-augmented osteosynthesis (n = 33), tumor prosthesis (n = 31), and total knee arthroplasty with long cemented stems (n = 10). Overall implant survival was 88% at 6 months and 1 year, and 67% at 3 years. After stratification by technique, the implant survival was 82% and 71% at 1 and 3 years with tumor prosthesis, 100% at 1 and 3 years with total knee arthroplasty, and 91% at 1 year and 47% at 3 years with osteosynthesis. Preoperative radiotherapy decreased implant survival. Complications were observed in 19/74 patients. Treatment complications led to amputation in 5 patients. Interpretation — In this study, the best results were seen with both types of prothesis reconstructions, with good implant survival, when compared with treatment with osteosynthesis. However, patients treated with tumor prosthesis showed an increased incidence of postoperative infection, which resulted in poor implant survival. Osteosynthesis with cement is a good alternative for patients with short expected survival whereas endoprosthetic replacement achieved good medium-term results.

Bisphosphonate-Functionalized Imaging Agents, Anti-Tumor Agents and Nanocarriers for Treatment of Bone Cancer.

Bone metastases result from the invasion of primary tumors to bone. Current treatment modalities include local treatments such as surgery and radiotherapy, while systemic treatments include chemotherapy and (palliative) treatment of skeletal metastases. Nevertheless, once bone metastases have been established they remain incurable leading to morbidity and mortality. Bisphosphonates are a well-established class of drugs, which are increasingly applied in the treatment of bone cancers owing to their effective inhibition of tumor cells and suppression of bone metastases. The increased understanding of the mechanism of action of bisphosphonates on bone and tumor cells has prompted the development of novel bisphosphonate-functionalized imaging and therapeutic agents. This review provides an update on the preclinical efficacy of bisphosphonate-functionalized fluorophore, anti-tumor agents and nanocarriers for the treatment of bone metastases. After an overview of the general characteristics of bisphosphonates and their mechanisms of action, an outline is provided on the various conjugation strategies that have become available to functionalize imaging agents, anti-tumor agents and nanocarriers with bisphosphonates. Finally, the efficacy of these bisphosphonate-modified agents and carriers in preclinical studies is evaluated by reviewing their potential to target tumors and inhibit tumor growth in clinically relevant animal models for the treatment of bone cancer.

Abstract P2-04-23: A monoclonal antibody against hypo-glycosylated bone sialoprotein II has application for diagnostic purposes in samples of breast cancer patients and for treatment of skeletal metastasis caused by MDA-MB-231 breast cancer cells in rats

Abstract The SIBLING protein bone sialoprotein II (BSP) has been implicated in lytic skeletal metastasis as it is expressed in a subset of primary breast cancers and can be detected at elevated levels in the serum of patients with increased risk to develop skeletal metastasis. The aim of this study was to investigate the potential application of a rat monoclonal antibody against hypo-glycosylated BSP (IDK1) for diagnostic and therapeutic purposes. The diagnostic part of this study was based on breast cancer specimens from the biobank / repository of the Institute of Pathology of the Municipal Hospital Kassel, Germany. Immune-histochemical analyses were performed with IDK1 for comparing BSP expression between ten human primary breast tumor sections and their corresponding bone metastatic tissue samples. The therapeutic part of this study was based on a model in nude rats, in which the rats were implanted with human MDA-MB-231 breast cancer cells for selective and orthotopic appearance of osteolytic skeletal lesions. Tumor bearing rats were treated with IDK1 starting at two or four weeks after tumor cell inoculation into the femoral artery of one hind leg. Tumor growth was monitored by light emission, caused by luciferase mediated metabolism of luciferin. Photon emission was recorded at regular intervals by a Xenogen IVIS 100 imaging system. After sacrifice, samples of lesions and apparently healthy tissues were investigated by H&E staining as well as by immune-histological staining for BSP. BSP staining was found within the cytoplasm of tumor cells. Increased expression of BSP was also detected in healthy bone cells, e.g. osteoblasts, as soon as breast tumor cells invaded bone tissue. An elevation of BSP expression near necrotic centers was also found. Expression of BSP in primary breast tumors was positively correlated with BSP expression in bone metastases. Furthermore, bone metastases showed higher and more intensive expression of BSP than their respective primary breast tumors (p<0.0039). In the experimental treatment part, all but one untreated tumor bearing rats showed rapid tumor growth accompanied with lytic destruction of femur and tibia of the respective hind leg (18/19; tumor take rate 95%). In contrast, rats treated with the anti-BSP antibody did not show a significant increase in light emission nor a clinical deterioration. In fact, 8 of 10 rats receiving the antibody at a dose of 10 mg/kg/week starting at two weeks after tumor implantation did not show any light emission after 4 to 6 weeks (p = 0.01 versus control) as well as 6 of 10 rats receiving the antibody at the same dose starting at four weeks after tumor implantation (p < 0.05). Radiological and histological examination confirmed that animals without light emission were free of tumor growth, corresponding to a complete remission. In conclusion, the rat monoclonal antibody directed against BSP is a powerful tool with potential for diagnostic and therapeutic applications in breast cancer skeletal metastasis and warrants further development. Citation Format: Berger MR, Zepp M, Westphal G, Berger I, Armbruster FP. A monoclonal antibody against hypo-glycosylated bone sialoprotein II has application for diagnostic purposes in samples of breast cancer patients and for treatment of skeletal metastasis caused by MDA-MB-231 breast cancer cells in rats [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-04-23.

Team Approach: The Treatment of Metastatic Tumors of the Femoral Diaphysis.

➢ The differential diagnosis of an aggressive bone lesion includes metastatic disease, multiple myeloma, lymphoma, and primary sarcoma of bone. Evaluation includes radiographs of the entire bone; laboratory tests; computed tomography (CT) scanning of the chest, abdomen, and pelvis; bone scintigraphy; and biopsy.➢ Except in rare circumstances, the treatment of skeletal metastasis is palliative and the goals of care center around pain relief and the maintenance of function.➢ Nonoperative interventions include chemotherapy, bone-modulating agents such as bisphosphonates and denosumab, radiation therapy, and ablation with cementoplasty.➢ When prophylactic operative stabilization is indicated to prevent pathological fracture, a cephalomedullary nail is preferred for femoral diaphyseal lesions. Postoperative external-beam radiation is indicated for local disease control.➢ High-quality treatment of these patients relies on the close coordination of multiple different specialists.

Treatment of skeletal metastases with 223Ra-chloride

Bone metastases cause significant morbidity to patients with prostate cancer, the most commonly diagnosed solid cancer in men. In the last decade, the approach to metastatic castrate-resistant prostate cancer has evolved remarkably, with approval of multiple new medications with survival benefit. We review the radiobiology and phases of development of 223Ra (radium), an α-emitter radiopharmaceutical, and discuss the clinical implications of its use and its future role in the treatment of prostate cancer. A review of the literature was performed through searches of PubMed and Medline databases and related links in these databases, along with recently published abstracts from major medical meetings. 223Ra is an α-emitter, with high affinity to areas of bone metastases. α-Particles have high energy and short range, causing cytotoxicity to targeted cancer cells without affecting surrounding normal tissues. It has been proven to prolong overall survival, delay symptomatic skeletal events, and improve quality of life, while having a minimal toxicity profile. 223Ra is effective and safe in the treatment of bone metastatic castration-resistant prostate cancer. Additional studies are planned to assess the efficacy of 223Ra in combination with other agents known to be active in advanced prostate cancer.

Breast Cryoablation in Patients with Bone Metastatic Breast Cancer

PurposeTo assess retrospectively the safety and feasibility of palliative breast cryoablation to treat primary breast tumors in patients with stage IV breast cancer. Materials and MethodsIn 17 female patients (mean age ± SD, 59 y ± 13; range, 37–81 y) with 22 bone metastatic ductal invasive breast lesions (2.5 cm × 1.6 cm ± 1.4 × 1.1; range, 1.0 cm × 0.5 cm to 6.7 cm × 5.5 cm), 19 computed tomography (CT)–guided percutaneous cryoablation sessions were performed for treatment of primary breast tumors. All patients had radiologic evidence (contrast-enhanced CT or magnetic resonance imaging) of persistence or progression of the primary breast cancer despite systemic therapy. The radiologic outcome was evaluated with a mean follow-up period of 13 months (range, 3–31 mo). Treatment of skeletal metastases was unnecessary during the follow-up period. ResultsAll of the cryoablation sessions were completed and well tolerated. Complete regression of the disease was achieved in 15 (88%) patients 2 months after the cryoablation. Two (12%) patients underwent a second cryoablation treatment because of a minimal persistence of viable tumor (residual disease). No relapse of primary tumors was observed on breast imaging during the follow-up period. One patient (6%) developed a new lesion localized to the contralateral breast. ConclusionsThese data suggest that palliative cryoablation of primary advanced breast cancer is a well-tolerated, feasible, and effective treatment option. Given the palliative effects of breast cryoablation demonstrated in this series, larger studies replicating these results are warranted.

P2-059 - Skeletal Complications and Survival in Gastric Cancer Patients with Skeletal Metastases

ABSTRACT Background The skeleton is one of the most frequent sites for metastases in patients with advanced cancer. Several guidelines have been proposed covering diagnosis and management of skeletal metastases in patients with breast and prostate cancer. As skeletal metastases in gastric cancer are less frequent events, there have been limited reports that evaluated the incidence, influence on survival of skeletal metastases and the role of bisphosphonate in the treatment of advanced gastric cancer. Material and methods Between 2002 and 2011, we retrospectively reviewed the medical records of 138 patients with metastatic gastric cancer in our institute. We investigated incidence of skeletal metastases, percentage of patients who developed skeletal-related events (SREs) and differences in the therapeutic outcome between patients with and without skeletal metastases. Results Of the 138 patients, 23 patients (median age: 59.5 years; ranged from 29 to 76) were found to have skeletal metastases during their clinical course. Almost all patients have multiple sites of disease that appeared osteoblastic on radiography. Among them, only three (13%) patients experienced SREs (two had spinal cord compression and one had pathological fracture), because most of the patients died of systemic disease progression before the clinical development of SREs. Of the 23 patients, 18 patients (78.3%) had skeletal metastases at the time of initial diagnosis, and 5 patients (21.7%) developed skeletal metastases later in the course of their disease. For 18 patients who presented skeletal metastases at the diagnosis, the median survival time (MST) was 7.4 months, whereas it was 11 months for those without such metastases. Hematological complications, including microangiopathic hemolytic anemia (MAHA) and disseminated intravascular coagulation (DIC), occurred more often with skeletal metastases than with non-skeletal metastases (44 versus 0.9%, respectively), which may relate to the shorter survival of patients with skeletal metastases. Conclusions Our study suggests that the prognosis of gastric cancer with skeletal metastases is poor. Earlier identification and the novel treatment of skeletal metastases would be crucial for improving survival in this patient group.

Oral bisphosphonate use in the elderly is not associated with acute kidney injury

Intravenous bisphosphonates can cause acute kidney injury; however, this risk was not found with oral bisphosphonates in randomized clinical trials with restrictive eligibility criteria. In order to provide complementary safety data, we studied the risk of acute kidney injury in a population-based cohort of 122,727 patients aged 66 years and older discharged from hospital following a new fragility fracture and no history of bisphosphonate use in the prior year. Bisphosphonate treatment was identified within 120 days after discharge and event rates were measured from 90 days of therapy initiation. The primary outcome was hospitalization with acute kidney injury with secondary outcomes of new nephrology consultation and, in a subset of patients with laboratory values, acute kidney injury was defined as an increase in serum creatinine. We identified 18,286 bisphosphonate users and 104,441 non-users with a mean age of 81 years. Of 5772 patients with laboratory values, 40% had chronic kidney disease (eGFR <60 ml/min per 1.73 m(2)). Overall, there was no statistically significant difference in the risk of acute kidney injury among bisphosphonate users compared to non-users (adjusted odds ratio 1.03), and no significant differences in other outcomes or in subgroups of patients with baseline chronic kidney disease. Thus, in this older population-based cohort, oral bisphosphonate use was not associated with acute kidney injury.

Chirurgische Behandlung von Skelettmetastasen

Die Metastasierung stellt eine Generalisierung eines Tumorleidens im Körper dar. Die Behandlung von Skelettmetastasen ist daher interdisziplinär vorzunehmen und erfordert ein stadien- und patientenadaptiertes Vorgehen. Bei unbekanntem Primarius oder langem Intervall zwischen Tumor und Auftreten einer Metastasierung muss auch an das Vorliegen eines primären Knochentumors bzw. eines Zweitkarzinoms gedacht werden. Bei Zweifel ist hier dringend eine Biopsie zu empfehlen. An chirurgischen Therapiemöglichkeiten stehen die alleinige Stabilisierung, die Stabilisierung mit Radiatio, die intraläsionale Resektion mit Radiatio sowie die weite bzw. marginale Resektion zur Verfügung. Verschiedene Rekonstruktionsverfahren bieten Vor- und Nachteile. Die Therapieentscheidung muss der aktuellen und zu erwartenden Situation des Patienten Rechnung tragen. Der onkologische Fortschritt mit deutlicher Verbesserung der Lebenserwartung führt zu einer deutlich aggressiveren Herangehensweise in der chirurgischen Lokaltherapie.

Imaging response to systemic therapy for bone metastases

In patients with osteotropic primary tumours such as breast and prostate cancer, imaging treatment response of bone metastases is essential for the clinical management. After treatment of skeletal metastases, morphological changes, in particular of bone structure, occur relatively late and are difficult to quantify using conventional X-rays, CT or MRI. Early treatment response in these lesions can be assessed from functional imaging techniques such as dynamic contrast-enhanced techniques by MRI or CT and by diffusion-weighted MRI, which are quantifiable. Among the techniques within nuclear medicine, PET offers the acquisition of quantifiable parameters for response evaluation. PET, therefore, especially in combination with CT and MRI using hybrid techniques, holds great promise for early and quantifiable assessment of treatment response in bone metastases. This review summarises the classification systems and the use of imaging techniques for evaluation of treatment response and suggests parameters for the early detection and quantification of response to systemic therapy.

Palliative care in orthopaedic surgical oncology

Hundreds of thousands of Americans are affected every year by skeletal complications of oncologic disease. Recent developments in medical oncology, radiation oncology and radiology, particularly with respect to the use of bisphosphonate medication and radiofrequency techniques, have served to greatly lessen the morbidity associated with metastatic skeletal disease. Similarly, there has been significant advancement in the field of orthopaedic oncology in the areas of internal fixation, endoprosthetic implant design, and minimally invasive kyphoplasty technology. Given the palliative intent of intervention in this patient population, the goal of treatment of skeletal metastases must be optimization of limb function and ultimately, quality of life.

Evaluating distant metastases in breast cancer: from biology to outcomes

There is an urgent need to understand distant metastases in breast cancer as they are the most lethal form of recurrence and a major cause of mortality in patients. Some predictors for distant metastases, including nodal status, tumor grade, and hormonal status, are useful in identifying patients at increased risk for distant metastases. Adjuvant endocrine therapy has been the treatment of choice for postmenopausal women with hormone-sensitive breast cancer, and some therapies have shown significant reductions in the risk of distant metastases. Skeletal metastases in breast cancer are treated with bisphosphonates with a certain level of success. With more new agents undergoing clinical trials, a thorough review of the specific and long-term safety of these agents is essential, as is a better understanding of the deterioration in the quality of life and cost concerns of patients who develop distant metastases. Gene-expression profiling is a new entrant in the field of distant metastases diagnosis, which is largely successful in defining gene signatures that predict the development of distant metastases. This review will discuss the biology and the impact of distant metastases on outcomes for patients with breast cancer; it also encompasses the current status, emerging focus, and future perspectives in treatment of skeletal metastases in patients with breast cancer.

E06-03: Management of bone metastasis - role of bisphosphonates

Bisphosphonates are used in patients with metastatic bone disease to prevent skeletal-related events (SREs) such as bone pain, fractures and spinal cord or nerve compression and hypercalcemia of malignancy. (1Body JJ Bisphosphonates for malignancy-related bone disease: current status, future developments.Support Care Cancer. 2006; 14: 408-418Crossref PubMed Scopus (77) Google Scholar) Bisphosphonates are synthetic analogs of pyrophosphate. The four bisphosphonates used are Clodronate, Pamidronate, Zoledronic acid and Ibandronate. (2Selvaggi G Scagliotti GY Management of bone metastases in cancer: A review.Crit Rev Oncol/Hem. 2005; 56: 365-378Abstract Full Text Full Text PDF PubMed Scopus (146) Google Scholar) The latter drug is the newest and it is used outside of the U.S. since it has not been approved yet by the U.S. Food and Drug Administration. Bisphosphonates work mainly by inhibiting normal and pathologic osteoclast-mediated bone resorption thereby preventing bone loss. They do this by accumulating in sites of active bone formation making the sites more resistant to dissolution by osteoclasts. In lung cancer patients who die from their disease, 30%-40% will be diagnosed with bone metastases. The majority of these patients will have symptomatic bone involvement. In the U.S., Zoledronic acid, 4 mg infused for 15 minutes every 3-4 weeks is used to treat lung cancer patients with metastatic bone disease. In a randomized phase III double-blind, placebo controlled trial, in patients with non-small cell lung cancer (NSCLC) and other solid tumors, in a 21-month follow-up of the patients, the patients receiving Zoledronic acid, 4 mg experienced less SRE's (38%) compared to the patients receiving the placebo (47%).(3Rosen LS Gordon D Tchekmedyian NS et al.Long-term efficacy and safety of Zoledronic acid in the treatment of skeletal metastases in patients with non-small cell lung carcinoma and other solid tumors.Cancer. 2004; 100: 2613-2621Crossref PubMed Scopus (559) Google Scholar) Median times to first SRE were 230 days and 163 days respectively. Bisphosphonates are generally well tolerated. The most common side effects include flu-like symptoms (e.g. fever, myalgia, arthralgia) occurring in 10%-20% of patients which usually occurs 12 to 48 hours after the infusion and lasting 6 to 24 hours. Other side effects include bone pain, weakness, anemia, nausea, dyspnea and peripheral edema. These are usually mild to moderate. Ocular effects include uveitis which is rare. Oral bisphosphonates are generally associated with gastrointestinal intolerance, esophagitis and diarrhea. Two more serious complications include renal dysfunction and osteonecrosis of the jaw (ONJ). Since all bisphosphonates undergo renal clearance, their administration may result in elevated serum creatinine levels. Therapy should be withheld with increase in serum creatinine levels > 0.5 mg/dL above upper limits of normal. ONJ is a rare disorder characterized by temporary or permanent lose of blood supply to the jaw resulting in the development of necrotic bone in the mandible or maxilla. Symptoms include pain, swelling or infection of gums, loosening of teeth and poor healing of the gums. To minimize the risk of ONJ, patients must maintain excellent oral hygiene, limit alcohol and tobacco use, obtain dental assessments prior to starting bisphosphonates and avoid dental procedures while being treated with bisphosphonates. Bisphosphonates should be discontinued for 3 months prior to undergoing a dental procedure. Future development of the use of bisphosphonates include (1Body JJ Bisphosphonates for malignancy-related bone disease: current status, future developments.Support Care Cancer. 2006; 14: 408-418Crossref PubMed Scopus (77) Google Scholar) trials investigating whether high-dose bisphosphonates can reduce metastatic bone pain, (2Selvaggi G Scagliotti GY Management of bone metastases in cancer: A review.Crit Rev Oncol/Hem. 2005; 56: 365-378Abstract Full Text Full Text PDF PubMed Scopus (146) Google Scholar) studies of adjuvant therapy with bisphosphonates in order to prevent bone metastases and (3Rosen LS Gordon D Tchekmedyian NS et al.Long-term efficacy and safety of Zoledronic acid in the treatment of skeletal metastases in patients with non-small cell lung carcinoma and other solid tumors.Cancer. 2004; 100: 2613-2621Crossref PubMed Scopus (559) Google Scholar) Use of bisphosphonates to prevent cancer-therapy induced bone loss.

P1-262: Economic value of zoledronic acid versus placebo in the treatment of skeletal metastases in patients with lung cancer: Applications to France and Germany

P1-262: Economic value of zoledronic acid versus placebo in the treatment of skeletal metastases in patients with lung cancer: Applications to France and Germany

Economic value of zoledronic acid versus placebo in the treatment of skeletal metastases in patients with lung cancer: The case of the United Kingdom (UK)

6617 Objectives: Zoledronic acid (ZA) reduces the risk of skeletal-related events (SREs) in lung cancer patients with bone metastases and may improve survival among those patients with high levels of bone metabolism. This analysis assessed, from the UK National Health Service's perspective, the economic impact of ZA therapy in patients with bone metastases secondary to lung cancer. Methods: A literature-based decision analytic model was developed to compare the direct costs and quality adjusted life years (QALY) experienced by lung cancer patients with bone metastases receiving placebo or ZA. Survival, SRE incidence, and number of infusions administered were obtained from a randomized clinical trial comparing 4 mg ZA with placebo. Drug acquisition and administration costs and SRE costs were estimated using published sources and national fee schedules (i.e., NHS reference costs, British National Formulary, Personal Social Services Research Unit reference costs). The impact of SREs on quality of life was estimated using the literature. Consistent with previous economic analyses of bisphosphonates in cancers (e.g., Hillner et al, 2000), patients avoiding SREs were assumed to experience quality of life improvements for 1 month. Results: The average remaining life expectancy was conservatively assumed equal in both groups and was 8.50 months (median, 5.89 months). During those months, patients receiving placebo were projected to experience 2.07 SREs on average compared to 1.32 SREs among ZA patients. QALYs were estimated at 0.3523 per patient (pp) and 0.3350 pp in the ZA and placebo groups, respectively. ZA drug-related costs were estimated at £1,473 pp, based on 5.87 infusions pp and a cost of £251.01 per infusion. The use of ZA was associated with a reduction of £1,562 pp in SRE costs. Overall, ZA saved costs and increased QALYs compared to no therapy, by £89 pp and 0.0173 QALYs pp, respectively. In sensitivity analyses, ZA cost £25,000 or less per QALY under a wide range of assumptions. Conclusions: The use of ZA leads to fewer SREs, better estimated quality of life, and lower costs relative to placebo in UK lung cancer patients with bone metastases. The use of ZA in this population therefore appears highly cost effective. No significant financial relationships to disclose.

Economic value of zoledronic acid compared with placebo in the treatment of skeletal metastases in patients with solid tumors: The case of the United Kingdom (UK)

6603 Background: Zoledronic acid (ZA) reduces the risk of skeletal-related events (SREs) in patients with solid tumors (i.e., renal cell carcinoma, thyroid, head and neck, small cell lung, or others cancers, excluding breast, prostate and non small cell lung [NSCLC] cancers) and bone metastases. This analysis assessed, from the perspective of the UK National Health Service, the economic impact of ZA in this patient population. Methods: A literature-based decision-analytic model was developed to compare the direct costs and quality adjusted life years (QALY) of patients with bone metastases secondary to solid tumors receiving ZA or placebo. Survival, SRE incidence, and number of infusions administered were obtained from a clinical trial comparing patients randomized to 4 mg ZA or placebo for up to 21 months. Drug acquisition and administration costs and SRE costs were estimated using published sources and national fee schedules (e.g., NHS reference costs, British National Formulary). The impact of SREs on quality of life was estimated using the literature. Consistent with previous economic analyses of bisphosphonates in cancers (e.g., Hillner et al, 2000), patients were assumed to experience quality of life improvements lasting 1 month for each SRE avoided. Results: The average remaining life expectancy was conservatively assumed equal in both groups and was 9.54 months (median, 6.61 months). Patients receiving placebo were projected to experience 2.64 SREs on average v. 1.64 SREs among ZA patients. QALYs were estimated at 0.3917 per patient (pp) and 0.3728 pp in the ZA and placebo groups, respectively. ZA drug- related costs were estimated at £1,386 pp, based on an average of 5.52 infusions pp. The use of ZA was associated with a reduction of £1,830 pp in SRE costs. Overall, ZA saved costs and increased QALYs v. no therapy, by £445 pp and 0.0189 QALYs pp, respectively. In sensitivity analyses, ZA cost £25,000 or less per QALY under a wide range of assumptions. Conclusions: The use of ZA leads to fewer SREs, better estimated quality of life, and lower costs relative to placebo in UK patients with bone metastases secondary to solid tumors other than breast, prostate or NSCLC cancer. ZA appears therefore highly cost effective in this population. No significant financial relationships to disclose.

High-Linear Energy Transfer Irradiation Targeted to Skeletal Metastases by the α-Emitter 223Ra: Adjuvant or Alternative to Conventional Modalities?

Abstract The bone-seeking, α-particle-emitting radiopharmaceutical Alpharadin, 223RaCl2 (half-life = 11.4 days), is under clinical development as a novel treatment for skeletal metastases from breast and prostate cancer. This article summarizes the current status of preclinical and clinical research on 223RaCl2. Potential advantages of 223Ra to that of external beam irradiation and registered β-emitting bone seekers are discussed. Published data of 223Ra dosimetry in mice and a therapeutic study in a skeletal metastases model in nude rats have indicated significant therapeutic potential of bone-seeking α-emitters. This article provides short-term and long-term results from the first clinical single dosage trial. We also present data from a repeated dosage study of five consecutive injections of 50 kBq/kg body weight, once every 3rd week, or two injections of 125 kBq/kg body weight, 6 weeks apart. Furthermore, interim results are described for a randomized phase 2 trial involving 64 patients with hormone-refractory prostate cancer and painful skeletal metastases who received four monthly injections of 223Ra or saline as an adjuvant to external beam radiotherapy. Lastly, we present preliminary dose estimates for 223Ra in humans. Results indicate that repeated dosing is feasible and toxicity is low, and that opportunities are available for combined treatment strategies.

Activin A circulating levels in patients with bone metastasis from breast or prostate cancer

Recent studies have highlighted that Activin A, a member of the transforming growth factor-beta (TGF-beta) superfamily, may be involved in the regulation of osteoblastic activity and in osteoclast differentiation. Therefore, we have investigated the clinical significance of its circulating levels in patients with bone metastasis. Activin A serum concentrations were determined, by a commercially available enzyme-linked immunosorbent assay kit, in 72 patients with breast cancer (BC) or prostatic cancer (PC) with (BM+) or without (BM-) bone metastases, in 15 female patients with age-related osteoporosis (OP), in 20 patients with benign prostatic hypertrophy (BPH) and in 48 registered healthy blood donors (HS) of both sex (25 female and 23 male). Activin A serum concentrations were significantly increased in BC or PC patients as compared to OP (P < 0.0001) or BPH (P = 0.045), respectively, or to sex matched HS (P < 0.0001). Additionally, these levels resulted more elevated in PC patients as compared to BC patients (P = 0.032). Interestingly, Activin A was significantly higher in BM+ patients than in BM- patients (BC, P = 0.047; PC, P = 0.016). In BC patients, a significant correlation was observed only between Activin A and number of bone metastases (P = 0.0065) while, in PC patients, Activin A levels were strongly correlated with the Gleason score (P = 0.011) or PSA levels (P = 0.0001) and, to a lessen extent, with the number of bone metastases (P = 0.056). Receiver operating characteristic curve (ROC) analysis showed a fair diagnostic accuracy of Activin A to discriminate between BM+ and BM- patients (BC: AUC = 0.71 +/- 0.09, P = 0.03; PC: AUC = 0.73 +/- 0.081, P = 0.005). These findings indicate that Activin A may be implicated in the pathogenesis of bone metastasis. Therefore, this cytokine may be considered a novel potential target for a more selective therapeutic approach in the treatment of skeletal metastasis and may be also useful as additional biochemical marker of metastatic bone disease.