Contemporary outcomes of metastatic breast cancer among 22,000 women from the multicentre ESME cohort 2008-2016.

AIM: Real-world data inform the outcome comparisons and help the development of new therapeutic strategies. To this end, we aimed to describe the full characteristics and outcomes in the Epidemiological Strategy and Medical Economics (ESME) cohort, a large national contemporary observational database of patients with metastatic breast cancer (MBC). METHODS: Women aged ≥18 years with newly diagnosed MBC and who initiated MBC treatment between January 2008 and December 2016 in one of the 18 French Comprehensive Cancer Centers (N = 22,109) were included. We assessed the full patients' characteristics, first-line treatments, overall survival (OS) and first-line progression-free survival, as well as updated prognostic factors in the whole cohort and among the 3 major subtypes: hormone receptor positive and HER2-negative (HR+/HER2-, n = 13,656), HER2-positive (HER2+, n = 4017) and triple-negative (n = 2963) tumours. RESULTS: The median OS of the whole cohort was 39.5 months (95% confidence interval [CI], 38.7-40.3). Five-year OS was 33.8%. OS differed significantly between the 3 subtypes (p < 0.0001) with a median OS of 43.3 (95% CI, 42.5-44.5) in HR+/HER2-; 50.1 (95% CI, 47.6-53.1) in HER2+; and 14.8 months (95% CI, 14.1-15.5) in triple-negative subgroups, respectively. Beyond performance status, the following variables had a constant significant negative prognostic impact on OS in the whole cohort and among subtypes: older age at diagnosis of metastases (except for the triple-negative subtype), metastasis-free interval between 6 and 24 months, presence of visceral metastases and number of metastatic sites ≥ 3. CONCLUSIONS: The ESME program represents a unique large-scale real-life cohort on MBC. This study highlights important situations of high medical need within MBC patients. DATABASE REGISTRATION: clinicaltrials.gov Identifier NCT032753.

A cost-effectiveness analysis of denosumab for the prevention of skeletal-related events in patients with multiple myeloma in the United States of America.

OBJECTIVE: A large, pivotal, phase 3 trial in patients with newly diagnosed multiple myeloma (MM) demonstrated that denosumab, compared with zoledronic acid, was non-inferior for the prevention of skeletal-related events (SREs), extended the observed median progression-free survival (PFS) by 10.7 months, and showed significantly less renal toxicity. The cost-effectiveness of denosumab vs zoledronic acid in MM in the US was assessed from societal and payer perspectives. METHODS: The XGEVA Global Economic Model was developed by integrating data from the phase 3 trial comparing the efficacy of denosumab with zoledronic acid for the prevention of SREs in MM. SRE rates were adjusted to reflect the real-world incidence. The model included utility decrements for SREs, administration, serious adverse events (SAEs), and disease progression. Drug, administration, SRE management, SAEs, and anti-MM treatment costs were based on data from published studies. For the societal perspective, the model additionally included SRE-related direct non-medical costs and indirect costs. The net monetary benefit (NMB) was calculated using a willingness-to-pay threshold of US$150,000. One-way deterministic and probabilistic sensitivity analyses were conducted. RESULTS: From a societal perspective, compared with zoledronic acid, the use of denosumab resulted in an incremental cost of US$26,329 and an incremental quality-adjusted life-year (QALY) of 0.2439, translating into a cost per QALY gained of US$107,939 and a NMB of US$10,259 in favor of denosumab. Results were sensitive to SRE rates and PFS parameters. LIMITATIONS: Costs were estimated from multiple sources, which varied by tumor type, patient population, country, and other parameters. PFS and overall survival were extrapolated beyond the follow-up of the primary analysis using fitted parametric curves. CONCLUSION: Denosumab's efficacy in delaying or preventing SREs, potential to improve PFS, and lack of renal toxicity make it a cost-effective option for the prevention of SREs in MM compared with zoledronic acid.

Cost-effectiveness of denosumab as a bone protective agent for patients with castration resistant prostate cancer.

Fortunately, novel agents are nowadays available for the management of patients with castration-resistant prostate cancer (CRPC). Denosumab is a new bone-protective agent, approved for the prevention and management of skeletal-related events. Studies have demonstrated that denosumab has better efficacy and similar rate of adverse effects in comparison with zoledronic acid, which was the standard bone-protective agent. In the present review we study the cost-effectiveness of denosumab in patients with CRPC.

Reducing Skeletal-Related Events in Metastatic Castration-Resistant Prostate Cancer.

Skeletal-related events contribute substantially to morbidity, mortality and cost in men with metastatic castration-resistant prostate cancer (mCRPC). There are five agents available for treatment in mCRPC that reduce skeletal-related events. Here we discuss the efficacy and safety of zoledronic acid, denosumab, enzalutamide, abiraterone, and radium-223. We include data on and a discussion of duration of treatment with zoledronic acid and denosumab, the only two of these agents that do not have a clinically proven anticancer effect. Finally, we review the available data regarding the cost of denosumab compared with that of zoledronic acid.

Spanish Menopause Society position statement: Use of denosumab in postmenopausal women.

Denosumab is a new drug developed for the treatment of osteoporosis. Moreover, increasing evidences link denosumab with benefits in cancer, an area of interest for those in charge of the postmenopausal health. Denosumab has shown efficacy in the control of bone loss associated with hypogonadic states created by chemotherapy in breast and other cancers. Moreover, some studies reveal efficacy in reducing the progression of metastases. A panel of experts from the Spanish Menopause Society has met to develop usage recommendations based on the best available evidence.

Zoledronic acid and skeletal complications in patients with solid tumors and bone metastases: analysis of a national medical claims database.

BACKGROUND: Bone is among the most common sites of metastasis in patients with advanced cancer, and the development of bone metastases places patients at increased risk for skeletal complications. METHODS: This retrospective claims analysis included only patients with a diagnosis of bone metastasis who had a single type of solid tumor of the breast (women), prostate, or lung and experienced >or=1 skeletal complication between January 2002 and October 2005. RESULTS: The mean follow-up (+/-standard deviation) for zoledronic acid (ZA)-treated patients versus untreated patients was 12.2 +/- 9.05 months versus 8.7 +/- 9.28 months, respectively (P < .001). The monthly rate of skeletal complications in ZA-treated patients versus untreated patients was 0.29 +/- 0.3 per month versus 0.43 +/- 0.4 per month, respectively (P < .001). Persistent ZA use was associated with longer follow-up duration (P < .05) and a greater probability of continuing follow-up. Greater persistency was associated with lower monthly rates of skeletal complications (P < .05). The length of follow-up for ZA use according to the recommended dosing schedule was 17.11 months compared with 9.93 months for nonrecommended schedules and 8.68 months for no treatment (analysis of variance; P < .001). The rate of skeletal complications with ZA use on the recommended schedule was 0.16 events per month versus 0.31 events per month for nonrecommended schedules and 0.43 events per month for no treatment. In the subgroup analysis, the mean time to first complication was 185 +/- 210 days in the ZA-treated group versus 98 +/- 161 days in the untreated group (P < .0001). The mean time from the first complication to the second complication was 111 +/- 124 days in the ZA-treated group versus 86 +/- 114 days in the untreated group (P < .05). CONCLUSIONS: Real-world evidence indicated that ZA reduced the skeletal morbidity rate and delayed the time to skeletal complications.

The role of bisphosphonates in the management of advanced cancer with a focus on non-small-cell lung cancer. Part 2: Clinical studies and economic analyses.

Newer-generation intravenous bisphosphonates have resulted in the reduction of skeletal-related complications, i.e. skeletal-related events (SREs) such as pain, hypercalcemia, pathologic fractures and spinal cord and nerve compression, as well as improvements in the quality of life in patients with metastatic bone disease who are likely to have a prolonged clinical course. Highly potent, nitrogen-containing bisphosphonates such as zoledronic acid reduce SREs in patients with bone metastases from other solid tumors (including lung cancer). Part one of our review discussed the mechanisms of action by bisphosphonates as well as potential roles for bone markers and imaging in lung cancer. In this article, part two of our review, we examine the economic and clinical impact of bisphosphonates in lung cancer, with a focus on the potential role of newer-generation bisphosphonates in the management of advanced, metastatic bone disease of lung cancer.

[Diagnosis and assessment of therapeutic response of bone metastases by bone scintigraphy and PET study]. / Diagnóstico y valoración de la respuesta terapéutica de las metástasis óseas mediante gammagrafía ósea y estudio PET.

Nuclear medicine plays an important role in staging and evaluation of the initial extension and response to treatment of bone metastases. In order to accurately read Bone Scintigraphy (BS) and Positron Emission Tomography scan (PET) procedures, it is essential to understand the different behavior of these studies. We present a case report of a woman treated for breast cancer, with suspicion of recurrent disease due to increase of tumor markers. Initial BS showed non-conclusive findings, whereas PET study was consistent with a spread of bone metastases. The patient underwent both procedures again after a course of chemotherapy. Post-treatment BS showed progression of bone lesions, while PET showed good therapeutic response. The PET demonstrates lesions earlier and more effectively than the bone scintigraphy in the evaluation of the therapeutic response of bone metastases.

Cost-effectiveness of zoledronic acid for the prevention of skeletal complications in patients with prostate cancer.

PURPOSE: We estimated the cost-effectiveness of zoledronic acid vs placebo for decreasing skeletal complications in men with prostate cancer. MATERIALS AND METHODS: We performed a cost-effectiveness analysis alongside a multinational clinical trial of zoledronic acid. Cost estimation was based on prospectively collected resource use data for 85.3% of enrolled patients. Cost-effectiveness ratios were based on within-trial data on clinical outcomes, quality of life and study medication cost. RESULTS: Patients receiving zoledronic acid experienced fewer hospital days during a mean followup of 9 months (average 5.6 vs 8.0 days; p = 0.1910). Mean direct costs excluding study medication were US dollars 5365 for patients receiving zoledronic acid and US dollars 5689 for patients receiving placebo, a difference of US dollars 324 (95% CI US dollars 1781 to US dollars 1146). The global average cost of zoledronic acid plus its administration during the trial was US dollars 5677 (US dollars 450 per dose). The nominal cost per skeletal complication avoided was US dollars 112300 (95% CI US dollars 6900 to US dollars 48700) and the cost per additional patient free of skeletal complications was US dollars 51400 (95% CI US dollars 26900 to US dollars 243700). Nominal within-trial cost per quality adjusted life-year was US dollars 159200, which varied widely in sensitivity analyses. CONCLUSIONS: The nominal base case estimate of the cost per quality adjusted life-year for zoledronic acid in the prevention of skeletal complications of prostate cancer is consistent with that of bisphosphonates in breast cancer. However, the cost-effectiveness ratios for bisphosphonates are higher than commonly cited thresholds for conferring cost-effectiveness.

The clinical and cost considerations of bisphosphonates in preventing bone complications in patients with metastatic breast cancer or multiple myeloma.

The bisphosphonates are potent inhibitors of osteoclast-mediated bone resorption and are now the treatment of choice for the management of hypercalcaemia of malignancy. The incidences of hypercalcaemia and other skeletal complications (bone pain, pathological fracture) remain high despite apparent responses to systemic therapy, with particularly high event rates in women with advanced skeletal metastases of breast cancer. This review focuses on studies addressing the long-term efficacy of bisphosphonates to reduce skeletal complications in breast cancer (5 studies) and multiple myeloma (4 studies), with particular reference to controlled studies of sufficient magnitude and duration to allow confidence in the estimation of efficacy. Bearing in mind the limitations of differences in trial design and the lack of direct studies comparing drugs, adequate exposure to a bisphosphonate reduces the incidence of skeletal complication by 30 to 40% in both breast cancer and multiple myeloma. Oral clondronate and intravenous pamidronate have similar efficacy in both diseases, but the duration of efficacy may differ between drugs. Both agents have shown intriguing survival benefits in subgroups of patients. The numbers needed to treat (NNT) to prevent a skeletal complication during one year are lowest in metastatic skeletal disease in breast cancer (NNT < 8) but also compare very favourably with other disease for patients with recurrent nonskeletal breast cancer or multiple myeloma (NNTs 7 to 31 depending on the complication to be prevented). Treatment costs of both breast cancer and multiple myloma are driven by inpatient and outpatient hospital visits so that bisphosphonate regimens should be developed that reduce both. Further research is required to determine if subgroups of patients can be better identified that will derive particular benefit, or perhaps no benefit at all, from bisphosphonate therapy. It is not known whether more potent bisphosphonates will deliver greater clinical efficacy in the future.

[Follow-up of patients with osteosarcoma and Ewing's sarcoma: a retrospective cost-benefit analysis]. / Nachsorge bei Patienten mit Osteosarkom und Ewing-Tumoren. Eine retrospektive Nutzenanalyse.

PURPOSE: Determination of the respective roles of clinical investigation, laboratory tests and various imaging techniques in the follow up of children and adolescents with osteosarcoma and Ewing's sarcoma. METHODS: In a retrospective monocenter analysis, charts of 72 patients with osteosarcoma and 47 patients with Ewing's sarcoma were reviewed with respect to ability of different diagnostic methods to detect the relapse, and correlated outcome. RESULTS: In about 25% of relapses, a second remission could be achieved. The most sensitive methods to detect a potentially curable relapse were clinical investigations and chest x-ray in the case of osteosarcoma and chest x-ray and whole body scintigraphy in the case of Ewing's sarcoma. CONCLUSIONS: The different value of diagnostic methods in the follow-up of the two illnesses may be explained by the different tumor biologies and by distinct therapeutic strategies for the treatment of relapses in the two tumor entities. However, an ongoing evaluation of current follow-up strategies is necessary to take into account new therapeutic developments which may shift the importance of certain imaging techniques.

Pamidronate in prevention of bone complications in metastatic breast cancer: a cost-effectiveness analysis.

PURPOSE: Pamidronate is effective in reducing bony complications in patients with metastatic breast cancer who have known osteolytic lesions. However, pamidronate does not increase survival and is associated with additional financial costs and inconvenience. We conducted a post-hoc evaluation of the cost-effectiveness of pamidronate using the results of two randomized trials that evaluated pamidronate 90 mg administered intravenously every month versus placebo. PATIENTS AND METHODS: The trials differed only in the initial systemic therapy administered (hormonal or chemotherapy). Total skeletal related events (SREs), including surgery for pathologic fracture, radiation for fracture or pain control, conservatively treated pathologic fracture, spinal cord compression, or hypercalcemia, were taken directly from the trials. Using a societal perspective, direct health care costs were assigned to each SRE. Each group's monthly survival was equal and was projected to decline using observed median survivals. The cost of pamidronate reflected the average wholesale price of the drug plus infusion. The value or disutility of an adverse event per month was evaluated using a zero value (events avoided) or an assigned one (range, 0.2 to 0.8). RESULTS: The cost of pamidronate therapy exceeded the cost savings from prevented adverse events. The difference between the treated and placebo groups was larger with hormonal systemic therapy than with chemotherapy (additional $7,685 compared with $3,968 per woman). The projected net cost per SRE avoided was $3,940 with chemotherapy and $9,390 with hormonal therapy. The cost-effectiveness ratios were $108,200 with chemotherapy and $305, 300 with hormonal therapy per quality-adjusted year. CONCLUSION: Although pamidronate is effective in preventing a feared, common adverse outcome in metastatic breast cancer, its use is associated with high incremental costs per adverse event avoided. The analysis is most sensitive to the costs of pamidronate and pathologic fractures that were asymptomatic or treated conservatively.

Cost utility analysis of prophylactic pamidronate for the prevention of skeletal related events in patients with advanced breast cancer.

Metastatic bone disease is a common complication of advanced breast cancer. Recently, the results of a large randomized placebo-controlled trial demonstrated that monthly pamidronate infusions reduce the incidence of skeletal related events in these patients. In the current study, a cost-utility analysis was performed from a Canadian health care system perspective to estimate the incremental cost-effectiveness of pamidronate in patients with advanced breast cancer. Twenty-five advanced breast cancer patients who were bisphosphonate naYve and had developed skeletal related complications were identified. Total hospital resource consumption was then collected for all patients. This included direct costs for hospitalization and costs for radiation treatment to bone, surgery, analgesics, blood products, diagnostic imaging, paramedical services and all related physician fees. Treatment preferences were estimated from a random sample of 25 women selected from the general population and 25 female health care professionals, using the Time Trade-Off technique. The outcomes were then generated through a decision-analytic model. Over a 12-month period, total costs in the pamidronate arm were approximately 44% higher than those in the no-treatment alternative (Can$ 9,180 vs Can$ 6,380). When treatment preferences were incorporated into the analysis, the results of the decision model revealed an incremental pamidronate cost of $18,700 per quality-adjusted life year gained. The results of the sensitivity analysis suggested that this estimate was dependent on the cost of treating skeletal related events, particularly bone surgery. Even though pamidronate has a high drug acquisition cost, the results of the cost-utility analysis suggest that this agent does provide patients with a substantial quality-adjusted survival benefit at a reasonable cost to the Canadian health care system.

[Magnetic resonance imaging in screening for bone metastasis? A prospective comparison with bone scintigraphy]. / Kernspintomographie zum Metastasen-Screening? Ein prospektiver Vergleich mit der Skelettszintigraphie.

To define the value of magnetic resonance imaging (MRI) in screening for bone metastases (BM) compared to bone scintigraphy (BSc) 102 patients with tumours with frequent BM were examined also by MRI of spine, pelvis, femora, and proximal tibiae. All patients had normal BSc and 96 (94%) normal MRI. Only 6% of the patients had focal abnormalities within the bone marrow. This indicates that there is a 94% probability of absence of BM if BSc is normal. Therefore, BSc should currently remain the method of choice for screening for BM. Despite MRI is sensitive and specific, with the common technique up to now it should not be used instead of BSc in screening because of costs, duration, and lack of whole body examination. MRI is a valuable adjunct in equivocal findings in BSc with negative results on radiographs.