A comprehensive value-based method for new nuclear medical service pricing: with case study of radium [223Ra] bone metastases treatment.

IMPORTANCE: Innovative nuclear medicine services offer substantial clinical value to patients. However, these advancements often come with high costs. Traditional payment strategies do not incentivize medical institutes to provide new services nor determine the fair price for payers. A shift towards a value-based pricing strategy is imperative to address these challenges. Such a strategy would reconcile the cost of innovation with incentives, foster transparent allocation of healthcare resources, and expedite the accessibility of essential medical services. OBJECTIVE: This study aims to develop and present a comprehensive, value-based pricing model for new nuclear medicine services, illustrated explicitly through a case study of the radium [223Ra] treatment for bone metastases. In constructing the pricing model, we have considered three primary value determinants: the cost of the new service, associated service risk, and the difficulty of the service provision. Our research can help healthcare leaders design an evidence-based Fee-For-Service (FFS) payment reference pricing with nuclear medicine services and price adjustments. DESIGN, SETTING AND PARTICIPANTS: This multi-center study was conducted from March 2021 to February 2022 (including consultation meetings) and employed both qualitative and quantitative methodologies. We organized focus group consultations with physicians from nuclear medicine departments in Beijing, Chongqing, Guangzhou, and Shanghai to standardize the treatment process for radium [223Ra] bone metastases. We used a specially designed 'Radium Nuclide [223Ra] Bone Metastasis Data Collection Form' to gather nationwide resource consumption data to extract information from local databases. Four interviews with groups of experts were conducted to determine the add-up ratio, based on service risk and difficulty. The study organized consultation meeting with key stakeholders, including policymakers, service providers, clinical researchers, and health economists, to finalize the pricing equation and the pricing result of radium [223Ra] bone metastases service. MAIN OUTCOMES AND MEASURES: We developed and detailed a pricing equation tailored for innovative services in the nuclear medicine department, illustrating its application through a step-by-step guide. A standardized service process was established to ensure consistency and accuracy. Adhering to best practice guidelines for health cost data analysis, we emphasized the importance of cross-validation of data, where validated data demonstrated less variation. However, it required a more advanced health information system to manage and analyze the data inputs effectively. RESULTS: The standardized service of radium [223Ra] bone metastases includes: pre-injection assessment, treatment plan, administration, post-administration monitoring, waste disposal and monitoring. The average duration for each stage is 104 min, 39 min, 25 min, 72 min and 56 min. A standardized monetary value for medical consumables is 54.94 yuan ($7.6), and the standardised monetary value (medical consumables cost plus human input) is 763.68 yuan ($109.9). Applying an agreed value add-up ratio of 1.065, the standardized value is 810.19 yuan ($116.9). Feedback from a consultation meeting with policymakers and health economics researchers indicates a consensus that the pricing equation developed was reasonable and well-grounded. CONCLUSION: This research is the first study in the field of nuclear medicine department pricing methodology. We introduce a comprehensive value-based nuclear medical service pricing method and use radium[223Ra] bone metastases treatment pricing in China as a case study. This study establishes a novel pricing framework and provides practical instructions on its implementation in a real-world healthcare setting.

Treatment outcomes of radium-223 in patients with metastatic castration-resistant prostate cancer: An experience before National Health Insurance reimbursement in Taiwan.

BACKGROUND: Radium-223 (Ra-223), an α-particle-emitting isotope, inhibits bony metastases and prevents patients from skeletal-related events in metastatic castration-resistant prostate cancer (mCRPC). We retrospectively reviewed the treatment response, predictive factors, and adverse events (AEs) of Ra-223 before the National Health Insurance reimbursement in a Taiwanese tertiary institute. METHODS: Patients treated with Ra-223 before January 2019 were enrolled and categorized into progressive disease (PD) and clinical benefits (CB) groups. Laboratory data before and after the treatment were collected, and spider plots concerning percentage changes of alkaline phosphatase (ALP), lactate dehydrogenase (LDH), and prostate-specific antigen (PSA) were prepared and calculated statistically. CB/PD, baseline ALP, LDH, and PSA levels were also adopted as stratification factors for overall survival (OS). RESULTS: Among 19 patients included, 5 (26.3%) and 14 (73.4%) belonged to the PD and CB groups, respectively, with no significant difference observed in the baseline laboratory data. The percentage changes in ALP, LDH, and PSA levels after Ra-223 treatment were statistically significant among the two groups (ALP: CB 54.3 ± 21.4% vs PD 77.6 ± 11.8%, p = 0.044; LDH: CB 88.2 ± 22.8% vs PD 138.3 ± 49.0%, p = 0.046; PSA: CB 97.8 ± 61.7% vs PD 277.0 ± 101.1%, p = 0.002). The trends of LDH between the two groups in spider plot were separated significantly. There were no differences in the AEs between the two groups. CB had a longer median OS than the PD group (20.50 months vs 9.43 months, p = 0.009). Patients with LDH <250 U/L at baseline tended to have longer OS but without significance. CONCLUSION: The CB rate of Ra-223 was 73.7%. No predictive factor for treatment response was obtained from pretreatment data. The mean percentage changes in ALP, LDH, and PSA levels compared with baseline significantly differed between the CB and PD groups, especially the LDH levels. The CB and PD groups showed different OS, with LDH levels exhibiting the potential to predict OS.

S-values for radium-223 and absorbed doses estimates for 223RACL2 using three computational phantoms.

Radium-223 dichloride (223RaCl2), approved by FDA (Food and Drug Administration) in 2013 and in Brazil by ANVISA (Agência Nacional de Vigilância Sanitária) in 2016, offers a new therapeutic option for bone metastases from castration-resistant prostate cancer (CRPC). The advantages of radionuclide therapy for bone metastases include the simultaneous treatment of multiple lesions at the same time. The activity prescription is based on the patient's body weight, disregarding the absorbed dose limit of 2 Gy in the organ at risk: bone marrow. This study focuses on Internal Dosimetry for 223RaCl2 therapy aiming to apply biokinetic models described in the literature to estimate absorbed doses in the organs of interests, especially for the bone marrow. For this purpose, the present paper compares and validates the GATE Monte Carlo simulation with the Radioactive Decay Module (RDM) and calculates a set of S-values for Radium-223 radionuclide using male and female XCAT computational models. Moreover, a comparison of S-values for Radium-223 for three male computational models with different anatomies is also evaluated, Male (standard), Pat1 (lower body weight) and Pat2 (highest body weight). A comprehensive set of S-values was calculated for the Male model, 30 source-regions and 47 target-regions, and for Female model, 30 source-regions and 42 target-regions for Radium-223 and its decay scheme: Radon-219, Polonium-215, Lead-211, Bismuth- 211, Polonium-211 and Thallium-207. The new set of S-values will facilitate absorbed dose calculations for Radium-223 therapy. In addition, Absorbed Dose Evaluation for 223RaCl2 therapy was estimated for three different biodistributions described in the literature within three male computational models. For all biodistributions, the Pat2 phantom has a greatest absorbed dose within the red marrow, when compared with Male and Pat1.

A qualitative research study in Japan investigating patients' experience with metastatic castration-resistant prostate cancer: from diagnosis to decision for Ra-223 treatment.

Aim: This qualitative study aimed to reveal symptoms and impacts among bone metastatic castration-resistant prostate cancer (or mCRPC) Japanese patients, prior to Radium-223 (Ra-223) treatment. Materials & Methods: Twenty-three mCRPC patients designated to receive Ra-223 and three treating physicians (Ra-223 prescribers) in Japan, were interviewed. All interview data were assessed for concept frequency, themes and saturation. Results: Forty-five percent of the patients (mean age: 75.8 years) were symptomatic at the time of enrollment. Interviews with all patients revealed 47 mCRPC symptoms, including back pain and bone-specific pain, and 45 life impacts, including worry about disease progression and the impact on daily, physical activities. Conclusion: The symptoms and impacts of living with mCRPC and the associated burden of bone metastasis and skeletal-related symptoms are varied and are important considerations for treatment.

Lay abstract Aim: This study looked at symptoms and impacts among patients with a type of prostate cancer called metastatic castration-resistant prostate cancer. This cancer has spread to other parts of the body including patients' bones. Patients' prostate-specific antigen levels continue to rise despite surgical or medical treatment and their doctors decided the next best treatment is Radium-223 (Ra-223), a radiopharmaceutical therapy. Materials & methods: Twenty-three metastatic castration-resistant prostate cancer patients designated to receive Ra-223 and three treating physicians (Ra-223 prescribers) in Japan, were interviewed. All interview data were assessed for the number of times some words or themes are mentioned by the patients. Results: Ten of the 23 patients (average age of 76 years) had symptoms when the study started. Interviewed patients talked about symptoms including back pain and pain in their bones, and how their cancer caused them to worry about their physical activities and disease progression. Conclusion: The symptoms impact on patients' daily living and the burden of bone metastasis and bone-related symptoms are varied and are important considerations for treatment.

Modeling bystander effects that cause growth delay of breast cancer xenografts in bone marrow of mice treated with radium-223.

RATIONALE: The role of radiation-induced bystander effects in cancer therapy with alpha-particle emitting radiopharmaceuticals remains unclear. With renewed interest in using alpha-particle emitters to sterilize disseminated tumor cells, micrometastases, and tumors, a better understanding of the direct effects of alpha particles and the contribution of the bystander responses they induce is needed to refine dosimetric models that help predict clinical benefit. Accordingly, this work models and quantifies the relative importance of direct effects (DE) and bystander effects (BE) in the growth delay of human breast cancer xenografts observed previously in the tibiae of mice treated with 223RaCl2. METHODS: A computational model of MDA-MB-231 and MCF-7 human breast cancer xenografts in the tibial bone marrow of mice administered 223RaCl2 was created. A Monte Carlo radiation transport simulation was performed to assess individual cell absorbed doses. The responses of the breast cancer cells to direct alpha particle irradiation and gamma irradiation were needed as input data for the model and were determined experimentally using a colony-forming assay and compared to the responses of preosteoblast MC3T3-E1 and osteocyte-like MLO-Y4 bone cells. Using these data, a scheme was devised to simulate the dynamic proliferation of the tumors in vivo, including DE and BE propagated from the irradiated cells. The parameters of the scheme were estimated semi-empirically to fit experimental tumor growth. RESULTS: A robust BE component, in addition to a much smaller DE component, was required to simulate the in vivo tumor proliferation. We also found that the relative biological effectiveness (RBE) for cell killing by alpha particle radiation was greater for the bone cells than the tumor cells. CONCLUSION: This modeling study demonstrates that DE of radiation alone cannot explain experimental observations of 223RaCl2-induced growth delay of human breast cancer xenografts. Furthermore, while the mechanisms underlying BE remain unclear, the addition of a BE component to the model is necessary to provide an accurate prediction of the growth delay. More complex models are needed to further comprehend the extent and complexity of 223RaCl2-induced BE.

A cell-based dosimetry model for radium-223 dichloride therapy using bone micro-CT images and GATE simulations.

Dosimetry at the cellular level has outperformed macrodosimetry in terms of agreement with toxicity effects in clinical studies. This fact has encouraged dosimetry studies aiming to quantify the absorbed doses needed to reach radiotoxicity at the cellular level and to inform recommendations on the administration of radium-223. The aim of this work is to qualitatively and quantitatively evaluate the absorbed doses of radium-223 and the interactions of the doses at the cellular level. The analysis was performed by Monte Carlo simulations in GATE using micro-CT image of a mouse. Two physics lists available in the GATE code were tested. The influence of single and multiple scattering models on the absorbed dose distribution and number of particle hits was also studied. In addition, the fuzzy c-means clustering method was used for data segmentation. The segmentation method was suitable for these analyses, particularly given that it was unsupervised. There was no significant difference in the estimated absorbed dose between the two proposed physics lists. The absorbed dose values were not significantly influenced by scattering, although single scattering resulted in twice as many interactions as multiple scattering. The absorbed dose histogram at the voxel level shows heterogeneous absorbed dose values within each shell, but the observations from the graph of the medians were comparable to those in the literature. The interaction histogram indicates 104 events, although some voxels had no interactions with alpha particles. However, the voxels did not show absorbed doses capable of deterministic effects in the deepest part of the bone marrow. The absorbed dose distribution in images of mouse trabecular bone was compatible with simple geometric models, with absorbed doses capable of deterministic effects near the bone surface. The interaction distributions need to be correlated with in vivo studies for better interpretation.

Dose-Dependent Growth Delay of Breast Cancer Xenografts in the Bone Marrow of Mice Treated with 223Ra: The Role of Bystander Effects and Their Potential for Therapy.

The role of radiation-induced bystander effects in radiation therapy remains unclear. With renewed interest in therapy with α-particle emitters, and their potential for sterilizing disseminated tumor cells (DTCs), it is critical to determine the contribution of bystander effects to the overall response so they can be leveraged for maximum clinical benefit. Methods: Female Foxn1nu athymic nude mice were administered 0, 50, or 600 kBq/kg 223RaCl2 to create bystander conditions. At 24 hours after administration, MDA-MB-231 or MCF-7 human breast cancer cells expressing luciferase were injected into the tibial marrow compartment. Tumor burden was tracked weekly via bioluminescence. Results: The MDA-MB-231 xenografts were observed to have a 10-day growth delay in the 600 kBq/kg treatment group only. In contrast, MCF-7 cells had 7- and 65-day growth delays in the 50 and 600 kBq/kg groups, respectively. Histologic imaging of the tibial marrow compartment, α-camera imaging, and Monte Carlo dosimetry modeling revealed DTCs both within and beyond the range of the α-particles emitted from 223Ra in bone for both MCF-7 and MDA-MB-231 cells. Conclusion: Taken together, these results support the participation of 223Ra-induced antiproliferative/cytotoxic bystander effects in delayed growth of DTC xenografts. They indicate that the delay depends on the injected activity and therefore is dose-dependent. They suggest using 223RaCl2 as an adjuvant treatment for select patients at early stages of breast cancer.

Assessment of the radiation absorbed dose produced by 177Lu-iPSMA, 225Ac-iPSMA and 223RaCl2 to prostate cancer cell nuclei in a bone microenvironment model.

This research aimed to assess the radiation absorbed dose produced by 177Lu-iPSMA (177Lu-prostate specific membrane antigen inhibitor), 225Ac-iPSMA and 223RaCl2 to prostate cancer cell nuclei in a simplified model of bone by using an experimental in-vitro prostate cancer LNCaP cell biokinetic study and Monte Carlo simulation with the MCNPX code. Results showed that 225Ac-iPSMA releases a nine hundred-fold radiation dose greater than 177Lu-iPSMA and 14 times more than 223RaCl2 per unit of activity retained in bone. 225Ac-iPSMA could be the best option for treatment of bone metastases in prostate cancer.

Comparison of microdosimetry-based absorbed doses to control tumours and clinically obtained tumour absorbed doses in treatments with 223Ra.

We performed Monte Carlo simulations in order to determine by means of microdosimetry calculations the average number of hits to the cell nucleus required to reach a tumour control probability (TCP) of 0.9, [Formula: see text], for the source geometry of a nucleus embedded in a homogeneous distribution of 223Ra atoms. From the results obtained and following the MIRD methodology, we determined the values of lesion absorbed doses needed to reach a TCP of 0.9, [Formula: see text], for different values of mass density, cell radiosensitivity, nucleus radius and lesion volume. The greatest variation of those absorbed doses occurred with cell radiosensitivity and no dependence was found on mass density. The source geometry used was chosen because we aimed to compare the values of [Formula: see text] with the lesion absorbed doses obtained from image-based macrodosimetry in treatments of metastatic castration-resistant prostate cancer with 223Ra which were obtained assuming a homogeneous distribution of 223Ra atoms within the lesion. In a comparison with a study including 29 lesions, results showed that even for the case of the most radiosensitive cells simulated, 45% of the lesions treated following a schedule of two cycles of 110 kBq kg-1 body mass would receive absorbed doses below the values of [Formula: see text] determined in this study.

223Ra Therapy of Advanced Metastatic Castration-Resistant Prostate Cancer: Quantitative Assessment of Skeletal Tumor Burden for Prognostication of Clinical Outcome and Hematologic Toxicity.

The aim of this study was to investigate the prognostic value of the quantitative assessment of skeletal tumor burden on bone scintigraphy (Bone Scan Index [BSI]) in patients who have advanced metastatic castration-resistant prostate cancer (mCRPC) and are receiving 223RaCl2 We hypothesized that the BSI can serve as a prognostic biomarker of overall survival (OS) and hematologic toxicity and as a tool for response assessment in patients with mCRPC treated with 223RaCl2Methods: This study was a retrospective investigation of a Danish cohort of mCRPC patients who received 223RaCl2 therapy between March 2014 and October 2015 and for whom baseline bone scintigraphy was available. Bone scintigraphy studies were reviewed and graded according to the extent of disease. Furthermore, an automated BSI (EXINI BoneBSI) was obtained for baseline scintigraphy studies and follow-up scans after 3 cycles as well as at the end of therapy. Clinical outcomes were OS and occurrence of hematologic toxicity of grades 2-5. Associations between the BSI and clinical outcomes were investigated in multivariate regression models including the visual assessment of bone scintigraphy and other relevant covariates. Results: A total of 88 patients were included. The median number of completed 223RaCl2 cycles was 4, and 27 patients (31%) completed 6 cycles. The BSI was significantly associated with OS in the multivariate analysis; the median OS for patients with a BSI of greater than 5 was 8.2 mo, and the median OS for patients with a BSI of less than or equal to 5 was 15.0 mo (hazard ratio, 2.65 [95% confidence interval, 1.5-4.71]; P = 0.001). Likewise, the baseline BSI was prognostic for the occurrence of hematologic toxicity; patients with a BSI of greater than 5 had an odds ratio of 3.02 (95% confidence interval, 1.2-7.8; P = 0.02) for toxicity. The BSI declined during therapy in 44% of the patients who completed 3 cycles of 223RaCl2 (n = 52) and in 84% of the patients after the end of therapy (n = 32). There was no significant association between a change in the BSI during therapy and OS. Conclusion: The BSI is a promising biomarker for prognostication of OS and hematologic toxicity in late-stage mCRPC patients receiving 223RaCl2 Further prospective studies are needed to evaluate the potential of the BSI for response assessment in 223RaCl2 therapy.

Evaluation of bone metastatic burden by bone SPECT/CT in metastatic prostate cancer patients: defining threshold value for total bone uptake and assessment in radium-223 treated patients.

OBJECTIVES: To establish a new three-dimensional quantitative evaluation method for bone metastasis, we applied bone single photon emission tomography with computed tomography (SPECT/CT). The total bone uptake (TBU), which measures active bone metastatic burden, was calculated as the sum of [mean uptake obtained as standardized uptake value (SUV) above a cut-off level] × (the volume of the lesion) in the trunk using bone SPECT/CT. We studied the threshold value and utility of TBU in prostate cancer patients treated with radium-223 (Ra-223) therapy. METHODS: To establish the threshold value of TBU, we compared bone metastatic and non-metastatic regions in 61 prostate cancer patients with bone metastasis and 69 without. Five fixed sites in each patient were selected as evaluation points and divided into bone metastatic and non-metastatic sites. Sensitivity and specificity analysis was applied to establish the threshold level. Using the obtained threshold value, we then calculated the TBU in nine prostate cancer patients who received Ra-223 therapy, and compared the results with the bone scan index (BSI) by BONENAVI® and visual evaluation of bone scintigraphy. RESULTS: Uptake was significantly lower in non-metastatic sites in patients with bone metastasis than in patients without metastasis. Sensitivity and specificity analysis revealed SUV = 7.0 as the threshold level. There was a discrepancy between TBU and BSI change in two of the nine patients, in whom TBU change correlated with visual judgement, but BSI change did not. In two patients, BSI was nearly 0 throughout the course, but the TBU was positive and changed, although the change was not large. These results suggest that TBU may be more accurate and sensitive than BSI for quantitative evaluation of active bone metastatic burden. CONCLUSION: We established a threshold value (SUV > 7.0) for three-dimensional TBU for evaluating active bone metastatic burden in prostate cancer patients using bone SPECT/CT. Despite the small number of patients, we expect the change in TBU could be more accurate and sensitive than the change in BSI among patients who received Ra-223.

Detection and quantification of 223Ra uptake in bone metastases of patients with castration resistant prostate carcinoma, with the aim of determining the absorbed dose in the metastases. / Detección y cuantificación de la captación de 223Ra en metástasis óseas en pacientes con carcinoma de próstata resistente a la castración con vistas a la determinación de la dosis absorbida en dichas metástasis.

PURPOSES: To obtain the necessary acquisition and calibration parameters in order to evaluate the possibility of detecting and quantifying 223Ra uptake in bone metastases of patients treated for castration resistant prostate carcinoma. Furthermore, in the cases in which the activity can be quantified, to determine the absorbed dose. MATERIAL AND METHODS: Acquisitions from a Petri dish filled with 223Ra were performed in the gamma camera. Monte Carlo simulations were also performed to study the partial volume effect. Formulae to obtain the detection and quantification limits of 223Ra uptake were applied to planar images of two patients 7 days post-administration of 55kBq/kg of 223Ra. In order to locate the lesions in advance, whole-body scans and SPECT/CT images were acquired after injecting 99mTc-HDP. RESULTS: The optimal energy window was found to be at 82keV with a medium-energy collimator MEGP. Of the lesions found in the patients, only those that had been detected in both the AP and PA projections could be quantified. These lesions were those which had shown a higher 99mTc-HDP uptake. The estimated values of absorbed doses ranged between 0.7Gy and 7.8Gy. CONCLUSIONS: Of the lesions that can be detected, it is not possible to quantify the activity uptake in some of them, which means that the absorbed dose cannot be determined either. This does not mean that the absorbed dose in these lesions can be regarded as negligible.

Dutch Economic Value of Radium-223 in Metastatic Castration-Resistant Prostate Cancer.

BACKGROUND: The treatment of metastatic castration-resistant prostate cancer has changed with the introduction of radium-223, cabazitaxel, abiraterone and enzalutamide. To assess value for money, their cost effectiveness in patients with metastatic castration-resistant prostate cancer previously treated with docetaxel from the Dutch societal perspective was investigated. METHODS: A cost-effectiveness analysis was conducted using efficacy, symptomatic skeletal-related event and safety data obtained from indirect treatment comparisons. Missing skeletal-related event data for cabazitaxel were conservatively assumed to be identical to radium-223. A Markov model combined these clinical inputs with Dutch-specific resource use and costs for metastatic castration-resistant prostate cancer treatment from a societal perspective. Total quality-adjusted life-years and costs in 2017 euros were calculated over a 5-year (lifetime) time horizon. RESULTS: Radium-223 resulted in €6092 and €4465 lower costs and 0.02 and 0.01 higher quality-adjusted life-years compared with abiraterone and cabazitaxel, respectively, demonstrating dominance of radium-223. Sensitivity analyses reveal a 64% (54%) chance of radium-223 being cost effective compared with abiraterone (cabazitaxel) at the informal €80,000 willingness-to-pay threshold. Compared with enzalutamide, radium-223 resulted in slightly lower quality-adjusted life-years (-0.06) and €7390 lower costs, revealing a 61% chance of radium-223 being cost effective compared with enzalutamide. The lower costs of radium-223 compared with abiraterone and enzalutamide are driven by lower drug costs and prevention of expensive skeletal-related events. Compared with cabazitaxel, the lower costs of radium-223 are driven by lower costs of the drug, administration and adverse events. CONCLUSION: Radium-223 may be a less costly treatment strategy offering similar gains in health benefits compared with abiraterone, cabazitaxel and enzalutamide in patients with metastatic castration-resistant prostate cancer previously treated with docetaxel from the Dutch societal perspective.

Response Assessment of 223Ra Treatment: Should a Fluorocholine PET/CT Be Performed?

We present 3 cases of patients with castration-resistant prostate cancer and bone metastases treated with Ra, belonging to our prospective and multicenter ChoPET-Rad study. All patients underwent clinical, hematological, and biochemical monitoring between each Ra administration. Initial and follow-up F-fluorocholine PET/CT and Tc-biphosphonate bone scintigraphy were performed previously and after the third Ra administration. Both techniques correctly established the response to treatment, in agreement to the biochemical response, although differences in the disease expression (concordant and discordant patterns) were found because of the different radiotracer biodistribution and molecular information derived from them.

Radium-223: Insight and Perspectives in Bone-metastatic Castration-resistant Prostate Cancer.

223Ra prolongs overall survival in symptomatic patients affected by multiple bone-metastatic castration-resistant prostatic cancer, without visceral or nodal involvement. However, many questions remain about its mechanisms of action, and its use in clinical practice is still unresolved. First of all, what is the main target of alpha-particle emission, that is, in what way does it influences the tumor microenvironment? When is the best timing in the course of the disease, extending its use to asymptomatic low-volume or even to the micrometastatic phase? What are suitable biomarkers to be employed as prognostic factors and response indicators? Which associations with other drugs and their sequence can offer the best results, and is their effect additive or synergistic? Ultimately, in the current climate of spending review, what is the optimal cost and benefit ratio regarding available treatments? In this review, we tried to answer these questions by analyzing the available scientific literature.

Budget Impact of Enzalutamide for Chemotherapy-Naïve Metastatic Castration-Resistant Prostate Cancer.

BACKGROUND: Prostate cancer is expected to account for approximately one quarter of all new diagnoses of cancer in American men in 2015. The cost of prostate cancer care is expected to reach $15.1 billion by the year 2020, up from $11.9 billion in 2010. Given the high burden of prostate cancer, health care payers are interested in quantifying the potential budget impact of new therapies. OBJECTIVE: To estimate the budget impact of enzalutamide for the treatment of chemotherapy-naïve metastatic castration-resistant prostate cancer (mCRPC) from a U.S. payer perspective. METHODS: A model was developed to assess the budget impact of enzalutamide for treatment of chemotherapy-naïve mCRPC patients in a hypothetical 1-million-member U.S. health plan over a 1-year time horizon. Comparators included abiraterone acetate, sipuleucel-T, radium Ra 223 dichloride, and docetaxel. Epidemiologic data, including National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) incidence rates, were used to estimate the number of chemotherapy-naïve mCRPC patients. Dosing, administration, duration of therapy, and adverse event rates were based on package inserts and pivotal studies. Drug costs were obtained from RED BOOK and Centers for Medicare & Medicaid Services (CMS) average sales price pricing files, costs of administration and monitoring from the CMS physician fee schedule, and adverse events from the Agency for Healthcare Research and Quality Healthcare Cost and Utilization Project and published literature. Market shares were estimated for each comparator before and after adoption of enzalutamide. The incremental aggregate budget impact, per patient per year (PPPY), per patient per month (PPPM), and per member per month (PMPM), was calculated. One-way sensitivity analyses were performed. RESULTS: In a population of 115 chemotherapy-naïve mCRPC patients, adopting enzalutamide had an annual incremental budget impact of $510,641 ($4,426 PPPY, $369 PPPM, and $0.04 PMPM). Results were most sensitive to enzalutamide drug cost, size of the chemotherapy-naïve mCRPC patient population, and enzalutamide adoption rate. CONCLUSIONS: Results indicate a modest 1-year budget impact of adopting enzalutamide for chemotherapy-naïve mCRPC patients, partly because of the cost offset of a moderate incidence of adverse events and lack of additional required monitoring.

Health Economics and Radium-223 (Xofigo®) in the Treatment of Metastatic Castration-Resistant Prostate Cancer (mCRPC): A Case History and a Systematic Review of the Literature.

OBJECTIVES: Prostate cancer (PC) is the most common cancer in Western countries. Recent advances in the treatment of metastatic castration resistant prostate cancer (mCRPC) have caused significant pressure on health care budgets. We aimed to exemplify this dilemma presenting an example, radium-223 (Xofigo®), and review the literature. METHODS: A 74-year-old man diagnosed with mCRPC was referred to our department in October 2014 for radium-223 therapy. We faced the following dilemma: is radium-223 standard therapy? Is it cost-effective? Medline was searched employing the following search criteria: "radium-223", "alpharadin", "Xofigo" and "prostate". Exclusion and inclusion criteria were applied. Guidelines and cost-effectiveness analyses were focused. We also searched the websites of ASCO, ESMO and ISPOR. The web was searched, using Yahoo and Google search engines, for Health Technology Assessments (HTAs). RESULTS: 181 publications were identified in the Medline database. Only four studies included the word "cost", three "economics" and none "budget" in heading or abstract. None of the publications were thorough of cost analysis (cost-effectiveness, cost-utility, cost-minimizing or cost-of-illness analysis). Six HTAs and eight national guidelines were identified. The cost per quality adjusted life years was indicated €80.000-94,000. HTAs concluded reimbursement being not recommendable or no ultimate statement could be made. One pointed towards a limited use with caution. CONCLUSION: Guidelines were based on data from randomized clinical trials (RCTs). Health economics was not considered when guidelines were made. Most HTAs concluded this therapy not cost-effective or there was insufficient data for final conclusions. Licensing and reimbursement processes should be run simultaneously.

Stochastic simulation of radium-223 dichloride therapy at the sub-cellular level.

Radium-223 dichloride ((223)Ra) is an alpha particle emitter and a natural bone-seeking radionuclide that is currently used for treating osteoblastic bone metastases associated with prostate cancer. The stochastic nature of alpha emission, hits and energy deposition poses some challenges for estimating radiation damage. In this paper we investigate the distribution of hits to cells by multiple alpha particles corresponding to a typical clinically delivered dose using a Monte Carlo model to simulate the stochastic effects. The number of hits and dose deposition were recorded in the cytoplasm and nucleus of each cell. Alpha particle tracks were also visualized. We found that the stochastic variation in dose deposited in cell nuclei ([Formula: see text]40%) can be attributed in part to the variation in LET with pathlength. We also found that [Formula: see text]18% of cell nuclei receive less than one sigma below the average dose per cell ([Formula: see text]15.4 Gy). One possible implication of this is that the efficacy of cell kill in alpha particle therapy need not rely solely on ionization clustering on DNA but possibly also on indirect DNA damage through the production of free radicals and ensuing intracellular signaling.

Radiation Dose and Hazard Assessment of Potential Contamination Events During Use of 223Ra Dichloride in Radionuclide Therapy.

An analysis is presented of the possible dosimetric consequences of various potential contamination events involving 223Ra dichloride (Xofigo), the FDA-approved therapeutic agent used in the treatment of bone metastases in patients with castration-resistant prostate cancer. Three exposure scenarios are considered: inhalation dose to an individual due to the hypothetical inhalation of 219Rn and its progeny assumed to be released into the air from a liquid spill on the floor, external dose from direct photon exposure of an individual assigned to clean up a spill, and skin dose to an individual should the liquid material come into contact with their skin. Doses from the first two scenarios were very small; 2.8 × 10(-3) mSv and 8.1 × 10(-4) mSv, respectively. Using extremely conservative assumptions, the skin dose was estimated to be 72 mSv; in a realistic scenario, this dose would likely be an order of magnitude or more lower. These doses are very small compared to regulatory limits, and good health physics practices likely to be employed in such incidents would lower them still further. The authors conclude that the medical use of Xofigo does not pose any significant radiation safety issue with respect to potential contamination events, even if multiple incidents might occur during the course of a year, since all worst-case potential contamination events considered in this study will not result in significant radiation exposures to workers.