Costs of radium-223 and the pharmacy preparation 177Lu-PSMA-I&T for metastatic castration-resistant prostate cancer in Dutch hospitals.

OBJECTIVE: The radiopharmaceuticals radium-223 and the pharmacy preparation 177Lu-PSMA-I&T are reimbursed in the Netherlands for metastatic castration-resistant prostate cancer (mCRPC) treatment. Although shown to be life-prolonging in patients with mCRPC, the treatment procedures associated with these radiopharmaceuticals can be challenging for both patients and hospitals. This study investigates the costs of mCRPC treatment in Dutch hospitals for currently reimbursed radiopharmaceuticals with a demonstrated overall survival benefit. METHODS: A cost model that calculated the direct medical per-patient costs of radium-223 and 177Lu-PSMA-I&T was developed, following clinical trial regimens. The model considered six 4-weekly administrations (i.e. ALSYMPCA regimen) of radium-223. Regarding 177Lu-PSMA-I&T, the model used both the VISION regimen (i.e. five 6-weekly administrations) and the SPLASH regimen (i.e. four 8-weekly administrations). Based on health insurance claims, we also estimated the coverage a hospital would receive for providing treatment. No fitting health insurance claim for 177Lu-PSMA-I&T is currently available; therefore, we calculated a break-even value for a potential health insurance claim that would exactly counterbalance the per-patient costs and coverage. RESULTS: Radium-223 administration is associated with per-patient costs of €30,905, and these costs are fully covered by the coverage a hospital receives. The per-patient costs of 177Lu-PSMA-I&T range between €35,866 and €47,546 per administration period, depending on the regimen. Current healthcare insurance claims do not fully cover the costs of providing 177Lu-PSMA-I&T: hospitals must pay €4,414-€4,922 for each patient out of their own budget. The break-even value for the potential insurance claim covering 177Lu-PSMA-I&T administration with a VISION (SPLASH) regimen is €1,073 (€1,215). CONCLUSION: This study shows that, without consideration of the treatment effect, radium-223 treatment for mCRPC leads to lower per-patient costs than treatment with 177Lu-PSMA-I&T. The detailed overview of the costs associated with radiopharmaceutical treatment provided by this study is relevant for both hospitals and healthcare insurers.

Prostate cancer is the most common form of cancer among men in the Netherlands, and its treatment is increasingly expensive. Given the limited hospital budget, it is important to consider costs in the treatment of prostate cancer. Radiopharmaceuticals are one of the multiple treatment options for metastatic prostate cancer. The current study looked at the costs of two radiopharmaceuticals, radium-223 and 177Lu-PSMA-I&T, while using multiple treatment regimens.The cost of radium-223 treatment is €30,905 per patient and is fully covered by insurance. The cost of 177Lu-PSMA-I&T treatment ranges from €35,866 to €47,546 per patient and is partially paid from the budget of the hospitals considering current reimbursement amounts. The study shows that, without consideration of the treatment effects, radium-223 treatment for prostate cancer leads to lower per-patient costs than treatment with 177Lu-PSMA-I&T. The detailed overview of the costs associated with radiopharmaceutical treatment provided by this study is relevant for both hospitals and healthcare insurers to manage prostate cancer treatment costs.

Exploratory Analysis of the Economically Justifiable Price of a Hypothetical RSV Vaccine for Older Adults in the Netherlands and the United Kingdom.

BACKGROUND: In older adults, the burden of respiratory syncytial virus (RSV) resembles that of influenza and may even be considered worse due to the lack of preventive interventions. This study was performed to identify the available literature on RSV infection in older adults, and to provide updated exploratory results of the cost-effectiveness of a hypothetical RSV vaccine in the Netherlands and the United Kingdom. METHODS: A literature search was performed in Medline and EMBASE on 11 November 2019, which served as input for a static decision-tree model that was used to estimate the EJP, for an RSV vaccine applying different willingness-to-pay (WTP) thresholds. WTP thresholds applied were €20 000 and €50 000 per quality-adjusted life-year for the Netherlands, and £20 000 and £30 000 per quality-adjusted life-year for the United Kingdom. Analyses were-in line with country-specific guidelines-conducted from a societal perspective for the Netherlands and a third-party payer perspective for the United Kingdom. The robustness of the cost-effectiveness results was tested in sensitivity analysis. RESULTS: After screening the literature, 3 studies for the Netherlands and 6 for the United Kingdom remained to populate the country-specific models. In the base case analysis for the Netherlands (mean RSV incidence, 3.32%), justifiable vaccine prices of €16.38 and €50.03 were found, based on applying the lower and higher WTP thresholds, respectively. Similarly, for the United Kingdom (mean incidence, 7.13%), vaccine prices of £72.29 and £109.74 were found, respectively. CONCLUSION: RSV vaccination may well be cost-effective in both the Netherlands and the United Kingdom, depending on the exact RSV incidence, vaccine effectiveness and price. However, sensitivity analysis showed that the results were robust based on varying the different parameter estimates and assumptions. With RSV vaccines reaching the final stages of development, a strong need exists for cost-effectiveness studies to understand economically justifiable pricing of the vaccine.

Are PROMs sufficient to record late outcome of breast cancer patients treated with radiotherapy? A comparison between patient and clinician reported outcome through an outpatient clinic after 10years of follow up.

AIM: To investigate whether breast cancer patients' visits to an outpatient clinic for late outcome (OCLO) can be replaced by patient reported outcome measures (PROMs), by comparing late toxicity scored at the OCLO with PROMs. METHODS: All breast cancer patients treated in our institute with adjuvant radiotherapy 10-11years ago were invited to visit the OCLO, and for filling out PROM-questionnaires. Concordance rate between PROMs and OCLO-reported outcome and the percentage of patients with ≥2 degrees difference in toxicity level between patient and clinician was assessed. RESULTS: 686 of 1029 patients were still alive. 249 patients visited the OCLO, and 341 patients returned a questionnaire. At a group level, patients reported higher toxicity rates than clinicians. The mean concordance for individual patients was 58% between patient and clinician reported outcome. In 2.8%, the clinician reported ≥2 degrees higher toxicity than the patients did, whereas in 6.8% patients reported ≥2 degrees higher toxicity. CONCLUSION: PROMs do not underestimate late side-effects at a group level. In spite of the low concordance rate, PROMS can be used to identify patients who experience a heavy burden of side-effects, requiring specific attention. Therefore, patients can be spared a visit to the OCLO.

Treatment preferences and involvement in treatment decision making of patients with endometrial cancer and clinicians.

BACKGROUND: Vaginal brachytherapy (VBT) in high-intermediate-risk endometrial cancer (EC) provides a significant reduction in the risk of local cancer recurrence, but without survival benefit and with increased mucosal atrophy. Five-year local control is estimated to be similar for VBT and a watchful waiting policy (WWP), in which patients receive VBT combined with external radiation in case of a recurrence. Our aim was to assess treatment preferences of EC patients and clinicians regarding VBT and WWP, and to evaluate their preferred and perceived involvement in treatment decision making. METHODS: Interviews were held with 95 treated EC patients. The treatment trade-off method was used to assess the minimally desired benefit from VBT in local control. Patients' preferred and perceived involvement in decision making were assessed using a questionnaire. Seventy-seven clinicians completed a questionnaire assessing their minimally desired benefit and preferred involvement in decision making. RESULTS: Minimally desired benefit of VBT was significantly lower for patients than for clinicians (median=0 vs 8%, P<0.001), for irradiated than for non-irradiated patients (median=0 vs 6.5%, P<0.001), and for radiation oncologists than for gynaecologists (median=4 vs 13%, P<0.001). Substantial variation existed within the groups of patients and clinicians. Participants preferred the patient and clinician to share in the decision about VBT. However, irradiated patients indicated low perceived involvement in actual treatment decision making. CONCLUSIONS: We found variations between and within patients and clinicians in minimally desired benefit from VBT. However, the recurrence risk at which patients preferred VBT was low. Our results showed that patients consider active participation in decision making essential.

Excess mortality in two-year rodent carcinogenicity studies.

This paper considers the impacts of various patterns of differential or excess mortality on the biological and statistical interpretation of 2-year rodent carcinogenicity studies. It provides suggestions on experimental design that are intended to maximize the value of such studies for carcinogenic risk assessment. Specifically, it recommends dose reduction, possibly to the level of dose cessation, when biologically feasible and considers the merits of termination of the entire study as alternatives to the commonly employed strategy of terminating particular dose groups. It then recommends statistical analysis modifications that are appropriate when these suggestions on experimental design are adopted. One of the recommended modifications is a new statistical test to determine whether a dose group exceeds the maximum tolerated dose (MTD) on the basis of mortality. While the authors provide recommendations for the most commonly occurring exigencies, they acknowledge the need for and strongly support the practice of active engagement of the appropriate regulatory agency, e.g., the FDA, prior to any action.

Historical vehicle and positive control micronucleus data in mice and rats.

The rodent bone marrow micronucleus (MN) assay has been widely used as part of an in vivo genotoxicity test battery in product safety evaluation. In this assay, the historical vehicle and positive control data form an important component in the assay performance and data interpretation. Also, in light of minimizing animal use in research and still obtain required data from a study, the routine use of positive control in every MN assay has been questioned by the scientific community, especially in laboratories which have demonstrated assay reproducibility and conduct studies under Good Laboratory Practice regulations. In this paper, mouse and rat vehicle and positive control MN data, collected manually, are described as a reference for a period of 12 years (1987-1998) in our laboratory. The vehicles generally included a variety of aqueous solutions and suspensions and cyclophosphamide dosed intraperitoneally at 20mg/kg (rats) or 40 mg/kg (mice) served as positive control, in all studies. Based on combined sex data (430 animals), for CD(1) mice, the vehicle control MN polychromatic erythrocyte (PCE) range was 0.9-3.1 with a mean of 1.75 per 1000 PCE and the positive control range (220 animals) was 8.8-42.1 with a mean of 23.1 MNPCE per 1000 PCE. Similarly, for Wistar rats, the vehicle control range (360 animals) was 1.3-5.3 with a mean of 2.6 MNPCE per 1000 PCE and the positive control range (240 animals) was 10.4-33.8 MNPCE per 1000 PCE. Vehicle control ranges reported here are comparable to the literature database and the positive control response was > or = 4-fold over vehicle control, in all studies. These data demonstrate the reproducibility of positive control response in MN assay in our laboratory and support the MN Assay Expert Panel's view that the use of positive control may not be necessary in every study.

Efficacy and local tolerance of a low-dose, 7-day matrix estradiol transdermal system in the treatment of menopausal vasomotor symptoms.

OBJECTIVE: To determine the efficacy and local tolerance of a new matrix transdermal drug-delivery system that delivers 0.02 mg of 17 beta-estradiol (E2) daily for 7 days for the relief of vasomotor symptoms. METHODS: A total of 324 surgically or naturally menopausal women, all with prior hysterectomy and moderate to severe vasomotor symptoms (56-140 hot flushes per week, with episodes of sweating, during a baseline observation period), participated in two independent, 12-week, randomized, double-blind, placebo-controlled studies. After a 4-week, treatment-free period, each woman received a continuous regimen of either one E2 transdermal system, two E2 transdermal systems, or placebo transdermal system(s) applied every week for 12 weeks. Efficacy was measured as reduction in hot flush frequency, determined from subject diaries. To measure local tolerance, skin irritation (erythema and edema) was objectively and systematically evaluated under blue light after removal of the transdermal system(s). Serum E2 and estrone concentrations were determined in one of the studies during baseline and on days 1, 9, 30, 58, 79, and 84. RESULTS: Mean hot flush frequency decreased from 80 hot flushes per week at baseline to approximately 13 hot flushes per week (84% decrease) after 12 weeks of transdermal E2 treatment. Compared with placebo, the decrease in hot flush frequency was significant as early as weeks 2 and 3, and was maintained through the end of the study. Few clinically significant skin reactions occurred, and only nine (3%) of the subjects withdrew because of a skin effect. After initial increase, serum E2 concentrations remained stable throughout the study, achieving values of approximately 20 and 40 pg/mL above baseline for one and two E2 transdermal systems, respectively. CONCLUSION: The E2 transdermal system effectively reduced the frequency of moderate to severe vasomotor symptoms as early as the second week of therapy and was very well tolerated. The decrease in hot flush frequency was similar to that reported for oral and other transdermal estrogens, but at lower serum E2 concentrations. This result may be due to the stable E2 blood level achieved with this transdermal system.

Recombinant bovine somatotropin improves growth performance in finishing beef steers.

The objectives of this study were to determine the efficacy of various doses of rbST on ADG and feed efficiency (FE) and to describe carcass composition changes in finishing beef steers. In Exp. 1, 96 crossbred beef steers (393 kg) received daily i.m. injections of buffer or 33, 100, or 300 micrograms/kg of BW of rbST (0ST, 33ST, 100ST, 300ST). In Exp. 2, 200 crossbred beef steers (417 kg) received daily i.m. injections of buffer or 8.25, 16.5, 33, or 66 micrograms/kg of BW or rbST (0ST, 8.25ST, 16.5ST, 33ST, 66ST). Treatments were administered until steer BW per pen averaged 540 kg in Exp. 1 and 560 kg in Exp. 2. An 86% concentrate: 14% roughage diet was fed once daily (CP: 16.5% in Exp. 1, 20.2% in Exp. 2). In Exp. 1, growth performance of steers receiving rbST was dose-dependent; ADG changed linearly (P = .01), DMI decreased linearly (P = .03), and FE changed quadratically (P less than .03). The 33ST steers responded with improved ADG and FE, 100ST with improved FE, and 300ST with lower ADG and poorer FE, compared with 0ST. In Exp. 2, the ADG response was quadratic (P = .01), DMI decreased linearly (P = .003), and FE improved quadratically (P = .004) with increasing dose of rbST. Steers receiving 16.5ST and 33ST responded with improved ADG and FE, whereas steers receiving 8.25ST and 66ST responded with improved FE but not ADG relative to 0ST steers. In Exp. 1 and 2, rbST administration altered carcass composition by increasing carcass protein and decreasing carcass fat.(ABSTRACT TRUNCATED AT 250 WORDS)

New microbiological method for determining spectinomycin in pelleted and meal feeds using trifluoroacetic acid as primary extractant.

A new microbiological method, identified as the spectinomycin trifluoroacetic (SPE-TFA) method, was compared with the current AOAC method for analyzing spectinomycin in meal and pelleted feeds fortified with LS-20 premix. Feeds containing 3 concentrations of drugs and a zero level were tested in a correlation study. The data showed no significant differences in the percent of theory assayed between meal and pelleted samples using the SPE-TFA method, but the percent of theory found using the AOAC method was significantly lower for the pelleted samples than for the meal samples. The within-sample variation of the AOAC assay was also not the same for all samples; the SPE-TFA assay variation was relatively constant for all samples. The SPE-TFA method produced an overall average recovery of 98% with a range of 89-109% compared with an 85% recovery ranging from 64 to 102% for the AOAC method. In addition to producing better recoveries, the SPE-TFA method features a more sensitive response line, and final test solutions have viscosities and clarity more comparable to the standard solutions than those produced by the current AOAC method.

The effects of diet on water flux and volatile fatty acid concentrations in the rumen of growing beef steers fed once daily.

In vivo temporal changes in ruminal liquid flow, liquid volume and VFA concentrations were determined in growing steers following once-daily feeding. Crossbred beef steers (n = 8; 278 +/- 8 kg), used in a crossover design, were trained to consume 180% of their maintenance energy intake within 2 h of either a high-forage (54% hay: 46% concentrate; HF) or high-concentrate (28% hay: 72% concentrate; HC) diet. For each animal on each diet, ruminal VFA concentrations, liquid volumes and liquid dilution rates were determined during a 2-h period before feeding and during three consecutive 2-h periods following feeding. Water was withheld during these periods to observe physiologically rather than behaviorally induced changes. At equal energy intakes, diet alone had no effect on VFA concentrations (P greater than .10), although changes in total VFA, acetic and isobutyric acids differed during the time periods following feeding due to diet (diet x time period interaction; P less than or equal to .10). Ruminal volume and dilution rate were altered in a reciprocal manner due to diet, with greater volumes and lower dilution rates observed in HC than in HF steers. Differences among time periods were observed for dilution rate and propionic acid concentrations. In general, these differences can be explained by comparison of the prefeeding time period with the postfeeding time periods. A numerical, but not statistically significant, increase in ruminal volume was observed following feeding. The effects of diet on volume and liquid dilution rate of the rumen must be considered when assessing total nutrients available for animal absorption.

Efficacy of ceftiofur hydrochloride for treatment of experimentally induced colibacillosis in neonatal swine.

Ceftiofur hydrochloride was tested for effectiveness against induced colibacillosis in neonatal swine. In this model, pigs less than 12 hours old were inoculated via stomach tube with a virulent, K99+, nalidixic acid-resistant strain of Escherichia coli. Six hours after challenge exposure, 1 dose of ceftiofur was administered either IM or orally in experiment 1 and orally only in experiment 2. Mortality, shedding of bacteria, fecal consistency scores, and body weight changes were monitored for 10 days. In experiment 1 (n = 383 pigs), all treatments at dosage that ranged between 0.5 and 64.0 mg of ceftiofur/kg of body weight significantly (P less than 0.001) reduced mortality, bacterial shedding, and diarrhea and increased weight gain, compared with findings in untreated controls. There were no detectable differences between oral and IM routes, except that there was greater reduction in bacteria shedding associated with the oral route of administration. In experiment 2 (n = 505 pigs), ceftiofur was administered orally either once at 6 hours after challenge exposure or twice at 6 and at 48 hours after the first dose. Dosage of ceftiofur was 0, 5, 10, 20, 30, or 60 mg/kg administered once, or half the same dose was administered at each of 2 times. At the optimal dosage (10 mg/kg), a single dose was as effective as 2 doses. The single administration at all dosages reduced mortality, bacterial shedding, and diarrhea scores and increased body weight gain, compared with findings in untreated pigs (P less than 0.01). In this induced infection model, the optimal treatment dosage was determined to be 10 mg/kg administered once.

Factors affecting the in vitro production of volatile fatty acids by mixed bacterial populations from the bovine rumen.

Factors affecting in vitro ruminal bacterial VFA production were examined. Treatments consisted of high and low initial pH (6.7, 5.7), osmolality (600, 400 mOsm) and concentrations of acetic (40, 0 mM) and propionic acids (20, 0 mM). Response variables measured included the production of acetic, propionic and total VFA, total gas and methane. Initial pH affected (P less than .05) most variables either independently or in combination with one or more of the other factors. Acetic acid production was reduced 40% (P = .03) when initial acetic acid concentrations were 40 mM compared with 0 mM. Also, acetic acid production was less (P less than .01) at low initial pH (5.7) than at high initial pH (6.7). Propionic acid production was greater (P = .05) at high vs low initial acetic acid concentrations. Propionic acid production was greater in response to low vs high initial osmolality, although the magnitude of this difference depended on initial pH (interaction P = .02). Total production of VFA was greater (P less than .01) at high than at low initial pH; however, at low initial pH, no difference (P greater than .05) was observed due to initial osmolality, whereas at high pH, production was greater (interaction P = .04) for low than for high initial osmolality. The diminished production of total VFA at pH 5.7 occurred primarily due to reduced acetic acid production, although increased production of propionic and butyric acids was noted.(ABSTRACT TRUNCATED AT 250 WORDS)