Effectiveness, safety, and economic evaluation of topical application of a herbal ointment, Jaungo, for radiation dermatitis after breast conserving surgery in patients with breast cancer (GREEN study): Study protocol for a randomized controlled trial.

INTRODUCTION: This is a prospective, open-label, parallel-group, randomized controlled trial that evaluates the effectiveness and safety of adjuvant application of Jaungo (JUG) for radiation-induced dermatitis (RD) in breast cancer patients undergoing radiation therapy, in comparison with general supportive care (GSC). METHODS/DESIGN: Eighty female patients, who have been diagnosed with unilateral breast cancer, will be allocated to either the JUG or GSC group with an allocation ratio of 1:1 after breast conservation surgery, in the Kyung Hee University Korean Medicine Hospital, Seoul, Republic of Korea. Both the groups will be subjected to GSC, but only the JUG group participants will apply adjuvant JUG ointment on the irradiated skin for 6 weeks, twice a day. The primary outcome of this study is the assessment of incidence rate of RD using the Radiation Therapy Oncology Group (RTOG) for toxicity gradation of 2 or more. Maximum pain level, quality of life, adverse reactions, and pharmacoeconomic evaluations will also be included. DISCUSSION: The primary outcome will be statistically compared using the logrank test after estimating the survival curve using the Kaplan-Meier method. Continuous variables will be tested using independent t test or Mann-Whitney U test. The adverse events will be evaluated with Chi-square or Fisher exact test. All the data will be analyzed at a significance level of 0.05 (two-sided) with R software (The R Foundation). TRIAL REGISTRATION: CRIS (Clinical Research Information Service), KCT0003506, 14 February 2019.

Benefit-Cost Analysis of Radiocesium Decorporation by a Prussian Blue Treatment and Stockpiling.

In the case of an attack by a "dirty bomb" with cesium-137 there is a risk of internal contamination. The excretion of cesium-137 can be enhanced by Prussian Blue (PB), and thus the committed effective dose be reduced. We analyzed the benefit and costs of PB decorporation treatment. We simulated the reduction of the radiological dose by PB treatment after cesium-137 incorporation by inhalation. The saving of life time was quantified using the monetary "value of a statistical life" (VSL). Treatment costs were based on the market price of PB in Germany. Moreover we considered the holding costs of stockpiling. The benefit of PB treatment increases with its duration up to about 90 days. If treatment initiation is delayed, the maximum achievable benefit is decreased. For a VSL of 1.646 million €, the net benefit of a 90-days treatment started 1 day after the incorporation remains positive up to a stockpiling duration of 10 years. If starting PB treatment as late as the 180th day after incorporation, the costs will surpass the benefit. We conclude that a prompt decision making and early treatment initiation greatly impacts on the medical but also economic efficiency of a PB treatment.

Quantitative assessment of preventive behaviors in France during the Fukushima nuclear crisis.

BACKGROUND: The Fukushima nuclear disaster has generated worldwide concern on the risk of exposure to nuclear radiations. In Europe, health authorities had to issue statements about the lack of usefulness of iodine based preventive treatments within their borders. However a lack of confidence in official messages has developed in various European countries due to recent perceived failures in managing public health crises. The lay population preventive behaviors in this context are largely unknown. Consequently, to examine the effects of public health crisis on lay behaviors leading to pharmaceuticals purchases, we studied the sales of iodine-based products in France before, during and after the crisis. METHODS: We focused our study on 58 iodine-based drugs available with and without a physician prescription. Our data came from a stratified sample of 3004 pharmacies in metropolitan France. Our study period was from January 2010 to April 2012, with a focus on March-April 2011. We differentiated sales of drugs prescribed by physicians from sales of drugs obtained without a prescription. We used a CUSUM method to detect abnormal increases in sales activity and cross-correlations to assess shifts in sales timing. RESULTS: Sales of iodine-based nutritional complements, and later sales of iodine-based homeopathic remedies, substantially increased (up to 3-fold) during a period of 20 days. Their temporal patterns were correlated to specific events during the crisis. Prescriptions for iodine-based homeopathy increased (up to 35% of all sales). Iodine pills, strictly regulated by health authorities, have also been sold but on a very small scale. CONCLUSION: These results indicate uncontrolled preventive behaviors resulting in the potentially unjustifiable consumption of available drugs. They have implications in public policy, and demonstrate the usefulness of drug sales surveillance for instantaneous evaluation of population behavior during a global crisis.

Evaluation, prevention and management of radiotherapy-induced xerostomia in head and neck cancer patients.

PURPOSE OF REVIEW: As part of the multidisciplinary approach to head and neck cancer patients, radiation therapy plays an essential role, improving locoregional control. Radiation therapy-induced xerostomia is a late side-effect that increases the risk for developing dental caries and compromises oral mucosal integrity, resulting in oral pain, loss of taste, difficulties with swallowing and chewing, sleep disorders and worse quality of life. This review focuses on evaluation, prevention and management of radiation therapy-induced xerostomia. RECENT FINDINGS: In terms of xerostomia prevention, some clinical trials evaluating amifostine and intensity-modulated radiation therapy have shown positive results. Pilocarpine is a useful agent as a treatment of radiation-induced xerostomia in head and neck cancer patients. SUMMARY: Despite some advances in radiation therapy-induced xerostomia prevention, its treatment is an area in which advances are urgently needed.

Cytoprotective effect of amifostine in the treatment of childhood neoplastic diseases--a clinical study including the pharmacoeconomic analysis.

Amifostine is an active aminothiol, which has unique properties as a radio- and chemoprotective agent. It has been reported to prevent myelosuppression and reduce the toxic effects of intensive cancer treatment. In the study, 57 courses of chemotherapy in 18 children treated because of neoplastic disease were analyzed to assess the early side effects induced by cytotoxic anticancer therapy. In 18 of them amifostine was used as the cytoprotective agent. The estimation of adverse effects was made in accordance to WHO scale of toxicity, and the pharmacoeconomic analysis was based on the costs of intravenous antibiotics, G-CSF, GM-CSF, blood preparations, immunoglobulins and days of hospitalization. The amifostine use in supportive therapy of neoplastic diseases in children decreases the number of infections thanks to the diminishing of myelotoxic effect. This not only improves the comfort of the patient but also shortens the time of hospitalization. The amifostine therapy limits the costs of treatment, but high price of the drug itself, makes however, the chemotherapy with cytoprotection comparable in pharmacoeconomic analysis to the standard treatment.

Costs of treatment intensification for head and neck cancer: concomitant chemoradiation randomised for radioprotection with amifostine.

This study presents an overview of costs of a chemoradiation protocol in head and neck cancer patients and an analysis of whether prevention of acute toxicity with amifostine results in a reduction to costs. Fifty-four patients treated with weekly paclitaxel concomitant with radiation were randomised for treatment with subcutaneously administered amifostine (500 mg) and analysed with respect to costs of treatment. Total costs for work-up, treatment and toxicity were calculated per treatment arm. No significant differences were found between treatment arms in preliminary results regarding response (98%), toxicity and 2-year survival (77%). Average costs for toxicity were Euro 3.789, largely influenced by hospital admissions (Euro 3.013). Total costs for amifostine administration amounted to Euro 6.495 per patient. The average total costs of treatment were Euro 19.647 versus Euro 13.592 with or without amifostine, respectively. The applied (subcutaneous) dose of amifostine appeared to be insufficient for radioprotection and reduction of related costs in the concomitant chemoradiation scheme, whereas total costs increased remarkably. Although it would be accompanied by a further cost raise, applying a higher amifostine dose might reduce (mucosal) toxicity and therefore in the long run lower related costs for hospital admission and tube feeding.

Amifostine: an update on its clinical status as a cytoprotectant in patients with cancer receiving chemotherapy or radiotherapy and its potential therapeutic application in myelodysplastic syndrome.

UNLABELLED: Amifostine (WR-2721) is a cytoprotective agent that protects a broad range of normal tissues from the toxic effects of chemotherapy and radiotherapy without attenuating tumour response. This selective protection is due to the greater conversion and uptake of the active metabolite, WR- 1065, in normal versus neoplastic tissues. In a pivotal phase III trial, 242 patients with advanced ovarian cancer were randomised to receive treatment with cisplatin 100 mg/m2 and cyclophosphamide 1000 mg/m2 every 3 weeks with or without pretreatment with intravenous amifostine 910 mg/m2. Over 6 cycles of therapy, amifostine significantly reduced haematological, renal and neurological toxicities: treatment delays, treatment discontinuation and days in hospital related to these adverse events were also significantly reduced in patients receiving amifostine versus patients receiving chemotherapy alone. In another randomised phase III trial in 303 patients with head and neck cancer undergoing irradiation therapy (total dose 50 to 70Gy), pretreatment with intravenous amifostine 200 mg/m2 significantly reduced the incidence of acute and late grade > or =2 xerostomia. However, mucositis was not significantly reduced in amifostine recipients compared with patients receiving radiotherapy alone, although this has been shown in smaller randomised trials. Amifostine (340 mg/m2) also provided significant protection against pneumonitis and oesophagitis in patients with lung cancer receiving thoracic irradiation in a preliminary report from a phase III trial (n = 144). Other studies have demonstrated protective effects of amifostine in other tumour types and other chemotherapy, radiation and radiochemotherapy regimens; however, evidence is still limited in these indications. No evidence of tumour protection by amifostine has been demonstrated in any clinical trials. Amifostine has also been shown to stimulate haematopoietic stem cells and has been investigated as a therapy for patients with myelodysplastic syndrome in number of small preliminary studies. At the recommended dose and schedule, amifostine is generally well tolerated. Adverse effects are usually reversible and manageable and those most frequently experienced include nausea and vomiting, transient hypotension and somnolence and sneezing. CONCLUSION: The results of phase III trials have confirmed the safety and efficacy of amifostine as a cytoprotectant to ameliorate cisplatin-induced cumulative renal toxicity, for which it is the only agent proven to be effective, and neutropenia in patients with advanced ovarian cancer, and to reduce xerostomia in patients with head and neck cancer receiving irradiation therapy. Depending on the outcome of numerous ongoing clinical trials, amifostine may eventually find broader clinical applications, both as a cytoprotectant and as a potential therapy in myelodysplastic syndrome.

Economic analysis of amifostine as adjunctive support for patients with advanced head and neck cancer: preliminary results from a randomized phase II clinical trial from Germany.

In a randomized phase II trial in Germany, we investigated the clinical and economic impact of amifostine protection against the hematological and oral toxicities of carboplatin administered concurrently with standard fractions of radiotherapy. 28 patients with squamous cell carcinomas of the head and neck received adjunctive or primary radiotherapy (5 days per week with daily fractions of 2 Gy, up to a total dose of 60 Gy) in conjunction with carboplatin (70 mg/m2) on days 1-5 and days 21-26. All patients received radiation encompassing at least 75% of the major salivary glands. Patients were randomized to receive radiation and carboplatin (RCT) alone or RCT preceded by rapid infusion of amifostine (500 mg) on days carboplatin was administered. The 14 patients who received amifostine, in comparison to 14 patients in the control arm, had significantly fewer episodes of grade 3 or 4 thrombocytopenia (p = 0.001), mucositis (p = 0.001), and xerostomia (p = 0.001). The patients receiving amifostine accrued significantly lower supportive care costs for resources related to infection ($241 vs. $1,275, p < 0.01), red blood cell and platelet support ($286 vs. $1,276 p = 0.06) alimentation ($343 vs. $894, p = .01), and hospitalization ($286 vs. $2,429, p < 0.01). Overall, including the costs of amifostine, mean per patient supportive care costs were $4,401 for the amifostine group and $5,873 (p = .02) for the control group. Our results from a randomized phase II trial indicate that selective cytoprotection with amifostine potentially offers clinical and economic benefits in patients with advanced head and neck cancer receiving radiochemotherapy. Additional economic studies alongside randomized phase III trials and from other countries are needed.

Choices of methodology in pharmacoeconomics studies.

OBJECTIVES: The goal of this paper is to evaluate the comparative value of economic methodologies in assessing the benefit of a new cytoprotective agent (amifostine) delivered before cisplatin/cyclophosphamide in the treatment of ovarian cancer. BACKGROUND: Data from a randomized controlled multinational multicenter ovarian cancer trial were used as the basis for a retrospective pharmacoeconomic analysis. Trial results demonstrated amifostine had no significant effect on oncolytic efficacy, but side effect profiles improved for febrile neutropenia (absolute risk reduction [ARR] 11%), neurotoxicity (ARR 11%), and nephrotoxicity (ARR 26%). Although, the methodology most commonly used in this type of analysis is cost utility (CU), we investigated a "willingness to pay" (WTP) approach. RESEARCH DESIGN SUBJECTS: Four pharmacy managers were given an informal telephone interview to assess their preferences. Two managers understood, and preferred, the CU data. The others, who had no education or training on CU principles, preferred WTP data. All managers understood the outputs from WTP studies. RESULTS/MEASURES: WTP for reductions in febrile neutropenia, neurotoxicity, and nephrotoxicity were collected from 50 healthy volunteers and measured against the cost of delivering the new therapy. Results revealed WTP values of $141 per year for reductions in febrile neutropenia, $86 per year for reductions in neurotoxicity, and $71 per year for reductions in nephrotoxicity. The base case analysis showed that amifostine was cost neutral ($350 net cost, CI = -850 to +1551). CONCLUSIONS: The results were well-received by decision-makers. This manager survey illustrates that the methodologic choice should be determined not only by the nature of the comparison, but also by the stakeholder the data is meant to influence.