Cost minimization comparison of oral UFT/leucovorin versus 5-fluorouracil/leucovorin as adjuvant therapy for colorectal cancer in Taiwan

We performed a cost-minimization procedure to compare the cost–effectiveness of oral UFT/LV and intravenous 5-FU/LV, since they were found to have similar efficacy [7–10]. Regimens from NASBP-C-06 [7] were used for the cost calculation, because it was the largest study comparing oral UFT/LV to 5-FU/LV in an adjuvant setting. In brief, the oral UFT/LV regimen comprised five 5-week cycles consisting of 4 weeks of UFT (300 mg/m²/day) and LV (90 mg/day) and a 1-week rest period. The intravenous 5-FU/LV regimen consisted of three 8-week cycles of weekly 5-FU (500 mg/m²) and LV (500 mg/m²) for 6 weeks and a 2-week resting period (Rosewell Park regimen). The costs of chemotherapy drugs were based on the 2012 NHI reference list for drugs, and the costs of medical consultation, drug infusion and hospital admissions were based on the Fee Schedule for Medical Services [18]. All the costs used in the analysis were referenced from the NHI reimbursement price list to reflect Taiwan's condition from the payer's perspective. The direct cost of each treatment was calculated by multiplying the unit cost by medical resource utilization.

In Taiwan, there are two brands of oral uracil–tegafur: UFT (Otsuka Pharmaceutical, Tokyo, Japan) and UFUR (TTY Biopharm, Taipei, Taiwan). NHI covers these two brands and intravenous 5-FU for Stages II and III colorectal cancer adjuvant therapy. It was also suggested in the treatment guidelines to treat high-risk Stages II and III colorectal cancer patients with oral UFT/LV or 5-FU/LV adjuvant therapy. Cost–effectiveness calculations included both UFT and UFUR owing to their different NHI prices of NT$69 and NT$73, respectively. Since there are numerous brands of infusion regimens for 5-FU and both infusion and oral LV, the lower and upper price range of each chemotherapy agent is shown in the table, but for the ease of calculation, only the price of the most commonly used agent at the time of analysis for each product is selected. It is assumed that the body surface area is 1.6 for all colorectal patients. All calculations are in US$ (US$1.00 = NT$31.687, exchange rate in 2017) [19]. Moreover, data from a local expert panel survey were considered to provide a true comparison of the cost–effectiveness of the oral and intravenous regimens. In brief, the expert panel consisted of 12 Taiwanese colorectal surgeons and medical oncologists. The survey revealed that approximately 69.6% patients received outpatient department bolus 5-FU regimen and approximately 30.4% received an in-patient department infusion. The cost of hospital stay was also included in treatment cost calculation for patients who required in-patient department infusion.

With respect to time saving, as was shown in the Maroun et al. study [12], this study also included calculation based on the number of clinic visits and treatment duration. In brief, patients receiving oral chemotherapy would require a monthly clinical checkup, and five visits in the whole course of treatment. Patients on intravenous chemotherapy would require a weekly clinical checkup, six visits per cycle, and 18 visits in the whole treatment course. Additionally, these patients would need to spend 4 h in the chemotherapy unit (CTU) for premedication and chemotherapy infusion. Moreover, 5-FU/LV patients would require a one-time central venous catheter implantation for approximately 100 min.

One-way sensitivity analyses were performed to test the robustness of the model. The sensitivity analyses varied key assumptions in the model, including the acquisition costs of chemotherapy drugs and medications for AEs, drug administration costs, utilities and discount rates.

While we found lower costs for 5-FU/LV chemotherapy than oral uracil–tegafur/LV regimen, the lower costs were offset by the higher administration cost of 5-FU/LV, leading to a remarkably lesser total treatment cost for UFT/LV and UFUR/LV regimen. This result was similar to another cost-effective analysis comparing another oral chemotherapy with 5-FU/LV as adjuvant therapy for stage III colon cancer in Taiwan. In that study, the cost of the oral chemotherapy was higher than 5-FU/LV, but the overall cost saving was found to be significant after considering drug administration costs [12]. In our study, UFT/LV and UFUR/LV showed a total cost saving of $3709.16 and $3620.80 per patient per treatment, respectively (Table 2). However, the cost for 5-FU/LV was underestimated in our report since the cost and time spent on cleaning central venous catheter and infection handling were not included in this calculation. In addition, Rosewell Park regimen for 5-FU/LV was used for the calculation. This intravenous regimen is a weekly bolus 5-FU/LV, which could be administered within four infusion time so patients could complete the administration in an out-patient CTU. According to a Taiwan local expert panel survey on intravenous 5-FU adjuvant treatment of colorectal cancer, approximately 30.4% of patients would receive an in-patient department infusion of 5-FU regimen for adjuvant treatment. Thus, some patients treated with 5-FU/LV might spend at least a night or longer if physicians chose to have longer 5-FU infusion time regimens. In our net saving calculation, we found that UFT/LV and UFUR/LV regimen for a needed in-patient infusion could save up to a maximum of $5049.77 and $4961.41 per patient, respectively.

A cost comparison of UFT/LV to 5-FU/V in metastatic setting was done in Canada [16] based on data from two randomized trials showing a cost saving of CAN$ 3221 per patient per treatment and 4.5 h saved per patient per month. Maroun et al. described that one of the key advantages in oral uracil–tegafur treatment is to increase the efficiency in hospital setting [16]. In their studies, UFT treatment saved 225 h per month in the CTU. Alternating chemotherapy regimens with similar efficacy and requiring less space and time allocation in the CTU would be a great relief for the medical staff [16]. In our study, patient on oral uracil–tegafur/LV regimen required 13 less clinic visits and saved 72 h (Tables 3 & 4).

From the hospitals' perspectives, a total of 3683 h could be saved from treatment of 50 colorectal patients. It is very likely for a hospital to have >50 colorectal patients since it is the most common malignancy in Taiwan. This would be equivalent to 600 h saved per month in CTU. Medical staff could spend less time administering therapy that could otherwise been given orally. Administration by infusion using a central vein catheter involves substantial costs, whereas replacing 5-FU/LV with oral therapy results in savings in health resources for the hospital and the government.

The oral uracil–tegafur regimen also provides patients a better treatment alternative over 5-FU/LV. The advantage of oral regimen out-weighted intravenous regimen is mainly due to its convenience [20] and lesser toxicity [8]. Oral uracil–tegafur regimen may be associated with less inpatient services and less work loss [21]. At least two studies have shown that patients prefer oral chemotherapy over intravenous therapies if efficacy is not compromised [22,23]. In Borner et al. study, 84% of the patients preferred the oral uracil–tegafur regimen. The roles of oral UFT/LV in adjuvant [7,10] and metastatic settings have been proven to have similar efficacy as with intravenous 5-FU/LV [8,9]. Reasons for preference of the oral uracil–tegafur regimen include being able to take medication at home, less stomatitis and being able to use a capsule instead of an injection [23]. In addition, some patients may need to stay at hospital for infusion and a longer stay would mean productivity loss, higher economic burden for the family and a higher chance of central vein catheter complications, such as infection, bleeding, pneumothorax and venous thromboembolism.

Several limitations should be noted when interpreting the study results. The price used was based on the NHI price in Taiwan so it may not reflect condition in other counties. In addition, the reimbursement price of chemotherapy was based on values collected in 2013, which may not reflect the price of chemotherapy in 2014 or later. Nonetheless, our study focused on the real condition in Taiwan, where both 5-FU/LV and oral UFT/LV are reimbursed by NHI. Finally, the costs for intravenous drug administration and for oral 5-FU and uracil–tegafur adverse event management were estimated based on one single hospital and an expert panel survey, respectively, and thus may not reflect the real range of these costs. We attempted to address this issue by varying the estimated costs by ±20% to assess the robustness of the study results. Our finding suggested that even with a 20% variation in the costs of intravenous drug administration and adverse event management, the total costs for the UFT/LV regimen remained lower than the 5-FU/LV regimen.

In Taiwan, NHI reimburses the medical cost of oral uracil–tegafur (UFUR and UFT) and 5-FU for Stages II and III colorectal cancer adjuvant chemotherapy. The government's viewpoint is that the oral chemotherapy has an advantage over the intravenous regimen, attributed to the savings in administration and improvements seen during adverse events. The study reflected a total cost saving per patient of US$3620.80–$4961.41 (UFUR) and US$3709.16–$5094.77 (UFT), along with 72 h less time spent per patient. This would lead to cost- and time-effective utilization of the wards.

The authors thank I-Ting Wendy Wang for her assistance.

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.