Journal of Medical Economics

ISSN: 1369-6998 (Print) 1941-837X (Online) Journal homepage: http://www.tandfonline.com/loi/ijme20

Cost minimization analysis of capecitabine versus

5-fluorouracil-based treatment for gastric cancer
patients in Hong Kong

Keary R Zhou, Ashley Cheng, WT Ng, TY Kwok, Elton YP Yip, Rosa Yao, PY
Leung & VWY Lee

To cite this article: Keary R Zhou, Ashley Cheng, WT Ng, TY Kwok, Elton YP Yip, Rosa Yao,
PY Leung & VWY Lee (2017): Cost minimization analysis of capecitabine versus 5-fluorouracil-
based treatment for gastric cancer patients in Hong Kong, Journal of Medical Economics, DOI:
10.1080/13696998.2017.1296452

To link to this article: http://dx.doi.org/10.1080/13696998.2017.1296452

Accepted author version posted online: 15

Feb 2017.

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Cost minimization analysis of capecitabine versus 5-fluorouracil-based treatment for gastric cancer
patients in Hong Kong

Keary R Zhou1, Ashley Cheng2, WT Ng3, TY Kwok1, Elton YP Yip4, Rosa Yao4, PY Leung5, and VWY Lee1

1
School of Pharmacy, The Chinese University of Hong Kong
2
Department of Oncology, Pamela Youde Nethersole Eastern Hospital
3
Department of Oncology, Princess Margaret Hospital
4
Department of Pharmacy, Princess Margaret Hospital
5
Department of Pharmacy, Pamela Youde Nethersole Eastern Hospital

Transparency

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Declaration of funding
This project was funded by Roche (Hong Kong) Company Ltd.

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Declaration of financial/other relationships
KRZ and VWYL report receiving research funding from Roche Hong Kong. JME peer reviewers on this
manuscript have no relevant financial or other relationships to disclose.
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Acknowledgments
None reported.
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Abstract:
Background: EOX (epirubicin, oxaliplatin, Xeloda®- capecitabine) and FOLFOX4 (5-fluorouracil (5-FU),
leucovorin, oxaliplatin) are the common chemotherapy regimens used in the treatment of advanced
gastric cancer (aGC) in Hong Kong. This study aimed to compare the costs of these therapies for aGC
patients from both the healthcare and societal perspectives. It should be noted that while FOLFOX4 is
routinely administered in an outpatient setting in North America and Europe, inpatient setting is
adopted in Hong Kong instead, incurring hospitalization cost as a result.
Methods: Fifty-eight patients were identified from the electronic records in two public tertiary hospitals,
with 45 and 13 received EOX and FOLFOX4 regimens respectively. Healthcare cost was direct medical
costs including drugs, clinic follow-up, hospitalization, diagnostic laboratories and radiographs. Societal
cost refers to indirect costs such as patient time and travel costs. Cost items were further classified as
“expected” or “unexpected”. All cost data was expressed in US dollars.
Results: Patients in the EOX and FOLFOX4 arm received an average of 5.3 and 7.8 cycles of treatment

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respectively. The capecitabine-based regimen group had a higher expected medication cost per cycle
when compared to the 5-FU-based treatment group (US$290.3 vs. US$66.9, p<0.001) but lower

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expected hospitalization costs (US$76.9 vs. US$1,269.2, p<0.001). The total healthcare cost and total
societal cost per patient was reduced by 67.2% (US$5,691.9 vs. US$17,357.4, p<0.001) and 25.3%
(US$3,090.5 vs. US$4,135.1, p=0.001) respectively in the capecitabine-based regimen group. Sensitivity
analyses based on full cycle regimen costs and net capecitabine or 5-FU/leucovorin costs still showed
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EOX to be less costly than FOLFOX4.
Conclusion: The capecitabine-based regimen, EOX, was found to generate significant cost saving from
both the healthcare and societal perspectives in regions in which FOLFOX4 is given in an inpatient
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setting.
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Background:
Xeloda®, capecitabine-based chemotherapy regimen, has shown to be more cost-effective than 5-
fluorouracil (5-FU) considering they had equivalent clinical efficacy in gastric cancer treatment. [1,2] The
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total cost for 5-FU-based regimen was higher for the healthcare provider and society as a whole. [1]
Gastric cancer ranks fourth in cancer-related cause of death in the Hong Kong population. 5-FU has
known antitumor activity and has been used successfully in advanced gastric cancer (aGC) with cisplatin
(FP), as well as with oxaliplatin ± epirubicin (FOLFOX4, EOF). When substituted with capecitabine, the XP
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and EOX regimens have demonstrated to be non-inferior in terms of progression-free survival when
compared with FP and EOF, respectively. [2,12] In an economics evaluation done by the manufacturer
for NICE submission on the use of capecitabine for treatment of aGC, the use of XP regimen allowed a
cost reduction while eliminating possible complication related to intravenous therapy. Moreover,
FOLFOX4, one of the common 5-FU-based regimens used locally, has demonstrated to produce a
median overall survival of 10 months in advanced/metastatic gastric cancer patients, an effect similar to
that of EOX. [14] Xeloda®, capecitabine, was recently extended by the Hong Kong Hospital Authority as
subsidized therapy for the treatment of colorectal cancer. Currently, there is no local-regional data
suggesting similar economic impact with capecitabine-based regimen for gastric cancer when compared
with 5-FU-based regimens. In fact, the current study is the first one done in Asia to examine this
question. It is worthwhile to see if capecitabine-based therapy for gastric cancer is a cost-effective
alternative. This study assumed equal clinical effectiveness between the EOX and FOLFOX4 regimens.
The study was designed to ensure comparability of the selected samples of treated patients and to
compare the costs of treatment of the two chemotherapy regimen groups. This study aimed to
compare the costs of these therapies for aGC patients from both the healthcare and societal
perspectives. One point to note is that while FOLFOX4 is routinely administered in North America and
Europe in an outpatient setting, central venous catheters and out-patient ambulatory pumps are not
used in Hong Kong. Instead, FOLFOX4 is administered in an inpatient setting. Therefore, the planned
hospitalization for each cycle of FOLFOX4 administration is expected to be one of the major cost factors
accounting for the cost difference between FOLFOX4 and EOX therapies in Hong Kong. The cost for
FOLFOX4 administration would actually be substantially lower in North America and Europe.

Methods:

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Study Design
This study was a retrospective study comparing the cost of EOX and FOLFOX4 regimen in the treatment

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of advanced gastric cancer (aGC). Patients with aGC were identified from medical records of the
oncology department at Princess Margaret Hospital (PMH, 1500 beds) and Pamela Youde Nethersole
Eastern Hospital (PYNEH, 1800 beds), which are two of the largest general public hospitals in Hong Kong.
Information related to the use of hospital resources by each patient, including outpatient visits,
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inpatient admissions, laboratory tests and procedures as well as medications, were collected up to one
month after the last cycle of therapy. Cost data was analyzed from the healthcare provider and societal
perspectives. Under each perspective, costs were further divided into two categories, expected and
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unexpected. Expected costs were defined as costs directly incurred for chemotherapy administration,
such as costs for chemotherapies, pre-medications and fluids for infusion, as well as associated
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laboratory tests, hospital bed-days and outpatient follow-up visits. Unexpected costs were described as
costs unrelated to the actual chemotherapy treatment, and costs due to adverse events, disease
progression or toxicity management. The study protocol has obtained the Clinical Research Ethics
Committee (CREC) approval from both the Kowloon West Cluster (PMH) and the Hong Kong East Cluster
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(PYNEH).
Patient Population
Patients who were 18 years of age and older with aGC were eligible for this study. Patients were
selected according to reverse chronological order, starting from the most recent cases. A target sample
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size was predefined to be sixty originally, with thirty patients in each arm respectively. They were
included between August 2007 and April 2012. The latest start date of chemotherapy was February
2012.
Treatment Schedules
The EOX regimen follows the chemotherapy protocol issued by the National Health Service in the United
Kingdom. It consists of an intravenous bolus injection of epirubicin 50 mg/m2 and an intravenous
infusion of oxaliplatin 130 mg/m2 over 2 hours on day 1 of every 3 week cycles, together with oral
capecitabine tablets 625 mg/m2 twice daily for six months. As for the FOLFOX4 regimen, it consists of an
intravenous infusion of oxaliplatin 85 mg/m2 over 2 hours on day 1, and an intravenous infusion of
folinic acid (leucovorin) 200 mg/m2 over 2 hours on days 1 and 2. This is followed by an intravenous
bolus injection of 5-FU 400 mg/m2 and then continuous intravenous infusion of 5-FU 600 mg/m2 over 22
hours every 2 weeks. The schedule and dosage for FOLFOX4 regimen is the same in the two hospitals.
Both chemotherapy regimens were meant to be given for 24 weeks, with 8 cycles of EOX or 12 cycles of
FOLFOX. However, they were also administered until disease progression or toxicity, if these conditions
were reached before having finished full number of cycles.
Data Collection
Patient demographics, clinical characteristics such as Eastern Cooperative Oncology Group (ECOG)
performance score and metastases, schedules of outpatient, inpatient and day ward visits, laboratory
tests and procedures performed, as well as medications associated with chemotherapy administration
were extracted from electronic patient records. Data on medications used during hospitalizations were
gathered from patient medical charts, whereas adverse events related to the chemotherapy were taken
down from doctors’ progress notes.
Cost Evaluation

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Healthcare Provider’s Perspective
Costs under healthcare providers’ perspective are known as direct medical costs, which include all the

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costs for clinic visits, follow-up, hospitalization, as well as laboratory investigations and medications
used in either inpatient or outpatient settings. Expected costs only include the costs directly associated
with chemotherapy administration. From the electronic patient records, the hospital bed-days required
for delivery of EOX and FOLFOX4 chemotherapy were 1 and 3 respectively. FOLFOX4 patients were
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admitted at 9 am on Day1 and discharged at 3 pm on Day 3. Therefore, any further days of
hospitalization and the associated laboratory tests performed and medications consumed were
classified as unexpected costs. Any walk-in clinic visits, specialist clinic visits due to delay of
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chemotherapy and Accident & Emergency Department (AED) visits were also deemed as unexpected.
All adverse event costs were also included within these unscheduled costs.
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The costs for healthcare resources usage, including hospital visits and laboratory investigations,
were valued according to the Hong Kong Government Gazette 2003 [21], which is the most updated
version of official source for costs of public hospital services. The charges for different hospital services
are listed as follows: specialist outpatient visits - HK$700, general outpatient visits - HK$215, AED visits -
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HK$570, inpatient stay - HK$3,300 per day, day procedure at Clinical Oncology Clinic - HK$600. These
prices are regarded as the expected costs incurred by the healthcare provider to provide these services.
The costs for any services consumed by patients at the private hospital sector were also valued based on
the costs at the public hospital sector. Medication costs were calculated based on drug acquisition costs
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of the hospital, which were obtained from PMH and PYNEH procurement lists in 2011. All costs were
expressed in US dollars (1 US$ = 8.00 HK$).
Societal Perspective
Costs under societal perspective are known as indirect medical costs, which include patients’ time and
travel costs spent during outpatient visits, AED visits and hospitalization. Apart from the time spent in
administration of EOX regimen at day ward as well as AED visits, the time consumed during other
hospital visits were estimated only as actual information was not able to be extracted from patient
medical records. Both specialist and general outpatient visits were estimated to take two hours every
time while time to carry out laboratory investigations was estimated to be one hour. Time costs for the
above were calculated based on the median hourly wages of different sex and age groups in Hong Kong.
For the time costs spent by patients during hospitalization, they were calculated by multiplying the
number of hospital bed-days with the daily salary estimated based on the median monthly employment
earnings of all employed persons of different sex and age groups in Hong Kong. (See Appendix I)
As for the estimation of travel costs, they were calculated based on the urban taxi fare for the
distance between the home address of patients and their respective institution. The distance was
estimated with Google Map, while the taxi fare was calculated according to the fare table issued by the
Transport Department in Hong Kong. (See Appendix II)
Subgroup Analysis
Two subgroup analyses were performed to test the robustness of this cost model. The first one was to
evaluate the total healthcare and societal cost of EOX and FOLFOX4 regimens when full number of cycles
was carried out. This would mean a total of 8 cycles of EOX and 12 cycles of FOLFOX4 were given. The
second analysis was to assess the actual and the full cycle healthcare cost of EOX and FOLFOX4 group
after removing the costs of epirubicin, oxaliplatin, associated pre-medications as well as liquids for

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infusion. This aimed to investigate the net effect of capecitabine and 5-FU/leucovorin on the total
healthcare cost.

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Statistical Analysis
All data was analyzed with the statistical software Statistics Package for Social Sciences (SPSS for
Windows, version 19.0, 2010, SPSS Inc., Chicago, IL, United States). The distributions of all data were
compared by Mann-Whitney U test. Also, due to the uneven distribution of patients in each group (45
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EOX vs. 13 FOLFOX4), a p-value less than 0.01 was considered as statistically significant, in which the null
hypothesis assuming there was no difference between the two groups would be rejected. Means and
standard deviations were used to describe all the statistics.
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Results:
Patient Baseline Characteristics
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A total of 58 subjects were identified with only thirteen in the FOLFOX4 arm. More patients seem to
have chosen EOX over FOLFOX4 to avoid the inpatient stay for the prolonged administration of FOLFOX4.
The two groups were then arranged for comparison in an approximate 3:1 ratio (45 EOX and 13
FOLFOX4). Table 1 shows the baseline characteristics of patients in EOX or FOLFOX4 treatment arms.
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There is no difference in terms of gender distribution, median age, body surface area, performance
status, percent with metastasis when diagnosed, and median survival since diagnosis. More patients
who received EOX had an ECOG performance status score of 0 or 1 than the FOLFOX4 group (P> 0.01).
Treatments
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The full number of cycles for EOX and FOLFOX4 regimens was 8 and 12 respectively. However, a number
of patients experienced either disease progression or toxicity before reaching full cycles. As a result,
only an average of 5.3 cycles of EOX and 7.9 of FOLFOX4 were given among the patients. This yields a
completion rate of 66.3% for the EOX group and 65.8% for the FOLFOX4 group. In addition, a majority of
patients received dosage reduction throughout their treatment. In the EOX group, an overall of 83.3%
dose of epirubicin, 90.6% of oxaliplatin and 80.7% of capecitabine were given to the patients. On the
other hand, in the FOLFOX group, patients received an overall dosage reduction for oxaliplatin and 5-
FU/leucovorin of 86.7% and 92.5% respectively.
Use of Healthcare Resources
Table 2 indicates the pattern of healthcare resources used by patients in both groups during the whole
period of treatment and their associated follow-up period for the last cycle. There was a statistically
significant difference in the usage of medications between patients in both groups. The number of drug
items necessary for chemotherapy delivery was fewer for EOX group than FOLFOX4 group by 3 (5.3 for
EOX and 8.2 for FOLFOX4). The usage of unexpected medications per patient was also found to be less
frequent for EOX group (7.8 for EOX and 14.1 for FOLFOX4). Both differences were found to be
statistically significant. Besides, there was also a significant difference in the hospitalization between
both groups. The average expected hospital bed-days for FOLFOX4 patients were more than 4 times
higher than that for EOX patients (5.3 days for EOX and 23.5 days for FOLFOX4). The usage of hospital
services including specialist outpatient clinic, general outpatient clinic, A&E department, laboratory tests
as well as radiological examinations such as X-rays and scans did not differ significantly between the two
groups.

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Comparison of costs of treatment
Healthcare Costs

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Table 3 shows the healthcare costs spent in both groups. Among all types of expected costs, only the
cost for radiological investigations was not proven to have statistically significant difference between
EOX and FOLFOX4 groups. For EOX arm, the average expenditure on expected medications, laboratory
tests, and outpatient visits were all significantly high than those incurred in the FOLFOX4 treatment arm.
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As a result, compared with patients in FOLFOX4 group, patients in EOX group spent around 4 times more
on medications, and 1.3 times more on both laboratory investigations and outpatient visits.
Nevertheless, the money that EOX patients spent on hospital days required for chemotherapy delivery
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was 16.5 times less than that for FOLFOX4 patients (US$600 vs US$9900). Overall, the sum of money
that was used in EOX group as chemotherapy related costs was US$5,854.4 per cycle and US$30,963.1
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per patient, which was 54.9% and 69.6% less than the corresponding costs in FOLFOX4 group
(US$12,979.8 and US$101,841.3). As far as unexpected costs are concerned, the inpatient stay cost per
cycle of chemotherapy for FOLFOX4 was higher than that for EOX.
The total healthcare cost spent per patient, with the expected healthcare cost in particular, was higher
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for FOLFOX4 group than for EOX group. EOX patients spent a total of US$44,397.1 direct medical costs
whereas FOLFOX4 patients spent a total of US$135,387.9, indicating that EOX regimen was around 67.2%
less expensive than FOLFOX4 regimen from the perspective of healthcare provider. A net cost savings of
more than US$90,000 was generated for giving the EOX regimen.
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For both groups, nausea and vomiting were the most commonly associated adverse events;
hence the most frequently used medications were anti-emetic drugs. Metoclopramide tablets,
famotidine tablets and dexamethasone tablets were the most common anti-emetics prescribed to EOX
patients, while metoclopramide tablets and injections were more common in FOLFOX4 group. In EOX
group, the second most common adverse event was grade 1 to 2 hand foot syndrome and diarrhea,
followed by myelosuppression and peripheral neuropathy. As for FOLFOX4 group, the second most
common adverse event was grade 1 to 2 peripheral neuropathy, followed by constipation, bone marrow
suppression, and phlebitis.
Societal Costs
Table 4 shows the societal costs spent in both groups. It is found that patients’ time cost was higher for
the FOLFOX4 group, while their travel cost was higher for the EOX group. The patient treatment cost
includes the cost of oxaliplatin injections for each respective regimen/dose as well as the day-ward stay
or inpatient stay costs responsible to be paid by the patients.
Statistical significant differences were proven in all expected societal but in none of the unexpected
costs. Overall, the total indirect medical cost per patient for EOX group, including both expected and
unexpected costs, was 25.3% lower than that for FOLFOX4 group (US$24,105.9 vs. US$32,253.4).
Sensitivity Analyses
Full Cycle Costs
Assuming that the full 8 and 12 cycles had been administered successfully, along with the cost of
medication, the total cost with healthcare provider and societal combined should be $103,618.4 for EOX
and $255,706.8 for FOLFOX4. The reduction in cost for giving EOX is now 59.5% instead. Thus using the

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full number of cycles of the drugs would not change the relative cost-effectiveness.
Healthcare Costs based on Net Cost for Capecitabine or 5-FU/Leucovorin

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Actual Healthcare Costs
The healthcare cost analysis after removing the acquisition costs of epirubicin, oxaliplatin, pre-
medications and fluids for infusion and leaving only capecitabine, 5-FU and leucovorin costs for
comparison. Results showed that the net medication cost difference between EOX and FOLFOX4 group
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has become larger, with the drug cost in EOX group increasing from 2 to 3.5 times higher than FOLFOX
group for each cycle ($1463.3 vs $412.6). However, a higher total expected cost per cycle and for each
patient was still achieved by the FOLFOX4 group. As far as the overall healthcare costs per patient,
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including both expected and unexpected were concerned, EOX regimen was 69.5% much less expensive
than FOLFOX4 regimen.
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Discussions:
Findings Favoring FOLFOX Regimen

From the result findings, as far as expected chemotherapy drug cost is concerned, FOLFOX4
regimen was more favorable as the cost is only half of that for EOX regimen. This is because
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capecitabine is a newer drug than 5-FU, hence the acquisition cost for capecitabine tablets is higher than
that for 5-FU and leucovorin injectables. In addition, FOLFOX group was discovered to have a lower
expected cost for laboratory investigations. It was because EOX is a tri-weekly regimen while FOLFOX4 is
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bi-weekly. Due to the shorter interval between each FOLFOX4 cycle, fewer laboratory tests including
biochemistry and hematology investigations than EOX group were necessary to monitor patients’
conditions for each cycle. Nevertheless, the total number of laboratory tests performed for both groups
did not have a significant difference.

For the expected patient travel cost, although the difference was relatively less significant,
FOLFOX4 patients seemed to pay less. This was because three of the patients in EOX group lived
relatively far away from the hospital, rendering the mean travel cost to be higher as a result. Besides, a
lot of patients in EOX group had their blood taken for laboratory tests on the previous day before follow-
up at specialist outpatient clinic, while all patients in the FOLFOX4 group had their blood test done on
the same day as follow-up. Therefore, EOX patients had to pay extra travel costs for blood tests, which
may account for the higher expenses in transport as well. Nevertheless, the total number of hospital
visits intended for chemotherapy delivery or follow-up was in fact similar for both groups (18.4 vs 19.3).

Findings Favoring EOX Regimen

According to the results, EOX therapy is more favorable in terms of expected hospitalization cost
and time cost for delivery of chemotherapy. Among all the chemotherapeutic drugs of interest in this
study, all of them are given intravenously except capecitabine, which is the only oral agent that can be
taken by patients in the form of tablets. Therefore, a great difference in the necessary hospitalization
time for intravenous chemotherapy delivery might be observed in EOX and FOLFOX4 group, thus
accounting for the significant difference in the number of expected hospital bed-days and their
associated costs between both groups. Due to less time for intravenous administration, the lower
expected time cost found for EOX patients than FOLFOX4 patients could also be explained. In addition,

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intravenous agents are always administered together with additional items like solvents, water for
injections, fluids for infusion and/or heparin block set (also known as saline drip) for flushing purpose.

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For instance, epirubicin is given via normal saline running drip, oxaliplatin is administered in 5% dextrose
solution, while leucovorin and 5-FU are given in normal saline.[19] Since less intravenous administration
is involved in EOX regimen, the usage as well as the corresponding cost of these subsidiary items was
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also lower than FOLFOX4 group, hence justifying the results.

Findings in Unexpected Costs

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The number of unexpected medications taken by FOLFOX4 patients was discovered to be higher
than EOX patients, indicating patients in FOLFOX4 group had used more drugs for treatment or
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prevention of adverse events. Since capecitabine is more selective to tumor cells than 5-FU, EOX might
have fewer adverse effects.[25,26] Epirubicin and oxaliplatin are agents of moderate emetic risk (30%-
90% frequency of emesis), whereas capecitabine and 5-FU are of low emetic risk (10%-30% frequency of
emesis).[27] Combination therapy hence makes EOX and FOLFOX regimens highly emetic (>90%
frequency).[27] Therefore, nausea and vomiting were the most commonly observed side effects in both
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groups. Peripheral neuropathy (dose-limiting toxicity (DLT) of oxaliplatin) together with

myelosuppression (DLT of epirubicin and 5-FU) were also noted in both groups. Due to slow marrow
recovery leading to neutropenia, patients sometimes had to delay the next chemotherapy cycle and
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attend additional follow-ups, which caused an increase in unexpected cost. Hand foot syndrome and
diarrhea were more frequently seen in EOX group since these are the DLTs of capecitabine. In addition,
superficial phlebitis was another adverse event that was noted more commonly in FOLFOX4 than EOX
patients. It is one of the major complications of intravenous administration as a result of infection at the
site of catheter insertion.[28] The catheter should be removed as soon as possible, as prolonged
insertion is associated with a greater risk of insertion-site infection, which would in turn bring about
complications like phlebitis, cellulitis and even sepsis.[28] Since FOLFOX4 requires more than 50 hours
for intravenous delivery while EOX only requires several hours, the risk of superficial phlebitis is actually
higher in FOLFOX group, which might lead to a higher unexpected management cost.
Comparison with Other Studies

From the results of this study, it was discovered that although the purchase price of EOX regimen was
nearly twice more expensive than FOLFOX4 regimen, EOX was indeed the more cost-effective one in
Hong Kong when all other usage of healthcare resources were taken into consideration. The subgroup
analysis based on the net cost of capecitabine versus 5-FU/ leucovorin even provides further
demonstration on the cost-saving effects of capecitabine. The total direct medical expenses could be
saved up to 60% for EOX therapy, and the total indirect societal costs could also be reduced by more
than 40%. These findings were consistent with the study conducted by Giuliani et al in 2007, which
evaluated the economic impact of capecitabine plus cisplatin (XP) and 5-FU plus cisplatin (FP) regimens
on the treatment for advanced gastric cancer in an Italian setting.[29] Although the regimens compared
are not exactly the same for both studies, the targeted therapies were still either being a capecitabine-
based or 5-FU-based treatment with the involvement of a platinum agent. Therefore, comparison could
still be considered applicable. The Italian study also revealed oral capecitabine to be capable of saving

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both healthcare and societal costs by reducing the hospital bed-days required for infusion and time
spent in receiving treatment.[29] A similar cost-minimization study on capecitabine-based and 5-FU-

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based regimens in colorectal cancer management was also been performed by Tse et al. in Hong
Kong.[30] Since both gastric cancer and colorectal cancer belong to gastrointestinal diseases which are
treated with similar chemotherapeutic drugs, comparison between these two studies could be workable
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as well. XELOX (oxaliplatin plus capecitabine) and FOLFOX4 (same as FOLFOX4 in gastric cancer)
regimens were compared in Tse’s study, the result of which also showed XELOX to cost less than
FOLFOX4 due to less usage of hospital resources.[30] As a result, it can be concluded from the above
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studies that capecitabine is indeed able to promote cost savings from both healthcare and societal
perspectives.
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Limitations
There are several limitations concerning this study. First of all, the uneven distribution of patient cases
in each regimen arm and the small sample size. However, this was already the maximum number of
cases that can be retrieved from the databases in the two hospitals. EOX and FOLFOX4 regimens are not
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adopted in all public hospitals in Hong Kong for patients with aGC. In Hong Kong, there are only seven
hospitals with clinical oncology services provided. Among these seven hospitals, PMH and PYNEH are
the few that are known to use both EOX and FOLFOX4 regimens.
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Secondly, two patients in EOX group were admitted to other public and private hospitals in Hong
Kong for care during the treatment period as a result of adverse events. Since the inpatient records at
these hospitals were not accessible at the time of this study, the healthcare resources or services used
by patients during the hospitalization period, such as medications, laboratory tests and radiological
examinations were unknown. Therefore, this would lead to an underestimation of unscheduled
healthcare costs in the EOX arm.
Finally, as quite a large number of patients were elderly, they may have some caretakers from
their families or friends to take care of their daily life, including hospital and clinic visits. These
caretakers have probably accompanied the patients for the chemotherapy delivery, outpatient visits, as
well as laboratory tests and procedures. However, there has been no information concerning their time
costs and travel costs. As a result, both expected and unexpected societal costs may be underestimated.
Nevertheless, if these data were taken into consideration as well, the savings on EOX regimen compared
with FOLFOX4 regimen could become greater, since the caretakers may spend less time on the
administration of EOX therapy.
Conclusion:
From a healthcare provider's perspective, EOX is more cost-effective than FOLFOX4 given similar efficacy
and adverse event outcomes as indicated from previously published trials in regions which FOLFOX4 is
given in an inpatient setting. Although the apparent cost per dose is higher for EOX, most patients
require fewer cycles than that required by the FOLFOX4 regimen. Added to this is the saving in hospital
costs due to the route of administration of capecitabine versus 5-FU/leucovorin. EOX also imposes
fewer costs on the patient and results in fewer days lost from work. Altogether with provider and
societal costs combined, the capecitabine-based regimen, EOX, is cost-effective compared to the 5-FU-
based regimen, FOLFOX4, and should be advocated when appropriate.

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fluorouracil/ cisplatin as first-line therapy in patients with advanced gastric cancer: a randomized
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3. Ahmedin Jemal, Freddie Bray, Melissa M. Center, Jacques Ferlay, Elizabeth Ward, David Forman.
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5. American Cancer Society, Inc.: Cancer facts and figures 2012.
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prospective trial. Ann Sur 2005; 241:232-7.

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7. Layke JC, Lopez PP. Gastric cancer: diagnosis and treatment options. Am Fam Physician. 2004;
1;69(5):1133-40.

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8. Allum WH, Blazeby JM, Griffin SM, Cunningham D, Jankowski JA, Wong R. Guidelines for the
management of oesophageal and gastric cancer. Gut 2002; 50(Suppl V):v1–v23.
9. Jaffer A. Ajani. Evolving Chemotherapy for Advanced Gastric Cancer. The Oncologist 2005; 10(suppl
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3):49–58.
10. M. MacKenzie, K. Spithoff, D. Jonker and the Gastrointestinal Cancer Disease Site Group. Systemic
therapy for advanced gastric cancer: a clinical practice guideline. Curr Oncol 2011; 18 (4):202-209.
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11. Roche Laboratories: Xeloda (Capecitabine) patient package insert.
12. Cunningham D, Starling N, Rao S, Iveson T, Nicolson M, Coxon F, Middleton G, Daniel F, Oates J,
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Norman AR. Capecitabine and oxaliplatin for advanced esophagogastric cancer. N Engl J Med 2008;
358:36-46.
13. A F C Okines, A R Norman, P McCloud, Y-K Kang, D Cunningham. Meta-analysis of the REAL-2 and ML
17032 trials: evaluating capecitabine-based combination chemotherapy and infused 5-fluorouracil-
based combination chemotherapy for the treatment of advanced oesophago-gastric cancer. Ann
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Oncol 2009; 20(9):1529-1534.

14. Luigi Cavanna, Fabrizio Artioli, Claudio Codignola, Antonio Lazzaro, Anna Rizzi, Alessandro Gamboni,
Luigina Rota, Carmelina Rodino`, Fabrizio Boni, Aldo Iop, and Alberto Zaniboni. Oxaliplatin in
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Combination With 5-Fluorouracil (5-FU) and Leucovorin (LV) in Patients With Metastatic Gastric
Cancer (MGC). Am J Clin Oncol 2006;29: 371–375.
15. Yan D, Dai H. FOLFOX regimen in the patients with locally advanced or metastatic gastric cancer.
Zhonghua Zhong Liu Za Zhi. 2009 Mar;31(3):217-9.
16. Hospital Authority: Statistical Report 2009 – 2010.
[http://www.ha.org.hk/upload/publication_15/321.pdf] (Accessed on 15/4/2012)
17. Hong Kong Special Administrative Region: Budget Highlights 2011-2012.
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18. National Health Service: Chemotherapy Protocol – Gastrointestinal (Upper Cancer): Capecitabine,
Epirubicin and Oxaliplatin (EOX). January 2011 (Version 1.1)
19. Princess Margaret Hospital: PMH Chemotherapy Protocol.
20. Princess Margaret Hospital: PMH Formulary 2011.
21. The Government of the Hong Kong Special Administrative Region: Special Supplement No. 4 to the
Government of the Hong Kong Special Administrative Region Gazette. Supplement to Gazette No 13
2003, 7.
22. Census and Statistics Department at the Government of the Hong Kong Special Administrative
Region: Women and Men in Hong Kong Key Statistics 2011 Edition.
23. Transport Department at the Government of the Hong Kong Special Administrative Region: Taxi Fare
Information 2011.
24. Shirasaka T, Taguchi T. Timeline from discovery of 5-FU to development of an oral anticancer agent
S-1 and its drug concept. Gan To Kagaku Ryoho 2006; 33 Suppl 1:4-18.
25. Ishitsuka H, Shimma N, Horii I. Discovery and development of novel anticancer drug capecitabine.
Yakugaku Zasshi. 1999; 119(12):881-97.

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26. Ishitsuka H. Capecitabine: preclinical pharmacology studies. Invest New Drugs 2000; 18(4):343-54.
27. Richard J. Gralla. New Agents, New Treatment, and Antiemetic Therapy. Seminars in Oncology 2002:

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29(1) Suppl 4:119-124.
28. Naomi P. O'Grady, Mary Alexander, Lillian A. Burns, E. Patchen Dellinger, Jeffery Garland, Stephen O.
Heard, Pamela A. Lipsett, Henry Masur, Leonard A. Mermel, Michele L. Pearson, Issam I. Raad,
Adrienne Randolph, Mark E. Rupp, Sanjay Saint, and the Healthcare Infection Control Practices
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Infections, 2011. Centers for Disease Control and Prevention.
29. G. Giuliani, A. Falcone and L. Garrison. Economic evaluation of the cost of treating advanced gastric
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cancer (AGC) with capecitabine/cisplatin (XP) vs. 5-FU/cisplatin (FP) regimens in an Italian setting. J
Clin Oncol 2007;25(18S):15022.
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30. Vicki C Tse, Wai Tong Ng, Victor Lee, Anne WM Lee, Daniel TT Chua, June Chau and Sarah M McGhee.
Cost-analysis of XELOX and FOLFOX4 for treatment of colorectal cancer to assist decision making on
reimbursement. BMC Cancer 2011, 11:288.
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Appendix I Median wages in Hong Kong

Wage Levels for Different Age and Sex Groups in Hong Kong (HK$)

Female Male

Age Median Hourly Wage Median Hourly Wage

15 $42.5 $38.4

25 $65.5 $68.0

35 $68.5 $73.0

45 $43.3 $68.6

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55 $37.0 $50.0

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Female Male
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Age Median Monthly Wage Median Monthly Wage

15 $5,500.0 $5,500.0
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20 $9,500.0 $9,500.0
AC

30 $13,000.0 $14,200.0

40 $11,000.0 $15,000.0

50 $8,000.0 $12,000.0
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60 $6,000.0 $9,000.0
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Appendix II Taxi fare from the Transportation Department

Fare Table – Urban Taxi

Fare (HK$)

First 2 kilometres or any part thereof $20

Every subsequent 200 metres or part thereof, or

Every period of 1-minute waiting time or part thereof

 Until the chargeable amount reaches $72.5 $1

 After the chargeable amount has reached $72.5 $1.5

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Surcharge for Every Hiring Involving the Use of Toll Tunnel,
Toll Road or Toll Area
EP
Cross-Harbour Tunnel Amount of toll paid by driver + $ 10*
(Return toll)

Eastern Harbour Crossing Amount of toll paid by driver + $ 15*

C

(Return toll)
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Western Harbour Crossing Amount of toll paid by driver + $ 15*

(Return toll)

* The return toll is not payable by passenger if:

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 the hiring begins from a cross-harbour taxi stand; or

 the final destination is not on the opposite side of the
harbor.
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Lantau Link $ 30

Other toll tunnel, toll road or toll area Amount of toll paid by driver
Table 1 – Baseline Characteristics of Patients in Both Groups

EOX FOLFOX4 Statistical Significance

(n=13)
(n=45) p-value

% of Male 57.8 61.5 0.81

% of Chinese Ethnicity 100 100 -

Mean Age / years (S.D.) 56.6 (10.0) 56.5 (13.3) 0.955

Mean Body Surface Area 1.57 (0.18) 1.52 (0.18) 0.381

/ m2 (S.D.)

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% of Patients with <2 93.3 76.9 0.09
ECOG Performance
≧2 6.7 23.1 0.09

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Score

% of Patients with Normal 73.3 84.6 0.598

Alkaline Phosphatase
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which was Elevated 24.4 15.4

% of Patients with No. of 0 6.7 7.7 0.867

Metastatic Sites =
C

≧1 93.3 92.3
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% of Patients with Liver 20.0 15.4 0.711

Metastases
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Mean Survival from 503.8 (295.5) 610.7 (438.0) 0.447

Diagnosis / days (S.D.)
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Table 2 – Healthcare Resources Used by Patients in Both Groups

EOX FOLFOX Statistical

(n=45) (n=13) Significance
Mean (SD) Mean (SD) p-value

No. of 5.3 (1.0) 7.9 (3.5) 0.011

Chemotherapy
Cycles
No. of Drugs Expected 5.3 (2.0) 8.2 (2.1) <0.001*
Used Unexpected 7.8 (5.1) 14.1 (6.2) 0.001*
No. of Hospital Expected 5.3 (1.0) 23.5 (10.2) <0.001*
Bed-days Unexpected 2.1 (5.8) 4.7 (5.1) 0.001*
No. of Hospital Expected 20.3 (5.1) 21.1 (10.0) 0.963

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Visits Unexpected 5.6 (4.3) 5.9 (5.1) 0.97

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No. of Expected 22.9 (6.4) 25.5 (12.9) 0.867
Laboratory Unexpected 7.2 (6.4) 13.7 (15.6) 0.08
Investigations
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No. of Xray & Expected 1.5 (0.8) 3.1 (5.2) 0.194
Scans Unexpected 0.7 (1.8) 0.7 (0.9) 0.359
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AC

Table 3 – Healthcare Cost for Patients in Both Groups

EOX FOLFOX Statistical

Significance
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(n=45) (n=13)
p-value
Mean (S.D.) Mean (SD)
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Expected Cost
(USD)/ cycle

Medication 290.3 (45.4) 66.9 (13.4) <0.001*

Day Ward/ Inpatient 76.9 (0) 1269.2 (0) <0.001*

Visits

Laboratory Tests 145.6 (37.7) 108.5 (25.7) 0.002*

Xrays & Scans 97.5 (46.3) 108.6 (47.1) 0.479

 Outpatient Visits 140.3 (33.7) 110.9 (20.9) 0.002*

Total Expected Cost 750.6 (86.8) 1664.1 (82.6) <0.001*

(USD)/ cycle

Total Expected Cost 3969.6 (459.2) 13056.6 (648.1) <0.001*

(USD)/ patient

Unexpected Cost
(USD)/ cycle

Medication 14.5 (31.9) 14.0 (21.2) 0.202

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A&E 4.9 (9.3) 10.7 (13.7) 0.068

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Hospital Bed-days 191.4 (576.0) 353.8 (544.8) 0.005*

Laboratory Tests 37.1 (32.1) EP62.2 (58.8) 0.167

Xrays & Scans 26.5 (65.0) 39.5 (98.2) 0.63

Outpatient Visits 43.0 (31.4) 50.6 (54.2) 0.758

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Total Unexpected 317.5 (633.1) 530.8 (609.4) 0.028
Cost (USD)/ cycle
AC

Total Unexpected 1679.3 (3348.2) 4193.3 (4781.4) 0.002*

Cost (USD)/ patient
ST

Total Cost (USD)/ 5549.6 (3388.2) 16923.5 (4885.5) <0.001*

patient
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Table 4 – Societal Cost for Patients in Both Groups

EOX FOLFOX Statistical

(n=45) (n=13) Significance
Mean (SD) Mean (SD) p-value

Expected Cost
(USD)/ cycle
Patient Time Cost 68.0 (19.3) 126.6 (58.9) <0.001*
(USD)
Patient Travel Cost 50.3 (36.3) 29.6 (14.8) 0.097
(USD)
Patient Treatment 387.1 (58.5) 290.3 (33.5) <0.001*
Cost (USD)
Total Expected Cost 505.5 (88.5) 446.5 (44.4) 0.259

D
(USD)/ cycle
Total Expected Cost 2673.3 (467.8) 3527.6 (348.1) <0.001*

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(USD)/ patient

Unexpected Cost
(USD)/ cycle
EP
Patient Time Cost 40.4 (61.1) 38.3 (50.0) 0.107
(USD)
Patient Travel Cost 13.3 (13.8) 8.68 (7.9) 0.195
(USD)
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Patient Treatment 10.6 (17.6) 16.8 (17.2) 0.043

Cost (USD)
AC

Total Unexpected 64.3 (80.6) 63.8 (67.3) 0.267

Cost (USD)/ cycle
Total Unexpected 340.0 (439.6) 504.1 (527.7) 0.023
Cost (USD)/ patient
ST

Total Cost (USD)/ 3013.2 (710.7) 4031.7 (698.0) 0.001*

patient
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