Surg Today (2007) 37:923–943
DOI 10.1007/s00595-007-3578-5
Review Article
UFT (Tegafur and Uracil) as Postoperative Adjuvant Chemotherapy
for Solid Tumors (Carcinoma of the Lung, Stomach, Colon/Rectum,
and Breast): Clinical Evidence, Mechanism of Action,
and Future Direction
FUMIHIRO TANAKA
Department of Thoracic Surgery, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya 663-8501, Japan
Abstract
UFT (tegafur and uracil) is an oral anticancer drug that
has been developed in Japan. Owing to its mild toxicity
profile, UFT can be suitable in an adjuvant setting fol-
lowing a complete tumor resection, whereas its direct
antitumor effect achieved may be insufficient for
advanced unresectable disease. Therefore, a variety of
adjuvant chemotherapy trials with UFT have been con-
ducted, and results of well-designed randomized con-
trolled trials have recently shown a survival benefit of
postoperative UFT treatment in resected lung, gastric,
colorectal, and breast cancer. In the present article,
postoperative adjuvant trials with UFT-containing che-
motherapy are reviewed, and the mechanism of action
and future directions are also discussed.
Key words Tegafur · Uracil · UFT · Solid tumor · Adju-
vant chemotherapy
Introduction
UFT, a combination drug of tegafur (FT) and uracil (U)
in a molecular ratio of 1 : 4, is an oral anticancer agent
which has been developed in Japan (Fig. 1).1–3 FT is
gradually converted to 5-fluorouracil (5-FU), and 5-FU
is phosphorylated into active metabolites such as 5-
fluoro-2′-deoxyuridine-5′-monophosphate (FdUMP);
FdUMP shows cytotoxic effect mainly through the inhi-
bition of enzyme activity of thymidylate synthase (TS)
which is a key enzyme in de novo DNA synthesis. 5-FU
is also degraded into F-β-alanine by dihydropyrimidine
dehydrogenase (DPD), and a rapid degradation of 5-
FU results in a reduced anti-tumor effect caused by 5-
Reprint requests to: F. Tanaka
Received: March 5, 2007 / Accepted: April 18, 2007
FU and its derivatives such as FT. UFT is defined as
DPD-inhibitory fluoropyrimidine (DIF), as an inhibitor
of DPD, uracil (U), is added to FT. Through inhibition
of 5-FU degradation, DIF such as UFT can achieve a
higher maximum plasma 5-FU level for a longer period,
thus resulting in an enhanced antitumor effect.1–4
According to a pooled analysis of Japanese phase II
trials of UFT-alone treatment for advanced unresect-
able solid tumors originating from a variety of organs
including the lung, stomach, colorectal, and breast, the
objective response rate (RP) was 25.1%.5 In another
phase II trial of UFT-alone treatment conducted in the
United Kingdom, lower RRs (16.7% and 6.2% for
gastric and colorectal cancer, respectively) were docu-
mented.6 These results show that UFT may be active in
a variety of malignant tumors, but the direct antitumor
effect is insufficient in comparison with that achieved
with modern intravenous chemotherapeutic agents such
as platinum agents and taxanes. Considering its lower
antitumor effect as well as the milder toxicity of UFT,
oral UFT administration may be therefore clinically
useful as an adjuvant treatment following a complete
tumor resection rather than as an aggressive treatment
for unresectable disease. Thus, in Japan, a variety of
clinical trials of postoperative adjuvant chemotherapy
using UFT have been conducted since the 1980s. Some
trials have suggested the efficacy of adjuvant UFT treat-
ment, while others have failed to show any efficacy
partly due to inappropriate trial designs. Recently, the
results of well-designed randomized controlled trials
(RCTs) comparing adjuvant chemotherapy with UFT
following surgery with surgery alone have been reported,
and they clearly showed a survival benefit of adjuvant
UFT treatment for lung,7–9 gastric,10 colorectal,11 and
breast cancer.12 In addition, recent experimental and
translational studies have revealed UFT to have a novel
mechanism of action, i.e., angiogenesis inhibition, in
addition to its cytotoxic effect via 5-FU derived from
FT,13,14 which may answer the question why UFT is
924
active in a postoperative adjuvant setting whereas UFT
shows an insufficient antitumor effect for unresectable
disease. More recently, it has been reported that the
postoperative administration of S-1, a novel DIF with a
more potent antitumor activity, significantly improves
the survival of curatively-resected stage II–III gastric
cancer patients,15 which may provide a new insight into
postoperative adjuvant chemotherapy for more
advanced-stage patients. In the present article, reported
clinical studies of adjuvant therapy using UFT are
reviewed, and the mechanism of action and future direc-
tions are also discussed.
UFT in Postoperative Adjuvant Setting: Review of
Clinical Studies
In most solid malignant tumors, early detection and a
complete resection is the most effective therapy for the
cure. However, even when a complete resection can be
achieved, postoperative recurrence may occur. Local
recurrence can be reduced with improved surgical tech-
niques and/or modern radiotherapy, and, if it occurs, it
can then be effectively controlled with salvage surgery
and/or radiotherapy. Therefore, the prevention or
control of distant metastasis after surgery plays a critical
role in improving postoperative survival, and a number
of adjuvant trials of systemic chemotherapy have been
conducted to assess its survival benefit. We herein
review postoperative adjuvant chemotherapy trials,
while focusing on those using UFT, for lung (Table 1A
and B), gastric (Table 2), colorectal (Table 3), and
breast cancer (Table 4).
Lung Cancer
Primary lung cancer is the leading cause of cancer
deaths in most industrialized countries, and it is
clinically classified into small cell lung cancer (SCLC)
or into non-small cell lung cancer (NSCLC) including
adenocarcinoma and squamous cell carcinoma. SCLC
patients should be primarily treated with chemotherapy
with or without radiation because of early develop-
ment of nodal and distant metastasis as well as an
excellent response to chemo (-radio) therapy. For
patients with NSCLC, which accounts for 75%–80% of
primary lung cancer, a surgical resection should be con-
sidered as the primary therapy, but the postoperative
prognosis remains unsatisfactory.16–18 The 5-year overall
survival (OS) rates of patients with pathologic (p-) N2
disease, in which mediastinal nodes are involved, have
been reported to be less than 20%; even in p-stage
I disease, in which no nodal or distant metastasis is
documented, the 5-year OS rates remain less than
80%.16–19
F. Tanaka: UFT as Postoperative Adjuvant Chemotherapy
To improve the survival of resected NSCLC patients,
numerous adjuvant therapy regimens had been exam-
ined in clinical trials, but the efficacy had not been
established for a long time; a meta-analysis conducted
by the PORT Meta-analysis Trialists Group in 199820
(updated in 200521) showed that postoperative radio-
therapy provided no survival benefit, and a meta-
analysis conducted by the Non-small Cell Lung Cancer
Collaborative Group in 1995 showed that postoperative
cisplatin (CDDP)-based chemotherapy provided a mar-
ginal survival benefit (a 5% improvement in OS at 5
years after surgery; P = 0.08).22 Since 2003, however,
consistent results of RCTs have been reported, showing
that the OS and recurrence-free survival (RFS) of
patients treated with CDDP-based chemotherapy
are significantly higher than those of surgery-alone
patients,23–25 and a meta-analysis of these RCTs revealed
that adjuvant CDDP-based chemotherapy significantly
reduced the risk of postoperative death with the hazard
ratio (HR) of 0.89 (95% confidence interval [CI]: 0.82–
0.96; P < 0.005) thus corresponding to a 4.2% OS
improvement at 5 years.26 Whereas these results clearly
showed the efficacy of postoperative adjuvant CDDP-
based chemotherapy in NSCLC, attention should be
paid to the 1%–2% mortality rate caused by adjuvant
CDDP-based chemotherapy.23–25 In addition, CDDP-
based chemotherapy showed either no effect or a reverse
effect on earlier-stage patients (HR: 1.41 and 0.93 for
stage IA and for stage IB disease, respectively), whereas
it achieved a significant survival benefit on stage II–III
patients (HR: 0.83 for both stage II and III diseases).26
Therefore, adjuvant chemotherapy with a mileder tox-
icity profile such as UFT should be considered for
earlier-stage NSCLC patients.
Nine RCTs of postoperative adjuvant chemotherapy
with UFT alone (Table 1A)7–9,27–29 or UFT following
CDDP-based regimen (Table 1B)7,9,30–32 have been
reported. The 2nd study conducted by the West Japan
Study Group for Lung Cancer Surgery (WJSG) is the
landmark trial showing the efficacy of postoperative
adjuvant chemotherapy for resected NSCLC.7 This is a
three-arm trial, and 323 patients with resected p-stage
I–III NSCLC were randomly assigned to a surgery-
alone group, a UFT-alone group, or a CDDP plus vin-
desine (VDS) followed by UFT (CVUft) group. The
5-year OS rates were 49.0% for the surgery-alone
group, 64.1% for the UFT group, and 60.6% for the
CVUft group, thus showing a significant difference
among the three groups (P = 0.044); the most favorable
finding was that for the UFT group with a significant
improvement as compared with that for the surgery-
alone group (P = 0.022 and HR = 0.55 [95% CI: 0.36–
0.86]). The Japan Lung Cancer Research Group on
Postsurgical Adjuvant Chemotherapy (JLCRG) study
is the largest trial of postoperative adjuvant chemo-
F. Tanaka: UFT as Postoperative Adjuvant Chemotherapy 925

Table 1A. Phase III randomized controlled trials (RCTs) of postoperative adjuvant chemotherapy with UFT-alone for resected
non-small cell lung cancer (NSCLC)
Results (survival rate at 5 years
after surgery)

Recurrence-free
Overall survival survival
Trial (year)Ref. p-Stage Postoperative treatment (OS) (RFS)

WJSG (II) (1996)7 I–III Surgery alone (n = 98) 49.0% —

UFTa (n = 103) 64.1% —
P = 0.022
WJSG (IV) (2005)27 I Surgery alone (n = 169) 75.9% (61.2% at —
8 years)
UFTa (n = 163) 82.2% (73.0% at —
8 years)
P = 0.105
for T1 disease (stage 5-/8-year OS: 77.9/57.6% vs
IA) 83.6/82.1% (UFT) (P = 0.036)
for T2 disease (stage 5-/8-year OS: 76.1/62.3% vs
IB) 75.7/59.1% (UFT) (P = 0.807)
OLCSG (2006)9 I Surgery alone (n = 87) 57.6% (at 8 years) —
UFT† (n = 85) 74.2% (at 8 years) —
P = 0.045
Northeast Japan I–II Surgery alone (n = 110) 75% 71%
(2003)28 UFTb (n = 109) 79% 78%
P = 0.7013 P = 0.2427
ACTLC (2005)29 I Surgery alone (n = 50) 66.3% 66.5%
UFT§ (n = 50) 67.7% 68.8%
P = 0.844 P = 0.907
JLCRG (2004)8 I (adenocarcinoma) Surgery alone (n = 488) 85% —
UFTc (n = 491) 88% —
P = 0.04 (HR = 0.48 [95%CI,
0.52–0.98])
for T1 disease (stage 5-year OS: 90% vs 89% (UFT)
IA) (P = 0.87; HR = 0.97 [0.64–1.46])
for T2 disease (stage 5-year OS: 74% vs 85% (UFT)
IB) (P = 0.005; HR = 0.48 [0.29–0.81])

CI, confidence interval; p.o., oral administration

a
UFT (400 mg/body/day [p.o.], daily for 1 year); † UFT (400 mg/body/day [p.o.], daily for 1 year or more)
b
UFT (260 mg/m2/day or 400 mg/body/day [p.o.], daily for 2 years); § UFT (400 mg/body/day [p.o.], daily for 2 years)
c
UFT (250 mg/m2/day [p.o.], daily for 2 years)

therapy with UFT, in which a total of 979 patients with
resected p-stage I (T1 or T2) adenocarcinoma of the
lung were randomly assigned to receive UFT adminis-
tration (UFT group) or to only undergo observation
(surgery-alone group).8 The 5-year OS rates were 88%
for the UFT group and 85% for the surgery-alone
group, thus showing a significant survival benefit of
postoperative UFT administration (P = 0.04 and HR =
0.48 [95% CI: 0.52–0.98]). The survival benefit disap-
peared in stage IA (T1) subset (5-year OS, 89% for the
UFT group and 90% for the surgery-alone group; P =
0.87 and HR = 0.97 [95% CI: 0.64–1.46]), and was
enhanced in stage IB (T2) subset (5-year OS, 85% and
74%, respectively; P = 0.005 and HR = 0.48 [95% CI:
0.29–0.81]). According to an exploratory analysis, even
in stage IA subset, a significant survival benefit was
documented when the tumor measured greater than
2 cm in diameter.33
The efficacy of postoperative adjuvant UFT treat-
ment was confirmed in a meta-analysis of six RCTs
comparing UFT-alone treatment following surgery with
surgery alone (Table 5).34 Of the 2003 patients included
in the meta-analysis, most patients had p-stage I disease
and 1679 patients (83.8%) had adenocarcinoma. The
5- and 7-year OS rates were significantly higher in the
surgery plus UFT group (81.5% and 76.5%, respec-
tively) than in the surgery-alone group (77.2% and
69.5%, respectively), thus showing a significant reduc-
tion in postoperative death with UFT treatment (P =
0.001 and HR = 0.74 [95% CI: 0.61–0.88]).
926 F. Tanaka: UFT as Postoperative Adjuvant Chemotherapy

Table 1B. Phase III randomized controlled trials (RCTs) of postoperative adjuvant chemotherapy with UFT following cisplatin
(CDDP)-based chemotherapy for resected non-small cell lung cancer (NSCLC)
Results (survival rate at 5 years
after surgery)

Recurrence-free
Overall survival survival
Trial (year)Ref. p-Stage Postoperative treatment (OS) (RFS)

Chubu-Japan (1995)30 I–III Surgery alone (n = 154) 58.1% 57.4%

CDDP/DXR→UFTa (n = 155) 61.8% 61.8%
P = 0.347 P = 0.449
(P = 0.044**) (P = 0.036**)
(**P-value after adjustment by patients’
characteristics)
WJSG (II) (1996)7 I–III Surgery alone (n = 98) 49.0% —
CDDP/VDS→UFTb (n = 109) 60.6% —
P = 0.083
WJSG (III) (1999)31 I–II Surgery alone (n = 116) 71.1% —
CDDP/VDS/MMC→UFTc (n = 109) 76.8% —
P = 0.39 (P = 0.03
for T1N0)
OLCSG (2006)9 II–IIIA Surgery alone (n = 48) 36.8% (at 8 years) —
CDDP/VDS→UFTd (n = 47) 38.0% (at 8 years) —
P = 0.52
WJSG (V) (2005)32 IIIA–N2 UFTe (n = 30) 47% 18%
CDDP/VDS→UFTf (n = 28) 46% 31%
P = 0.401 P = 0.163

CDDP, cisplatin; DXR, doxorubicin; VDS, vindesine; MMC, mitomycin C; i.v., intravenous injection; p.o., oral administration
a
1 cycle of CDDP (66 mg/m2 [i.v.] on day 1) plus DXR (26 mg/m2 [i.v.] on day 1), followed by UFT (8 mg/kg/day [p.o.], daily for 6 months)
b
1 cycle of CDDP (50 mg/m2 [i.v.], once) plus VDS (2–3 mg/body [i.v.], 3 times), followed by UFT (400 mg/body/day [p.o.], daily for 1 year)
c
2 cycles of CDDP (80 mg/m2 [i.v.] on day 1), VDS (2–3 mg/m2 [i.v.] on day 1 and/or day 8) plus MMC (8 mg/m2 [i.v.] on day 1), followed by
UFT (400 mg/body/day [p.o.], daily for 1 year)
d
UFT (400 mg/body/day [p.o.], daily for 1 year)
e
1–2 cycles of CDDP (80 mg/m2 [i.v.], on day 1) plus VDS (2–3 mg/kg [i.v.], on days 1, 8, and 15), followed by UFT (400 mg/body/day [p.o.], daily
for 1 year)
f
2 cycles of CDDP (80 mg/m2 [i.v.], on day 1) plus VDS (3 mg/m2 [i.v.], on days 1 and 8), followed by UFT (400 mg/body/day [p.o.], daily for 1
year or more)

These results clearly showed a survival benefit of
UFT treatment in earlier-stage NSCLC, and postopera-
tive chemotherapy with UFT alone is recommended for
p-stage IB patients; p-stage IA patients, especially when
the tumor size is 2 cm or greater, can thus be candidates
for adjuvant UFT treatment. For more advanced
disease, however, there has been no reported evidence
of a survival improvement with UFT-alone treatment,
and more potent chemotherapy should be prescribed.
The WJSG-5th study is a unique trial comparing UFT-
alone with UFT following CDDP-based chemotherapy
in resected p-stage IIIA-N2 NSCLC.32 This study failed
to show any significant advantage of CDDP-based
chemotherapy (CDDP plus VDS) followed by UFT
(CVUft) over UFT-alone treatment, but the 5-year RFS
seemed higher in the CVUft group (31%) than in the
UFT-alone group (18%), which may suggest that UFT
following platinum-based chemotherapy is a promising
adjuvant chemotherapy regimen. Among modern
platinum-based regimens, carboplatin (CBDCA) plus
paclitaxel (PTX) is a well-tolerated regimen, and may
be preferably prescribed in postoperative adjuvant
setting. We conducted a single-institute phase II trial of
adjuvant chemotherapy with CDBCA/PTX followed by
UFT for completely resected node-positive (p-stage II-
N1 or IIIA-N2) NSCLC. An interim analysis showed a
favorable OS (74% at 3 years) and RFS (49% at 3
years) with only minimal toxicity (Fig. 2),35 which may
warrant a future phase III trial of adjuvant chemother-
apy with platinum-based chemotherapy followed by
UFT for resected advanced-stage NSCLC.
Gastric Cancer
The efficacy and optimal therapeutic regimen of post-
operative adjuvant therapy for completely resected
gastric cancer has not yet been established,36–38 although
a series of meta-analyses conducted in Western coun-
F. Tanaka: UFT as Postoperative Adjuvant Chemotherapy 927

Table 2. Phase III randomized controlled trials (RCTs) of postoperative adjuvant chemotherapy with UFT for resected gastric
cancer
Results (survival rate at 5 years
after surgery)
Recurrence-free
Overall survival survival
Trial (year)Ref. p-Stage Postoperative treatment (OS) (RFS)

JCOG8401-1 (1995)48 II–III MFC (MMC/5-FU/CA)→ 79.0% —

5-FUa (n = 173)
MFC (MMC/5-FU/CA)→ 70.0% —
UFTa (n = 174)
MF (MMC/5-FU)→UFTa 61.0% —
(n = 176)
P = 0.1228
JCOG8801 (1999)50,51 T1–2 Surgery alone (n = 285) 82.9% —
(serosa-negative) MF (MMC/5-FU)→UFTb 85.8% —
(n = 288)
P = 0.174 (HR = 0.738 [95%CI,
0.498–1.093])
for T1 disease 5-year OS: 94.9% vs 92.0% (MF+UFT)
(P = 0.619; HR = 1.273 [0.491–3.300])
for T2 disease 5-year OS: 76.9% vs 83.0% (MF+UFT)
(P = 0.059; HR = 0.670 [0.441–1.019])
JCOG9206-2 (2005)52 T3–4 Surgery alone (n = 133) 61.6% 57.1%
(serosa-positive) CDDP/5-FU→UFTc 62.7% 59.0%
(n = 135)
P = 0.482 P = 0.500
(HR = 0.992 (HR = 1.005
[0.697–1.412]) [0.711–1.422])
NSAS-GC01 (2005)10 T2N1–2 Surgery alone (n = 95) 73.6% (at 4 years) 68.1% (at 4 years)
(serosa-negative) UFTd (n = 93) 86.3% (at 4 years) 84.5% (at 4 years)
P = 0.0176 P = 0.0040
(HR = 0.46 (HR = 0.41
[0.23–0.89]) [0.22–0.77])

MMC, mitomycin C; 5-FU, 5-fluorouracil; CA, cytosine arabinoside; CDDP, cisplatin; NS, not significant; i.v., intravenous injection; p.o., oral
administration; i.p., intraperitoneal injection
a
6 cycles of MFC or MC (i.v., MMC [0.04 mg/kg] + 5-FU [5 mg/kg] ± CA[0.4mg/kg]) for 3 weeks, followed by oral 5-FU (200 mg/body/day, daily
for 10 months) or followed by oral UFT (400 mg/body/day, daily for 18 months)
b
6 cycles of MF (i.v., MMC [1.4 mg/m2] + 5-FU [166.7 mg/m2]) for 3 weeks, followed by UFT (300 mg/body/day [p.o.], daily for 18 months)
c
CDDP (70 mg/m2, i.p. during operation) and CDDP (70 mg/m2 [i.v.], day 14) plus 5-FU (700 mg/m2 [i.v.], days 14–16), followed by UFT (267 mg/
m2/day [p.o.], daily for 1 year)
d
UFT (360 mg/m2/day [p.o.], 5 days every 7 days for 16 months)

tries showed a small or borderline survival benefit of
postoperative chemotherapy39–44 and a RCT conducted
in the USA demonstrated a significant survival benefit
of postoperative chemo-radiotherapy.45 In Japan, a
meta-analysis of six Japanese RCTs conducted during
1959–1985 demonstrated a significant survival benefit of
postoperative adjuvant chemotherapy,46 but several
issues concerning study design as well as quality of clini-
cal trials included in the meta-analysis have been pro-
posed.39 Therefore, it is generally accepted in Japan that
surgery alone remains a standard therapy for respect-
able gastric cancer.37,38
As UFT is an active and well-tolerated chemothera-
peutic agent for gastric cancer,47 a series of RCTs of
adjuvant chemotherapy containing UFT for resected
gastric cancer have been conducted by the Japan Clini-
cal Oncology Group (JCOG)48–52 and other cooperative
study groups in Japan37 (Table 2). In the JCOG-8801
trial, a total of 579 patients with curatively resected
gastric cancer (T1 with nodal metastasis or T2 disease)
were randomly assigned to the surgery-alone group or
surgery followed by the chemotherapy group; chemo-
therapy consisted of intravenous chemotherapy (mito-
mycin C [MMC] plus 5-FU, MF) followed by oral UFT
administration.50,51 This study failed to show a significant
survival benefit of postoperative adjuvant chemother-
apy with MF plus UFT for T1-2 gastric cancer, but it did
show a trend in favor of the adjuvant chemotherapy
928 F. Tanaka: UFT as Postoperative Adjuvant Chemotherapy

Table 3. Phase III randomized controlled trials (RCTs) of postoperative adjuvant chemotherapy with UFT for resected colorec-
tal cancer
Results (survival rate at 5 years after surgery)

Recurrence-free
Overall survival survival
Trial (year)Ref. p-Stage Postoperative treatment (OS) (RFS)

Colorectal cancer
TAC-CR (2002)69 Dukes’ B–C Surgery alone (n = 144) 76.5% 60.1%
UFTa (n = 145) 80.4% 75.7%
P = 0.2877 P = 0.0081
(P = 0.0039 by ITT)
for colon cancer 84.0% vs 84.2% 74.0% vs 77.4%
(UFT) (P = (UFT) (P =
0.9712) 0.7087)
for rectal cancer 66.7% vs 75.9% 42.4% vs 73.6%
(UFT) (P = (UFT) (P =
0.1669) 0.0016)
Colon cancer
NSABP C-06 (2006)70 II–III 5-FU/LVb (n = 770) 78.7% 68.2%
UFT/LV (oral regimen)c 78.5% 67.0%
(n = 781)
P = 0.90 P = 0.96
HR = 1.014 HR = 1.004
[0.825–1.246] [0.847–1.190]

Rectal cancer
JFMC7-1 (1998)79 T3–4/n1–3 Surgery alone (n = 418) 66.3% 59.3%
MMC→UFTd (n = 416) 70.1% 68.9%
P = 0.338 P = 0.006
JFMC15-R (1 + 2) II, III, IV Surgery alone (n = 351) 72.9% 63.5%
(2004)80,81 MMC/5-FU (±OK-432) 74.4% 67.0%
→UFTe (n = 487)
P = 0.611 P = 0.209
NSAS-CC01 (2006)11 III Surgery alone (n = 135) 81% (at 3 years) 60% (at 3 years)
UFTf (n = 139) 91% (at 3 years) 78% (at 3 years)
P = 0.0048 P = 0.0014
HR = 0.42 [0.21–0.83] HR = 0.52 [0.33–0.81]

5-FU, 5-fluorouracil; LV, leucovorin; MMC, mitomycin C; p.o., oral administration; i.v., intravenous injection; ITT, intent-to-treatment analysis
a
UFT (400 mg/body/day [p.o.], daily for 2 years)
b
Weekly 5-FU (500 mg/m2 [i.v.]) plus LV (500 mg/m2 [i.v.]) for 6 weeks with 2 weeks’ rest, repeated for 3 cycles
c
Daily UFT (300 mg/m2/day [p.o.]) plus LV (90 mg/body/day [p.o.]) administration for 4 weeks with 1 week’s rest, repeated for 5 cycles
d
7 times of MMC (6 mg/m2 [i.v.]), followed by UFT (400 mg/body/day [p.o.], daily for 1 year); 20 mg/body of MMC was sprinkled on the opera-
tion field upon completion of surgery
e
8 times of MMC (6 mg/m2 [i.v.]) for 6 months plus daily i.v. of 5-FU (250 mg/day) for 1 week with (JFMC 15R-1) or without OK432 (JFMC
15R-2), followed by UFT (400 mg/body/day [p.o.], daily for 1 year)
f
UFT (400 mg/m2/day [p.o.], daily for 5 consecutive days with 2 days’ rest for 1 year)

group for T2 disease (P = 0.059). Based on this result,
a new RCT of adjuvant chemotherapy targeting for T2
patients was thus conducted by the National Surgical
Adjuvant Study of Gastric Cancer (NSAS-GC).10 In the
NSAS-GC01 trial, a total of 188 patients with com-
pletely resected serosa-negative T2 (N1–2) gastric
cancer were assigned to receive UFT treatment (360 mg/
m2/day, daily for 16 months) or to undergo observation,
and there proved to be a significant improvement with
adjuvant UFT treatment in both OS (73.6% versus
86.3% at 4 years; P = 0.0176) and RFS (68.1% versus
84.5% at 4 years; P = 0.0040). In contrast to the NSAS-
GC01 trial, the JCOG9206-2 trial showed no survival
benefit of postoperative adjuvant chemotherapy with
CDDP plus 5-FU followed by UFT for resected T3–4
gastric cancer (5-year OS, 61.6% for the surgery-alone
group and 62.7% for the chemotherapy group; P =
0.500).37,52
Recent meta-analyses of RCTs of adjuvant chemo-
therapy conducted in Japan showed a small or border-
line survival benefit of postoperative adjuvant
chemotherapy, especially UFT-containing chemother-
apy, for resected gastric cancer.53,54 More recently, a
meta-analysis of centrally randomized adjuvant UFT
F. Tanaka: UFT as Postoperative Adjuvant Chemotherapy 929

Table 4. Phase III randomized controlled trials (RCTs) of postoperative adjuvant chemotherapy with UFT for resected breast
cancer
Results (survival rate at 5 years after surgery)

Recurrence-free
Overall survival survival
Trial (year)Ref. p-Stage Postoperative treatment (OS) (RFS)

Grupo Oncologico de Selvilla (Spain) – First

(1997)99 Node-positive CMF (CPA/MTX/5-FU)a 67% 40%
(premenopausal) (n = 96)
UFT+Prednimustineb (n = 91) 66% 50%
P = 0.51 P = 0.47
Grupo Oncologico de Selvilla (Spain) – Second
(1997)99 Node-positive TAMc (n = 109) 75% 58%
(postmenopausal) TAM+UFTd(n = 113) 73% 54%
P = 0.507 P = 0.662
ACET-BC03: Pooled analysis of 5 RCTs*
(2003)102 Various UFT (−) (n = 933) 92.6% 83.3%
(according to UFT (+)e (n = 965) 93.8% 86.5%
each RCT)
P = 0.33 P = 0.060

[
Hokkaido Stage II, ER (+) MMC→TAM versus
*
Tohoku
Kanto-A
Stage I, n0
Stage I–II, n0, ER(−)
MMC→TAM+UFT
Surgery alone versus UFT
Surgery alone versus UFT
[
Kanto-B Stage I–II, n+, ER(+) TAM versus UFT+TAM
Nishi-Nihon Stage II–IIIa, ER(+) TAM versus UFT+TAM
ACET-BC-04: Pooled analysis of 6 RCTs†
(2005)12 Node-negative Surgery alone (Control, n = 860) 93.4%
(size ≤ 5 cm) TAMf (n = 865) 95.0% (HR = 0.73 [0.48–1.11], P = 0.14)
UFTg (n = 860) 96.0% (HR = 0.60 [0.39–0.94], P = 0.02)
UFT+TAM (n = 349) 95.7% (HR = 0.62 [0.34–1.14], P = 0.13)
→UFT (−), 94.0% vs UFT(+), 95.9% (P = 0.036)
→TAM (−), 93.9% vs TAM(+), 95.2% (P = 0.12)

[
† Tohoku, Kanto, Surgery alone versus TAM versus UFT [
and Chubu
Hokkaido, Kinki, Surgery alone versus TAM versus UFT versus TAM+UFT
and Nishi-Nihon
CUBC (2005)106 Node-positive CMF (CPA/MTX/5-FU)+TAMh 93.9% (at 3 years) 82.4% (at 3 years)
(I–IIIa) (n = 173)
UFT+TAMi (n = 177) 93.3% (at 3 years) 81.8% (at 3 years)
P = 0.81 P = 0.92
(HR = 1.11 [0.54–2.27]) (HR = 1.01
[0.67–1.58])
Kinki (2006)107 Node-positive CAFj (n = 82) 66.2% 46.3%
(I–IIIa) UFT+TAMk (n = 82) 82.1% 61.8%
P = 0.04 P = 0.07

CPA, cyclophosphamide; MTX, methotrexate; 5-FU, 5-fluorouracil; MMC, mitomycin C; TAM, tamoxifen; DXR, doxorubicin; p.o., oral adminis-
tration; i.v., intravenous injection
a
CPA (600 mg/m2, i.v.), MTX (40 mg/m2, i.v.) plus 5-FU (600 mg/m2, i.v.), repeated every 28 days for 6 cycles
b
Prednimustine (60 mg/m2/day, p.o., daily for 7 consecutive days; repeated every 28 days for 6 cycles) plus UFT (400 mg/body/day [p.o.], daily for
24 weeks)
c
TAM (20 mg/body/day [p.o.], daily for 1 year)
d
TAM (20 mg/body/day [p.o.], daily for 1 year) plus UFT (400 mg/body/day [p.o.], daily for 6 months)
e
UFT (300 mg/body/day [p.o.], daily for 2 years) in most RCTs; UFT (400 mg/body/day [p.o.], daily for 2 years) in the “Hokkaido” trial and UFT
(300 mg/body/day [p.o.], daily for 1 year) in the “Tohoku” trial
f
TAM (20 mg/body/day [p.o.], daily for 2 years)
g
UFT (300 mg/body/day [p.o.], daily for 2 years) for most RCTs; UFT (400 mg/body/day [p.o.], daily for 2 years) in the “Hokkaido” trial
h
CPA (65 mg/m2 [p.o.], days 1–14), MTX (40 mg/m2 [i.v.], days 1 and 8) plus 5-FU (500 mg/m2 [i.v.], days 1 and 8), repeated every 28 days for 6
cycles, and TAM (20 mg/body/day [p.o.], daily for 2 years)
i
UFT (270 mg/m2/day [p.o.], daily for 2 years) plus TAM (20 mg/body/day [p.o.], daily for 2 years)
j
CPA (100 mg/body/day [p.o.], days 1–14), DXR (20 mg/m2 [i.v.], days 1 and 8) plus 5-FU (300 mg/m2 [i.v.], days 1 and 8), repeated for 6 cycles
k
UFT (400 mg/body/day [p.o.], daily for 3 years) plus TAM (20 mg/body/day [p.o.], daily for 3 years)
930 F. Tanaka: UFT as Postoperative Adjuvant Chemotherapy

Table 5. Meta-analysis of randomized controlled studies (RCTs) comparing surgery plus postoperative adjuvant chemotherapy
using UFT with surgery alone
Postoperative treatment
Author No. of UFT (daily dose
(year)Ref. Trials included patients & duration) Other treatment Results

Lung cancer (non-small cell, NSCLC)

Hamada WJSG (II) n = 201 400 mg/body 1 year No 5-year/7-year OS:
(2005)34 WJSG (IV)
OLCSG
Northeast Japan
n = 332
n = 172
n = 219
400 mg/body
400 mg/body
260 mg/m2
1 year
≥1 year
2 years
No
No
No
[ 81.5%/76.5% (Surgery+
UFT, n = 1001)
77.2%/69.5% (Surgery
ACTLC n = 100 400 mg/body 2 years No alone, n = 1002)
JLCRG n = 979 250 mg/m2 2 years No P = 0.001, HR =
0.74[0.61–0.88]
Gastric cancer
Sakamoto Pre-JCOG8401 n = 223 670 mg/m2 (FT) 2 years MMC/5-FU/CA P = 0.011, HR =
(2006)54

JCOG8801
JCOG9206-2
n = 573
n = 268
or 133 mg/m2
(5-FU)
300 mg/body
267 mg/m2
18 months
12 months
MMC/5-FU
CDDP/5-FU
[ 0.71[0.54–0.92]

NSAS-GC01 n = 188 360 mg/m2

(5 days
every 7 days)
16 months No
Rectal cancer
Hamada JFMC 7-1 n = 834 400 mg/body 12 months MMC 5-year OS/RFS:
(2005)82 JFMC 15-2A
JFMC-15-2P
TAC-CR
NSAS-CC
n = 447
n = 391
n = 143
n = 276
400 mg/body
400 mg/body
400 mg/body
400 mg/m2
12 months
12 months
24 months
12 months
MMF+5FU
MMC+5FU
No
No
[ 74.0%/67.6%
(Surgery+UFT,
n = 1115)
69.0%/57.9% (Surgery
(5 days every alone, n = 976)
7 days) P = 0.03, HR = 0.83
[0.71–0.98] for OS
P < 0.0001, HR = 0.72
[0.62–0.83] for RFS

FT, tegafur; 5-FU, 5-fluorouracil; MMC, mitomycin C; CA, cytosine arabinoside; CDDP, cisplatin; OS, overall survival; RFS, recurrence-free
survival

trials for gastric cancer has been reported55 (Table 5).
In the meta-analysis, a total of 1503 patients were ana-
lyzed, and there proved to be a significant survival
benefit for the postoperative adjuvant UFT treatment
(HR = 0.70 [95% CI: 0.54–0.89] and P = 0.01). In com-
bination with the results of the NSAS-CG01 trial
showing a significant survival benefit for T2 disease and
that of the JCOG9206-2 trial showing no survival benefit
for T3-4 disease, postoperative adjuvant UFT chemo-
therapy is thus considered to be active enough for
earlier disease but not for advanced disease. A more
potent adjuvant therapy, such as S-115 as discussed later,
may be appropriate for resected advanced-stage gastric
cancer patients.
Colorectal Cancer
5-Fluorouracil is the key drug in chemotherapy for
colorectal cancer, and chemotherapy regimens contain-
ing 5-FU or its derivatives are recommended not only
for patients with unresectable disease but also for
patients after complete resection. As the prognosis and
optimal therapy are somewhat different between colon
cancer and rectal cancer, postoperative adjuvant therapy
for each disease is discussed separately.
Colon Cancer
It is generally accepted that postoperative adjuvant
therapy is not recommended as a standard care
of therapy for p-stage I–II colorectal cancer patients
because of the favorable survival with surgery-alone
(5-year OS, 91% for stage I and 84% for stage
II disease, respectively).56,57 Regarding p-stage II
patients, however, a marginal survival benefit of
postoperative adjuvant chemotherapy has been docu-
mented in a pooled analysis of data from four
National Surgical Adjuvant Breast and Bowel Project
(NSABP) trials (C-01, C-02, C-03, and C-04).58 There-
F. Tanaka: UFT as Postoperative Adjuvant Chemotherapy
fore, patients with p-stage II disease at high risk for
recurrence as well as those with p-stage III disease may
be appropriate candidates for postoperative adjuvant
chemotherapy.56,58–60
A number of RCTs showed a survival benefit of post-
operative chemotherapy with the intravenous infusion
of 5-FU plus leucovorin (LV).58,59,61–66 Recently, two
RCTs, the NSABP C-07 trial67 and the Multicenter
International Study of Oxaliplatin/5-Fluorouracil/Leu-
covorin in the Adjuvant Treatment of Colon Cancer
(MOSAIC) study,68 demonstrated the oxaliplatin plus
5-FU/LV was superior to FU/LV as a postoperative
adjuvant chemotherapy for resected p-stage II–III colon
cancer. Whereas these oxaliplatin-containing chemo-
Fig. 1. Metabolic pathway of UFT, a combination drug of
tegafur (FT) and uracil (U). FT is metabolized to 5-fluoroura-
cil (5-FU), and 5-FU is phosphorylated into active metabolites
showing cytotoxic effect mainly through inhibition of enzyme
activity of thymidylate synthase (TS) which is a key enzyme
of de novo DNA synthesis. 5-FU is also degraded into F-β-
alanine by dihydropyrimidine dehydrogenase (DPD), and a
rapid degradation of 5-FU results in a reduced anti-tumor
effect of 5-FU and the derivatives such as FT. Uracil can
inhibit enzyme activity of DPD, which can maintain certain
5-FU concentration through inhibition of 5-FU degradation
931
therapy regimens may be promising in a postoperative
adjuvant setting, their safety and efficacy in clinical
practice, especially for Japanese population, have not
yet been established.56 Therefore, it is generally recog-
nized that 5-FU/LV remains a standard adjuvant che-
motherapy regimen for curatively resected colon cancer
patients with stage III disease as well as high-risk stage
II disease.56,57
There has been reported only one RCT comparing
surgery alone with surgery plus postoperative UFT
treatment for resected colon cancer (the Tokai Adju-
vant Chemotherapy Study Group for Colorectal Cancer
[TAC-CR] study)69 (Table 3). In this trial, 320 patients
with curatively-resected Dukes’ B–C cancer of the
Fig. 2. A single-institute phase II trial of postoperative adju-
vant chemotherapy with UFT following carboplatin (CBDCA)
plus paclitaxel (PTX) for completely resected node-positive
(pathologic stage II-N1 or IIIA-N2) non-small cell lung cancer
(NSCLC) conducted at Kyoto University. The primary end-
point was overall survival (OS), and secondary endpoints were
recurrence-free survival (RFS) and toxicity35
Fig. 3. Metabolic pathway of UFT
(tegafur [FT] and uracil [U]). FT is metab-
olized to 5-fluorouracil (5-FU), which
shows cytotoxic effects. Other metabo-
lites of FT, gamma-hydroxybutyric acid
(GHB) and gamma-butyrolactone (GBL),
can induce apoptotic cell death through
the inhibition of angiogenesis, although
they do not show direct cytotoxicity. Inhi-
bition of tumor angiogenesis by UFT or
its metabolites (GHB and GBL) in an in
vivo model is shown in the right upper box
(tumor microvessels were stained with
anti-CD31 antibody)113
932
colon or the rectum were randomly assigned to received
UFT treatment or to undergo observation. Overall, this
trial showed a significantly better RFS in UFT-treated
patients than in surgery-alone patients (75.7% versus
60.1% at 5 years; P = 0.0081). In a subset-analysis
among colon cancer patients, however, there was no
survival advantage of postoperative UFT treatment (P
= 0.9712 in OS and P = 0.7087 in RFS). On the other
hand, a RCT conducted in the USA (NSABP protocol
C-06 trial) showed an indirect survival benefit of post-
operative adjuvant UFT treatment for colon cancer
patients; the trial compared the relative activity of oral
UFT plus LV with the efficacy of intravenous 5-FU
plus LV after a curative resection for stage II–III colon
cancer, thus showing that oral UFT/LV achieved a
similar OS and RFS in comparison with intravenous
5-FU/LV70 (Table 3). The NSAPB-06 trial suggests that
oral UFT/LV shows an equivalent survival advantage
and it can be an alternative to the standard regimen,
i.e., intravenous 5-FU/LV, for resected colon cancer
patients. To confirm no inferiority of oral UFT/LV in
comparison with intravenous 5-FU/LV in a Japanese
population, a RCT (JCOG0205) is now ongoing.
With regard to oral adjuvant chemotherapy for colon
cancer patients, capecitabine, another 5-FU derivative
drug, may be another alternative to intravenous 5-FU/
LV,59 as a RCT of adjuvant chemotherapy for stage III
colon cancer showed that both RFS and OS in the
capecitabine group were at least equivalent to those in
the 5-FU/LV group (RFS, 64.2% versus 60.6% [P =
0.12]; OS, 81.3% versus 77.6% [P = 0.07].71
Rectal Cancer
It is generally recognized in rectal cancer, the same as
in colon cancer, that postoperative adjuvant therapy
should be prescribed for stage III patients as well as
high-risk stage II patients. In the USA, radiotherapy in
combination with chemotherapy including 5-FU is rec-
ommended as a postoperative treatment for resected
stage II–III rectal cancer patients,72 as two RCTs showed
some clinical benefit when radiotherapy is combined
with chemotherapy.73–76 In the NSABP R-01 trial75 and
R-02 trial,76 the addition of postoperative radiotherapy
to chemotherapy in resected rectal cancer significantly
reduced the occurrence of a locoregional relapse, but it
failed to achieve a significant survival advantage. There-
fore, the clinical benefit of postoperative adjuvant
radiotherapy remains unclear. In addition, the impact
of postoperative adjuvant radiotherapy in locoregional
control may be obscure when an adequate surgical
resection can be performed.
In Japan, a total mesorectal excision (TME) plus
selective lateral pelvic lymphadenectomy is the stan-
dard surgical technique,11,56,77 whereas TME alone is the
F. Tanaka: UFT as Postoperative Adjuvant Chemotherapy
standard in Western countries. Therefore, postopera-
tive radiotherapy may not be necessary to prevent a
locoregional relapse for resected rectal cancer patients
in Japan where sufficient surgical techniques are preva-
lent, and a series of RCTs of postoperative adjuvant
therapy with chemotherapy alone have been conducted
by several groups such as the Japanese Foundation for
Multidisciplinary Treatment for Cancer (JFMC).78–81
Among these adjuvant trials, three JMFC trials (JMFC
trial 7-1,79 15-1,80 and 15-281) showed no significant
improvement in OS with postoperative adjuvant che-
motherapy including UFT plus MMC, although RFS
might improve to some degree (Table 3). Similarly, a
subset analysis among rectal cancer patients in the
TAC-CR trial showed that postoperative chemotherapy
including UFT achieved a significant improvement in
RFS (P = 0.0016) but did not in OS (P = 0.1669)69 (Table
3). Recently, however, a RCT to compare surgery-alone
with surgery plus postoperative UFT-alone treatment,
which was conducted by the National Surgical Adjuvant
Study of Colorectal Cancer (NSAS-CC), showed that
adjuvant UFT treatment achieved a significant improve-
ment in OS as well as in RFS11 (Table 3). In addition, a
meta-analysis of five RCTs (three JMFC trials [7-1, 15-
1, 15-2], the TAC-CR trial, and the NSAS-CC trial)
comparing UFT-containing chemotherapy following
surgery with surgery-alone showed a significant improve-
ment with adjuvant UFT treatment in OS (74.0% versus
69.0% at 5 years; P = 0.03 and HR = 0.83 [95% CI:
0.71–0.98]) as well as in RFS (67.6% versus 57.9% at 5
years; P < 0.0001 and HR = 0.72 [95% CI: 0.62–0.83])82
(Table 5). These results strongly support the use of UFT
following a curative resection for stage (II–) III rectal
cancer in Japan.
Breast Cancer
Standard systemic adjuvant therapy for resected breast
cancer is determined based on the status of nodal metas-
tasis, hormonal status (estrogen-receptor [ER] expres-
sion and/or progesterone-receptor [PR] expression),
and prognosis (risk category classification). Hormone
therapy, especially tamoxifen (TAM), is recommended
for most patients with ER-positive or PR-positive
tumor. In addition, chemotherapy is recommended for
most patients with positive axillary nodal metastasis;
even when axillary nodal metastasis is negative, chemo-
therapy is recommended for some intermediate-risk
patients and most high-risk patients.83–85
As postoperative adjuvant chemotherapy regimen,
CMF (cyclophosphamide [CPA], methotrexate [MTX],
plus 5-FU) was the first established regimen to improve
the outcome of node-positive breast cancer patients,86
and other chemotherapy regimens containing anthra-
cycline agent (doxorubicin [DXR] or epirubicin [EPI])
F. Tanaka: UFT as Postoperative Adjuvant Chemotherapy
also proved to be effective in postoperative adjuvant
setting.87 In 1998, the Early Breast Cancer Trialists’
Collaborative Group reported a meta-analysis showing
that anthracycline-containing regimens were superior
to CMF in RFS (57.3% versus 54.1% at 5 years;
P = 0.006) as well as in OS (71.5% versus 68.8% at
5 years; P = 0.02),87 and a recent meta-analysis re-
ported in 2005 has continued to show the superiority of
anthracycline-based regimens over CMF.88 Accordingly,
anthracycline-based regimens such as AC (DXR plus
CPA), EC (EPI plus CPA), FAC/CAF (5-FU, DXR
plus CPA), and FEC/CEF (5-FU, EPI plus CPA) are
recommended as a standard of postoperative adjuvant
chemotherapy.83–85,89
Recent clinical trials have attempted to examine the
role of taxane (PTX90–92 or docetaxel [DOC]93–95) in a
postoperative adjuvant setting, and most trials showed
a significant improvement in RFS and/or OS with the
use of taxane. For example, the CALGB 934490 and the
NSABP B-2892 trials showed the superiority of AC
followed by PTX over AC alone (5-year RFS, 70%
versus 65% [P = 0.0023] in the CALGB trial and 76%
versus 72% [P = 0.006] in the NSABP trial, respec-
tively; 5-year OS, 80% versus 77% [P = 0.006] and 85%
versus 85% [P = 0.46], respectively), and the FNCLCC
PACS 01 trial93 showed the superiority of FEC fol-
lowed by DOC over FEC alone (5-year DFS, 78.4%
versus 73.2% [P = 0.012]; 5-year OS, 90.7% versus
86.7% [P = 0.017]); the Breast Cancer International
Research Group (BCIRG) 001 trial94 showed the supe-
riority of the substitution of DOC for 5-FU in a regimen
that included DXR plus CPA (5-year DFS, 75% for
TAC [DOC/DXR/CPA] versus 68% for FEC
[P = 0.001]; 5-year OS, 87% versus 81%, respectively
[P = 0.008]). More recently, it has been reported
that the addition of an anti-HER2/neu monoclonal
antibody (trastuzumab) to EPI-containing chemother-
apy may improve the survival of HER2/neu-positive
breast cancer patients (3-year RFR, 89.3% with
chemotherapy with trastuzumab versus 77.6% with
chemotherapy without trastuzumab [P = 0.01]; 3-year
OS, 96.3% versus 89.7%, respectively [P = 0.07].96 In
combination with the promising results of an interim
analysis of three large-scale RCTs (the NSABP B-31
trial, the NCCTG N9831 trial, and the HERA trial),97
adjuvant chemotherapy including trastuzumab may
thus be recommended for HER2/neu-positive
patients.
Whereas these results clearly demonstrated the effi-
cacy of anthracycline-based chemotherapy alone, or
that with taxane for node-positive patients and that with
trastuzumab for HER2/neu-positive patients, as an
adjuvant systemic therapy for resected breast cancer
patients,83–85,89 anthracycline-based chemotherapy is
sometimes associated with severe toxicity. In fact, a
933
large-scale RCT (Intergroup protocol INT-0102) com-
paring CAF with CMF (±TAM) for node-negative
breast cancer patients showed CAF to be associated
with a greater toxicity whereas the survival advantage
was minimal (no significant difference in DFS [P = 0.13;
HR = 1.09 {95% CI: 0.94–1.27}] and a marginal advan-
tage in OS [P = 0.03 by one-sided test; HR = 1.19 {95%
CI: 0.99–1.43}]), thus suggesting that anthracycline-
based chemotherapy may not be recommended for
node-negative patients.98 Postoperative adjuvant che-
motherapy should be determined based on the toxicity
as well as the benefit of the chemotherapy. Therefore,
node-positive patients should be treated with aggressive
chemotherapy which may achieve a greater benefit, but
node-negative patients may be treated with less toxic
chemotherapy because of the smaller benefit achieved
with anthracycline-based chemotherapy with a definite
toxicity.
UFT, with a less toxic profile, has been examined in
a variety of Spanish99 and Japanese12,100–107 adjuvant
trials of resected breast cancer (Table 4). In Japan,
the Collaborative Study Group of Adjuvant Chemoen-
docrine Therapy for Breast Cancer (ACETBC)
has conducted a series of RCTs of postoperative adju-
vant therapy for breast cancer. In the 3rd ACETBC
study,100–102 five RCTs to examine the efficacy of
UFT with or without TAM for both node-negative and
node-positive patients were conducted in different
districts of Japan. (The title of ACET-BC 3rd Study
that appeared in the published article102 was “meta-
analysis.” However, only 5 controlled trials conducted
by the ACET-BC groups in different areas of Japan
were included in the study, which is not a systematic
review analysis of randomized trials. Thus, the ACET-
BC 3rd study may be a “pooled analysis” of several
studies like the ACET-BC 4th study12 and is not cited
as a meta-analysis in the present review.) A pooled
analysis of these trials showed a trend toward a favor-
able RFS in UFT-treated patients (5-year RFS, 86.5%
for UFT-treated patients versus 83.3% for UFT-
untreated patients; P = 0.060), whereas it showed no
OS benefit of UTF treatment.102 In the 4th ACETBC
study, six RCTs were conducted to examine the efficacy
of postoperative UFT treatment exclusively for node-
negative breast cancer patients.12 A pooled analysis
of these trials showed a significantly higher OS in
the UFT-treated patients than that in patients without
UFT-treatment (5-year OS, 95.9% versus 94.0%;
P = 0.036) (Table 4), whereas it showed no significant
OS advantage with TAM treatment (5-year OS, 95.2%
for TAM-treated patients versus 93.9% for TAM-
untreated patients; P = 0.12).12 These results suggest
that postoperative adjuvant UFT treatment is effective
for node-negative breast cancer patients. The final
results of a large-scale RCT comparing UFT with UFT
934 F. Tanaka: UFT as Postoperative Adjuvant Chemotherapy

with CMF for node-negative high-risk breast cancer Mechanism of Action:

patients, the NSAS-BC01 trial,103–104 has been just pre-
sented at the ASCO meeting in 2007.105 No inferiority
of oral UFT treatment to intravenous CMF treatment
has been documented in the NSAS-BC01 trial (5-year
RFS, 87.7% in the UFT group and 88.2 in the CMF
group, respectively), and UFT may be an alternative
postoperative adjuvant regimen to intravenous chemo-
therapy such as CMF.
For node-positive breast cancer patients, a RCT
conducted in Japan (the Comparative Trial with UFT/
TAM and CMF/TAM in Adjuvant-therapy for Breast
Cancer [CUBC trial]106) showed that OS and RFS
achieved with oral chemotherapy containing UFT (UFT
plus TAM) were similar to those achieved with intrave-
nous CMF chemotherapy. In addition, a small RCT con-
ducted by the Kinki Research Group for Breast Cancer
Adjuvant Therapy (Japan) showed a significantly better
OS (P = 0.04) and a trend toward a favorable RFS
(P = 0.07) for patients treated with UFT plus TAM
as compared with those for patients treated with an
anthracylcine-based chemotherapy (CAF).107 These
results may suggest that UFT is an effective postopera-
tive adjuvant therapy not only for node-negative patients
but also for node-positive patients, but it is not possible
to propose that the efficacy of UFT is comparable to
that or that standard adjuvant chemotherapy for node-
positive patients, i.e., anthracycline-based chemother-
apy, as no definite efficacy of postoperative adjuvant
UFT treatment has yet been established.
UFT as an Angiogenesis Inhibitor
As described in the previous section, UFT is effective
in the postoperative adjuvant setting for a variety of
solid tumors. Patients who undergo surgery may not
tolerate intensive chemotherapy with severe toxicity,
and the compliance is usually a critical issue in postop-
erative adjuvant therapy.108–109 UFT with a mild toxicity
profile may be superior, in terms of the compliance, to
“standard” adjuvant chemotherapy regimens such as
CDDP-based chemotherapy for NSCLC, 5-FU/LV for
colon cancer, and anthracycline-based chemotherapy
for breast cancer. However, in terms of antitumor effect,
UFT may be inferior to these “standard” chemotherapy
regimens5,6 (Table 6). A pooled analysis of Japanese
trials for a various advanced solid tumors showed a risk
ratio (RR) of 25.1% (108/438), and the RR for each
tumor was 7.0% (3/43) for lung, 27.7% (52/188) for
gastric, 25.0% (14/56) for colorectal, and 32.0% (16/50)
for breast cancer.5 These results suggest that UFT may
thus have a definite antitumor effect for gastric, colorec-
tal and breast cancer, but only one responder of 16
gastric cancer patients (RR, 6.3%) was documented in
a British phase II trial.6 In addition, the RR achieved
with UFT for lung cancer in a Japanese population was
less than 10%, and this lower objective response rate
can be due to higher enzyme activity of DPD, which
inactivates 5-FU released from UFT, documented in
lung cancer tissues110 (Table 6). The question remains

Table 6. Activity of thymidylate synthase (TS) and dihydropyrimidine dehydrogenase (DPD), and antitumor effect (response
rate) achieved with 5-fluorouracil (5-FU) and DPD-inhibitory fluoropyrimidines (DIFs, UFT and S-1) in advanced unresectable
cancer of the lung, stomach, colon/rectum, and breast
Response rate
Enzyme activitya
S-1d
TS DPD b c
5-FU UFT DPD-inhibitor:
(pmol/mg-protein) (pmol/min/mg-protein)
DPD-inhibitor: DPD-inhibitor: CDHP
Tumor n Mean Median n Mean Median No Uracil (Gimeracil)

Lung 197 0.043 0.030 236 278.6 253.2 9.1% (1/11) 8.7% (4/46) 18.2% (18/99)
Stomach 458 0.071 0.040 719 140.8 122.6 27.3% (41/150) 25.4% (58/228) 46.5% (60/129)
6.3% (1/16) [108]
Colon and rectum 889 0.058 0.039 1097 106.9 94.8 41.9% (13/31) 18.3% (15/82) 32.6% (42/129)
16.7% (6/36) [108]
Breast 338 0.094 0.061 520 126.3 98.6 35.1% (13/37) 30.2% (29/96) 21.8% (12/55)

CDHP, 5-chloro-2,4-dihydroxypyridine
a
Data from Table II in Fukushima M, et al. Int J Mol Med 2003;12:841110
b
Data from Japanese trials drawn from Kyowa-hakko Kogyo Co. Ltd website (http://iyaku.kyowa.co.jp/Temp/tenpubun/LIST2.
cfm?FN=5FU-1_15)
c
Data from Japanese phase II trials drawn from Taiho Pharmaceutical Co. Ltd website (http://www.taiho.co.jp/medical/di/detail.php) and data
from a British phase II study6
d
Data from Japanese phase II trials drawn from Taiho Pharmaceutical Co. Ltd website (http://www.taiho.co.jp/medical/di/detail.php)
F. Tanaka: UFT as Postoperative Adjuvant Chemotherapy
as to why UFT, with a minimal antitumor effect for
advanced unresectable cancer, especially for that of the
lung, is active in a postoperative adjuvant setting. The
efficacy of adjuvant UFT treatment cannot be reason-
ably explained by the direct antitumor effect through
5-Fu released from FT/UFT.
Angiogenesis Inhibition by UFT treatment
As shown in Fig. 1, FT is converted into 5-FU that
shows an antitumor effect; during the metabolic process,
other metabolites (gamma-butyrolactone [GBL] and
gamma-hydroxybutyric acid [GHB]) are also released
from FT. GBL or GHB had been shown to have no
significant pharmacological activity. Yonekura and
coworkers, however, revealed that UFT and its metabo-
lites inhibited tumor-induced angiogenesis in a in vivo
mode13 via a pathway linked with vascular endothelial
growth factor (VEGF) that was the most potent angio-
genic factor.111,112 To further examine antiangiogenic
effect of UFT and its metabolites, we performed an in
vivo experiment as follows: mice were implanted with a
human NSCLC cell line (Lu99 or LC11), and then mice
were treated with UFT, 5-FU, GBL, or GHB after the
establishment of subcutaneous tumors. As a result,
tumor angiogenesis represented as a density of endo-
thelial cells (ECs) highlighted with an anti-CD31 anti-
body (microvessel-density [MVD]) was significantly
inhibited with GBL and GHB administration (see right
upper box in Fig. 3), whereas GBL or GHB did not
inhibit tumor cell growth in vitro. Angiogenesis was also
inhibited with 5-Fu administration, probably due to the
inhibition of angiogenic factors derived from tumor
cells through anti-tumor effect of 5-FU; angiogenesis
was markedly inhibited with UFT treatment through
the direct antiangiogenic effect of GBL/GHB and indi-
rect antiangiogenic effect of 5-FU (Fig. 3).113 In addi-
tion, in an in vivo experimental model, Munoz and
coworkers showed that UFT-containing long-term che-
motherapy significantly improved the survival through
the inhibition of angiogenesis.114
Angiogenesis Inhibition and Improvement in
Postoperative Survival
The development of distant metastasis after a complete
resection is the most critical factor influencing the post-
operative survival. Even after a complete resection of
clinically detectable tumor, micrometastatic foci may
remain to be left undetectable, which can grow during
postoperative course. When the diameter of metastatic
tumor exceeds 1 cm, then the tumor can be clinically
detectable and development of postoperative distant
recurrence is confirmed. Angiogenesis thus plays and
essential role in the development and/or growth of
935
micrometastatic foci which may leads to fatal postop-
erative distant recurrence, because sold tumors cannot
growth beyond 1–2 mm in diameter without angiogene-
sis115–117 (Fig. 4A). Tumor growth is dependent on the
balance between an increasing number of tumor cells
through tumor cell proliferation and a decreasing
number through apoptotic cell death.118–120 If angiogen-
esis is not sufficient to supply adequate nutrients and/or
oxygen, tumor growth is inhibited through the accelera-
tion of apoptosis,121 which leads to a favorable progno-
sis.114,122,123 In fact, a less aggressive angiogenic phenotype,
represented as lower MVD, is associated with a favor-
able postoperative prognosis in clinical studies of a
variety of tumors including lung,124,125 gastric,126 colorec-
tal,127 and breast cancer.128,129
Angiogenesis is thus considered to be an important
therapeutic target in a variety of malignant tumors.114,130,131
For advanced unresectable tumor, recent RCTs showed
a survival benefit of the addition of an anti-VEGF anti-
body (bevacizumab) to conventional chemotherapy in
colorectal cancer132,133 and NSCLC,134 or showed an
increased objective response in breast cancer.135 In the
postoperative adjuvant setting, it may be expected that
a successful inhibition of tumor angiogenesis with the
postoperative therapy may improve postoperative sur-
vival through a reduction in the probability of postop-
erative distant recurrence. It may be speculated that
long-term UFT administration after surgery can thus
inhibit the development of postoperative recurrence
through an antiangiogenic effect as well as a cytotoxic
effect (Fig. 4B), which may explain the efficacy of UFT
in postoperative adjuvant setting.113,114 This speculation
may be supported not only by experimental results
showing that UFT treatment can inhibit development
of lung micrometastases whereas it shows no objective
response to bulky tumor,136 but also by results of clinical
studies showing that the efficacy of postoperative adju-
vant UFT treatment correlates with tumor angiogenesis
(MVD)14,112,137 as well as apoptosis.138 “Standard” intra-
venous chemotherapeutic agents may have a superior
direct antitumor effect, and can kill a larger number of
tumor cells. However, cytotoxic agents can kill only
cells in the proliferating phase, whereas a tumor tissue
contains a definite proportion of nonproliferating tumor
cells as well as proliferating cells.118,119 These nonprolif-
erating cells that did not respond to “shorter-term” che-
motherapy after surgery may thus change to proliferating
cells during the postoperative course, thus leading to
postoperative recurrence (Fig. 4C). “Long-term” UFT
administration has an advantage of inhibiting postop-
erative recurrence throughout the treatment (Fig.
4B).14,114,137 When many micrometastatic foci may be
expected, for example in the case of advanced-stage
disease, UFT alone may not control all metastatic
foci, and long-term UFT administration following
936 F. Tanaka: UFT as Postoperative Adjuvant Chemotherapy

Fig. 4. A. Development of distant meta-

static recurrence after surgery. After a
complete resection of a clinically detect-
able tumor, micrometastatic foci that
cannot be detectable at the operation
C may grow, and postoperative recurrence
can be detected when the tumor diameter
reaches 1 cm or more. Nonproliferative
tumor cells in the micrometastatic foci
may change to proliferating cells during
postoperative course. B. Long-term
administration of UFT may inhibit post-
operative recurrence through direct anti-
tumor effects and inhibitory effect of
angiogenesis. C. The influence of short-
term postoperative chemotherapy on
postoperative recurrence. Chemotherapy
does not kill nonproliferating tumor cells
in metastatic foci; these nonproliferating
tumor cells may change to proliferating
cells during the postoperative course,
which may cause postoperative
recurrence
F. Tanaka: UFT as Postoperative Adjuvant Chemotherapy
“standard” intravenous chemotherapy, i.e., CBDCA/
PTX followed by UFT for p-stage IIIA-N2 NSCLC,35
may be promising.
Future Directions: From UFT to S-1
Adjuvant therapy following surgery is principally an
“unnecessary” treatment, when complete resection is
achieved. In other words, all patients after a complete
resection will be expected to survive without tumor
recurrence. However, a definite proportion of com-
pletely resected patients may actually die of tumor
recurrence, as clinically undetectable tumors do exist
Fig. 5. Necessity and effect of postoperative adjuvant therapy,
when postoperative 5-year survival rates of patients who
receive no treatment after surgery is 70% and postoperative
adjuvant therapy can achieve a survival benefit of 10% at 5
years after surgery. Adjuvant therapy is essentially unneces-
sary for “70%” of all resected patients; among the remaining
30% of the patients who need adjuvant therapy to obtain a
cure, two thirds of patients (20% of all patients) may die
because adjuvant therapy fails to inhibit postoperative recur-
rence. Overall, adjuvant therapy can bring a clinical benefit in
only 10% of all patients who receive adjuvant therapy
937
and grow after surgery (Fig. 4A). Suppose that a post-
operative adjuvant treatment regimen can achieve a
significant survival benefit of 10% at 5 years after surgery
(5-year survival rate, 70% for surgery-alone group
versus 80% for surgery plus adjuvant treatment group)
(Fig. 5). Once such a significant survival benefit is dem-
onstrated in a RCT, especially when demonstrated in a
series of RCTs with a meta-analysis, then the postopera-
tive treatment regimen is recommended for all resected
patients as a rule of evidence-based medicine. Here, the
majority (70%) of all patients shall essentially need no
adjuvant chemotherapy, because these patients can be
cured by surgery alone; adjuvant treatment may thus
only result in some adverse effects, which can some-
times even be fatal, to these patients. Among the
remaining 30% of all patients of whom postoperative
therapy is necessary for the cure because of expected
tumor recurrence with surgery alone, two thirds of
patients (20% of all patients) will die with tumor recur-
rence that cannot be controlled with adjuvant chemo-
therapy. Therefore, only 10% of all patients who receive
postoperative adjuvant therapy will be cured owing to
the “true” effect of adjuvant therapy, while for the other
90% of patients, adjuvant therapy may cause adverse
effects without any clinical benefit. We should be aware
of such disadvantages of adjuvant therapy in addition
to the advantages, and carefully select patients in whom
adjuvant therapy should actually be performed. Recent
clinical studies have focused on biomarkers to select
patients who need adjuvant therapy (prognostic factors)
and to predict patients for whom adjuvant therapy is
effective (predictive factors). In some retrospective
clinical studies, the efficacy of UFT has been suggested
to be influenced by tumor angiogenesis and status of
angiogenesis-related factors14,137,138 as well as by the
status of enzymes involved in 5-Fu metabolism such as
TS and DPD.139,140 The clinical significance of such bio-
Fig. 6. Postoperative adjuvant chemo-
therapy for carcinoma of the lung,
stomach, colon and rectum, and breast
cancer. When the efficacy of an adjuvant
therapy regimen is established in multiple
randomized clinical trials (RCTs), the
therapy is indicated in a “red” box; when
the efficacy is shown in one or a few
RCTs, the therapy is indicated in an
“orange” box. CBDCA, carboplatin; PTX,
paclitaxel; 5-FU, 5-fluorouracil; LV, leu-
covorin; CPT-11, irinotecan; VEGF, vas-
cular endothelial growth factor; EGFR,
epidermal growth factor receptor; EKI,
tyrosine kinase inhibitor; mAb, mono-
clonal antibody
938
markers should be established in future clinical trials,
which may thus result in the use of adjuvant treatment
based on these biomarkers.
Once we decide to perform adjuvant chemotherapy,
the regimen should be carefully selected based on the
toxicity as well as the efficacy. Generally speaking, as
agents showing a higher antitumor effect show some-
times severe toxicity, such agents should be prescribed
to patients with a higher risk of postoperative recur-
rence such as node-positive patients. Regarding lower-
risk patients, agents with mild toxicity such as UFT or
an alternative to a “standard” chemotherapy regimen
can be recommended; in fact, UFT is the only recom-
mended agent for completely resected p-stage IB
NSCLC patients for whom CDDP-based chemotherapy
provide no survival benefit probably due to its toxicity
(Fig. 6). Nevertheless, the antitumor effect achieved
with UFT treatment is not sufficient to control the post-
operative recurrence of higher-stage disease with an
increased number of tumor cells in micrometastatic
foci, or UFT cannot control postoperative recurrence
of 5-FU resistant tumors such as tumors with higher
DPD activity. In such cases, more potent chemothera-
peutic agents or targeting agents for a targeting-
population, i.e., trastuzumab for HER2/neu-positive
breast cancer patients,96,97 should thus be prescribed.
One promising cytotoxic agent for UFT-refractory
cases is S-1, which is a novel oral DIF composed of FT,
5-chloro-2,4-dihydroxypyridine (CDHP, gimeracil), and
potassium oxonate.139,140 Because CDHP shows a potent
Table 7. Phase III randomized controlled trials (RCTs) of postoperative adjuvant chemotherapy with S-1 for solid tumors
Trial design
Planned
Organ Trial Stage accrual
Stomach ACTS-GC Stage II–III n = 1000
Stomach SAMIT T3–4 n = 1500
(serosa-
positive)
Colon and ACTS-RC Stage II–III n = 800
Rectum
Head and ACTS-HNC Stage III/IVa/IVb n = 600
Neck (squamous cell)
OS, overall survival; RFS, recurrence-free survival; HR, hazard ration; PTX, paclitaxel
F. Tanaka: UFT as Postoperative Adjuvant Chemotherapy
inhibitory effect on DPD, that is 180-times higher than
that achieved with uracil,143 an enhanced 5-FU concen-
tration can thus be expected with S-1 administration.
Potassium oxonate is a reversible competitive inhibitor
of orotate phosphoribosy1 transferase (OPRT) that is
responsible for gastrointestinal (GI) toxicity through
phosphorylation of 5-FU. Therefore, the oral adminis-
tration of S-1 can achieve a more potent antitumor
effect through an increased 5-FU concentration without
enhancement of GI toxicity such as diarrhea144,145 for a
variety of tumors such as lung, gastric, colorectal, and
breast cancer.146–149 In fact, even in NSCLC which is a
typical 5-FU-refractory tumor due to its higher DPD
activity, S-1 monotherapy achieved a favorable RR
(18%) in phase II clinical trials for advanced unresect-
able cases,146,147 which is comparable to modern chemo-
therapeutic agents such as taxanes (Table 6). In gastric
cancer for which the highest RR (46.5%) was docu-
mented in a phase II trial of S-1 monotherapy for unre-
sectable disease, and adjuvant trial, the Adjuvant
Chemotherapy Trial of TS-1 for Gastric Cancer (ACTS-
GC), had been started in 2001150 (Table 7). This is a
large-scale RCT comparing surgery alone with surgery
followed by S-1 administration (80–120 mg/body weight/
day, daily for 28 consecutive days with a 14 days’ rest;
repeated for 12 months after surgery) to examine the
efficacy of postoperative chemotherapy using S-1 for
resected stage II (excluding T1-disease), IIIA, or IIIB
gastric cancer. A planned accrual of more than 1 000
patients (n = 1 059) had been completed at the end of
Treatment arm Status
A) Surgery alone Completed
B) S-1 (*interim analysis presented in 2007/01)
Results* 3-year OS 3-year RFS
A) (n = 530) 70.1% 60.1%
B) (n = 529) 80.5% 72.2%
P = 0.0024 P < 0.0001
HR = 0.68 HR = 0.62
[0.52–0.87] [0.50–0.77]
A) UFT Ongoing (2005/10–)
B) S-1
C) PTX→UFT
D) PTX→S-1
A) UFT Ongoing (2006/4–)
B) S-1
A) UFT Ongoing (2006/4–)
B) S-1
F. Tanaka: UFT as Postoperative Adjuvant Chemotherapy
2004, and the results of the interim analyses have been
recently presented at the Gastrointestinal Cancer Sym-
posium of the American Society of Clinical Oncology
(ASCO) in January 2007.15 According to the results,
postoperative S-1 treatment showed a significant sur-
vival benefit with a 32% reduction of postoperative
death (HR = 0.68 [95% CI: 0.52–0.87]; P = 0.0024), thus
conferring a 10.4% improvement in OS at 3 years after
surgery (3-year OS, 80.5% for S-1 group [n = 529] and
70.1% for the surgery-alone group [n = 530]). These
results, albeit drawn from an interim analysis, may
suggest that S-1 should be prescribed in a postoperative
adjuvant setting for resected stage II–III gastric cancer,
UFT can be an alternative when S-1 administration is
inappropriate for some reasons such as higher age,
impaired renal function, and active interstitial pneumo-
nia. The use of S-1 in postoperative adjuvant setting
may therefore be promising for other cancers as well
(Table 7).
Conclusions
Recent clinical studies have demonstrated that UFT is
an active oral chemotherapeutic agent in the postopera-
tive adjuvant setting for completely resected early-stage
lung, gastric, colorectal, and breast cancer patients,
without remarkable toxicity. For advanced-stage
patients, postoperative adjuvant therapy with more
potent chemotherapeutic agents such as a novel oral
agent, S-1, is required. In future clinical trials, biomark-
ers to indicate the patients who need postoperative
adjuvant therapy to obtain a cure (prognostic factors)
and to predict the efficacy of adjuvant therapy (predic-
tive factors) should be examined, and then the most
effective adjuvant therapy for appropriate candidates
should be prescribed based on these biomarkers as well
as each tumor stage.
Acknowledgment. I thank Ms. Saori Toyonaga for helpful
assistance in the preparation of the manuscript.
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