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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 FU and its derivatives such as FT. UFT is defined as


UFT (tegafur and uracil) is an oral anticancer drug that DPD-inhibitory fluoropyrimidine (DIF), as an inhibitor
has been developed in Japan. Owing to its mild toxicity of DPD, uracil (U), is added to FT. Through inhibition
profile, UFT can be suitable in an adjuvant setting fol- of 5-FU degradation, DIF such as UFT can achieve a
lowing a complete tumor resection, whereas its direct higher maximum plasma 5-FU level for a longer period,
antitumor effect achieved may be insufficient for thus resulting in an enhanced antitumor effect.1–4
advanced unresectable disease. Therefore, a variety of According to a pooled analysis of Japanese phase II
adjuvant chemotherapy trials with UFT have been con- trials of UFT-alone treatment for advanced unresect-
ducted, and results of well-designed randomized con- able solid tumors originating from a variety of organs
trolled trials have recently shown a survival benefit of including the lung, stomach, colorectal, and breast, the
postoperative UFT treatment in resected lung, gastric, objective response rate (RP) was 25.1%.5 In another
colorectal, and breast cancer. In the present article, phase II trial of UFT-alone treatment conducted in the
postoperative adjuvant trials with UFT-containing che- United Kingdom, lower RRs (16.7% and 6.2% for
motherapy are reviewed, and the mechanism of action gastric and colorectal cancer, respectively) were docu-
and future directions are also discussed. mented.6 These results show that UFT may be active in
a variety of malignant tumors, but the direct antitumor
Key words Tegafur · Uracil · UFT · Solid tumor · Adju- effect is insufficient in comparison with that achieved
vant chemotherapy 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
Introduction useful as an adjuvant treatment following a complete
tumor resection rather than as an aggressive treatment
UFT, a combination drug of tegafur (FT) and uracil (U) for unresectable disease. Thus, in Japan, a variety of
in a molecular ratio of 1 : 4, is an oral anticancer agent clinical trials of postoperative adjuvant chemotherapy
which has been developed in Japan (Fig. 1).1–3 FT is using UFT have been conducted since the 1980s. Some
gradually converted to 5-fluorouracil (5-FU), and 5-FU trials have suggested the efficacy of adjuvant UFT treat-
is phosphorylated into active metabolites such as 5- ment, while others have failed to show any efficacy
fluoro-2′-deoxyuridine-5′-monophosphate (FdUMP); partly due to inappropriate trial designs. Recently, the
FdUMP shows cytotoxic effect mainly through the inhi- results of well-designed randomized controlled trials
bition of enzyme activity of thymidylate synthase (TS) (RCTs) comparing adjuvant chemotherapy with UFT
which is a key enzyme in de novo DNA synthesis. 5-FU following surgery with surgery alone have been reported,
is also degraded into F-β-alanine by dihydropyrimidine and they clearly showed a survival benefit of adjuvant
dehydrogenase (DPD), and a rapid degradation of 5- UFT treatment for lung,7–9 gastric,10 colorectal,11 and
FU results in a reduced anti-tumor effect caused by 5- 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
Reprint requests to: F. Tanaka addition to its cytotoxic effect via 5-FU derived from
Received: March 5, 2007 / Accepted: April 18, 2007 FT,13,14 which may answer the question why UFT is
924 F. Tanaka: UFT as Postoperative Adjuvant Chemotherapy

active in a postoperative adjuvant setting whereas UFT To improve the survival of resected NSCLC patients,
shows an insufficient antitumor effect for unresectable numerous adjuvant therapy regimens had been exam-
disease. More recently, it has been reported that the ined in clinical trials, but the efficacy had not been
postoperative administration of S-1, a novel DIF with a established for a long time; a meta-analysis conducted
more potent antitumor activity, significantly improves by the PORT Meta-analysis Trialists Group in 199820
the survival of curatively-resected stage II–III gastric (updated in 200521) showed that postoperative radio-
cancer patients,15 which may provide a new insight into therapy provided no survival benefit, and a meta-
postoperative adjuvant chemotherapy for more analysis conducted by the Non-small Cell Lung Cancer
advanced-stage patients. In the present article, reported Collaborative Group in 1995 showed that postoperative
clinical studies of adjuvant therapy using UFT are cisplatin (CDDP)-based chemotherapy provided a mar-
reviewed, and the mechanism of action and future direc- ginal survival benefit (a 5% improvement in OS at 5
tions are also discussed. 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
UFT in Postoperative Adjuvant Setting: Review of patients treated with CDDP-based chemotherapy
Clinical Studies are significantly higher than those of surgery-alone
patients,23–25 and a meta-analysis of these RCTs revealed
In most solid malignant tumors, early detection and a that adjuvant CDDP-based chemotherapy significantly
complete resection is the most effective therapy for the reduced the risk of postoperative death with the hazard
cure. However, even when a complete resection can be ratio (HR) of 0.89 (95% confidence interval [CI]: 0.82–
achieved, postoperative recurrence may occur. Local 0.96; P < 0.005) thus corresponding to a 4.2% OS
recurrence can be reduced with improved surgical tech- improvement at 5 years.26 Whereas these results clearly
niques and/or modern radiotherapy, and, if it occurs, it showed the efficacy of postoperative adjuvant CDDP-
can then be effectively controlled with salvage surgery based chemotherapy in NSCLC, attention should be
and/or radiotherapy. Therefore, the prevention or paid to the 1%–2% mortality rate caused by adjuvant
control of distant metastasis after surgery plays a critical CDDP-based chemotherapy.23–25 In addition, CDDP-
role in improving postoperative survival, and a number based chemotherapy showed either no effect or a reverse
of adjuvant trials of systemic chemotherapy have been effect on earlier-stage patients (HR: 1.41 and 0.93 for
conducted to assess its survival benefit. We herein stage IA and for stage IB disease, respectively), whereas
review postoperative adjuvant chemotherapy trials, it achieved a significant survival benefit on stage II–III
while focusing on those using UFT, for lung (Table 1A patients (HR: 0.83 for both stage II and III diseases).26
and B), gastric (Table 2), colorectal (Table 3), and Therefore, adjuvant chemotherapy with a mileder tox-
breast cancer (Table 4). icity profile such as UFT should be considered for
earlier-stage NSCLC patients.
Nine RCTs of postoperative adjuvant chemotherapy
Lung Cancer
with UFT alone (Table 1A)7–9,27–29 or UFT following
Primary lung cancer is the leading cause of cancer CDDP-based regimen (Table 1B)7,9,30–32 have been
deaths in most industrialized countries, and it is reported. The 2nd study conducted by the West Japan
clinically classified into small cell lung cancer (SCLC) Study Group for Lung Cancer Surgery (WJSG) is the
or into non-small cell lung cancer (NSCLC) including landmark trial showing the efficacy of postoperative
adenocarcinoma and squamous cell carcinoma. SCLC adjuvant chemotherapy for resected NSCLC.7 This is a
patients should be primarily treated with chemotherapy three-arm trial, and 323 patients with resected p-stage
with or without radiation because of early develop- I–III NSCLC were randomly assigned to a surgery-
ment of nodal and distant metastasis as well as an alone group, a UFT-alone group, or a CDDP plus vin-
excellent response to chemo (-radio) therapy. For desine (VDS) followed by UFT (CVUft) group. The
patients with NSCLC, which accounts for 75%–80% of 5-year OS rates were 49.0% for the surgery-alone
primary lung cancer, a surgical resection should be con- group, 64.1% for the UFT group, and 60.6% for the
sidered as the primary therapy, but the postoperative CVUft group, thus showing a significant difference
prognosis remains unsatisfactory.16–18 The 5-year overall among the three groups (P = 0.044); the most favorable
survival (OS) rates of patients with pathologic (p-) N2 finding was that for the UFT group with a significant
disease, in which mediastinal nodes are involved, have improvement as compared with that for the surgery-
been reported to be less than 20%; even in p-stage alone group (P = 0.022 and HR = 0.55 [95% CI: 0.36–
I disease, in which no nodal or distant metastasis is 0.86]). The Japan Lung Cancer Research Group on
documented, the 5-year OS rates remain less than Postsurgical Adjuvant Chemotherapy (JLCRG) study
80%.16–19 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 in stage IA subset, a significant survival benefit was
resected p-stage I (T1 or T2) adenocarcinoma of the documented when the tumor measured greater than
lung were randomly assigned to receive UFT adminis- 2 cm in diameter.33
tration (UFT group) or to only undergo observation The efficacy of postoperative adjuvant UFT treat-
(surgery-alone group).8 The 5-year OS rates were 88% ment was confirmed in a meta-analysis of six RCTs
for the UFT group and 85% for the surgery-alone comparing UFT-alone treatment following surgery with
group, thus showing a significant survival benefit of surgery alone (Table 5).34 Of the 2003 patients included
postoperative UFT administration (P = 0.04 and HR = in the meta-analysis, most patients had p-stage I disease
0.48 [95% CI: 0.52–0.98]). The survival benefit disap- and 1679 patients (83.8%) had adenocarcinoma. The
peared in stage IA (T1) subset (5-year OS, 89% for the 5- and 7-year OS rates were significantly higher in the
UFT group and 90% for the surgery-alone group; P = surgery plus UFT group (81.5% and 76.5%, respec-
0.87 and HR = 0.97 [95% CI: 0.64–1.46]), and was tively) than in the surgery-alone group (77.2% and
enhanced in stage IB (T2) subset (5-year OS, 85% and 69.5%, respectively), thus showing a significant reduc-
74%, respectively; P = 0.005 and HR = 0.48 [95% CI: tion in postoperative death with UFT treatment (P =
0.29–0.81]). According to an exploratory analysis, even 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 platinum-based regimens, carboplatin (CBDCA) plus
UFT treatment in earlier-stage NSCLC, and postopera- paclitaxel (PTX) is a well-tolerated regimen, and may
tive chemotherapy with UFT alone is recommended for be preferably prescribed in postoperative adjuvant
p-stage IB patients; p-stage IA patients, especially when setting. We conducted a single-institute phase II trial of
the tumor size is 2 cm or greater, can thus be candidates adjuvant chemotherapy with CDBCA/PTX followed by
for adjuvant UFT treatment. For more advanced UFT for completely resected node-positive (p-stage II-
disease, however, there has been no reported evidence N1 or IIIA-N2) NSCLC. An interim analysis showed a
of a survival improvement with UFT-alone treatment, favorable OS (74% at 3 years) and RFS (49% at 3
and more potent chemotherapy should be prescribed. years) with only minimal toxicity (Fig. 2),35 which may
The WJSG-5th study is a unique trial comparing UFT- warrant a future phase III trial of adjuvant chemother-
alone with UFT following CDDP-based chemotherapy apy with platinum-based chemotherapy followed by
in resected p-stage IIIA-N2 NSCLC.32 This study failed UFT for resected advanced-stage NSCLC.
to show any significant advantage of CDDP-based
chemotherapy (CDDP plus VDS) followed by UFT
Gastric Cancer
(CVUft) over UFT-alone treatment, but the 5-year RFS
seemed higher in the CVUft group (31%) than in the The efficacy and optimal therapeutic regimen of post-
UFT-alone group (18%), which may suggest that UFT operative adjuvant therapy for completely resected
following platinum-based chemotherapy is a promising gastric cancer has not yet been established,36–38 although
adjuvant chemotherapy regimen. Among modern 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 adjuvant chemotherapy containing UFT for resected
postoperative chemotherapy39–44 and a RCT conducted gastric cancer have been conducted by the Japan Clini-
in the USA demonstrated a significant survival benefit cal Oncology Group (JCOG)48–52 and other cooperative
of postoperative chemo-radiotherapy.45 In Japan, a study groups in Japan37 (Table 2). In the JCOG-8801
meta-analysis of six Japanese RCTs conducted during trial, a total of 579 patients with curatively resected
1959–1985 demonstrated a significant survival benefit of gastric cancer (T1 with nodal metastasis or T2 disease)
postoperative adjuvant chemotherapy,46 but several were randomly assigned to the surgery-alone group or
issues concerning study design as well as quality of clini- surgery followed by the chemotherapy group; chemo-
cal trials included in the meta-analysis have been pro- therapy consisted of intravenous chemotherapy (mito-
posed.39 Therefore, it is generally accepted in Japan that mycin C [MMC] plus 5-FU, MF) followed by oral UFT
surgery alone remains a standard therapy for respect- administration.50,51 This study failed to show a significant
able gastric cancer.37,38 survival benefit of postoperative adjuvant chemother-
As UFT is an active and well-tolerated chemothera- apy with MF plus UFT for T1-2 gastric cancer, but it did
peutic agent for gastric cancer,47 a series of RCTs of 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, GC01 trial, the JCOG9206-2 trial showed no survival
a new RCT of adjuvant chemotherapy targeting for T2 benefit of postoperative adjuvant chemotherapy with
patients was thus conducted by the National Surgical CDDP plus 5-FU followed by UFT for resected T3–4
Adjuvant Study of Gastric Cancer (NSAS-GC).10 In the gastric cancer (5-year OS, 61.6% for the surgery-alone
NSAS-GC01 trial, a total of 188 patients with com- group and 62.7% for the chemotherapy group; P =
pletely resected serosa-negative T2 (N1–2) gastric 0.500).37,52
cancer were assigned to receive UFT treatment (360 mg/ Recent meta-analyses of RCTs of adjuvant chemo-
m2/day, daily for 16 months) or to undergo observation, therapy conducted in Japan showed a small or border-
and there proved to be a significant improvement with line survival benefit of postoperative adjuvant
adjuvant UFT treatment in both OS (73.6% versus chemotherapy, especially UFT-containing chemother-
86.3% at 4 years; P = 0.0176) and RFS (68.1% versus apy, for resected gastric cancer.53,54 More recently, a
84.5% at 4 years; P = 0.0040). In contrast to the NSAS- 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). ing 5-FU or its derivatives are recommended not only
In the meta-analysis, a total of 1503 patients were ana- for patients with unresectable disease but also for
lyzed, and there proved to be a significant survival patients after complete resection. As the prognosis and
benefit for the postoperative adjuvant UFT treatment optimal therapy are somewhat different between colon
(HR = 0.70 [95% CI: 0.54–0.89] and P = 0.01). In com- cancer and rectal cancer, postoperative adjuvant therapy
bination with the results of the NSAS-CG01 trial for each disease is discussed separately.
showing a significant survival benefit for T2 disease and
that of the JCOG9206-2 trial showing no survival benefit Colon Cancer
for T3-4 disease, postoperative adjuvant UFT chemo- It is generally accepted that postoperative adjuvant
therapy is thus considered to be active enough for therapy is not recommended as a standard care
earlier disease but not for advanced disease. A more of therapy for p-stage I–II colorectal cancer patients
potent adjuvant therapy, such as S-115 as discussed later, because of the favorable survival with surgery-alone
may be appropriate for resected advanced-stage gastric (5-year OS, 91% for stage I and 84% for stage
cancer patients. II disease, respectively).56,57 Regarding p-stage II
patients, however, a marginal survival benefit of
postoperative adjuvant chemotherapy has been docu-
Colorectal Cancer
mented in a pooled analysis of data from four
5-Fluorouracil is the key drug in chemotherapy for National Surgical Adjuvant Breast and Bowel Project
colorectal cancer, and chemotherapy regimens contain- (NSABP) trials (C-01, C-02, C-03, and C-04).58 There-
F. Tanaka: UFT as Postoperative Adjuvant Chemotherapy 931

fore, patients with p-stage II disease at high risk for therapy regimens may be promising in a postoperative
recurrence as well as those with p-stage III disease may adjuvant setting, their safety and efficacy in clinical
be appropriate candidates for postoperative adjuvant practice, especially for Japanese population, have not
chemotherapy.56,58–60 yet been established.56 Therefore, it is generally recog-
A number of RCTs showed a survival benefit of post- nized that 5-FU/LV remains a standard adjuvant che-
operative chemotherapy with the intravenous infusion motherapy regimen for curatively resected colon cancer
of 5-FU plus leucovorin (LV).58,59,61–66 Recently, two patients with stage III disease as well as high-risk stage
RCTs, the NSABP C-07 trial67 and the Multicenter II disease.56,57
International Study of Oxaliplatin/5-Fluorouracil/Leu- There has been reported only one RCT comparing
covorin in the Adjuvant Treatment of Colon Cancer surgery alone with surgery plus postoperative UFT
(MOSAIC) study,68 demonstrated the oxaliplatin plus treatment for resected colon cancer (the Tokai Adju-
5-FU/LV was superior to FU/LV as a postoperative vant Chemotherapy Study Group for Colorectal Cancer
adjuvant chemotherapy for resected p-stage II–III colon [TAC-CR] study)69 (Table 3). In this trial, 320 patients
cancer. Whereas these oxaliplatin-containing chemo- with curatively-resected Dukes’ B–C cancer of the

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 Fig. 2. A single-institute phase II trial of postoperative adju-
showing cytotoxic effect mainly through inhibition of enzyme vant chemotherapy with UFT following carboplatin (CBDCA)
activity of thymidylate synthase (TS) which is a key enzyme plus paclitaxel (PTX) for completely resected node-positive
of de novo DNA synthesis. 5-FU is also degraded into F-β- (pathologic stage II-N1 or IIIA-N2) non-small cell lung cancer
alanine by dihydropyrimidine dehydrogenase (DPD), and a (NSCLC) conducted at Kyoto University. The primary end-
rapid degradation of 5-FU results in a reduced anti-tumor point was overall survival (OS), and secondary endpoints were
effect of 5-FU and the derivatives such as FT. Uracil can recurrence-free survival (RFS) and toxicity35
inhibit enzyme activity of DPD, which can maintain certain
5-FU concentration through inhibition of 5-FU degradation

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 F. Tanaka: UFT as Postoperative Adjuvant Chemotherapy

colon or the rectum were randomly assigned to received standard in Western countries. Therefore, postopera-
UFT treatment or to undergo observation. Overall, this tive radiotherapy may not be necessary to prevent a
trial showed a significantly better RFS in UFT-treated locoregional relapse for resected rectal cancer patients
patients than in surgery-alone patients (75.7% versus in Japan where sufficient surgical techniques are preva-
60.1% at 5 years; P = 0.0081). In a subset-analysis lent, and a series of RCTs of postoperative adjuvant
among colon cancer patients, however, there was no therapy with chemotherapy alone have been conducted
survival advantage of postoperative UFT treatment (P by several groups such as the Japanese Foundation for
= 0.9712 in OS and P = 0.7087 in RFS). On the other Multidisciplinary Treatment for Cancer (JFMC).78–81
hand, a RCT conducted in the USA (NSABP protocol Among these adjuvant trials, three JMFC trials (JMFC
C-06 trial) showed an indirect survival benefit of post- trial 7-1,79 15-1,80 and 15-281) showed no significant
operative adjuvant UFT treatment for colon cancer improvement in OS with postoperative adjuvant che-
patients; the trial compared the relative activity of oral motherapy including UFT plus MMC, although RFS
UFT plus LV with the efficacy of intravenous 5-FU might improve to some degree (Table 3). Similarly, a
plus LV after a curative resection for stage II–III colon subset analysis among rectal cancer patients in the
cancer, thus showing that oral UFT/LV achieved a TAC-CR trial showed that postoperative chemotherapy
similar OS and RFS in comparison with intravenous including UFT achieved a significant improvement in
5-FU/LV70 (Table 3). The NSAPB-06 trial suggests that RFS (P = 0.0016) but did not in OS (P = 0.1669)69 (Table
oral UFT/LV shows an equivalent survival advantage 3). Recently, however, a RCT to compare surgery-alone
and it can be an alternative to the standard regimen, with surgery plus postoperative UFT-alone treatment,
i.e., intravenous 5-FU/LV, for resected colon cancer which was conducted by the National Surgical Adjuvant
patients. To confirm no inferiority of oral UFT/LV in Study of Colorectal Cancer (NSAS-CC), showed that
comparison with intravenous 5-FU/LV in a Japanese adjuvant UFT treatment achieved a significant improve-
population, a RCT (JCOG0205) is now ongoing. ment in OS as well as in RFS11 (Table 3). In addition, a
With regard to oral adjuvant chemotherapy for colon meta-analysis of five RCTs (three JMFC trials [7-1, 15-
cancer patients, capecitabine, another 5-FU derivative 1, 15-2], the TAC-CR trial, and the NSAS-CC trial)
drug, may be another alternative to intravenous 5-FU/ comparing UFT-containing chemotherapy following
LV,59 as a RCT of adjuvant chemotherapy for stage III surgery with surgery-alone showed a significant improve-
colon cancer showed that both RFS and OS in the ment with adjuvant UFT treatment in OS (74.0% versus
capecitabine group were at least equivalent to those in 69.0% at 5 years; P = 0.03 and HR = 0.83 [95% CI:
the 5-FU/LV group (RFS, 64.2% versus 60.6% [P = 0.71–0.98]) as well as in RFS (67.6% versus 57.9% at 5
0.12]; OS, 81.3% versus 77.6% [P = 0.07].71 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
Rectal Cancer cancer in Japan.
It is generally recognized in rectal cancer, the same as
in colon cancer, that postoperative adjuvant therapy
Breast Cancer
should be prescribed for stage III patients as well as
high-risk stage II patients. In the USA, radiotherapy in Standard systemic adjuvant therapy for resected breast
combination with chemotherapy including 5-FU is rec- cancer is determined based on the status of nodal metas-
ommended as a postoperative treatment for resected tasis, hormonal status (estrogen-receptor [ER] expres-
stage II–III rectal cancer patients,72 as two RCTs showed sion and/or progesterone-receptor [PR] expression),
some clinical benefit when radiotherapy is combined and prognosis (risk category classification). Hormone
with chemotherapy.73–76 In the NSABP R-01 trial75 and therapy, especially tamoxifen (TAM), is recommended
R-02 trial,76 the addition of postoperative radiotherapy for most patients with ER-positive or PR-positive
to chemotherapy in resected rectal cancer significantly tumor. In addition, chemotherapy is recommended for
reduced the occurrence of a locoregional relapse, but it most patients with positive axillary nodal metastasis;
failed to achieve a significant survival advantage. There- even when axillary nodal metastasis is negative, chemo-
fore, the clinical benefit of postoperative adjuvant therapy is recommended for some intermediate-risk
radiotherapy remains unclear. In addition, the impact patients and most high-risk patients.83–85
of postoperative adjuvant radiotherapy in locoregional As postoperative adjuvant chemotherapy regimen,
control may be obscure when an adequate surgical CMF (cyclophosphamide [CPA], methotrexate [MTX],
resection can be performed. plus 5-FU) was the first established regimen to improve
In Japan, a total mesorectal excision (TME) plus the outcome of node-positive breast cancer patients,86
selective lateral pelvic lymphadenectomy is the stan- and other chemotherapy regimens containing anthra-
dard surgical technique,11,56,77 whereas TME alone is the cycline agent (doxorubicin [DXR] or epirubicin [EPI])
F. Tanaka: UFT as Postoperative Adjuvant Chemotherapy 933

also proved to be effective in postoperative adjuvant large-scale RCT (Intergroup protocol INT-0102) com-
setting.87 In 1998, the Early Breast Cancer Trialists’ paring CAF with CMF (±TAM) for node-negative
Collaborative Group reported a meta-analysis showing breast cancer patients showed CAF to be associated
that anthracycline-containing regimens were superior with a greater toxicity whereas the survival advantage
to CMF in RFS (57.3% versus 54.1% at 5 years; was minimal (no significant difference in DFS [P = 0.13;
P = 0.006) as well as in OS (71.5% versus 68.8% at HR = 1.09 {95% CI: 0.94–1.27}] and a marginal advan-
5 years; P = 0.02),87 and a recent meta-analysis re- tage in OS [P = 0.03 by one-sided test; HR = 1.19 {95%
ported in 2005 has continued to show the superiority of CI: 0.99–1.43}]), thus suggesting that anthracycline-
anthracycline-based regimens over CMF.88 Accordingly, based chemotherapy may not be recommended for
anthracycline-based regimens such as AC (DXR plus node-negative patients.98 Postoperative adjuvant che-
CPA), EC (EPI plus CPA), FAC/CAF (5-FU, DXR motherapy should be determined based on the toxicity
plus CPA), and FEC/CEF (5-FU, EPI plus CPA) are as well as the benefit of the chemotherapy. Therefore,
recommended as a standard of postoperative adjuvant node-positive patients should be treated with aggressive
chemotherapy.83–85,89 chemotherapy which may achieve a greater benefit, but
Recent clinical trials have attempted to examine the node-negative patients may be treated with less toxic
role of taxane (PTX90–92 or docetaxel [DOC]93–95) in a chemotherapy because of the smaller benefit achieved
postoperative adjuvant setting, and most trials showed with anthracycline-based chemotherapy with a definite
a significant improvement in RFS and/or OS with the toxicity.
use of taxane. For example, the CALGB 934490 and the UFT, with a less toxic profile, has been examined in
NSABP B-2892 trials showed the superiority of AC a variety of Spanish99 and Japanese12,100–107 adjuvant
followed by PTX over AC alone (5-year RFS, 70% trials of resected breast cancer (Table 4). In Japan,
versus 65% [P = 0.0023] in the CALGB trial and 76% the Collaborative Study Group of Adjuvant Chemoen-
versus 72% [P = 0.006] in the NSABP trial, respec- docrine Therapy for Breast Cancer (ACETBC)
tively; 5-year OS, 80% versus 77% [P = 0.006] and 85% has conducted a series of RCTs of postoperative adju-
versus 85% [P = 0.46], respectively), and the FNCLCC vant therapy for breast cancer. In the 3rd ACETBC
PACS 01 trial93 showed the superiority of FEC fol- study,100–102 five RCTs to examine the efficacy of
lowed by DOC over FEC alone (5-year DFS, 78.4% UFT with or without TAM for both node-negative and
versus 73.2% [P = 0.012]; 5-year OS, 90.7% versus node-positive patients were conducted in different
86.7% [P = 0.017]); the Breast Cancer International districts of Japan. (The title of ACET-BC 3rd Study
Research Group (BCIRG) 001 trial94 showed the supe- that appeared in the published article102 was “meta-
riority of the substitution of DOC for 5-FU in a regimen analysis.” However, only 5 controlled trials conducted
that included DXR plus CPA (5-year DFS, 75% for by the ACET-BC groups in different areas of Japan
TAC [DOC/DXR/CPA] versus 68% for FEC were included in the study, which is not a systematic
[P = 0.001]; 5-year OS, 87% versus 81%, respectively review analysis of randomized trials. Thus, the ACET-
[P = 0.008]). More recently, it has been reported BC 3rd study may be a “pooled analysis” of several
that the addition of an anti-HER2/neu monoclonal studies like the ACET-BC 4th study12 and is not cited
antibody (trastuzumab) to EPI-containing chemother- as a meta-analysis in the present review.) A pooled
apy may improve the survival of HER2/neu-positive analysis of these trials showed a trend toward a favor-
breast cancer patients (3-year RFR, 89.3% with able RFS in UFT-treated patients (5-year RFS, 86.5%
chemotherapy with trastuzumab versus 77.6% with for UFT-treated patients versus 83.3% for UFT-
chemotherapy without trastuzumab [P = 0.01]; 3-year untreated patients; P = 0.060), whereas it showed no
OS, 96.3% versus 89.7%, respectively [P = 0.07].96 In OS benefit of UTF treatment.102 In the 4th ACETBC
combination with the promising results of an interim study, six RCTs were conducted to examine the efficacy
analysis of three large-scale RCTs (the NSABP B-31 of postoperative UFT treatment exclusively for node-
trial, the NCCTG N9831 trial, and the HERA trial),97 negative breast cancer patients.12 A pooled analysis
adjuvant chemotherapy including trastuzumab may of these trials showed a significantly higher OS in
thus be recommended for HER2/neu-positive the UFT-treated patients than that in patients without
patients. UFT-treatment (5-year OS, 95.9% versus 94.0%;
Whereas these results clearly demonstrated the effi- P = 0.036) (Table 4), whereas it showed no significant
cacy of anthracycline-based chemotherapy alone, or OS advantage with TAM treatment (5-year OS, 95.2%
that with taxane for node-positive patients and that with for TAM-treated patients versus 93.9% for TAM-
trastuzumab for HER2/neu-positive patients, as an untreated patients; P = 0.12).12 These results suggest
adjuvant systemic therapy for resected breast cancer that postoperative adjuvant UFT treatment is effective
patients,83–85,89 anthracycline-based chemotherapy is for node-negative breast cancer patients. The final
sometimes associated with severe toxicity. In fact, a 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- UFT as an Angiogenesis Inhibitor
sented at the ASCO meeting in 2007.105 No inferiority
of oral UFT treatment to intravenous CMF treatment As described in the previous section, UFT is effective
has been documented in the NSAS-BC01 trial (5-year in the postoperative adjuvant setting for a variety of
RFS, 87.7% in the UFT group and 88.2 in the CMF solid tumors. Patients who undergo surgery may not
group, respectively), and UFT may be an alternative tolerate intensive chemotherapy with severe toxicity,
postoperative adjuvant regimen to intravenous chemo- and the compliance is usually a critical issue in postop-
therapy such as CMF. erative adjuvant therapy.108–109 UFT with a mild toxicity
For node-positive breast cancer patients, a RCT profile may be superior, in terms of the compliance, to
conducted in Japan (the Comparative Trial with UFT/ “standard” adjuvant chemotherapy regimens such as
TAM and CMF/TAM in Adjuvant-therapy for Breast CDDP-based chemotherapy for NSCLC, 5-FU/LV for
Cancer [CUBC trial]106) showed that OS and RFS colon cancer, and anthracycline-based chemotherapy
achieved with oral chemotherapy containing UFT (UFT for breast cancer. However, in terms of antitumor effect,
plus TAM) were similar to those achieved with intrave- UFT may be inferior to these “standard” chemotherapy
nous CMF chemotherapy. In addition, a small RCT con- regimens5,6 (Table 6). A pooled analysis of Japanese
ducted by the Kinki Research Group for Breast Cancer trials for a various advanced solid tumors showed a risk
Adjuvant Therapy (Japan) showed a significantly better ratio (RR) of 25.1% (108/438), and the RR for each
OS (P = 0.04) and a trend toward a favorable RFS tumor was 7.0% (3/43) for lung, 27.7% (52/188) for
(P = 0.07) for patients treated with UFT plus TAM gastric, 25.0% (14/56) for colorectal, and 32.0% (16/50)
as compared with those for patients treated with an for breast cancer.5 These results suggest that UFT may
anthracylcine-based chemotherapy (CAF).107 These thus have a definite antitumor effect for gastric, colorec-
results may suggest that UFT is an effective postopera- tal and breast cancer, but only one responder of 16
tive adjuvant therapy not only for node-negative patients gastric cancer patients (RR, 6.3%) was documented in
but also for node-positive patients, but it is not possible a British phase II trial.6 In addition, the RR achieved
to propose that the efficacy of UFT is comparable to with UFT for lung cancer in a Japanese population was
that or that standard adjuvant chemotherapy for node- less than 10%, and this lower objective response rate
positive patients, i.e., anthracycline-based chemother- can be due to higher enzyme activity of DPD, which
apy, as no definite efficacy of postoperative adjuvant inactivates 5-FU released from UFT, documented in
UFT treatment has yet been established. 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 935

as to why UFT, with a minimal antitumor effect for micrometastatic foci which may leads to fatal postop-
advanced unresectable cancer, especially for that of the erative distant recurrence, because sold tumors cannot
lung, is active in a postoperative adjuvant setting. The growth beyond 1–2 mm in diameter without angiogene-
efficacy of adjuvant UFT treatment cannot be reason- sis115–117 (Fig. 4A). Tumor growth is dependent on the
ably explained by the direct antitumor effect through balance between an increasing number of tumor cells
5-Fu released from FT/UFT. 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
Angiogenesis Inhibition by UFT treatment
oxygen, tumor growth is inhibited through the accelera-
As shown in Fig. 1, FT is converted into 5-FU that tion of apoptosis,121 which leads to a favorable progno-
shows an antitumor effect; during the metabolic process, sis.114,122,123 In fact, a less aggressive angiogenic phenotype,
other metabolites (gamma-butyrolactone [GBL] and represented as lower MVD, is associated with a favor-
gamma-hydroxybutyric acid [GHB]) are also released able postoperative prognosis in clinical studies of a
from FT. GBL or GHB had been shown to have no variety of tumors including lung,124,125 gastric,126 colorec-
significant pharmacological activity. Yonekura and tal,127 and breast cancer.128,129
coworkers, however, revealed that UFT and its metabo- Angiogenesis is thus considered to be an important
lites inhibited tumor-induced angiogenesis in a in vivo therapeutic target in a variety of malignant tumors.114,130,131
mode13 via a pathway linked with vascular endothelial For advanced unresectable tumor, recent RCTs showed
growth factor (VEGF) that was the most potent angio- a survival benefit of the addition of an anti-VEGF anti-
genic factor.111,112 To further examine antiangiogenic body (bevacizumab) to conventional chemotherapy in
effect of UFT and its metabolites, we performed an in colorectal cancer132,133 and NSCLC,134 or showed an
vivo experiment as follows: mice were implanted with a increased objective response in breast cancer.135 In the
human NSCLC cell line (Lu99 or LC11), and then mice postoperative adjuvant setting, it may be expected that
were treated with UFT, 5-FU, GBL, or GHB after the a successful inhibition of tumor angiogenesis with the
establishment of subcutaneous tumors. As a result, postoperative therapy may improve postoperative sur-
tumor angiogenesis represented as a density of endo- vival through a reduction in the probability of postop-
thelial cells (ECs) highlighted with an anti-CD31 anti- erative distant recurrence. It may be speculated that
body (microvessel-density [MVD]) was significantly long-term UFT administration after surgery can thus
inhibited with GBL and GHB administration (see right inhibit the development of postoperative recurrence
upper box in Fig. 3), whereas GBL or GHB did not through an antiangiogenic effect as well as a cytotoxic
inhibit tumor cell growth in vitro. Angiogenesis was also effect (Fig. 4B), which may explain the efficacy of UFT
inhibited with 5-Fu administration, probably due to the in postoperative adjuvant setting.113,114 This speculation
inhibition of angiogenic factors derived from tumor may be supported not only by experimental results
cells through anti-tumor effect of 5-FU; angiogenesis showing that UFT treatment can inhibit development
was markedly inhibited with UFT treatment through of lung micrometastases whereas it shows no objective
the direct antiangiogenic effect of GBL/GHB and indi- response to bulky tumor,136 but also by results of clinical
rect antiangiogenic effect of 5-FU (Fig. 3).113 In addi- studies showing that the efficacy of postoperative adju-
tion, in an in vivo experimental model, Munoz and vant UFT treatment correlates with tumor angiogenesis
coworkers showed that UFT-containing long-term che- (MVD)14,112,137 as well as apoptosis.138 “Standard” intra-
motherapy significantly improved the survival through venous chemotherapeutic agents may have a superior
the inhibition of angiogenesis.114 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
Angiogenesis Inhibition and Improvement in
contains a definite proportion of nonproliferating tumor
Postoperative Survival
cells as well as proliferating cells.118,119 These nonprolif-
The development of distant metastasis after a complete erating cells that did not respond to “shorter-term” che-
resection is the most critical factor influencing the post- motherapy after surgery may thus change to proliferating
operative survival. Even after a complete resection of cells during the postoperative course, thus leading to
clinically detectable tumor, micrometastatic foci may postoperative recurrence (Fig. 4C). “Long-term” UFT
remain to be left undetectable, which can grow during administration has an advantage of inhibiting postop-
postoperative course. When the diameter of metastatic erative recurrence throughout the treatment (Fig.
tumor exceeds 1 cm, then the tumor can be clinically 4B).14,114,137 When many micrometastatic foci may be
detectable and development of postoperative distant expected, for example in the case of advanced-stage
recurrence is confirmed. Angiogenesis thus plays and disease, UFT alone may not control all metastatic
essential role in the development and/or growth of 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 937

“standard” intravenous chemotherapy, i.e., CBDCA/ and grow after surgery (Fig. 4A). Suppose that a post-
PTX followed by UFT for p-stage IIIA-N2 NSCLC,35 operative adjuvant treatment regimen can achieve a
may be promising. 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)
Future Directions: From UFT to S-1 (Fig. 5). Once such a significant survival benefit is dem-
onstrated in a RCT, especially when demonstrated in a
Adjuvant therapy following surgery is principally an series of RCTs with a meta-analysis, then the postopera-
“unnecessary” treatment, when complete resection is tive treatment regimen is recommended for all resected
achieved. In other words, all patients after a complete patients as a rule of evidence-based medicine. Here, the
resection will be expected to survive without tumor majority (70%) of all patients shall essentially need no
recurrence. However, a definite proportion of com- adjuvant chemotherapy, because these patients can be
pletely resected patients may actually die of tumor cured by surgery alone; adjuvant treatment may thus
recurrence, as clinically undetectable tumors do exist 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
Fig. 5. Necessity and effect of postoperative adjuvant therapy, clinical studies have focused on biomarkers to select
when postoperative 5-year survival rates of patients who
receive no treatment after surgery is 70% and postoperative patients who need adjuvant therapy (prognostic factors)
adjuvant therapy can achieve a survival benefit of 10% at 5 and to predict patients for whom adjuvant therapy is
years after surgery. Adjuvant therapy is essentially unneces- effective (predictive factors). In some retrospective
sary for “70%” of all resected patients; among the remaining clinical studies, the efficacy of UFT has been suggested
30% of the patients who need adjuvant therapy to obtain a to be influenced by tumor angiogenesis and status of
cure, two thirds of patients (20% of all patients) may die
because adjuvant therapy fails to inhibit postoperative recur- angiogenesis-related factors14,137,138 as well as by the
rence. Overall, adjuvant therapy can bring a clinical benefit in status of enzymes involved in 5-Fu metabolism such as
only 10% of all patients who receive adjuvant therapy 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 F. Tanaka: UFT as Postoperative Adjuvant Chemotherapy

markers should be established in future clinical trials, inhibitory effect on DPD, that is 180-times higher than
which may thus result in the use of adjuvant treatment that achieved with uracil,143 an enhanced 5-FU concen-
based on these biomarkers. tration can thus be expected with S-1 administration.
Once we decide to perform adjuvant chemotherapy, Potassium oxonate is a reversible competitive inhibitor
the regimen should be carefully selected based on the of orotate phosphoribosy1 transferase (OPRT) that is
toxicity as well as the efficacy. Generally speaking, as responsible for gastrointestinal (GI) toxicity through
agents showing a higher antitumor effect show some- phosphorylation of 5-FU. Therefore, the oral adminis-
times severe toxicity, such agents should be prescribed tration of S-1 can achieve a more potent antitumor
to patients with a higher risk of postoperative recur- effect through an increased 5-FU concentration without
rence such as node-positive patients. Regarding lower- enhancement of GI toxicity such as diarrhea144,145 for a
risk patients, agents with mild toxicity such as UFT or variety of tumors such as lung, gastric, colorectal, and
an alternative to a “standard” chemotherapy regimen breast cancer.146–149 In fact, even in NSCLC which is a
can be recommended; in fact, UFT is the only recom- typical 5-FU-refractory tumor due to its higher DPD
mended agent for completely resected p-stage IB activity, S-1 monotherapy achieved a favorable RR
NSCLC patients for whom CDDP-based chemotherapy (18%) in phase II clinical trials for advanced unresect-
provide no survival benefit probably due to its toxicity able cases,146,147 which is comparable to modern chemo-
(Fig. 6). Nevertheless, the antitumor effect achieved therapeutic agents such as taxanes (Table 6). In gastric
with UFT treatment is not sufficient to control the post- cancer for which the highest RR (46.5%) was docu-
operative recurrence of higher-stage disease with an mented in a phase II trial of S-1 monotherapy for unre-
increased number of tumor cells in micrometastatic sectable disease, and adjuvant trial, the Adjuvant
foci, or UFT cannot control postoperative recurrence Chemotherapy Trial of TS-1 for Gastric Cancer (ACTS-
of 5-FU resistant tumors such as tumors with higher GC), had been started in 2001150 (Table 7). This is a
DPD activity. In such cases, more potent chemothera- large-scale RCT comparing surgery alone with surgery
peutic agents or targeting agents for a targeting- followed by S-1 administration (80–120 mg/body weight/
population, i.e., trastuzumab for HER2/neu-positive day, daily for 28 consecutive days with a 14 days’ rest;
breast cancer patients,96,97 should thus be prescribed. repeated for 12 months after surgery) to examine the
One promising cytotoxic agent for UFT-refractory efficacy of postoperative chemotherapy using S-1 for
cases is S-1, which is a novel oral DIF composed of FT, resected stage II (excluding T1-disease), IIIA, or IIIB
5-chloro-2,4-dihydroxypyridine (CDHP, gimeracil), and gastric cancer. A planned accrual of more than 1 000
potassium oxonate.139,140 Because CDHP shows a potent patients (n = 1 059) had been completed at the end of

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 Treatment arm Status

Stomach ACTS-GC Stage II–III n = 1000 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]
Stomach SAMIT T3–4 n = 1500 A) UFT Ongoing (2005/10–)
(serosa- B) S-1
positive) C) PTX→UFT
D) PTX→S-1
Colon and ACTS-RC Stage II–III n = 800 A) UFT Ongoing (2006/4–)
Rectum
B) S-1
Head and ACTS-HNC Stage III/IVa/IVb n = 600 A) UFT Ongoing (2006/4–)
Neck (squamous cell)
B) S-1

OS, overall survival; RFS, recurrence-free survival; HR, hazard ration; PTX, paclitaxel
F. Tanaka: UFT as Postoperative Adjuvant Chemotherapy 939

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