Surg Today (2007) 37:923–943DOI 10.1007/s00595-007-3578-5

Reprint requests to: F. TanakaReceived: March 5, 2007 / Accepted: April 18, 2007

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 DirectionFUMIHIRO TANAKA

Department of Thoracic Surgery, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya 663-8501, Japan

AbstractUFT (tegafur and uracil) is an oral anticancer drug that has been developed in Japan. Owing to its mild toxicity profi le, UFT can be suitable in an adjuvant setting fol-lowing a complete tumor resection, whereas its direct antitumor effect achieved may be insuffi cient 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 benefi t 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-fl uorouracil (5-FU), and 5-FU is phosphorylated into active metabolites such as 5-fl uoro-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-"-alanine by dihydropyrimidine dehydrogenase (DPD), and a rapid degradation of 5-FU results in a reduced anti-tumor effect caused by 5-

FU and its derivatives such as FT. UFT is defi ned as DPD-inhibitory fl uoropyrimidine (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 insuffi cient 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 effi cacy of adjuvant UFT treat-ment, while others have failed to show any effi cacy 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 benefi t 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 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 effi cacy 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 benefi t, 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 benefi t (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 signifi cantly higher than those of surgery-alone patients,23–25 and a meta-analysis of these RCTs revealed that adjuvant CDDP-based chemotherapy signifi cantly reduced the risk of postoperative death with the hazard ratio (HR) of 0.89 (95% confi dence 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 effi cacy 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 signifi cant survival benefi t on stage II–III patients (HR: 0.83 for both stage II and III diseases).26 Therefore, adjuvant chemotherapy with a mileder tox-icity profi le 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 effi cacy 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 signifi cant difference among the three groups (P = 0.044); the most favorable fi nding was that for the UFT group with a signifi cant 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-

active in a postoperative adjuvant setting whereas UFT shows an insuffi cient 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, signifi cantly 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 benefi t. 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 classifi ed 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 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)

Trial (year)Ref. p-Stage Postoperative treatmentOverall survival

(OS)

Recurrence-free survival(RFS)

WJSG (II) (1996)7 I–III Surgery alone (n = 98) 49.0% —UFTa (n = 103) 64.1% —

P = 0.022WJSG (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 = 0.105for T1 disease (stage IA)

5-/8-year OS: 77.9/57.6% vs 83.6/82.1% (UFT) (P = 0.036)

for T2 disease (stage IB)

5-/8-year OS: 76.1/62.3% vs 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 = 0.045Northeast Japan (2003)28

I–II Surgery alone (n = 110) 75% 71%UFTb (n = 109) 79% 78%

P = 0.7013 P = 0.2427ACTLC (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 IA)

5-year OS: 90% vs 89% (UFT) (P = 0.87; HR = 0.97 [0.64–1.46])

for T2 disease (stage IB)

5-year OS: 74% vs 85% (UFT) (P = 0.005; HR = 0.48 [0.29–0.81])

CI, confi dence interval; p.o., oral administrationa 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 signifi cant survival benefi t of postoperative UFT administration (P = 0.04 and HR = 0.48 [95% CI: 0.52–0.98]). The survival benefi t 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 signifi cant survival benefi t was documented when the tumor measured greater than 2 cm in diameter.33

The effi cacy of postoperative adjuvant UFT treat-ment was confi rmed 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 signifi cantly 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 signifi cant 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)

Trial (year)Ref. p-Stage Postoperative treatmentOverall survival

(OS)

Recurrence-free survival(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 = 0.044**)

P = 0.449 (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 = 0.083WJSG (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 = 0.52WJSG (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 administrationa 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 benefi t 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 signifi cant 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 effi cacy 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)

Trial (year)Ref. p-Stage Postoperative treatmentOverall survival

(OS)

Recurrence-free survival(RFS)

JCOG8401-1 (1995)48 II–III MFC (MMC/5-FU/CA)# 5-FUa (n = 173)

79.0% —

MFC (MMC/5-FU/CA)# UFTa (n = 174)

70.0% —

MF (MMC/5-FU)#UFTa (n = 176)

61.0% —

P = 0.1228JCOG8801 (1999)50,51 T1–2 Surgery alone (n = 285) 82.9% —

(serosa-negative) MF (MMC/5-FU)#UFTb (n = 288)

85.8% —

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

(n = 135)62.7% 59.0%

P = 0.482 P = 0.500(HR = 0.992 [0.697–1.412])

(HR = 1.005 [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 [0.23–0.89])

(HR = 0.41 [0.22–0.77])

MMC, mitomycin C; 5-FU, 5-fl uorouracil; CA, cytosine arabinoside; CDDP, cisplatin; NS, not signifi cant; i.v., intravenous injection; p.o., oral administration; i.p., intraperitoneal injectiona 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 benefi t of postoperative chemotherapy39–44 and a RCT conducted in the USA demonstrated a signifi cant survival benefi t of postoperative chemo-radiotherapy.45 In Japan, a meta-analysis of six Japanese RCTs conducted during 1959–1985 demonstrated a signifi cant survival benefi t 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 signifi cant survival benefi t 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)

Trial (year)Ref. p-Stage Postoperative treatmentOverall survival

(OS)

Recurrence-free survival(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%

(UFT) (P = 0.9712)

74.0% vs 77.4% (UFT) (P = 0.7087)

for rectal cancer 66.7% vs 75.9% (UFT) (P = 0.1669)

42.4% vs 73.6% (UFT) (P = 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 (n = 781)

78.5% 67.0%

P = 0.90 P = 0.96HR = 1.014 [0.825–1.246]

HR = 1.004 [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)

#UFTe (n = 487)74.4% 67.0%

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 = 0.0014HR = 0.42 [0.21–0.83] HR = 0.52 [0.33–0.81]

5-FU, 5-fl uorouracil; LV, leucovorin; MMC, mitomycin C; p.o., oral administration; i.v., intravenous injection; ITT, intent-to-treatment analysisa 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 cyclesc 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 cyclesd 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 fi eld upon completion of surgerye 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 signifi cant 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 benefi t 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 benefi t 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)

Trial (year)Ref. p-Stage Postoperative treatmentOverall survival

(OS)

Recurrence-free survival(RFS)

Grupo Oncologico de Selvilla (Spain) – First (1997)99 Node-positive

(premenopausal)CMF (CPA/MTX/5-FU)a (n = 96)

67% 40%

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 each RCT)

UFT (+)e (n = 965) 93.8% 86.5%

P = 0.33 P = 0.060

*Hokkaido Stage II, ER (+) MMC#TAM versus

MMC#TAM+UFTTohoku Stage I, n0 Surgery alone versus UFTKanto-A Stage I–II, n0, ER($) Surgery alone versus UFTKanto-B Stage I–II, n+, ER(+) TAM versus UFT+TAMNishi-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, and Chubu

Surgery alone versus TAM versus UFT

Hokkaido, Kinki, and Nishi-Nihon

Surgery alone versus TAM versus UFT versus TAM+UFT

CUBC (2005)106 Node-positive (I–IIIa)

CMF (CPA/MTX/5-FU)+TAMh (n = 173)

93.9% (at 3 years) 82.4% (at 3 years)

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-fl uorouracil; MMC, mitomycin C; TAM, tamoxifen; DXR, doxorubicin; p.o., oral adminis-tration; i.v., intravenous injectiona 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 cyclesb 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” trialf 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” trialh 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 cyclesk 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

Author(year)Ref. Trials included

No. of patients

Postoperative treatment

ResultsUFT (daily dose & duration) Other treatment

Lung cancer (non-small cell, NSCLC) Hamada WJSG (II) n = 201 400 mg/body 1 year No 5-year/7-year OS:

81.5%/76.5% (Surgery+ UFT, n = 1001) 77.2%/69.5% (Surgery alone, n = 1002) P = 0.001, HR = 0.74[0.61–0.88]

(2005)34 WJSG (IV) n = 332 400 mg/body 1 year NoOLCSG n = 172 400 mg/body &1 year NoNortheast Japan n = 219 260 mg/m2 2 years NoACTLC n = 100 400 mg/body 2 years NoJLCRG n = 979 250 mg/m2 2 years No

Gastric cancer Sakamoto Pre-JCOG8401 n = 223 670 mg/m2 (FT) 2 years MMC/5-FU/CA P = 0.011, HR =

0.71[0.54–0.92] (2006)54 or 133 mg/m2 (5-FU)

JCOG8801 n = 573 300 mg/body 18 months MMC/5-FUJCOG9206-2 n = 268 267 mg/m2 12 months CDDP/5-FUNSAS-GC01 n = 188 360 mg/m2

(5 days every 7 days)

16 months NoRectal cancer Hamada JFMC 7-1 n = 834 400 mg/body 12 months MMC 5-year OS/RFS: (2005)82 JFMC 15-2A n = 447 400 mg/body 12 months MMF+5FU 74.0%/67.6%

(Surgery+UFT, n = 1115) 69.0%/57.9% (Surgery alone, n = 976) P = 0.03, HR = 0.83 [0.71–0.98] for OS P < 0.0001, HR = 0.72 [0.62–0.83] for RFS

JFMC-15-2P n = 391 400 mg/body 12 months MMC+5FUTAC-CR n = 143 400 mg/body 24 months NoNSAS-CC n = 276 400 mg/m2

(5 days every 7 days)

12 months No

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

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 CancerIt 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 benefi t 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-

[[[

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 signifi cant survival benefi t 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 signifi cant survival benefi t for T2 disease and that of the JCOG9206-2 trial showing no survival benefi t 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-

F. Tanaka: UFT as Postoperative Adjuvant Chemotherapy 931

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 benefi t 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-

therapy regimens may be promising in a postoperative adjuvant setting, their safety and effi cacy 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. 1. Metabolic pathway of UFT, a combination drug of tegafur (FT) and uracil (U). FT is metabolized to 5-fl uoroura-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-"-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

Fig. 3. Metabolic pathway of UFT (tegafur [FT] and uracil [U]). FT is metab-olized to 5-fl uorouracil (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 UFT treatment or to undergo observation. Overall, this trial showed a signifi cantly 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 benefi t of post-operative adjuvant UFT treatment for colon cancer patients; the trial compared the relative activity of oral UFT plus LV with the effi cacy 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 confi rm 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 CancerIt 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 benefi t 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 signifi cantly reduced the occurrence of a locoregional relapse, but it failed to achieve a signifi cant survival advantage. There-fore, the clinical benefi t 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

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 suffi cient 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 signifi cant 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 signifi cant 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 signifi cant improve-ment in OS as well as in RFS11 (Table 3). In addition, a meta-analysis of fi ve 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 signifi cant 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 classifi cation). 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 fi rst 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 933

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 signifi cant 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

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 signifi cant 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 benefi t of the chemotherapy. Therefore, node-positive patients should be treated with aggressive chemotherapy which may achieve a greater benefi t, but node-negative patients may be treated with less toxic chemotherapy because of the smaller benefi t achieved with anthracycline-based chemotherapy with a defi nite toxicity.

UFT, with a less toxic profi le, 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 fi ve RCTs to examine the effi cacy 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 benefi t of UTF treatment.102 In the 4th ACETBC study, six RCTs were conducted to examine the effi cacy of postoperative UFT treatment exclusively for node-negative breast cancer patients.12 A pooled analysis of these trials showed a signifi cantly 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 signifi cant 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 fi nal 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 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 signifi cantly 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 effi cacy of UFT is comparable to that or that standard adjuvant chemotherapy for node-positive patients, i.e., anthracycline-based chemother-apy, as no defi nite effi cacy of postoperative adjuvant UFT treatment has yet been established.

Mechanism of Action: 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 profi le 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 defi nite 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-fl uorouracil (5-FU) and DPD-inhibitory fl uoropyrimidines (DIFs, UFT and S-1) in advanced unresectable cancer of the lung, stomach, colon/rectum, and breast

Tumor

Enzyme activitya Response rate

5-FUb DPD-inhibitor:

No

UFTc DPD-inhibitor:

Uracil

S-1d DPD-inhibitor:

CDHP (Gimeracil)

TS (pmol/mg-protein)

DPD (pmol/min/mg-protein)

n Mean Median n Mean Median

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-dihydroxypyridinea 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 advanced unresectable cancer, especially for that of the lung, is active in a postoperative adjuvant setting. The effi cacy 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 signifi cant 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 signifi cantly 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 signifi cantly 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 infl uencing 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 confi rmed. Angiogenesis thus plays and essential role in the development and/or growth of

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 suffi cient 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 benefi t 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 effi cacy 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 effi cacy 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 defi nite 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

A

B

C

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 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 infl uence 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/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 defi nite proportion of com-pletely resected patients may actually die of tumor recurrence, as clinically undetectable tumors do exist

and grow after surgery (Fig. 4A). Suppose that a post-operative adjuvant treatment regimen can achieve a signifi cant survival benefi t 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 signifi cant survival benefi t 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 benefi t. 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 effi cacy of UFT has been suggested to be infl uenced 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 signifi cance of such bio-

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 benefi t 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 benefi t in only 10% of all patients who receive adjuvant therapy

Fig. 6. Postoperative adjuvant chemo-therapy for carcinoma of the lung, stomach, colon and rectum, and breast cancer. When the effi cacy of an adjuvant therapy regimen is established in multiple randomized clinical trials (RCTs), the therapy is indicated in a “red” box; when the effi cacy is shown in one or a few RCTs, the therapy is indicated in an “orange” box. CBDCA, carboplatin; PTX, paclitaxel; 5-FU, 5-fl uorouracil; 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, 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 effi cacy. 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 benefi t probably due to its toxicity (Fig. 6). Nevertheless, the antitumor effect achieved with UFT treatment is not suffi cient 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

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 effi cacy 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

Table 7. Phase III randomized controlled trials (RCTs) of postoperative adjuvant chemotherapy with S-1 for solid tumors

Organ Trial

Trial design

StatusStagePlanned accrual Treatment arm

Stomach ACTS-GC Stage II–III n = 1000 A) Surgery alone Completed(*interim analysis presented in 2007/01)B) S-1Results* 3-year OS 3-year RFS

A) (n = 530) 70.1% 60.1%B) (n = 529) 80.5% 72.2%

P = 0.0024 P < 0.0001HR = 0.68 [0.52–0.87]

HR = 0.62 [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-1Colon and Rectum

ACTS-RC Stage II–III n = 800 A) UFT Ongoing (2006/4–)

B) S-1Head and Neck

ACTS-HNC Stage III/IVa/IVb (squamous cell)

n = 600 A) UFT Ongoing (2006/4–)

B) S-1

OS, overall survival; RFS, recurrence-free survival; HR, hazard ration; PTX, paclitaxel

F. Tanaka: UFT as Postoperative Adjuvant Chemotherapy 939

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 signifi cant sur-vival benefi t 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 effi cacy 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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