Recent trials of adjuvant chemotherapy in Japan are characterized by
regimens that consist of intravenous (IV) induction chemotherapy and
oral administration of 5-FU (5-fluorouracil) or its derivatives.[1,2]
The combination drug UFT (uracil and tegafur) is the most frequently
employed anticancer drug in Japan where, until now, no previous
trials have evaluated the survival benefits of oral chemotherapy
alone. However, UFT had been used as part of maintenance chemotherapy
after IV induction chemotherapy. Therefore, given its proven survival
benefits and low toxicity profile, orally administered UFT may
prove convenient for treating patients at home.
From 1984 to 1998, the Gastric Cancer Surgical Study Group of the
Japan Clinical Oncology Group (JCOG) conducted a series of three
trials of adjuvant chemotherapy after curative gastrectomy. These
regimens were based mainly on various combinations of mitomycin
(Mutamycin): mitomycin plus 5-FU (MF) and mitomycin plus 5-FU plus
cytarabine (Ara-C, Cytosar) (MFC) with or without UFT (study 8801).
The results of this study led us to conduct a new trial, beginning
in 1998, to evaluate the survival benefits of UFT alone after
curative surgery for T2 gastric cancer with lymph node metastasis.
From 1988 to 1992, seven cancer centers in Japan participated in this
randomized, controlled trial of curative gastrectomy, followed by IV
mitomycin plus 5-FU followed by oral UFT, for serosa-negative gastric
cancer. A total of 579 patients were allocated randomly to undergo
surgery plus chemotherapy or surgery alone. Six patients were
excluded because they did not meet the eligibility criteria.
Entry criteria were histologically proven adenocarcinoma, age £
75 years, macroscopically serosa-negative cancer eradicated by
curative gastrectomy and normal liver, kidney, and bone marrow
functions. The chemotherapy consisted of IV mitomycin 1.4 mg/m²
twice a week for 3 weeks plus 5-FU 166.7 mg/m² twice a week for
3 weeks; oral UFT 300 mg/day was then administered for 18 months. The
control group received no additional therapy after surgery. The study
design is shown in Figure 1.
The primary end point was survival, although cause of death and type
of recurrence were also studied.
The distribution of main prognostic factors and the method of surgery
across the two groups were almost identical, although the proportion
of patients with absolute curative surgery was slightly higher in the
treatment group (Table 1).
Among the 573 eligible patients, 188 (32.8%) were in the pT1 category
and 304 (53.1%) had no lymph node metastasis on microscopy. Toxicity
was generally mild: leukocytopenia was observed in 9% of patients and
throm-bocytopenia in 0.7%.
At a median follow-up of 72 months, the overall 5-year survival rate
was 82.9% in the control group and 85.8% in the treatment group (Figure
2). Among T1 patients, 5-year survival was 94.9% in the control
group and 92.0% in the treatment group (Figure
3). Survival for T2 patients in the control and treated groups
was 76.9% and 83.0%, respectively (Figure
4). During follow-up, 39 (13.7%) patients in the control group
and 29 (10.9%) in the treatment group suffered cancer recurrence.
Hematogenous metastasis was the most common type of recurrence in
both groups, followed by peritoneal dissemination.
Due to a lack of evidence of any survival benefit, no standard
adjuvant chemotherapy has been established for gastric cancer.
However, a few recent meta-analyses of adjuvant chemotherapy
trials[6,7,8] have revealed survival benefits in patients with
locally advanced gastric cancer after curative gastrectomy for
locally advanced gastric cancer (T2-T3). These results, reported in
1999, showed no survival benefit with the MF plus UFT regimen in
postoperative T1-T2 gastric cancer, although a slightly higher
survival rate was observed for the treatment group in the T2 subset.
T2 cancer should remain the target of further adjuvant chemotherapy trials.
The response rate to UFT in advanced gastric cancer was 27%, with
no serious side effects observed. If oral administration of UFT could
result in increased survival in postoperative patients with T2
cancer, it might be useful as an adjuvant to surgery in terms of
improved quality of life for these patients.
A new trial has been under way since 1997 by the National Surgical
Adjuvant Study (NSAS) Group (Figure 5).
The goal of this study is to accumulate 500 cases of T2 cancer with
lymph node metastasis. Results of this study will provide important
data for future trial designs of adjuvant chemotherapy for gastric cancer.
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Present status and suggestions for rational clinical trials. Jpn J
Clin Oncol 20:30-42, 1990.
2. Sano T, Sasako M, Katai H, et al: Randomized controlled trials on
adjuvant therapy for gastric cancer: Japanese experience, in Nakajima
T, Yamaguchi T (eds): Multimodality Therapy for Gastric Cancer, pp
7-16. Tokyo, Springer Verlag, 1999.
3. Takiuchi H, Ajani JA: Uracil-tegafur in gastric carcinoma: A
comprehensive review. J Clin Oncol 16:2877-2885, 1998.
4. Kitamura M, Nakajima T, Ohta K, et al: Adjuvant chemotherapy of
gastric cancer: JCOG experience, in Nakajima T, Yamaguchi T (eds):
Multimodality Therapy for Gastric Cancer, pp 32-41. Tokyo, Springer
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fluorouracil followed by oral uracil plus tegafur in serosa-negative
gastric cancer: A randomized trial. Lancet 354:273-277, 1999.
6. Hermans J, Bonenkamp H: In reply to the editor. J Clin Oncol
7. Earle CC, Maroun JA: Adjuvant chemotherapy after curative
resection for gastric cancer in non-Asian patients: Revisiting a
meta-analysis of randomized trials. Eur J Cancer 35:1059-1064, 1999.
8. Nakajima T, Ohta K, Ohyama S, et al: Meta-analysis of adjuvant
chemotherapy trials for gastric cancer at the Cancer Institute
Hospital, Tokyo, in Nakajima T, Yamaguchi T (eds): Multimodality
Therapy for Gastric Cancer, pp 27-31. Tokyo, Springer Verlag, 1999.
9. Ota K, Taguchi T, Kimura K: Report on nationwide pooled data and
cohort investigation in UFT phase II study. Cancer Chemother
Pharmacol 22:333-338, 1998.
10. Hoff PM, Pazdur R, Benner SE, et al: UFT and leucovorin: A review
of its clinical development and therapeutic potential in the oral
treatment of cancer. Anticancer Drugs 9:479-490, 1998.