Japanese Journal of Clinical Oncology 31:450-453 (2001)
© 2001 Foundation for Promotion of Cancer Research
Complete Response Achieved Following Administration of S-1 in a Patient with Adrenal Gland Metastasis of 5-FU-resistant Gastric Cancer: a Case Report
Division of Gastrointestinal Oncology, Department of Medicine, National Cancer Center Hospital, Tokyo, Japan
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONCASE REPORTDISCUSSIONREFERENCES |
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A 62-year -old male patient who had undergone total extirpation of type 3 cancer of the greater curvature of the upper stomach body at another hospital received postoperative chemotherapy with 5-FU and methotrexate. The patient was subsequently treated with oral 5-FU. About 1 year later, a 4 cm tumor of the left adrenal gland was revealed by abdominal CT and diagnosed as gastric cancer metastasizing to the adrenal gland. The patient was referred to our hospital for close examination and treatment and admitted. After his informed consent had been obtained, the patient received one course (4-week administration and 2-week withdrawal) of S-1 at 50 mg/body x 2/day. Abdominal computed tomography performed after the end of the one course revealed that the tumor had become undetectable. This condition was still maintained at the end of two courses and judged to be complete response (CR) (in accordance with the WHO Efficacy Judgment Criteria). CR has continued to be maintained to the present time, even after seven courses. There has been no previous report of S-1 showing remarkable effectiveness in a patient with 5-FU-resistant gastric cancer metastasizing to the adrenal gland. We consider that the efficacy of S-1 for treatment of 5-FU-resistant gastric cancer should be verified.
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INTRODUCTION |
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Oral fluoropyrimidine anticancer agents have been classified as DPD-inhibitory fluoropyridine (DIF) drugs that inhibit dihydropyrimidine dehydrogenase (DPD), a 5-FU decomposition enzyme, in the liver and as other non-DIF drugs (1–3). The first of the DIF drugs developed was UFT and S-1 can be considered an improved formulation of UFT. Non-DIF drugs, including tegafur, carmofur, doxifluridine, capecitabine, etc., are also known. S-1, a DIF drug, and capecitabine, a non-DIF drug, are drawing attention clinically as new oral anticancer agents.
We observed attainment of complete response (CR) following administration of S-1 in a patient exhibiting metastasis to the adrenal gland, although the patient had received MTX/5-FU therapy as adjuvant chemotherapy following surgery for gastric cancer and subsequent administration of oral 5-FU.
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CASE REPORT |
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TOPABSTRACTINTRODUCTIONCASE REPORTDISCUSSIONREFERENCES |
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The patient was a 62-year-old male, with no chief complaint and unexceptional family history and previous history.
History of Present Disease
The patient had undergone total extirpation of advanced gastric cancer (type 3 and stage IIIb cancer of the greater curvature of the upper stomach body) at another hospital. Pathological examination showed poorly differentiated adenocarcinoma, se, int, inf 
, ly3, v2, n2, aw (–) and ow (–). He had received 5-FU and methotrexate twice as postoperative adjuvant chemotherapy and continuous administration of 150 mg/day of oral 5-FU was subsequently applied. The patient had received oral 5-FU for about 10 months before computed tomography (CT) of the abdomen revealed a tumor, about 4 cm in diameter, of the left adrenal gland. The patient was diagnosed with adrenal metastasis of gastric cancer in March 2000 (Fig. 1). He had hydronephrosis of the left kidney, which seemed to be caused by pressure from peritoneal dissemination or by metastasizing of the tumor to the adrenal gland. The patient was referred to our hospital to receive chemotherapy in April 2000. The patient’s condition was performance status (PS) 1 on admission.
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Laboratory Test Findings on Admission
RBC, 396 x 104/mm3; Hb, 12.8 g/dl; Ht, 41.7%; Plt, 35.9 x 104/mm3; WBC, 7300/mm3; T. prot, 7.0 g/dl; T. bil, 0.6 mg/dl; GOT, 46 IU/l; GPT, 35 IU/l; LDH, 527 IU/l; ChE, 178 IU/l; Glu, 120 mg/dl; BUN, 21 mg/dl; Crea, 1.3 mg/dl; Na, 141 mEq/l; K, 4.6 mEq/l; Cl, 103 mEq/l; CA125, 56 U/ml; CEA, 4.6 ng/ml; and CA19-9, 11 U/ml.
Details of Treatment
After the patient’s informed consent had been obtained, S-1 was administered at 50 mg/body x 2/day one month after the final administration of oral 5-FU as specified, since his body surface area was 1.39 m2. One course of medication comprised 4-week administration and 2-week withdrawal from medication. Abdominal CT performed at the end of one course revealed a markedly reduced adrenal tumor which was undetectable on imaging and the tumor was therefore considered to have disappeared (Fig. 2). This condition was maintained at the end of two courses in June 2000 and the overall evaluation of the efficacy of S-1 in this patient was judged to be CR (in accordance with the WHO Efficacy Judgment Criteria). At the end of three courses, an improvement in hydronephrosis was also observed and the serum creatinine level had recovered from 1.3 mg/dl before treatment to a level within the normal range. The CA125 value was 56 U/ml before treatment and decreased to a normal level of 7 U/ml (Fig. 3). Even after seven courses in March 2001, CR has been maintained with no observable relapse.
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Toxicities exhibited during treatment with S-1 included leukopenia, anemia, thrombocytopenia, malaise, anorexia, diarrhea, stomatitis and rash, but all the toxicities were grade 1 except anemia of grade 2. No toxicity of grade 3 or more was observed.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONCASE REPORTDISCUSSIONREFERENCES |
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The cytocidal mechanism of 5-FU is roughly divided into DNA synthesis inhibition and RNA dysfunction. It is known that the former depends on the time of exposure to 5-FU, whereas the latter depends on the 5-FU concentration (4). Many comparative clinical studies have been conducted to assess whether increasing the 5-FU concentration quickly, i.e. the bolus intravenous administration method, was better or whether continuous drip intravenous infusion with attention paid chiefly to the lengthening of exposure time was better. In view of the response rate, survival time and toxicity, a consensus has been reached on the superiority of the continuous drip infusion method (5). Dose-limiting toxicity (DLT) in continuous drip infusion of 5-FU includes gastrointestinal mucous membrane impairment such as diarrhea and stomatitis and hand–foot syndrome, rather than myelosuppression. S-1 was developed with the aim of maintaining the 5-FU concentration for a long period following oral administration to attain a more potent antitumor effect and reducing gastrointestinal toxicity (6,7).
S-1 is tegafur (FT), a prodrug of 5-FU, combined with gimeracil (5-chloro-2,4-dihydroxypyridine) (CDHP), a reversible inhibitor of dihydropyrimidine dehydrogenase (DPD), i.e. 5-FU degradation enzyme and oteracil potassium [monopotassium 1,2,3,4-tetrahydro-2,4-dioxo-1,3,5-triazine-6-carboxylate (Oxo)], an inhibitor of orotate phosphoribosyl transferase (OPRT), phosphorylation enzyme for 5-FU (FT:CDHP:Oxo= 1:0.4:1). CDHP inhibits DPD, a 5-FU degradation enzyme, reversibly with an inhibitory activity about 200 times that of uracil. If 1200 mg of FT, 300 mg of UFT (in terms of volume of FT), a combination of FT and uracil and 50 mg of S-1 (in terms of volume of FT) are administered orally, both the Cmax and AUC of S-1 are significantly higher (8). Although Oxo has been known to inhibit OPRT, Shirasaka et al. demonstrated that very little Oxo was detected in tumors following oral administration, since Oxo was distributed in the small and large intestines in higher concentrations and absorbed less through the intestines and was not transferred into the blood (6). Hence they described oral administration of Oxo as leading to inhibition of 5-FU activity specifically in the intestinal mucosa with the result that gastrointestinal toxicity was reduced, whereas 5-FU activity in tumor cells was little inhibited, in their view.
Clinical studies on S-1 have been conducted in Japan. The results of an early phase II study of advanced and recurrent gastrointestinal cancers (9) and late phase II studies on advanced gastric cancer conducted by group T (10) and group K (11) showed very high response rates of 53.6% (15/28 patients), 49.0% (25/51 patients) and 40.0% (20/50 patients), respectively. The response rates classified according to the metastatic region shown by an aggregate summary of the early and late phase II studies were 35.1% (20/57 patients) in metastatic hepatic cancer, 22.2% (2/9 patients) in metastatic pulmonary cancer, 49.2% (29/59 patients) in metastatic abdominal lymph node cancer and 68.4% (13/19 patients) in metastatic cervical lymph node cancer. A high efficacy against metastatic lymph node cancers was especially demonstrated. For primary cancer lesions, a response rate of 32.6% (30/92 patients) was achieved with S-1, a remarkably high response rate compared with those obtained with other drugs.
As far as the toxicity of S-1 is concerned, the occurrence of grade 2 or more severe leukopenia in 21.8% and of grade 3 or more severe leukopenia in 3.9% and the occurrence of grade 2 or more severe neutropenia in 26.8% and of grade 3 or more severe neutropenia in 8.6% were observed. Grade 2 or more severe diarrhea occurred in 6.4% and grade 3 or more severe diarrhea occurred in 3.2%. Since the hematological toxicity of S-1 was more severe than that of oral fluoropyrimidines currently in use, this drug should be administered under careful control, taking such measures as regular outpatient examinations, regular hematological tests and detailed explanations to patients of adverse events.
The patient reported on here was considered to be sufficiently 5-FU resistant, since he had received MTX/5-FU therapy twice and subsequent administration of oral 5-FU as post-gastric surgery adjuvant chemotherapy. Despite the 5-FU-based pretreatment, CR was achieved following treatment with 50 mg/body of S-1 x 2/day. All of the small number of patients achieving CR with S-1 therapy who have been reported previously were initial treatment cases (12) or cases in whom no 5-FU resistance had been demonstrated (13). The present patient, who exhibited CR with administration of S-1 despite having already demonstrated 5-FU resistance, is the first to be reported.
The possible reasons for the remarkable effectiveness of S-1 in this patient, who was considered to be refractory to 5-FU, are as follows. (1) A high 5-FU blood level, which cannot be attained with oral administration of 5-FU, was achieved and maintained by means of the DPD inhibition effect of CDHP in the liver. (2) The patient could receive an appropriate amount of S-1, since he had no symptoms such as severe diarrhea or nausea/vomiting due to the inhibitory effect of Oxo on 5-FU phosphorylation in the normal gastrointestinal mucosa. (3) CDHP may have inhibited DPD in the tumor so effectively that the tumor was significantly reduced in size. (4) The inhibitory effect of CDHP on the production of 
-fluoro-ß-alanine, a degradation product of 5-FU, might have contributed to enhancing the antitumor effect of 5-FU. This is based on a recent report that -fluoro-ß-alanine was able to reduce the antitumor effects of 5-FU (14).
We consider that the efficacy of S-1 for treatment of 5-FU-resistant gastric cancer should be verified. Based on our experience with this patient, we are currently conducting a clinical phase II study of S-1 in patients who have already received a 5-FU-containing regimen.
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FOOTNOTES |
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+ For reprints and all correspondence: Yasuhiro Matsumura, Division of Gastrointestinal Oncology, Department of Medicine, National Cancer Center Hospital, 1–1 Tsukiji 5-chome, Chuo-ku, Tokyo 104-0045, Japan. E-mail: yhmatsum@ncc.go.jp
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REFERENCES |
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Received February 19, 2001; accepted May 18, 2001.
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