S-1-Induced, Prolonged Complete Regression of ...

Jpn J Clin Oncol 2004;34(5)282–286

S-1-Induced, Prolonged Complete Regression of Lung Metastasis from Gastric Cancer Refractory to 5′-DFUR: a Case Report with Pharmacokinetic Study Yuji Ueda1, Hisakazu Yamagishi1, Tetsuro Yamashita1, Norio Itoh1, Hirosumi Itoi1, Tetsuhiko Shirasaka2 and Jaffer A. Ajani3 1Department

of Surgery and Oncology of the Digestive System, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto and 2Institute for Pathogenic Biochemistry in Medicine, Taiho Pharmaceutical Co., Ltd, Tokyo, Japan and 3Department of Gastrointestinal Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA Received October 14, 2003; accepted March 9, 2004

Key words: gastric cancer – S-1 – lung metastasis – complete response – pharmacokinetic study

INTRODUCTION S-1 (TS-1®, Taiho Pharmaceutical, Tokyo, Japan) is a novel oral dihydropyrimidine dehydrogenase (DPD)-inhibitory fluoropyrimidine (DIF) developed by Shirasaka et al. (1,2). It is designed to provide high, prolonged serum levels of 5-fluorouracil (5-FU) with minimal toxicity. S-1 contains tegafur and two types of enzyme inhibitors, 5-chloro-2,4-dihydropyrimidine (CDHP) and potassium oxonate, in a molar ratio of 1:0.4:

For reprints and all correspondence: Yuji Ueda, Department of Surgery and Oncology of the Digestive System, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto 602-8566, Japan. E-mail: [email protected]

1. CDHP enhances the efficacy of 5-FU by inhibiting DPD activity and potassium oxonate reduces adverse effects on the digestive system by suppressing orotate phosphoribosyltransferase activity (3,4). Two pivotal phase II studies of S-1 in advanced and recurrent gastric cancer were conducted concurrently in Japan (5,6) and reported response rates of 49% (25/51) and 40% (20/50), respectively. A combined analysis of these two studies showed an overall response rate of 44.6% (45/101). This response rate was higher than that reported for other agents (7). S-1 is thus rapidly becoming a first-line drug for the treatment of gastric cancer in Japan. However, the response rate for lung metastasis was lower [16.7% (1/6)] than those for other primary and metastatic lesions and no patient had a complete response. © 2004 Foundation for Promotion of Cancer Research

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S-1 is an oral fluoropyrimidine reported to be most active for gastric cancer. However, few studies have documented a complete response (CR) of lung metastasis to S-1 treatment. We describe a 66-year-old woman in whom S-1 induced complete regression of lung metastasis from gastric cancer, that had been refractory to another oral fluoropyrimidine, 5′-deoxy-5fluorouridine (5′-DFUR). After preoperative chemotherapy with a combination of etoposide, adriamycin and cisplatin and with methotrexate plus 5-fluorouracil, the patient underwent a total gastrectomy with lower esophagectomy for advanced diffuse-type gastric cancer with invasion of the esophagus in May 1993. She received postoperative adjuvant chemotherapy with 5′-DFUR (600 mg/day) for 3 years. However, a solitary metastasis to the left lung was detected in November 1996 and she underwent partial resection of the left lung. Chemotherapy with 5′-DFUR was reinitiated after operation, but re-metastasis to the left lung with elevation of the serum carcinoembryonic antigen (CEA) level was diagnosed in June 1999. Treatment with S-1 was started in August. S-1 was given orally in a dose of 100 mg/day for 28 consecutive days, followed by a 14-day recovery; treatment was repeated every 6 weeks. The metastatic lesion in the left lung completely regressed after two courses of S-1 and the serum CEA level returned to the normal range. The patient received a total of 10 courses of S-1. The dose of S-1 was reduced to 80 mg/day from the sixth course because of grade 2 skin rash. Pharmacokinetic studies after administration of S-1 revealed high and prolonged plasma 5-FU levels. Nearly 4 years have passed since complete regression of the lung metastasis. This may be the first report to document a prolonged complete response of lung metastasis from gastric cancer induced by single-agent chemotherapy with S-1.

Jpn J Clin Oncol 2004;34(5)

Moreover, no report to date has documented the complete regression of lung metastasis from gastric cancer in response to S-1. This paper describes a patient in whom S-1 induced complete regression of lung metastasis from gastric cancer. The metastasis was refractory to another oral fluoropyrimidine, 5′-deoxy-5-fluorouridine (5′-DFUR; doxifluridine). Nearly 4 years have passed since confirmation of complete regression. To our knowledge, this is the first report to document the prolonged, complete regression of lung metastasis from gastric cancer in a patient given single-agent chemotherapy with S-1.

CASE REPORT A 59-year-old woman presented with dysphagia and weight loss in September 1992. An upper gastrointestinal series and endoscopic examination demonstrated a large type 3 advanced gastric cancer, arising in the cardia and invading the lower esophagus (Fig. 1). Examination of a biopsy specimen showed mucinous adenocarcinoma. Moreover, abdominal and chest computed tomographic (CT) scans suggested direct invasion of cancer to the diaphragm and the pericardia. There was no evidence of lymph-node involvement or distant metastases on physical examination, CT scans, ultrasonography or bone scintigraphy. The initial diagnosis was a T4, N0, M0, stage IIIA locally advanced gastric cancer according to the TNM Classification of Malignant Tumors. The patient was given preoperative chemotherapy with a combination of etoposide, adriamycin and cisplatin and with methotrexate plus 5fluorouracil. The primary lesion partially responded to these treatments. Total gastrectomy with lower esophagectomy, splenectomy, partial resection of the diaphragm around the esophageal hiatus and D2 lymph node dissection was performed in June 1993. There was no direct invasion to the pericardia and no peritoneal dissemination or hepatic metastases.

Figure 2. Chest CT scans obtained at first recurrence (November 1996). A solitary metastasis appeared in the left lung. It was resected in January 1997.

Histopathological examination revealed a mucinous adenocarcinoma, pT4 (SI; diaphragm), pN0, sH0, sP0, sM0, stage IIIA, according to the Japanese Classification of Gastric Carcinoma, 13th edition. After gastrectomy, the patient received adjuvant chemotherapy with 5′-DFUR (600 mg/day; 200 mg three times daily after meals), an oral prodrug of 5-FU, for 3 years. However, a solitary metastasis was found in the left lung on a follow-up chest CT scan in November 1996, 3 years 5 months after gastrectomy and 5 months after the withdrawal of administration of 5′-DFUR (Fig. 2). The left lung was partially resected in January 1997. We discussed the adjuvant chemotherapy after lung resection with the patient. Because irinotecan (CPT-11) was not accepted widely for gastric cancer at that time in Japan, we recommended her to receive other 5-FU-based regimens or oral fluoropyrimidines. As a result, the patient opted to take 5′DFUR again. Therefore, chemotherapy with the same dosage of 5′-DFUR was resumed, but re-metastasis to the left lung with elevation of the serum carcinoembryonic antigen (CEA) level was diagnosed in June 1999 (Fig. 3a). Because the patient opted to continue treatment by oral drugs as an outpatient and S-1 was approved for the treatment of gastric cancer in March 1999, we decided to use this new agent. Single-agent chemotherapy with S-1 was started in August 1999. At this time, she was 155 cm tall and weighed 45 kg [body surface area (BSA) 1.36 m2]. Her performance status was 0. The results of laboratory examinations were within the normal range, except for an elevated serum CEA level (15.2 ng/ml, cutoff value 2.5 ng/ml). The initial dose of S-1 was decided on the basis of BSA as follows: BSA 1.5 m2, 120 mg/day (5,6). S-1 was therefore given in a daily oral dose of 100 mg/day (50 mg twice daily, after breakfast and dinner) for 28 consecutive days, followed by 14 days of rest. Treatment was repeated every 6 weeks. The patient’s clinical progress is shown in Fig. 4.

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Figure 1. Upper gastrointestinal series before gastrectomy showed a large type 3 advanced gastric cancer in the cardia, invading the lower esophagus (September 1992).

283

284

Lung metastasis treated by S-1

PHARMACOKINETIC STUDY OF 5-FU AND CDHP AFTER ADMINISTRATION OF 5′-DFUR OR S-1 It could be considered that this is a rare case of S-1-induced CR in patient with gastric cancer who was refractory to another fluoropyrimidine. Therefore, to investigate possible reasons for the effectiveness of S-1 in this patient, we decided to carry out pharmacokinetic studies of 5-FU and CDHP after administration of 5′-DFUR or S-1. The study was performed in January 2002, with the patient’s informed consent. As described above, the patient was receiving no anticancer treatment at that time, but she kindly agreed to join in the study because she also wanted to know the reason for her cancer regression in case the cancer relapses again in the future. STUDY PLAN AND BLOOD SAMPLE COLLECTION First, 5′-DFUR was studied. On the day before blood sampling, 5′-DFUR was administered at a dose of 200 mg three times after meals. On the following morning, 200 mg of 5′-DFUR were administered within 30 min after breakfast and blood samples were drawn 1, 3, 5, 7 and 9 h after this final dose. After a washout period of 7 days, S-1 was studied. On the day before blood sampling, S-1 was administered at a dose of 50 mg twice daily, after breakfast and dinner. On the following morning, the patient received 50 mg of S-1 within 30 min after breakfast. Blood samples were drawn 1, 3, 5, 7 and 9 h after this final dose. All peripheral blood samples (volume, 5 ml) were collected into heparinized tubes and were centrifuged at 3000 r.p.m. for 15 min at 4°C; the plasma was stored at –20°C until analysis. Figure 3. Chest CT scans obtained at second recurrence and after treatment with S-1. (a) A solitary re-metastasis in the left lung associated with elevation of the serum carcinoembryonic antigen (CEA) level was confirmed in June 1999. (b) Metastatic lesion in the left lung completely regressed after two courses of S-1 treatment. A faint scar remained (8 November 1999). The serum CEA level was normal at that time. (c) There was no sign of recurrence 3 years 7 months after the metastasis had completely regressed (27 May 2003).

DRUG ASSAY 5-FU and CDHP were analyzed as described by Matsushima et al. (8) at the Institute for Pathogenic Biochemistry in Medicine, Taiho Pharmaceutical. In brief, 5-FU and CDHP were

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After the patient had received two courses of S-1, metastasis had disappeared from the left lung, with a faint scar remaining after thoracotomy (Fig. 3b) and the serum CEA level (1.7 ng/ml) fell to within the normal range (Fig. 4). Therefore, the tumor was considered to have regressed completely. This response was reconfirmed at the beginning of the fourth course of S-1 (CR, in accordance with the WHO efficacy evaluation criteria). A total of 10 courses of S-1 were administered by the end of October 2000. Grade 2 skin rash (according to NCI Common Toxicity Criteria, Version 2.0) developed during the fifth course of treatment and the dose of S-1 was reduced to 80 mg/day from the sixth course. No toxicity of grade 3 or more occurred. All treatment was received on an outpatient basis. After completion of the 10th course of S-1 treatment, the patient has received no anticancer therapy. She is now being followed up at the outpatient clinic once a month and is doing well, with no signs of recurrence on CT scans (Fig. 3c) or tumor marker examinations (Fig. 4). Nearly 4 years have passed since complete regression of lung metastasis.

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extracted with ethyl acetate from the residue obtained after dichloromethane extraction. Plasma 5-FU and CDHP levels were determined using gas chromatography–negative ion chemical ionization mass spectrometry.

that after administration of 5′-DFUR. The plasma 5-FU level then decreased gradually and was 24.8 ng/ml even 9 h after treatment. This level was similar to the Cmax of 5-FU after administration of 5′-DFUR. The time course of the plasma 5FU level paralleled that of the plasma CDHP level.

RESULTS Table 1 shows the time course of plasma 5-FU levels after the final dose of 5′-DFUR and the time courses of plasma 5-FU and CDHP levels after the final dose of S-1. The maximum plasma concentration (Cmax) of 5-FU after administration of 5′-DFUR was 25.1 ng/ml at 1 h. The plasma 5-FU level then decreased rapidly and no 5-FU was detected in the plasma at 9 h. In contrast, the Cmax of 5-FU after administration of S-1 was 217.0 ng/ml at 1 h; this value was about nine times higher than

DISCUSSION Factors such as the quality of life (QOL), convenience and palliation are highly desirable in anticancer treatment (9). An oral formulation and a low incidence of adverse reactions permit treatment on an outpatient basis. Most currently available oral agents are prodrugs of 5-FU; the use of these drugs for the treatment of gastrointestinal malignancies is therefore of

Table 1. Plasma concentrations of 5-FU and CDHP after administration of 5′-DFUR or S-1 Time of blood sampling (h)*

Plasma concentration of agents (ng/ml) After administration of 5′-DFUR:

After administration of S-1

5-FU

5-FU

CDHP

1

25.1

217.0

366.3

3

3.8

198.3

274.1

5

2.9

122.3

185.0

7

1.1

62.2

97.8

9

ND†

24.8

58.4

*Time (h) after the last administration of 5′-DFUR or S-1. †ND: not detected.

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Figure 4. Patient’s clinical course and treatment. 1) CR, complete response. 2) Ten consecutive courses of single-agent chemotherapy with S-1 were given to the patient from August 1999 through October 2000.

286

Lung metastasis treated by S-1

We conclude that a poor response to 5-FU-based postoperative adjuvant chemotherapy does not necessarily imply that the cancer is refractory to 5-FU. A good antitumor response may be obtained with potent DPD-inhibitory oral fluoropyrimidines, such as S-1.

References 1. Shirasaka T, Shimamoto Y, Ohshimo H, Yamaguchi M, Kato T, Yonekura K, et al. Development of a novel form of an oral fluorouracil derivative (S-1) directed to the potentiation of the tumor selective cytotoxicity of 5-fluorouracil by two biochemical modulation. Anticancer Drugs 1996;7: 548–57. 2. Diasio RB. Clinical implication of dihydropyrimidine dehydrogenase inhibition. Oncology 1999;13(Suppl 3):17–21. 3. Shirasaka T, Nakano K, Takechi T, Satake H, Uchida J, Fujioka A, et al. Antitumor activity of 1 M tegafur–0.4 M 5-chloro-2,4-dihydroxypyrimidine–1 M potassium oxonate (S-1) against human colon carcinoma orthotopically implanted into nude rats. Cancer Res 1996;56:2602–6. 4. Hirata K, Horikoshi N, Aiba K, Okazaki M, Denno R, Sasaki K, et al. Pharmacokinetic study of S-1, a novel oral fluorouracil anti-tumor drug. Clin Cancer Res 1999;5:2000–5. 5. Sakata Y, Ohtsu A, Horikoshi N, Sugimachi K, Mitachi Y, Taguchi T. Late phase II study of novel oral fluoropyrimidine anticancer drug S-1 (1 M tegafur–0.4 M otastat potassium) in advanced gastric cancer patients. Eur J Cancer 1998;34:1715–20. 6. Koizumi W, Kurihara M, Nakano S, Hasegawa K. Phase II study of S-1, a novel oral derivative of 5-fluorouracil, in advanced gastric cancer. Oncology 2000;58:191–7. 7. Maehara Y. S-1 in gastric cancer: a comprehensive review. Gastric Cancer 2003;6(Suppl 1):2–8. 8. Matsushima E, Yoshida K, Kitamura R, Yoshida K. Determination of S-1 (combined drug of tegafur, 5-chloro-2,4-dihydroxypyrimidine and potassium oxonate) and 5-fluorouracil in human plasma and urine using high performance liquid chromatography and gas chromatography–negative ion chemical ionization mass spectrometry. J Chromatogr B 1997; 691:95–104. 9. Ajani JA. Chemotherapy for gastric carcinoma: new and old options. Oncology 1998;12:44–7. 10. Kurimoto N, Yasuzawa Y, Itoh N, Tamura T, Yoshimoto I. A case report: 5′-DFUR reduced multiple liver metastases of gastric cancer. Gan To Kagaku Ryoho 1992;19:1067–70 (in Japanese). 11. Miyoshi K, Matsui T, Gangi J, Shinoura S, Sezaki N. A case report of advanced gastric cancer that responded to long-term administration of low-dose 5′-DFUR. Gan To Kagaku Ryoho 1997;24:101–3 (in Japanese). 12. Takiguchi N, Nakajima N, Saitoh N, Fujimoto S, Nakazato H. A phase III randomized study comparing oral 5-fluorouracil after curative resection of gastric cancer. Int J Oncol 2000;16:1021–7. 13. Boku N, Ohtsu A, Shimada Y, Shirao K, Seki S, Saitoh H, et al. Phase II study of a combination of irinotecan and cisplatin against metastatic gastric cancer. J Clin Oncol 1999;17:319–23. 14. Takahashi K, Miyagawa K, Mitachi Y, Matsuda T, Oogoshi T. A case of gastric cancer with metastasis to cervical lymph node and pulmonary lymphangitis carcinomatosa responding to neoadjuvant chemotherapy with S-1 and CDDP. Gan To Kagaku Ryoho 2003;30:685–9 (in Japanese). 15. Nakamura T, Yamasaki K, Morikawa S, Ohnita T, Taura K, Isomoto H, et al. A case report of advanced gastric cancer responding to TS-1, a novel oral fluorouracil derivative. Gan To Kagaku Ryoho 2002;29:927–32 (in Japanese). 16. Tsukioka Y, Matsumura Y, Hamaguchi T, Goto M, Muro K, Yamada Y, et al. Complete response achieved following administration of S-1 in patient with adrenal gland metastasis of 5-FU resistant gastric cancer: a case report. Jpn J Clin Oncol 2001;31:450–3.

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interest not only in Japan but also in other countries. S-1 is a potentially ideal agent for the management of gastric cancer because of its high response rate and mild toxicity. S-1 may therefore become the drug of choice for gastric cancer in Japan. Although the dose of 5′-DFUR received by our patient was relatively low (600 mg/day), many previous studies have reported that low-dose treatment with 5′-DFUR is effective against gastric cancer (10–12). We therefore considered our patient’s tumor to be refractory to 5-FU and recommended CPT-11-based chemotherapy (13) for re-metastasis to the left lung. However, the patient preferred treatment that could be received on an outpatient basis and to maintain a good QOL rather than to receive intravenous intensive chemotherapy, even at the cost of potentially lower effectiveness. We therefore decided to try S-1 as second-line chemotherapy. S-1 is now considered to be one of the most active agents for gastric cancer; however, the response rate of lung metastasis to S-1 is relatively low. In two pivotal phase II studies of S-1 in advanced and recurrent gastric cancer in Japan (n = 101), the response rate was 33.8% (25/74) for primary lesions, 36.4% (16/44) for liver metastases, 51.5% (34/66) for lymph node metastases and 16.7% (1/6) for lung metastases (5,6). In fact, a CR of lung metastases has rarely been achieved by S-1 monotherapy, but has occasionally been induced by S-1-based combination chemotherapies (14). Nakamura et al. (15) reported a case of gastric cancer with diffuse lung metastases that showed a CR after two courses of S-1 monotherapy. However, the serum CEA level in their patient did not decrease to the normal range after treatment and follow-up chest films or CT scans obtained at least 1 month after confirmation of CR were not mentioned. In addition, the follow-up period after the initiation of treatment was 5 months. Therefore, our patient may be the first whose lung metastasis had a prolonged complete regression due to S-1. The S-1-induced dramatic regression of the lung metastasis in our patient, whose tumor was refractory to 5′-DFUR, may have resulted from the prolonged high concentration of 5-FU in plasma after treatment with S-1. In the pharmacokinetic study, we found that high plasma 5-FU levels were achieved and maintained after administration of S-1 and we attributed these high levels to the DPD-inhibitory effect of CDHP. Our findings are consistent with those of Hirata et al. (4), who conducted a detailed pharmacokinetic study of S-1 in patients with cancer. In contrast, the plasma 5-FU level after administration of 5′-DFUR was very low. Tsukioka et al. (16) also reported a case of CR achieved following administration of S-1 in patient with 5-FU-resistant gastric cancer. Although they raised other possible reasons which may account for the effectiveness of S1 for 5-FU-resistant gastric cancer, high and prolonged plasma 5-FU levels are considered mainly responsible for the regression of cancer in our patient.