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Old 04-11-2009, 10:54 AM   #1
Rich66
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S-1: a promising new (outside Japan) oral fluoropyrimidine derivati

1: Expert Opin Investig Drugs. 2009 Mar;18(3):335-48. Links
S-1: a promising new oral fluoropyrimidine derivative.

Saif MW, Syrigos KN, Katirtzoglou NA.
Yale University School of Medicine, Division of Medical Oncology, 333 Cedar Street, FMP 116 New Haven, CT 06520, USA. wasif.saif@yale.edu
The fluoropyrimidine anticancer agent 5-fluorouracil (5-FU) is active in a wide range of solid tumors, particularly gastric, colorectal, and head and neck cancers. Whilst infusional 5-FU is associated with higher response rates and a favorable safety profile compared with the classical i.v. bolus administration, prolonged infusions can be inconvenient for the patients, and catheter-related problems are common complications. An oral 5-FU formulation would allow for sustained 5-FU plasma concentrations, mimicking the pharmacokinetics (PK) of a continuous infusion with the addition of convenience of administration. The oral administration of 5-FU itself is not feasible owing to the high activity of dihydropyrimidine dehydrogenase (DPD) in the gut wall, which causes rapid metabolism of the drug and results in decreased and erratic absorption of 5-FU and nonlinear PK. To bypass this problem, oral fluoropyrimidine derivatives were developed either in the form of 5-FU prodrugs (i.e., tegafur, doxifluridine or capecitabine), or as enzyme inhibitors (i.e., eniluracil) administered with 5-FU, or as both prodrugs and enzyme inhibitors (i.e., S-1, UFT or BOF-A2). This review focuses on the oral fluoropyrimidine S-1, which consists of the 5-FU prodrug tegafur (ftorafur, FT) and two enzyme inhibitors, CDHP (5-chloro-2,4-dihydroxypyridine) and OXO (potassium oxonate), in a molar ratio of 1(FT):0.4 (CDHP):1(OXO). Phase II trials have demonstrated that S-1, as a single agent, is active for the treatment of gastric, colorectal, head and neck, breast, non-small cell lung, and pancreatic cancers. Phase III trials are currently underway in gastric cancer and these results are awaited to confirm the Phase II findings. Furthermore, the combination of S-1 with cisplatin (CDDP), irinotecan or docetaxel for the treatment of gastric cancer and with CDDP for non-small cell and pancreatic cancer is feasible and active. The activity observed with S-1 in the Phase II studies is at least equivalent to, if not better than, continuous i.v. and bolus 5-FU and the other oral fluoropyrimidines. Thus, we may finally be seeing the realization of oral treatments for the management of various solid tumors and could be on the brink of a new approach to treatment strategies.
PMID: 19243284 [PubMed - in process]
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Old 04-11-2009, 10:54 AM   #2
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1: Breast Cancer. 2006;13(2):220-4. Links
S-1 (TS-1) maintained complete response for approximately 10 years in a case of metastatic breast cancer.

Taira N, Aogi K, Ohsumi S, Takashima S, Nishimura R, Doihara H, Saeki T.
Department of Surgery, National Hospital Organization, National Shikoku Cancer Center, Matsuyama-city, Ehime, Japan. ntaira@shikoku-cc.go.jp
We present a patient with pulmonary metastasis from breast cancer who received S-1 (TS-1) and maintained complete response for approximately 10 years after recurrence. A 51-year-old woman underwent modified radical mastectomy for left breast cancer in November 1991. Her cancer was postoperatively classified as pT2 pN0 M0 Stage IIA. As postoperative adjunctive treatment, tamoxifen and hexylcarbamoyl 1-5-FU (HCFU) were given. During the administration period (30 months after surgery), a solitary pulmonary metastasis occurred. Three months after the start of S-1 (100 mg/body/day), the tumor disappeared on images. Thereafter she took S-1 orally for approximately 10 years, and the pulmonary metastatic focus maintained complete response. In addition, no recurrent focus was observed. The adverse events observed during S-1 treatment were nausea, low-grade neutropenia and pigmentation of fingers. All were mild, and S-1 could be continued. Our case illustrates two important characteristics of S-1. First, S-1 was effective even though this patient had a lung metastasis during adjuvant treatment with HCFU. S-1 is a combined formulation containing 5-chloro-2, 4-dihydroxypyrimidine (CDHP; gimestat), which inhibits an enzyme that metabolites 5-FU, dihydropyrimidine dehydrogenase (DPD). Therefore, high 5-FU concentrations are maintained with S-1, and S-1 may be effective in the patients who do not respond to other fluoropyrimidine agents. Second, since S-1 toxicity was mild, long-term treatment for approximately 10 years was possible. Since S-1 contains potassium oxonate (OXO; otastat), gastrointestinal toxicities, the main adverse events of 5-FU agents, could be reduced. The purpose of treatments for metastatic breast cancer is to maintain favorable quality of life (QOL), as well as to improve survival. S-1 could be a valuable agent for breast cancer treatments, since it showed clinical efficacy and mild toxicity, and can be given orally.
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Old 05-25-2009, 09:27 AM   #3
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TS-1 in patients with capecitabine-resistant breast cancer. (Japan)

TS-1 in patients with capecitabine-resistant breast cancer.


Sub-category: Metastatic Breast Cancer
Category: Breast Cancer--Metastatic Breast Cancer
Meeting: 2009 ASCO Annual Meeting

Citation: J Clin Oncol 27:15s, 2009 (suppl; abstr 1103)
Abstract No: 1103

Attend this session at the ASCO Annual Meeting!
Session: Breast Cancer - Metastatic
Type: General Poster Session
Time: Monday June 1, 1:00 PM to 5:00 PM
Location: Level 2, West Hall C

Personalize your Annual Meeting experience with a suggested or customized itinerary!


Author(s):
D. Yamamoto, H. Yoshida, S. Iwase, H. Odagiri, K. Kitamura; Surgery, Kansai Medical University, Hirakata, Japan; Tokyo University, Palliative Care, Tokyo, Japan; Hirosaki University, Hirosaki, Japan; Kyusyu Tyuou Hospital, Hukuoka, Japan
Abstract:
Background: TS-1 is a novel oral anticancer drug, composed of tegafur, gimestat and otastat potassium in a molar ratio of 1:0.4:1, based on the biochemical modulation of 5-Fuorouracil. To evaluate the efficacy and safety of TS-1 in patients with capecitabine-resistant metastatic breast cancer (MBC). Methods: Forty patients with MBC who failed capecitabine-based chemotherapy, received TS-1 (100 mg/m2) at four centers. Resistance to capecitabine was defined as either progression of disease during treatment, failure to achieve regression of disease after at least four courses, or rapid recurrence after completion of therapy. Results: From January 2006 to May 2008, 40 pts were enrolled. Baseline characteristics of the pts were: median age 50 years (range 34-78), median ECOG PS 0 (range 0-2), and adequate bone marrow, renal, and hepatic functions. Median number of metastatic sites was 2 (range 1-5). The pts were evaluable for response and toxicity. Ten pts (25 %) achieved a partial response, 12 patients (30 %) patients had stable disease, and 18 (45 %) progressive disease. The median time to disease progression was 26.6 weeks. The most treatment-related adverse events were grade 1/2 in intensity. 7 pts experienced serious TS-1- related gastrointestinal disorder requiring dose modifications in 3 pts and treatment discontinuation in 4 pt. Further, interestingly, 6 of the 40 patients (15.0%) who received TS-1 did hand-foot syndrome (HFS), although 20 of the 40 patients (50.0%) who had received capecitabine, developed HFS. Conclusions: This study confirms that TS-1 achieves a high tumor control rate in pretreated MBC pts and is active in patients with capecitabine-resistant breast cancer. Response rates were comparable to or better than those seen with other therapies for patients with capecitabine-resistant MBC. TS-1 should be considered the reference treatment in this setting based on consistently high efficacy and good tolerability.

Abstract Disclosures
Faculty and Discussant Disclosures
Annual Meeting Planning Committee Disclosures
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