Sequential paclitaxel followed by tegafur and uracil (UFT) or S-1 versus UFT or S-1 monotherapy as adjuvant chemotherapy for T4a/b gastric cancer (SAMIT): a phase 3 factorial randomised controlled trial

Tsuburaya, Akira; Yoshida, Kazuhiro; Kobayashi, Mariko; Yoshino, Shigefumi; Takahashi, Mutsuo; Takiguchi, Nobuhiro; Tanabe, Kazuaki; Takahashi, Naoto; Imamura, Hiroshi; Tatsumoto, Nobuhide; Hara, Akinori; Nishikawa, Kazuhiro; Fukushima, Ryoji; Nozaki, Isao; Kojima, Hiroshi; Miyashita, Yumi; Oba, Koji; Buyse, Marc; Morita, Satoshi; Sakamoto, Junichi

doi:10.1016/s1470-2045(14)70025-7

Cited by 100 publications

(68 citation statements)

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“…5FU is currently a key drug for adjuvant therapy following curative surgery (2)(3)(4) and for the treatment of metastatic gastric cancer (5,6). Three mechanisms have been proposed for its action: Incorporation into RNA (7), incorporation into DNA (8) and the inhibition of thymidine synthase (TS) leading to the inhibition of DNA de novo synthesis by forming a ternary complex composed of TS, 5,10-methylenetetrahydrofolate (CH2THF) and fluoro-deoxyuridine monophosphate (FdUMP) (9).…”

Section: Introductionmentioning

confidence: 99%

5FU resistance caused by reduced fluoro-deoxyuridine monophosphate and its reversal using deoxyuridine

et al. 2017

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Abstract. The mechanism of 5-fluorouracil (5FU) resistance was investigated, focusing on the level of thymidylate synthase (TS) ternary complex formed with fluoro-deoxyuridine monophosphate (FdUMP). MKN45 and 5FU-resistant MKN45/F2R cells were treated with 5FU and fluoro-deoxyuridine (FdU) in combination with deoxyuridine (dU) and thymidine (dT). Subsequently, the levels of ternary complex were determined by western blotting and the cell viability was calculated using an MTT assay. MKN45/F2R cells exhibited 5FU resistance (56.2-fold relative to MKN45 cells), and demonstrated decreased orotate phosphoribosyltransferase (OPRT) and increased TS levels, requiring a higher concentration of 5FU to induce ternary complex formation than MKN45 cells. Following transfection of small interfering RNA against OPRT, MKN45 exhibited increased resistance to 5FU and decreased ternary complex formation subsequent to treatment with 5FU, indicating that decreased OPRT led to increased 5FU resistance. However, MKN45/F2R also exhibited resistance to FdU, which can be converted to FdUMP without OPRT, and there was decreased ternary complex formation after treatment with FdU, indicating that the 5FU-resistant cells had the ability to decrease intracellular FdUMP. The addition of dU and thymidine dT to 5FU promoted the formation of ternary complexes and reversed 5FU resistance in MKN45/F2R cells, although dT inhibited the efficacy of raltitrexed (another TS inhibitor). These results suggested that 5FU-resistant cells had the ability to reduce intracellular FdUMP irrespective of decreased OPRT, which led to resistance to 5FU. This resistance was then inhibited by treatment with dT or dU. IntroductionDespite recent advances in the development of diagnostic tools for gastric cancer, many patients with gastric cancer continue to be diagnosed at a late stage, and even following curative surgery, recurrent tumors frequently occur. Therefore, gastric cancer remains a major cause for cancer-associated mortality worldwide (1) and the development of novel drug therapies for gastric cancer is important.5FU is currently a key drug for adjuvant therapy following curative surgery (2-4) and for the treatment of metastatic gastric cancer (5,6). Three mechanisms have been proposed for its action: Incorporation into RNA (7), incorporation into DNA (8) and the inhibition of thymidine synthase (TS) leading to the inhibition of DNA de novo synthesis by forming a ternary complex composed of TS, 5,10-methylenetetrahydrofolate (CH2THF) and fluoro-deoxyuridine monophosphate (FdUMP) (9). The first step in the activation of 5FU is the phosphorylation of 5FU by orotate phosphoribosyltransferase (OPRT), which metabolizes 5FU to 5-fluorouridine monophosphate (FUMP). FUMP is then metabolized into 5-fluorouridine triphosphate (FUTP), which can be incorporated into RNA and into 5-flurodeoxyuridine triphosphate (FdUTP), which can be incorporated into DNA (10). Although the incorporation into RNA and DNA is certainly an important aspect of the mechanism of action of 5FU,...

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Section: Introductionmentioning

confidence: 99%

5FU resistance caused by reduced fluoro-deoxyuridine monophosphate and its reversal using deoxyuridine

et al. 2017

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“…Another potential weakness may be that this study compares intraperitoneal PTX therapy, the new proposal, with intravenous PTX therapy, which has not been acknowledged as a standard treatment in the postoperative adjuvant setting. This may not be a serious problem, however, considering the results of a pivotal phase III trial to explore a sequential use of intravenous PTX therapy followed by S-1 therapy as postoperative adjuvant chemotherapy for serosa-positive (T4a or T4b) gastric cancer [30]. In that trial, the 3-year disease-free survival achieved with sequential therapy does not seem inferior to that achieved with S-1 monotherapy, the standard of care.…”

Section: Discussionmentioning

confidence: 99%

Feasibility of weekly intraperitoneal versus intravenous paclitaxel therapy delivered from the day of radical surgery for gastric cancer: a preliminary safety analysis of the INPACT study, a randomized controlled trial

et al. 2016

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Background Peritoneal carcinomatosis is common after curative resection of gastric cancer. Intraperitoneal administration of paclitaxel (PTX) is known to control ovarian peritoneal metastases. Patients and methods Patients with either linitis plastica or T4 cancer with high risk of peritoneal metastasis or recurrence but whose cancer was considered resectable were preregistered. After their cancer had been confirmed intraoperatively as resectable, the patients were randomized into either group A (PTX at 60 mg/m 2 intraperitoneally on the day of surgery and on days 14, 21, 28, 42, 49, and 56) or group B (PTX at 80 mg/m 2 administered intravenously by the identical schedule) before being treated by evidence-based chemotherapy. The primary end point was the 2-year survival rate. Safety, the secondary end point, was also analyzed. The study has been registered as UMIN000002957. Results Of 177 preregistered patients, 83 underwent treatment (39 by intraperitoneal administration and 44 by intravenous administration). There was no difference in patient demographics between the two groups. The incidences of surgical complications were similar between the groups, except for transient bowel obstruction observed exclusively in group A. The relative dose intensity of PTX was 81.4 % for group A and 76.3 % for group B. There was one death due to pulmonary thrombosis and a case of anaphylaxis that led to termination of the protocol treatment (group B). Other adverse events were mild and manageable. Conclusions Intraperitoneal administration of PTX from the day of gastrectomy did not result in a higher incidence of surgical complications and adverse reactions when compared with intravenous administration of PTX.

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“…Sequential paclitaxel did not improve disease-free survival and UFT was not non-inferior to S-1, while S-1 was superior to UFT as adjuvant treatment for T4a or T4b gastric cancer. While in subset analysis, sequential treatment was effective for patients with stage IIIB disease 1) . S-1 is still a standard adjuvant treatment in Japan 2,3) but the efficacy for those patients with poor prognosis is limited.…”

Section: Introductionmentioning

confidence: 93%

An ancillary biomarker study in the SAMIT randomized trial: Sequential paclitaxel followed by UFT or S-1 versus UFT or S-1 alone as adjuvant chemotherapy for T4a/b gastric cancer

Oshima

Tsuburaya²,

Yoshida

et al. 2018

Ann. Cancer Res. Therap.

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Sequential paclitaxel followed by tegafur and uracil (UFT) or S-1 versus UFT or S-1 monotherapy as adjuvant chemotherapy for T4a/b gastric cancer (SAMIT): a phase 3 factorial randomised controlled trial

Cited by 100 publications

References 42 publications

5FU resistance caused by reduced fluoro-deoxyuridine monophosphate and its reversal using deoxyuridine

5FU resistance caused by reduced fluoro-deoxyuridine monophosphate and its reversal using deoxyuridine

Feasibility of weekly intraperitoneal versus intravenous paclitaxel therapy delivered from the day of radical surgery for gastric cancer: a preliminary safety analysis of the INPACT study, a randomized controlled trial

An ancillary biomarker study in the SAMIT randomized trial: Sequential paclitaxel followed by UFT or S-1 versus UFT or S-1 alone as adjuvant chemotherapy for T4a/b gastric cancer

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