TW201039816A - Treatment of diffuse-type gastric cancers using S-1 and cisplatin - Google Patents

Abstract

The present invention provides an improved method for treating diffuse-type gastric cancer or a mixed-type gastric cancer, including advanced diffuse-type and mixed type gastric cancer and metastatic diffuse-type and mixed-type gastric cancer, by administering S-1 and cisplatin to patients in need of treatment for diffuse-type gastric cancer or mixed type gastric cancer.

Description

201039816 VI. INSTRUCTIONS: FIELD OF THE INVENTION Field of the Invention The present invention relates to the treatment of gastric cancer using a combination of s-1 and cisplatin. In particular, it relates to an improved method for treating patients with diffuse gastric cancer by administering S-i and cisplatin to a patient in need of such treatment. L·^tr ]| BACKGROUND OF THE INVENTION Gastric cancer is the fourth most common cancer in the world after lung, brain and colorectal cancer, and the second most common cause of cancer-related death, estimated to be 800,000 per year.

Death (Jemal A, Siegel R, Ward E, Hao Υ, Xu J, Murray Τ, Thun MJ. Cancer statistics, 2008. CA Cancer J Clin 2008; 58(2): 71-96; Parkin DM Bray F, Ferlay J, Pisani P. Global Cancer Statitstics, 2002. CA Cancer J Clin 2005; 55(2): 74-108). The incidence and mortality of gastric cancer vary greatly from region to region. Over the past seven decades, these ratios have gradually decreased in North America and Europe, but remain high in Eastern Europe, South America and Asia (Levi F, Lucchini F, Gonzales Jr, Fernandez E, Negri E, La Vecchia C., “Monitoring” Falls in Castric Cancer Mortality in Europe·, Ann Oncol 20〇4; I5: 338-345). Although gastric cancer is less common in the US than in many other regions, 21,500 new cases and 10,880 deaths due to gastric cancer are estimated Occurred in the United States in 2008 (Jemal A, Siegel R, Ward E, Hao Y, Xu J, Murry T, et al., Cancer Statistics, 2008. CA 3 201039816

Cancer J. Quinn. 2008; 58:71-96) ° The important predictor of gastric cancer in the histology department of gastric cancer. The pathological histological classification of gastric cancer in the World Health Organization (WHO) is divided into groups: full differentiation, moderate differentiation, poor differentiation, ring cell carcinoma, and: type: According to Lauren classification, gastric cancer is divided into two categories: Road type, and diffuse type. As used herein, unless otherwise specified, smear-type gastric cancer may be characterized by a single cell or small cell nest with little or no glandular formation, with a firm sheet, firming cluster, And the cell carcinoma of the cell, which has a small cell carcinoma with minimal intracellular mucin, an undifferentiated cell with very few intracellular mucins or an extracellular mucin with a pure ring cell morphology. . As used herein, unless otherwise specified, enteral gastric cancer includes pure intestinal type gastric cancer based on the Lauren classification, and parts of the papillary, tubular, and mucinous tissues classified by WHO. As used herein, unless otherwise specified, a mixed gastric cancer includes a tumor having a tissue characteristic of an unclassified/undetermined cancer under the Lauren classification and a component having diffuse gastric cancer as described above and as described above. A mixed tissue of components of intestinal type gastric cancer. Recent published data indicate that patients with diffuse gastric cancer have a lower survival rate than those with gastrointestinal type. Park et al. (2008) reviewed the medical records of 2,275 patients undergoing gastrectomy. The overall cumulative five-year survival rate for these patients was 67% for the intestinal type of gastric cancer versus 54% for the poorly differentiated or diffuse type of gastric cancer. . State stratification analysis showed that the tissue type was not statistically related to stage 1, 2 or 3 disease; however, the tissue type of patients with stage 4 disease was found to be related to survival on the leaf (Park KM, Jang YJ, Kim JH) , Park SS, 201039816

Park SH, Kim SJ, et al., Gastric Cancer Histology: Clinicopathological Characteristics and Predicted Values (Gastric Cancer Histology: Clinicopathologic

Characteristics and Prognostic Value) J Surg Oncol. 2008; 98:520-25). Patients with intestinal type of gastric cancer had significantly better survival than those with diffuse gastric cancer (64% vs. 42% of patients survived, p = 0.020) (Lee KH, Lee JH, Cho JK, Kim TW, Kang YK, Lee JS Et al., A prospective Correlation of LaurSn's Histological Classification of Stomach Cancer with Clinicopathological Findings Including DNA Flow Cytometry. Pathol. Res. Pract. 2001 197: 223-29). Patients with poorly differentiated tumors were also found to have shorter survival than fully differentiated or moderately differentiated tumors (Patel PR, Yao JC, Hess K, Schnirer I, Rashid A, Ajani JA. metastasis/relapse of disease and tissue differentiation time) Effect of Timing of Metastasis/Disease Recurrence and Histological Differentiation on Survival Patients with Advanced Gastric

Cancer)· Cancer 2007; 110; 2186-90; Adachi Y, Yasuda K, Inomata M, Sato K, Shiraishi N, Kitano S. Pathology and Prognosis of Gastric Carcinoma. CANCER 2000; 89 ( 7): 1418-24). In general, 5-fluorouracil (5-FU) is the mainstream of mixed drug chemotherapy for the development and testing of non-stage gastric cancer. In gastric cancer, 5-FU is administered via continuous intravenous infusion (CIV) for 5 to 21 days depending on the combination chemotherapy. In addition, 5 201039816 Several mixed drug chemotherapy have been developed and evaluated in randomized studies: FAM (5-FU, doxorubicin, and mitomycin), εαρ (etoporgan, doxorubicin, cis-chloroamine) Platinum), FAMTX (5-FU, doxorubicin, methotrexate), CF (cis-ammonia, 5-FU), ELF (etoporgan, 5-FU, leucovorin), ECF (pan Idiomycin, cisplatin, 5_FU), and more recently some combinations of new cytotoxic drugs, including DCF (docetaxel, cisplatin, and 5-FU), IF (irinotecan) , 5-FU), XP (capecitabine and cisplatin), and EOX (pan-mycin, oxaliplatin, and capecitabine). Even if these new drugs are used to treat unexplained diseases, the overall survival of patients with advanced gastric cancer is maintained for about nine months, and the current treatment-induced toxicity will impact the quality of life of these patients. A new combination of improved tolerance and improved safety that provides greater convenience and ease of patient treatment is needed for this soothing setting system. SUMMARY OF THE INVENTION In one aspect, the present invention relates to an improved method for treating sputum-diffuse or mixed-type gastric cancer in a patient in need of such treatment, comprising (1) an effective amount of S for the person skilled in the art. -1 and (ii) administering an effective amount of cisplatin to the patient. S-1 is a mixture of Tegafur and Gimeracii, which is a 1:4 molar mixture of 〇 cil cil cil cil cil cil , , , , , , , , , , , , , , , , , , : : : : : : : : : : : : : : The amount is based on the medication. Preferably, s_i is administered at least twice a day in a total amount of from about 20 mg/m2 to about 80 mg/m2 per day of tegafur in s_i. More preferably, the total daily amount is about 3 〇mg/m2 and about 8 〇mg/m^: for the initial application of tegafur in S_i, which is based on the event of non-201039816 It may be reduced. More preferably, the s-i system is initially administered at least once a day in a total amount of from about 50 mg/m2 to about 70 mg/m2 of tegafur in S-1. Preferably, the dose of S-1 is provided in equal amounts. Such doses can be administered for from about 7 to about 28 days for from about 7 to about 35 days. Although cisplatin can be administered at any time during the period of about 14 to about 35 days, it is typically more convenient to administer the cis-ammonia on the first or eighth day of administration of the S-1 agent. platinum. Preferably, S-1 can be administered with about 75 mg/m2 of cisplatin (which is also administered once during this 28-day period) for about 21 days for about 28 days, especially when the patient is Caucasian patients. S-1 can be used at least one hour before a meal or one hour after a meal. 8_丨 is preferably administered orally. In a preferred embodiment, the cisplatin is applied intravenously. In another preferred embodiment, the cisplatin is applied once in a period of from about 28 to about 35 days. More preferably, the cisplatin is applied once in about 28 days. In another preferred embodiment, the cisplatin is applied at a dose of from about 50 mg/m2 to about 1 mg/m2. More preferably, the cisplatin is applied at a dose of from about 60 mg/m2 to about 8 mg/m2. The invention can be used when the diffuse type gastric cancer system is not diffuse type gastric cancer, and includes the metastatic diffuse plastic gastric cancer in the late stage of the gastric cancer type. Similarly, the present invention can be applied to a mixed gastric cancer of a mixed gastric cancer type, which is a mixed gastric cancer of the latter type. In another preferred embodiment, the method according to the present invention is the first line of treatment, i.e., in addition to sputum or adjuvant chemotherapy, late diffuse plastic gastric cancer or late mixed gastric cancer has not been previously treated with chemotherapy. Preferably, the patient has not lost more than 1% of their basal body weight before the start of treatment. 7 201039816 Preferably, the present invention relates to a method of treating a pre-diffuse or mixed type gastric cancer in a patient in need of such treatment comprising (1) for a continuous period of from about 7 to about 28 days over a period of from about 14 to about 35 days, At least one hour before or after the meal, the patient is administered S-1 twice a day in an amount of about 1 〇mg/m2 to about 40 mg/m2 in S-1, and (1) Ii) The patient is administered intravenously from about 50 mg/m2 to about 100 mg/m2 of cisplatin during a period of from about 28 to about 38 days. More preferably, the present invention relates to a method for treating a patient in need of such treatment, which has not previously been treated with chemotherapy for diffuse or late-stage gastric cancer, comprising (1) about 15 mg/m2 to about each dose. Tegafur in an amount of 40 mg/m2 in S-1 was orally administered to patients with S-1. Most preferably, this patient is administered S-1 in tegafur in S-1 in an amount of from about 25 mg/m2 to about 35 mg/m2 per dose. The present invention is also directed to a therapeutically effective amount of S-1 wherein the S-1 system contains tegafur, gimester, and oxy-hypo-acid at a molar ratio of 1:0.4:1. The use of a composition of zhongzhi, a first preparation comprising the composition of a second preparation comprising a therapeutically effective amount of cisplatin, for the treatment of diffuse or mixed gastric cancer drug. Furthermore, the present invention relates to a kit for treating diffuse gastric cancer or mixed gastric cancer, comprising a therapeutically effective amount of S-1, wherein the S-1 system contains 1:0.4:1 a pharmaceutical composition of tifufloxacin, gemorest, and potassium oxonate in a molar ratio, a first preparation comprising a second preparation comprising a therapeutically effective amount of cisplatin. Furthermore, a therapeutically effective amount of S-1, wherein the S-1 system contains a dose of 1:0.4:1 molar ratio of tegafur, gimmost, and potassium oxonate 201039816 The composition, the composition of the first preparation and the composition comprising a therapeutically effective amount of a second preparation of cisplatin are prepared for the treatment of diffuse gastric cancer or mixed gastric cancer. ‘ Simple description of the diagram Figure 1 shows the overall survival of patients with diffuse type of late gastric cancer treated with 5-FU/cis chlorination. When s, chloramine (4) treatment

The difference in overall survival between patients with diffuse late gastric cancer and a limited number of patients with mucinous gastric cancer. ~ Figure 2 shows the difference in overall survival between patients with metastatic disease/diffuse late gastric cancer and a limited number of patients with mucinous gastric cancer, and the opposite of 5-FU/cisplatin treatment S_" Less than 10% basal weight loss in the treatment of cisplatin.

C Embodiment: J The invention details the s-1 system, a mixed tegafur (FT) (which is a 5-FU oral prodrug) and a second regulator (Gimhost (CDHP), which is inhibited by DPD. Inhibition of 5-1?1; degradation, and potassium oxonate (Oxo), which inhibits 5-FU phosphorylation of the digestive tract). S-1 is a fixed composition of tifufloxacin to gemesteride than potassium oxoacetate 1: 〇 4.1 molar ratio. S-1 is generally administered orally. The present invention is more fully described in U.S. Patent Application Serial No. 2008/0166427, the entire disclosure of which is incorporated herein by reference. S-ι is reasonably designed to promote anti-tumor efficacy while reducing adverse events. Tegafur is maintained in the blood for a long time when it is administered orally, and gradually converted to 5-FU in the presence of CYP 2Α6 (CYP = cytochrome ρ45〇 9 201039816. The enzyme is contained in the metabolism of various drugs). Therefore, it seems that it is possible to obtain a higher ash content of 5-FU by the use of espresso or ιν by oral administration. However, 疋' In fact, after oral administration of tegafur, the blood volume of 5_FU was lower than expected due to biodegradation of the coffee in the liver. A hypothetical person who is a combination of tegafur and a potent inhibitor (such as Gimester) can achieve a long-term high blood volume 5 with a relatively low amount of tegafur. This electrical person can also reduce the toxicity associated with metabolites by reducing the anti-chirping of FBAL. In addition, the hypothesized person is potassium oxocarbonate (an inhibitor of the lactate phosphoribosyltransferase (the enzyme responsible for the 5_FU phosphating enzyme in the gastrointestinal tract) which reduces gastrointestinal toxicity. S-1 has been evaluated in Japan for the first and second phases. In the first phase of the study, S-1 was studied as an oral dose once daily. A single dose of 25 to 200 mg (with tegafur) has been investigated. During the sy period, the drug was provided twice a day for 28 days, followed by a 2-week recovery study. Six of the 11 patients (two with gastric cancer) were reported to have tumor shrinkage at all doses (50 to 100 mg) studied. To date, Phase 2 studies have been performed in patients with post-auricular gastric cancer with S-1 of 50 mg and 75 mg per patient. The overall response reported by 28 patients with advanced gastric cancer (based on the modified World Health Organization (WHO) criteria) was 53.6%; and in 30 patients with metastatic colorectal itching, the overall response rate was 16.7%. (13 of 30 patients with colorectal cancer have prior treatment with fluorinated pyrimidine). Overall, approximately 800 patients were enrolled in the first phase of the first phase, the second phase of the second phase, the second phase of the second phase, and the PK study. Based on the results of the current clinical plan, a clinical evaluation of 3_1, called 201039816, began in the United States (USA) and Europe (EU) in 1990. The medication regimen and dosing regimen used in these studies is similar to that approved in Japan. H is administered orally at a dose of up to 60 mg/m2/day for twice daily for up to 28 consecutive days followed by a 7-day recovery period. The anti-tumor activity was consolidated and the results were consistent with those seen by the Japanese Research Institute. However, the unanticipated higher toxicity was seen in the USA/EU study when compared to the transcript. The possible explanation for the difference in toxicity reported in Japanese studies when compared to the USA/EU study may be the possible difference in the conversion of tegafur to 5-FU in Caucasian patients compared to Japanese patients. A comparison of the 5_FU pharmacokinetic parameters of s-i suggests that the higher dose of 5-FU is more likely to be confirmed by Caucasians at the same dose of S-1 compared to Japanese patients. Further analysis indicated that the area under the curve (AUC) of the ratio of tegafur/5-FU was administered to the patient at S-1 higher than when administered to a Caucasian patient. It is speculated that the conversion of fluorocarbon to 5-FU via CYP 2A6 in the Caucasian patients occurs more rapidly than in the sputum patients (Shimada T, Yamazaki Η, Guengerich FP. 曰 及 and Caucasian liver microsomes by cells Ethnic-related differences in coumarin 7-hydroxylation activities catalyzed by cytochrome P4502A6 in liver microsomes of Japanese and

Caucasian populations). Xenobiotica. 1996;26(4);359-403) 0 These findings may be related to differences in CYP 2A6 gene polymorphism between Caucasian and Japanese patients. Cisplatin is a cytotoxic active heavy metal compound. It inhibits DNA precursors, and secondaryly, it inhibits protein and RNA synthesis, and its DNA is cross-linked by strands, which is the main mechanism of action. Because cisplatin cytotoxicity appears to be non-cell-dependent, its toxicity is similar throughout all phases of the cell cycle. Several cytotoxic anticancer agents (including 5_FU) have been super-additive or multiplicative in the test tube or in vivo. 5·ρι^ 顺 The basis of the interaction of the chlorine gas is not clear. The present invention relates to a method of treating diffuse or mixed gastric cancer. Combination therapy comprising cisplatin and S-1 has been found to be effective in the treatment of advanced gastric cancer, and this combination therapy is particularly effective in the treatment of gastric cancer lines classified as diffuse gastric cancer. An open, international, multi-center, double-arm, parallel, random Phase III study was conducted, in which the combination of efficiency and safety of the combination of 5-FU and cis-ammonia The efficacy and safety were compared with patients who had not previously been treated with chemotherapy for patients with advanced gastric cancer. Patients are stratified by disease type (eg, local late stage, sputum metastatic position, >=2 metastatic position), whether innocent patients are treated with pre-treatment, whether the disease is measurable or unmeasurable, and randomized One of the two treatment options: S-1 / Shunqi Qi (CS) _ S-1, 25 mg / m2 - twice a day, from day 1 to day 21 'and cisplatin' 75 mg / m2 On the third day of treatment, repeated every four weeks, the maximum is 6 cycles of cisplatin. .5-FU/cisplatin (CF): 5-FU, 1000 mg/m2/24 hours, starting from day 1-5, and starting with cis-chloroaza, 1 〇〇mg/m2, on day ,, Repeat every 4 weeks, with a maximum of 6 cycles of cisplatin. The primary objective of this study was to compare the overall survival of patients with advanced gastric cancer with S_1 + cisplatin and 5-FU + cisplatin. The key secondary endpoints are the overall analysis of the analysis of the population of the study population. 12 201039816 Response rate and disease-free survival, and the safety and tolerability of the two chemotherapy regimens.

Several key findings have emerged since this study. First, although the overall survival difference is not significant between the two population groups, the combination of s-y cisplatin demonstrates a lower mortality crisis than the 5~FU/cis cisplatin arm. Second, compared with 5_FU/cisplatin, s_! combined with cisplatin proved improved safety and tolerability. Patients with 5-FU/cisplatin arm may be severely neutrophil Leukopenia is twice as high as that of S-1/cis-gas platinum arm; patients with 5-FU/cis-chlorine #arm may suffer from neutropenia caused by fever s _ i / cis-ammonia Nearly four times as many patients with platinum arm; patients with 5-FU/cis-gas platinum arm are 10 times more likely to suffer from stomatitis than patients with S-17 cisplatin arm; unfavorable overall incidence of kidney-related Compared with patients with 5-FU/cis-gasplatin arm between patients with cis-chloride arm, 'compared with 5_FU/cis-chlorine-starting group' due to toxicity mortality in S-1/cis-ammonia The ethnic group is cut in half. These results are compiled in the first table.

Neutral white ik ball reduction 荨 grade> _3 fever caused by neutropenia stomatitis and kidney-related adverse events due to toxicity mortality Table 1 S-1 / cis gas ammonia i 18.6% 1.7% 1.3% 18.8% 2.5% 40%

The data collected in this study was reviewed to assess the relevance of gastric cancer survival. The analysis was performed between patients with diffuse gastric cancer and patients with a limited number of 2010 20101616 patients with mucinous gastric cancer (292 patients with nz cisplatin arm; 298 with 5-FU/cis cisplatin arm), There is a significant difference in survival and is beneficial to the S-1/cis cisplatin regimen. The overall survival of patients with advanced diffuse gastric cancer in s_i/cis cisplatin arm was 9·〇 months, while the overall survival of patients with 5_FU/cis cisplatin arm was 7.1 months. These findings are shown in the figure. In addition, weight loss has been recognized as an increased risk of death in cancer patients. The weight loss of patients who have undergone chemotherapy has been associated with reduced survival. Patients with metastatic gastric cancer who have lost weight receive less chemotherapy than patients without weight loss (Andreyev et al, Eur J Cancer 34(4), 503-9, 1998; DeWys et al, Am J Med. 69 , 491-7, 1980; Ross PJ, Ashley S, When is chemotherapy for lung cancer? Br J Cancer 2004; 90, 1905-11). Recently, it has been reported that in addition to reducing dietary intake and mechanical obstruction due to tumors, systemic inflammation plays another role in nutrient consumption (Deans DAC, Tan BH, Wigmore SJ, Ross JA, de Beaux AC,

Paterson-Brown S et al., systemic inflammation, dietary intake, and disease of rate of disease in rate of weight loss in patients With gastro-oesophageal cancer)· Br J Cancer. 2009;100:63-69). Based on these findings, it is retrospective whether the weight loss before the start of treatment in the above study has an effect on the overall survival of the patient. This analysis showed that the overall survival of patients without prior weight loss was significantly longer for patients with S-1/cis chlorinated steroids than with 5-FU/cis-ammonia, and each group was 9.0 and Survival in the middle of 7.9. Consider this factor and the patients with metastatic diffuse 14 201039816 type gastric cancer when taking S · 1 / Shunqi money into the money, the further analysis of this data shows that S] / Wei ammonia (four) treatment with <1G % of patients with metastatic diffuse type of gastric cancer who lost weight (10) 5_FU/orbital treatment of similar patients (6.9 months) had a significantly longer intermediate overall survival (9.0 months). These results are shown in Figure 2.

Thus, in accordance with the present invention, a string of _ diffuse or mixed gastric cancer is treated by administering an effective amount of § to the patient and an effective amount of cis-L white. Diffuse the "mixed stomach shot" for any period of this type of diffuse or mixed gastric cancer. In particular, diffuse or mixed gastric cancer can be advanced. Generally, the late gastric cancer is the cancer of the nth, m, or Ιv stage. Further, the cancer to be treated by the present invention may have reached a metastatic disease state when the w (four) amount composition is administered. Furthermore, the method of the present invention can be used as a first line or as a pre-simplified treatment. However, the present method is used as a second (disambiguation) line treatment to treat the occlusal type of gastric vein therapy in advance (including, without limitation, tumor resection, radiation therapy, or the present invention) In one aspect, S] can be administered orally in Tegadon within s_i at a starting dose of from about 2 mg/m2 to about 80 mg/m2 per day. Preferably, S-1 can be about 3 per day. The starting dose of 〇mg/m2 to about 8〇mg/m2 is administered in the s]. More preferably, s] can be from (10) one to about 70 mg/m2 starting dose to S, Administration of tegafur can be administered in at least two separate doses, as such, "every day to: two doses. Any use in W, including the starting amount, W can be about 10 mg / mi each About 4〇mg/m2 of the two doses of tegafur in s_! 15 201039816 虿 The patient is given twice a day, so that the total daily dose of sl is about 2〇mg/m2 to about 80 mg/m2 to S. Tegafur in -1. In a preferred embodiment, si can be administered to a patient twice a day at a dose of about ls mg/m2 to about 4 Torr in s_i, such that S -1 daily total agent 1 system about 30 mg/m2 to about 8 〇mg/m2 of tegafur in S1. In another preferred embodiment, S·1 may each be from about 25 mg/m2 to about 35 mg/m2 to S-1. The second dose of tegafur is administered to the patient twice a day, such that the total daily dose of S_1 is from about 5 mg/m2 to about 7 mg/m2 of tegafur in S-1. After S-1, the dose of S-1 can be adjusted downward in the case where the patient suffers any adverse event due to administration of ^. S-1 can be administered as a medication regimen containing a medication period and a rest period. In one embodiment, the S-1 is administered to the patient at least twice a day for a period of from about 7 to about 28 days, followed by a rest period of from about 7 to about 14 days. Preferably, the combined medication and rest periods are Not less than 28 days. Preferably, the S-1 line is administered at least twice a day for about 21 days. During the rest period, the patient does not need to receive any dose of S-1. This results in the S-1 line being about 28 to It takes about 21 days to continue for about 35 days. In addition, some patients respond better to shorter rest periods, while others respond better to longer rest periods. For example, 'treatment in Japanese patients' A 14-day rest period may be more appropriate. However, for Caucasian patients, a 7-day rest period may be more appropriate. In one embodiment of the invention, the S-1 is administered at least one hour before a meal or at least one hour after a meal. It has been found that the plasma concentration of potassium oxonate (a component of S-1) is significantly higher when the S-1 system is administered at least one hour before a meal or at least one hour after a meal. Assuming potassium oxonate For the protection of the gastrointestinal tract, this dark 16 201039816 shows that the best is to use w in the fasted state. Therefore, it should not be taken within one hour of a meal.

On the one hand, chyle s can be administered intravenously. Shunqi nitrogen can be used by a person skilled in the art to pass the type of intravenous application. In another embodiment of the invention, the mouth gas (iv) is administered at a starting dose of from (10) mg/m2 to about 100 mg/m. Preferably, the cisplatin is administered at a starting dose of about 6 mg/ml _mg/m^. In another embodiment of the invention, the cis-ammonia uranium is used as a single dose, followed by a rest period of (10) to about 35 days. In particular, the dose of cis-molybdenum-molybdenum h is about 0.001, and the patient does not need to receive the mouth ammonia. If the patient suffers from an event with a start-up dose of money, it may be desirable to provide a lower dose of gas to the patient (4). Patients may receive multiple doses of Shunqi ammonia during this period as long as there is a rest period between these doses. (4) The heart ^ needs to be administered during the same period of about 28 to about 35 days. _ When the dose of W is applied to the patient, the amount of the technique is the same. Alternatively, the dose of cisplatin needs to be administered from about 28 to about 35 days _1 and the amount of m needs to be administered for 21 consecutive days from the foot to the approximate period. The weight of the stomach is understood to refer to the weight of S-ι as the weight of the gas mixture in the total mixture rather than the mass of the mouth, the potassium oxonate, or the total mixture. The actual dosage of the patient in the unit of mg/m2 in the unit of mg/m2 is adjusted by the total body surface area of the patient, and the weight is determined by the weight of the patient. . S-1 can be administered in a variety of oral dosage forms, including, but not limited to, tablets, coated tablets, tablets, pellets, capsules, solutions, suspensions, emulsions, and the like. These can be prepared by conventional methods using a suitable pharmaceutically acceptable carrier. Examples of useful carriers are those which are widely used in the manufacture of conventional pharmaceutical compositions such as fillers, extenders, binding agents, disintegrating agents, surfactants, lubricants, and possibly diluents and excipients. As the carrier for molding into a tablet form, various excipients such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, citric acid and the like can be used; Such as, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethyl cellulose, shellac, methyl cellulose, potassium phosphate, polyvinylpyrrolidone, gum arabic powder, sassafras powder, etc. a disintegrating agent such as dry starch, sodium alginate, acacia powder, kumbuchi powder, sodium strontium carbonate, calcium carbonate, polyoxyethylene-sorbitan fatty acid ester, sodium lauryl sulfate, stearic acid Monoglyceride, starch, lactose, etc.; anti-disintegrant, such as sucrose, stearic acid, cocoa butter, hydrogenated oil, etc.; absorption enhancer, such as quaternary ammonium salt, sodium lauryl sulfate, etc.; humectant, such as , glycerin, starch, etc.; absorbents such as starch, lactose, kaolin, bentonite, colloidal acid, and the like, and lubricants such as purified talc, stearate, boric acid powder, polyethylene glycol, and the like. If desired, the lozenge can be in the form of a coated lozenge, such as a sugar-coated lozenge, a gelatin-coated lozenge, an enteric lozenge, a film-coated lozenge, or two or more layers. Lozenges and the like. Capsules are made by mixing the antitumor composition with any of the carriers described above and encapsulating the mixture in a hard gelatin capsule, soft capsule or other capsule. Cisplatin can be administered via an intravenous dosage form such as a liquid. Preparations containing 18 201039816 cisplatin can be prepared by conventional methods using a pharmaceutically acceptable carrier. Examples of useful carriers are those which are widely used in the manufacture of conventional pharmaceutical compositions, such as diluents, and buffers. Cisplatin can be provided in liquid form, which is administered intravenously by itself or in a solid form that is made into a liquid form prior to use. The invention will be further exemplified with reference to the following non-limiting examples. Example 1 1053 patients with gastric/gastroesophageal adenocarcinoma after treatment with 1:1 randomized S-1/cisplatin Or 5-FU / cis gas ammonia platinum. Patients receiving S-1/cis-gas ammoniaplatin were treated with 25 mg/m2 of tegafur in S-1, on the first to 21st day of the treatment cycle, in oral capsule form, twice daily ( At least - hour before meal, or one hour after meal, followed by a 7-day rest period, and 75 mg/m2 of cisplatin on the first day of the treatment cycle, which is in the form of continuous intravenous infusion. It is followed by a 28-day rest period. Patients receiving 5-FU/cisplatin were treated daily with a continuous intravenous injection of 5 mg/kg of 1000 mg/m2 for 5 days, followed by a 23-day rest period, and 1 mg of the first day. /m2 Continuous intravenous infusion of cisplatin, followed by a 28-day rest period. The overall survival analysis was performed by pre-specified stratification and by the inferiority (NI) of the largest tissue subset (diffuse organization). The overall survival of patients with the S-1/cis chlorinated group compared with patients with the 5_FU/cis cisplatin group had a risk ratio (HR) of 0.92 (two sides 95% CI, 0 8 (M 〇 5). The book series 1·〇5 is much lower than the HR=1.22 derived from the literature. Using the strict book inferiority limit (HR=UG), the S__ chloroamidazine discovery system is significantly 19 201039816 no more than 5-FU/shun The cisplatin (ρ=〇·〇〇68) is poor. The preservation control effect of S-1/cis-ammonia platinum is much higher than that of Rothmann et al. (Statist-Med 2003; 22:239-264). 50% of the recommendations. Since 12 hierarchical sub-categories, S-1/cis-gas ammoniaplatin was produced in 9-line HR<= 1〇 and survived in 3 series HR>=1_0. Diffuse or mixed tissue (59 The overall survival analysis of the sputum W showed that S-1/cis-ammonia platinum (survival in the middle of 9 months) resulted in better overall survival than 5-FU/cis-gasplatin (survival between 7 and 1 month) (logarithmic scale p <0.05; HR, 0.83 [95% CI, 〇.7〇to 0.99]). This analysis resulted in patients with diffuse or mixed gastric cancer who were treated with S-1/cisplatin therapy. Compared with the 5-FU/cis-ammonia platinum treatment regimen The conclusion of a better overall survival is considered. Example 2 Patients with diffuse or mixed gastric & gastric esophageal adenocarcinoma after untreated 2:1 randomized individually receiving s-i/cisplatin or 5_FUA) Chloroplatin. Patients with localized late-stage disease and patients with more than 1% weight loss in the first 3 months of the study were excluded from the patient population. Patients receiving s-1/cis-gasplatin were treated with 25 mg/m2 of tegafur in S-1 for oral capsules on days 1 to 21 of the treatment cycle, twice daily. (at least one hour before meal or one hour after meal), followed by a 7-day rest period, with 75 mg/m2 of cisplatin, which is on the first day of the treatment cycle, in a continuous intravenous infusion pattern. After the 28-day rest period. Patients receiving 5-Fu/cisplatin were treated with a continuous intravenous infusion of 5_1?1 per day for 5 days during the 5-day period; followed by a 23-day rest period and 1 day on the 1st day. Continuous intravenous infusion of cis mg/m2 with cisplatin followed by a 28-day rest period. 20 201039816 The overall survival analysis of superiority was implemented. Patients with diffuse or mixed gastric cancer who received the s-i/cis-ammonia platinum treatment regimen had a statistically better overall survival than the 5-FU/cisplatin treatment regimen. Conclusions In patients with diffuse or mixed metastatic gastric cancer, S-1/cisplatin proved to be better overall survival than 5-FU/cisplatin. Example 3 Patients with diffuse or mixed gastric//gastroesophageal adenocarcinoma after untreated period 2:1 randomized individually to receive either S-1 or 5-FU. Patients with localized late-stage disease and patients with more than 10% weight loss in the first 3 months of the study were excluded from the patient population. Patients receiving S-1 were treated with 25 mg/m2 of tegafur in S-1 for oral capsules on days 1 to 21 of the treatment cycle, twice daily (at least one meal before meal) Hour, or one hour after meal, the total daily amount is 50 mg/m2, followed by a 7-day rest period. Patients receiving 5-FU were treated with a continuous intravenous infusion of 5-FU per day at 1000 mg/m2 for 5 days, followed by a 23-day rest period. The overall survival analysis of superiority was implemented. Patients with diffuse or mixed gastric cancer who were treated with S-1/cis-ammonia platinum had a statistically better overall survival than the 5-FU/cisplatin treatment regimen. The S-1 was also found to have a lower death crisis than the 5-FU. In addition, S-1 showed superior safety and tolerability than 5-FU. Conclusions In patients with diffuse or mixed metastatic gastric cancer, S-1 demonstrates better overall survival than 5-FU. The above examples suggest that S-1, which may or may not be administered with cisplatin, is effective in the treatment of diffuse gastric cancer and mixed gastric cancer with general treatment of other diffuse cancers. Other cancers present in diffuse tissue include the following: colorectal cancer, 21 201039816 bladder cancer, pancreatic cancer, biliary tract cancer, cecal cancer, esophageal cancer, non-small cell lung cancer (NSCLC)', and breast cancer. For the treatment of these types of cancer, the patient can be administered to the patient at least twice a day, at a total daily dose of from about 20 mg/m2 to about 80 mg/m2 to tegafur in S-1. The total daily dose of S_i administered to the patient is from about 30 mg/m2 to about 80 mg/m2 of tegafur in S-1, and the event causing unwanted side effects may be reduced. More preferably, S-1 can be administered to a patient at least twice a day at a total daily dose of 50 mg/m2 to 70 mg/m2 in s-l. S-1 can be provided as an oral composition as described above to treat diffuse gastric cancer or mixed gastric cancer. In some patients, S-1 can be administered to the patient from two to two times a day for a period of from about 7 to about 28 days, followed by a rest period of from about 7 to about 14 days. Japanese patients generally respond better to a regimen that includes at least two administrations of S-1 for about 28 days and a rest period of about 14 days thereafter. Thus, the S-1 is approximately 28 days in a 42-day period. Invested. In addition, non-sputum patients may respond better to medication regimens that include S-1 at least twice a day for about 14 days and a rest period of about 7 days thereafter, so that S-1 is within 21 days. It is used for about 14 consecutive days. S-1 can be provided as an oral composition as described above to treat diffuse gastric cancer or mixed gastric cancer. The disclosures of the present invention and the accompanying drawings, which are hereby incorporated by reference in their entirety herein in their entirety herein in their entirety herein In addition, the following publications are available to understand the present invention and are also incorporated herein by reference: 1. Mayer RJ. Gastrointestinal tract cancer. In: Kasper DL, Braunwald E, Fauci AS, Hauser SL, Longo 22 201039816 DL, Jameson, JL, Isselbacher KJ Editor. Harrison's Principles of Internal Medicine. 16th ed. New York, NY: McGraw Hill, 2005 2. Cunningham D, Allum WH, Stenning SP, Thompson JN, Van de Velde CJH, Nicolson M, et al., Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med 2006;355:11-20 3. Murad AM, Santiago FF , Petroianu A et al., Modified therapy with 5-fluorouracil, doxorubicin, and methotraxate in advanced gastric cancer in late gastric cancer. Cancer 1993;72 :37-41 4_ Pyrhanen S, Kuitunen T, Nyandoto P, et al., Fluorouracil, Epirubicin and A in patients with metastatic gastric cancer Chrysalis (FEMTX) plus randomized comparison of supportive care and individual supportive care (Randomised comparison of fluorouracil, epidoxorubicin and methotrexate (FEMTX) plus supportive care with supportive care alone in patients with metrastatic gastric cancer). Br J Cancer 1995: 71:587-91 5. Van Cutsem E, Moiseyenko VM, Tjulandin S, Majlis A, Constenla M, Boni C, etc., late paclitaxel and cisplatin plus fluorouracil as the first line of treatment for gastric cancer Phase study of the V325 study group (phase III study of docetaxel and 23 201039816 cisplatin lus fluorouracil as first-line therapy for advanced gastric cancer: a report of the V325 study group). J Clin Oncol 2006;24:4991-7

6. Kang Y ' Kang WK, Shin DB, Chen J, Xiong J, Wang J, etc., in patients with advanced gastric cancer (AGC), capecitabine / cisplatin (XP) and continuous infusion of 5-FU / cisplatin (FP) as a first-line treatment for randomized phase III trial of capecitabine/cisplatin (XP) vs. continuous infusion of 5-FU/cisplatin (FP) as first-line therapy In patients with advanced gastric cancer (AGC)). J Clin Oncol 2006;24:17S (abstr LBA4018)

7. Park JM, Jang YJ, Kim JH, Park SS, Park SH, Kim SJ, et al., Gastric cancer histology: Clinicopathologic characteristics and prognostic value. J Surg Oncol. 2008; 98:520-25 8. Lee KH, Lee JH, Cho JK, et al., A prospective correlation of Lauren's histological classification of stomach cancer with a classification of gastric cancer tissue classification of Lauren Canceropathological findings including DNA flow cytometry). Pathology Research and Practice. 2001:197 (4):223-9 9. Patel PR, Yao JC, Hess K, Schnirer I, Rashid A, Ajani JA. Metastasis/disease recurrence and tissue differentiation Effect of timing of metastasis/disease 24 201039816 recurrence and histological differentiation on survival of patients with advanced gastric cancer. Cancer. 2007;110:2186-90 10· Ichikawa et al. , Intern·J Caner 112, 967-73, 2004 11. Andreyev et al., EurJ Cancer 34(4), 503-9 , 1998 12. DeWys et al., Am J_ Med. 69, 491-7, 1980

G 13. Ross PJ ' Ashley S ' Norton A' Priest K' Waters JS ' Eisen T et al. Does a patient with weight loss have worse outcomes when undergoing chemotherapy for lung cancer? (Do patients with weight loss have a worse outcome when undergoing chemotherapy for lung cancers?) Br. J Cancer 2004;90,1905-11 14. Deans DAC, Tan BH, Wigmore SJ, Ross JA, de Beaux AC, Paterson-Brown S et al., systemic inflammation, dietary intake and stage of disease on rate of weight loss in patients with gastro-oesophageal Cancer). Br J Cancer. 2009;100:63-69 15. Takechi T, Nakano K, Uchida J et al, Sl, a new composition of oral tegafur, antitumor activity in experimental tumor models in rats <RTI ID=0.0>> , Kato T et al, Sl, Tiga 25 201039816 an oral composition of fluoride and two biochemical regulators, compared with 5-fluorouracil for intravenous infusion Anticancer activity and toxicity of Sl, an oral combination of tegafur and two biochemical modulators, compared with continuous iv infusion of 5-fluorouracil. Anti-Cancer Drugs. 1998;9:817-823 17. Fukushima M, Sataka H, Uchida J, et al., Sl: a new oral formulation of 5-fluorouracil for pre-clinical anti-tumor efficiency of human tumor xenografts (Preclinical antitumor efficacy of Sl: a new oral formulation of 5-fluorouracil on human tumor xenografts). International J Oncology. 1998; 13:693- 698 18· Koizumi W, Kurihara M, Nakano S et al, Sl, a novel oral derivative of 5-fluorouracil, Phase II study of late gastric cancer (Phase II study of Sl, a Oncology. 2000;58:191-197 19. Ohtsu A, Baba H, Sakata Y et al. and Sl Cooperative Colorectal Cancer Research Group. Sl, novel oral fluoride sigma Derivatives in a Phase II study of Sl patients with metastatic colorectal cancer (Phase II study of Sl, a novel oral fluoropyrimidine derivative, in patients w Ith metastatic colorectal carcinoma). Br J Cancer. 2000;83(2):141-145 20. Cohen SJ, Leichman CG, Yeslow G, etc., once daily oral administration of S1 in patients with advanced cancer Phase I and pharmacokinetic study of once daily oral administration of Sl in patients with advanced cancer. 26 201039816

Clin Cancer Res. 2002;8:2116-2122 21_Study on the safety and pharmacokinetics of the procedure for oral administration of BMS-247616 for patients with solid tumors for a daily 28-day and seven-day rest period Phase I study to determine the safety and pharmacokinetics of oral administration of , BMS-247616 on a once daily schedule for twenty-eight _ days with seven days rest in patients with solid tumors).

Bristol-Myers Squibb Company Clinical Study Report ou (CA 157004). 2003 22. Ajani J, Yao J, Faust J, et al. 'Sl plus cisplatin aids the first phase of drug power in patients with advanced gastric cancer (AGC) Phase I pharmacokinetic study of Sl plus cisplatin in patients with advanced gastric carcinoma (AGC). ASCO. 2004; Abstract 4043 23 · Yver AJ, Aj ani J, Moiseyenko VM, etc., with metastatic gastric adenocarcinoma (MGC) The final result of the randomized controlled phase III trial (TAX 325) of patients with cisplatin (C) and 5-fluorouracil (F) combined with docetaxel (T) and CF (Final results) Of a randomized controlled phase III trial (TAX 325) comparing docetaxel (T) combined with cisplatin (C) and 5-fluorouracil (F) to CF in patients (pts) with metastatic gastric adenocarcinoma (MGC)). ASCO. 2005;Abstract 4002 24. Comets E, Ikeda K, Hoff P, Fumoleau P, Wanders J, Tanigawara Y. S-1, Oral Anticancer Agent, Drugs for Western and Japanese Patients 27 201039816 Comparison of kinetics (Comparison of the Pharmakin Ecs of Sl, an oral anticancer agent, in Western and Japanese patients). J Pharmacokinetics and Pharmacodynamics 2003;30(4):257-283 25. Ohtsu A, Shimada Y, Shirao K, et al. Randomized phase III trial of fluorouracil plus cisplatin and uracil and tegafur plus mitomycin in patients with unresectable post-stage gastric cancer: Japanese Society of Clinical Oncology (JCOG9205) (Randomized phase III) Trial of fluorouracil alone versus fluorouracil plus cisplatin versus uracil and tegafur plus mitomycin in patients with unresectable, advanced gastric cancer: The Japan Clinical Oncology Group Study (JCOG9205)). J Clin Oncol. 2003;21:54-59 26. Lenz H, Lee FC, Haller DG, et al., Extended Safety and efficacy data on S-1 plus for S-1 plus Sodium Ammoniaplatin in patients with advanced gastric cancer. Ciplatin in patients with advanced gastric carcinoma in a multicenter phase II study). J Clin Oncol. 2006; ASCO Annual Meeting Proceedings Pa Rt 1. Vol 24, No. 18S. Abstract 4083 Although the present invention has been disclosed with reference to the details of the preferred embodiments of the present invention, it is understood that the disclosure is intended to be illustrative, not limiting, since the Those skilled in the art can readily occur within the spirit of the invention. 28 201039816 I: Simple illustration of the diagram 3 Figure 1 is compared with the overall survival of patients with _ diffuse type of late gastric cancer when treated with 5-FU/cis-ammonia platinum. 'When S-1/cis chloride At the time of ammonia treatment, the difference in overall survival between patients with diffuse late gastric cancer and a limited number of patients with mucinous gastric cancer. ~ Figure 2 shows the difference in overall survival between patients with metastatic disease/diffuse type of advanced gastric cancer, and the opposite of sputum X5 rain cisplatin treatment. When cisplatin ## is less than 2, the base weight is lost. Original time [main element description] (none)

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Claims (1)

201039816 VII. Patent application scope: 1. The use of a composition of a first preparation and a second preparation for preparing a medicament for treating a diffuse type gastric cancer or a mixed type gastric cancer, the first preparation being therapeutically effective Composition of S-1, wherein the S-1 system contains Tegafur, Gimeracil, and Oxycil at a molar ratio of 1:0.4:1. A pharmaceutical composition of Potassium), the second preparation comprising a therapeutically effective amount of cisplatin. 2. For the use of the scope of claim 1, wherein the total amount of tegafur in S-1 is from about 20 mg/m2 to about 80 mg/m2 per day. 3. For the use of the scope of claim 1, wherein the S-1 is administered for a period of from about 14 days to about 35 days for a continuous period of from about 7 to about 28 days. 4. The use of the first aspect of the patent application, wherein the cisplatin is applied once in a period of about 28 days. 5. The use of the first aspect of the patent application, wherein the therapeutically effective amount of cisplatin is from about 50 mg/m2 to about 100 mg/m2. 6. The use of the first aspect of the patent application, wherein the therapeutically effective amount of cisplatin is from about 60 mg/m2 to about 80 mg/m2. 7. A kit for treating a diffuse gastric cancer or a mixed gastric cancer comprising a first preparation consisting of a therapeutically effective amount of S-1, wherein the S-1 line contains 1: A pharmaceutical composition of tegafur, gimmost, and potassium oxonate in a molar ratio of 0.4:1, and a second preparation comprising a therapeutically effective amount of cisplatin. 8. For the kit of claim 7 of the patent scope, wherein the total amount of tegafur in S-1 is from about 20 mg/m2 to about 80 mg/m2 per day. 30 201039816 9. The kit of claim 7, wherein the S-1 is administered for a period of from about 14 days to about 35 days for a continuous period of from about 7 to about 28 days. 10. The kit of claim 7 wherein the cisplatin is applied once in a period of about 28 days. 11. The kit of claim 7 wherein the therapeutically effective amount of cisplatin is from about 50 mg/m2 to about 100 mg/m2. 12. The kit of claim 7 wherein the therapeutically effective amount of cisplatin is from about 60 mg/m2 to about 80 mg/m2. 〇 〇 31