Method for treating cancer patients with severe renal dysfunction

Abstract

To provide cancer treatment methods for cancer patients with severe renal dysfunction.SOLUTION: A method for treating cancer in patients with a creatinine clearance of 15 mL / min or more and less than 30 mL / min, including dividing a combination drug containing α,α,α-trifluorothymidine (FTD) and 5-chloro-6-[(2-iminopyrrolidine-1-yl)methyl]pyrimidine-2,4(1H,3H)-dione hydrochloride in a molar ratio of 1:0.5, with an FTD-equivalent dose of 30 to 50 mg / m2 / day, into two to four doses a day, and orally administering it to the patient.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a method of treatment for cancer patients with severe renal dysfunction. [Background technology]

[0002] Trifluridine (also known as α,α,α-trifluorothymidine, hereafter referred to as "FTD") The inhibitory effect of thymidylate synthesis is to inhibit DNA synthesis and to inhibit D It exerts an antitumor effect by impairing NA function. 1H,3-6-[(2-iminopyrrolidin-1-yl)methyl]pyrimidine-2,4(1H,3 H)-Dione hydrochloride (hereinafter referred to as "TPI") has a thymidine phosphorylase inhibitory effect. TPI inhibits the degradation of FTD by thymidine phosphorylase in vivo. It is known that the antitumor effect of FTD is enhanced by this (Patent Document 1). Currently, there is a combination drug containing FTD and TPI in a molar ratio of 1:0.5 (hereinafter referred to as "FTD·TPI"). The combination drug is currently under development as a treatment for solid cancers, and is being approved in the United States for the treatment of advanced and recurrent It has been approved as a treatment for colorectal cancer under the trade name Lonsurf combination tablets (Non-Patent Document References 1 and 2). The usual dosage regimen for FTD / TPI combination drugs in clinical practice is as follows for adults: Based on area, FTD is 70 mg / m 2 / day, twice a day for 5 consecutive days. This is repeated twice, followed by a 14-day break from the drug. This is called one cycle. The drug is defined as administering the drug repeatedly.

[0003] FTD / TPI combination drugs are effective in treating patients with reduced renal function because TPI is a renally excreted drug. It is theorized that administration to patients may increase exposure to FTD. In the clinical trial, the creatinine clearance (hereinafter referred to as The incidence of adverse events was compared according to renal dysfunction based on the CLcr value. Side effects related to the drug (decreased platelet count, decreased red blood cell count, decreased hemoglobin, decreased neutrophil count) The incidence of CLcr was higher in patients with mild renal dysfunction (C Lcr: 60-89mL / min) and moderate renal dysfunction (CLcr: 30-59mL / The creatinine clearance (CL The cr) value was calculated using the Cockcroft-Gault formula and is reported by the U.S. Food and Drug Administration ( FDA (Food and Drug Administration) Guidance ( Guidance for Industry Pharmacokinetics n Patients with Impaired Renal Function -Study Design, Data Analysis, and Impact Classified based on the Renal Function Classification Criteria of the National Institute of Clinical Nursing (NIH) on Dosing and Labeling Therefore, patients with severe renal dysfunction (CLcr: 15-29 mL) / min) is not indicated for these patients and no clinical trials have been conducted to date. The FTD / TPI combination drug has not been administered, and there is no information on its safety or efficacy. In general, the dosage and administration interval of drugs to patients with renal dysfunction should be determined according to the degree of renal function. Adjustments are necessary, and according to the FDA guidance, doses should be selected based on pharmacokinetics (PK). It is recommended to choose However, there are safer and more effective treatments for cancer patients with severe renal dysfunction. It is not easy to provide effective cancer treatment. [Prior art documents] [Patent documents]

[0004] [Patent Document 1] International Publication No. 1996 / 30346 [Non-patent literature]

[0005] [Non-Patent Document 1] Invest New Drugs 26(5):445-54,2008 [Non-Patent Document 2] Lancet Oncol.13(10):993-1001,2012 Summary of the Invention [Problem to be solved by the invention]

[0006] The present invention relates to providing a method for treating cancer in cancer patients with severe renal dysfunction. [Means for solving the problem]

[0007] The present inventors have developed a method for treating cancer patients with severe renal dysfunction, in which CLcr is 15 to 29 mL / min. When cancer treatment with a combination drug of FTD and TPI was attempted in a patient with cancer, 30-50mg / m 2 If the dose is divided and administered orally 2 to 4 times a day, serious side effects are unlikely to occur. It was found that, while avoiding cancer-related side effects, a significant anticancer effect was observed.

[0008] That is, the present invention provides the following inventions [1] to

[28] . [1] Method for treating cancer in patients with creatinine clearance less than 30 mL / min The method comprises the steps of: mixing α,α,α-trifluorothymidine (FTD) and 5-chloro-6-[(2- Iminopyrrolidin-1-yl)methyl]pyrimidine-2,4(1H,3H)-dione hydrochloride A combination containing salts at a molar ratio of 1:0.5 is used, with the FTD equivalent of 30-50 mg / m 2 / orally administering to said patient a daily dose of 2 to 4 divided doses per day. [2] The patient has a creatinine clearance of 15 mL / min or more and 29 mL / min or less. The method for treating cancer described in [1], wherein the patient is a patient of the cancer type. [3] 40 mg / m2 in terms of FTD 2 / day dose orally in 2 divided doses per day The method for treating cancer according to [1] or [2]. [4] The administration schedule is five consecutive days of oral administration and two days off per week. [1] The method for treating cancer according to any one of claims 1 to 3. [5] The administration schedule is five consecutive days of oral administration, two days off, repeated twice, followed by 14 days The method for treating cancer according to any one of [1] to [4], wherein the treatment is interrupted by a drug holiday. [6] The method for treating cancer according to any one of [1] to [5], wherein the cancer is digestive tract cancer or breast cancer. Law. [7] The method for treating cancer according to any one of [1] to [6] above, wherein the cancer is colorectal cancer. [8] Cancer treatment for patients with creatinine clearance of less than 30 mL / min α,α,α-trifluorothymidine (FTD) and 5-chloro-6-[(2-isopropyl) (1H,3H)-pyrimidine-2,4(1H,3H)-dione hydrochloride The FTD equivalent amount of the combination drug containing these in a molar ratio of 1:0.5 is 30-50 mg / m 2 / day The therapeutic agent is orally administered to the patient in divided doses of 2 to 4 times a day. [9] The patient has a creatinine clearance of 15 mL / min or more and 29 mL / min or less. The cancer therapeutic agent according to [8], wherein the patient is a patient of the above-mentioned group.

[10] 40 mg / m2 in terms of FTD 2 The daily dose is given orally in divided doses twice daily. The cancer therapeutic agent according to [8] or [9],

[11] The administration schedule is five consecutive days of oral administration and two days off per week. The cancer therapeutic agent according to any one of claims 1 to 10.

[12] The administration schedule was 5 consecutive days of oral administration, followed by 2 days of rest twice, followed by 14 The cancer therapeutic agent according to any one of [8] to

[11] , wherein the drug is suspended for days.

[13] The method for treating cancer according to any one of [8] to

[12] , wherein the cancer is digestive tract cancer or breast cancer. Therapeutic agent.

[14] The cancer therapeutic agent according to any one of [8] to

[13] , wherein the cancer is colorectal cancer.

[15] Treatment of cancer in patients with creatinine clearance less than 30 mL / min α,α,α-trifluorothymidine (FTD) and 5-chloro-6-[ (2-Iminopyrrolidin-1-yl)methyl]pyrimidine-2,4(1H,3H)-di Use of a combination drug containing 1:0.5 molar ratio of 1:0.5 of 1:1 FTD exchanger Calculated dosage: 30-50mg / m 2 The patient was orally administered a daily dose of 100 mg / kg / day in divided doses 2 to 4 times a day. To be given, to be used.

[16] Patients with creatinine clearance of 15 mL / min or more and 29 mL / min or more The use of the method described in

[15] above in patients with

[17] 40 mg / m2 in terms of FTD 2 The daily dose is given orally in divided doses twice daily. The use of the method according to

[15] or

[16] .

[18] The administration schedule is five consecutive days of oral administration and two days off per week. The use according to any one of claims 5 to 17.

[19] The administration schedule was 5 consecutive days of oral administration, followed by 2 days of rest twice, followed by 14 The use according to any one of

[15] to

[18] , wherein the drug is discontinued for days.

[20] The use according to any one of

[15] to

[19] , wherein the cancer is digestive tract cancer or breast cancer. .

[21] The use according to any one of

[15] to

[20] , wherein the cancer is colorectal cancer.

[22] Treatment of cancer in patients with creatinine clearance less than 30 mL / min α,α,α-Trifluorothymidine (FTD) and 5-chloro-6-[( 2-Iminopyrrolidin-1-yl)methyl]pyrimidine-2,4(1H,3H)-dione A combination agent containing hydrochloride at a molar ratio of 1:0.5, and the FTD equivalent is 30 to 50 ml g / m 2 A combination drug to be administered orally to the patient at a dose of 100 mg / day divided into 2 to 4 doses per day.

[23] Patients with creatinine clearance of 15 mL / min or more and 29 mL / min or more The combination drug described in

[22] above is used for patients with the following conditions:

[24] 40 mg / m2 in terms of FTD 2 The daily dose is given orally in divided doses twice daily. The combination preparation according to

[22] or

[23] ,

[25] The administration schedule is five consecutive days of oral administration and two days off per week. The combination formulation according to any one of [2] to

[24] .

[26] The administration schedule was 5 consecutive days of oral administration, followed by 2 days of rest twice, followed by 14 The combination preparation according to any one of

[22] to

[25] , wherein the administration is suspended for days.

[27] The combination according to any one of

[22] to

[26] , wherein the cancer is digestive tract cancer or breast cancer. Agent.

[28] The combination drug according to any one of

[22] to

[27] , wherein the cancer is colorectal cancer. Effect of the Invention

[0009] According to the treatment method of the present invention, it is possible to treat severe renal dysfunction without causing serious side effects. Thus, excellent cancer treatment effects can be obtained for cancer patients. [Brief description of the drawings]

[0010] [Figure 1] FIG. 1 shows the relationship between creatinine clearance 12 days after administration and oral clearance of FTD. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0011] In the present invention, α,α,α-trifluorothymidine and 5-chloro-6-[(2-iminopyridinyl) 1H,3H)-pyrimidine-2,4(1H,3H)-dione hydrochloride A combination containing the two in a ratio of 1:0.5 is used. FTD and TPI are known compounds, and are described in, for example, International Publication No. 1996 / 30. It can be synthesized according to the method described in the pamphlet of No. 346. In addition, FTD / TPI combination drugs in tablet form are also known (Non-Patent Documents 1 and 2). is approved in the United States for the treatment of advanced or recurrent colorectal cancer.

[0012] The FTD / TPI combination drug used in the present invention may be in any form that can be administered orally. Examples include tablets, coated tablets, pills, powders, granules, capsules, liquids, suspensions, emulsions, etc. These preparations can be prepared by using pharma- ceutically acceptable carriers and the like in a conventional manner generally known in the art. The pharmaceutical composition can be formulated by a conventional formulation method.

[0013] In addition, the FTD / TPI combination drug is 30-50 mg / m 2 / day dose divided into 2-4 doses per day It is also possible to divide the drug into separate packages so that it can be administered in separate doses. There are no particular limitations as long as the packaging method is a conventional method commonly known in the art. For example, in the case of tablets, It may be packaged in a moisture and oxygen protective packaging material.

[0014] Examples of pharma- ceutically acceptable carriers include those commonly used in conventional drugs, such as Excipients, binders, disintegrants, lubricants, disintegration inhibitors, absorption promoters, moisturizers, adsorbents, coatings, etc. Injection agents, solvents, solubilizing agents, suspending agents, isotonicity agents, pH adjusters, buffers, stabilizers, Examples include coloring agents, flavoring agents, and odorants.

[0015] Excipients include lactose, sucrose, D-mannitol, starch, crystalline cellulose, and silicic acid. Examples include calcium.

[0016] Binders include hydroxypropyl cellulose, methyl cellulose, polyvinylpyrrolidone, Examples include lysine, candy powder, and hypromellose.

[0017] Disintegrants include starch, sodium glycolate, calcium carmellose, and cloric acid. Sodium scalmellose, crospovidone, low-substituted hydroxypropyl cellulose, Partially pregelatinized starch and the like.

[0018] Lubricants include talc, magnesium stearate, sucrose fatty acid esters, stearyl alcohol, and glycerol. phosphoric acid, sodium stearyl fumarate, etc.

[0019] Examples of disintegration inhibitors include white sugar, stearic acid, cocoa butter, hydrogenated oil, etc. .

[0020] Examples of absorption enhancers include quaternary ammonium bases and sodium lauryl sulfate. do.

[0021] Moisturizing agents include glycerin, starch, and the like.

[0022] Adsorbents include starch, lactose, kaolin, bentonite, colloidal silicic acid, etc. Can be obtained.

[0023] Coating agents include ethyl cellulose and aminoalkyl methacrylate copolymer. -RS, hypromellose, white sugar, etc.

[0024] Solvents include water, propylene glycol, and saline.

[0025] Solubilizing agents include polyethylene glycol, ethanol, and α-cyclodextrin. , macrogol 400, polysorbate 80, etc.

[0026] Suspending agents include carrageenan, crystalline cellulose, sodium carmellose, and polio. Hydrogenated castor oil is an example of such an oil.

[0027] Examples of the isotonic agent include sodium chloride, glycerin, potassium chloride, and the like.

[0028] pH regulators and buffers include sodium citrate, hydrochloric acid, lactic acid, phosphoric acid, and phosphoric acid dihydrate. Examples include sodium hydroxide.

[0029] Stabilizers include sodium pyrosulfite, sodium edetate, erythorbic acid, and acid Examples of suitable toluene-based solvents include magnesium chloride and dibutylhydroxytoluene.

[0030] Coloring agents include titanium dioxide, ferric oxide, food blue No. 1, copper chlorophyll, etc. can be.

[0031] Flavoring agents include aspartame, saccharin, sucralose, l-menthol, Mint flavor, etc.

[0032] In the present invention, the FTD / TPI combination drug is used in an amount of 30 to 50 mg / m2 in terms of FTD. 2 The daily dose is given orally in divided doses 2 to 4 times daily. The dose of the FTD / TPI combination drug is 30-50 mg / m2 in terms of FTD. 2 / day However, preferably 30 to 48 mg / m 2 / day, preferably 35-45 mg / m 2 / day Preferably 40 mg / m 2 / day.

[0033] The number of administrations per day is 2 to 4 times, preferably 2 to 3 times, and more preferably Preferably, twice.

[0034] It is preferable to leave an interval of at least 6 hours between administrations.

[0035] The dosage for a patient is determined based on the patient's body surface area (BSA) calculated from the patient's height and weight. The method of calculating body surface area is determined by the patient's race, sex, health status, symptoms, etc. Conventional methods are used as appropriate, but examples of the calculation methods include the following 1 to 6. , preferably the following 1 or 2(a). 1.The Mosteller formula(N Engl J Med 198 7 Oct 22;317(17):1098(letter) BSA(m2 ) = ([height (cm) x weight (kg)] / 3600) 1 / 2 2.The DuBois and DuBois formula(Arch Int Med 1916 17:863-71;J Clin Anesth.1992;4 (1):4-10) (a) BSA(m 2 )=0.20247×Height (m) 0.725 ×Weight (kg) 0.425 (b) BSA(m 2 ) = 0.007184 × height (cm) 0.725 ×Weight(kg )0.425 3.The Haycock formula(The Journal of Ped (See IAtrics 1978 93:1:62-66) BSA(m 2 ) = 0.024265 × height (cm) 0.3964 ×Weight (kg) 0.5378 4.The Gehan and George formula(Cancer Ch (See Emother Rep 1970 54:225-35) BSA(m 2 ) = 0.0235 × height (cm) 0.42246 ×Weight (kg) 0.51456 5.The Boyd formula(Minneapolis:universit (See The Book of Minnesota Press, 1935) BSA(m 2 ) = 0.0003207 × height (cm) 0.3 ×Weight (grams) (0.7285- (0.0188 x LOG(grams)) 6.The Fujimoto formula(Nihon Eiseigaku Z (See Asshi, 1968 23(5):443-450) BSA(m 2 ) = 0.008883 × height (cm) 0.663 ×Weight (kg) 0.444

[0036] For example, the body surface area of ​​a cancer patient who is 175 cm tall and weighs 70 kg is calculated using formula 1 above. When calculated, the body surface area is ([175(cm)×70(kg)] / 3600) 1 / 2 =1. 84(m 2 The dose for this patient is calculated as 50 mg / m2 in FTD equivalent. 2 If the daily dose is 1.84 x 50 = 92 mg, the total daily dose is set at 92 mg. will be done.

[0037] In the present invention, the subjects of administration are cancer patients with CLcr of less than 30 mL / min. Preferably, the patient is a cancer patient with a blood flow rate of 15 mL / min or more and less than 30 mL / min. Cancer patients with a blood flow rate between 15mL / min and 29mL / min. The patient's CLcr value is an indicator of renal function, and patients with CLcr between 15 and 29 mL / min Includes patients with severe renal dysfunction (patients with severe renal dysfunction). are also called patients with severe renal dysfunction.

[0038] In the present invention, CLcr is calculated using the Cockcroft-Gault formula shown below. It is served. [Cockcroft-Gault style] Men: CLcr (mL / min) = {(140-age) × weight (kg)} ÷ {serum creatine Chronic thyroiditis (mg / dL) × 72 Women: CLcr (mL / min) = {(140-age) x weight (kg)} ÷ {serum creatine Thymine level (mg / dL) × 72 × 0.85 The serum creatinine level can be measured by a conventional method.

[0039] In the present invention, the administration schedule is five consecutive days of oral administration followed by two consecutive days of oral administration per week. It is also recommended to repeat oral administration for 5 consecutive days and then rest for 2 days twice. It is preferable to repeat the administration of one cycle of four days without medication.

[0040] The cancers that can be treated by the present invention include, for example, head and neck cancer, digestive tract cancer (esophageal cancer, gastric cancer, etc.) Duodenal cancer, liver cancer, biliary tract cancer (gallbladder, bile duct cancer, etc.), pancreatic cancer, small intestine cancer, colorectal cancer (colorectal cancer, colon cancer, rectal cancer, etc.), lung cancer (non-small cell lung cancer, small cell lung cancer), breast cancer, ovarian cancer, uterine cancer ( Examples of cancer include cervical cancer, uterine cancer, kidney cancer, bladder cancer, prostate cancer, and skin cancer. Cancer includes not only the primary lesion but also cancer that has metastasized to other organs (such as the liver). From the viewpoint of tumor efficacy and side effects, head and neck cancer, digestive tract cancer, lung cancer, breast cancer, kidney cancer, and skin cancer are preferred. More preferably, the patient has cancer of the digestive tract or breast cancer, and more preferably, esophageal cancer, colon cancer, or gastric cancer. The most preferably, the patient has colon cancer. The therapeutic method of the present invention is particularly preferred for preventing recurrence after surgical removal of a tumor. Adjuvant chemotherapy, even if given after surgery, is not recommended for those who are undergoing surgery to remove the tumor. It may be neoadjuvant chemotherapy. EXAMPLES

[0041] The present invention will now be described in more detail with reference to examples. There is no limitation to the present invention, and many variations are possible within the scope of the present invention. This is possible by anyone with knowledge of

[0042] Example 1: Estimation of dosage in cancer patients with severe renal dysfunction The combination of FTD and TPI (FTD and TPI) was administered to patients with solid tumors, including colorectal cancer. (1:0.5 molar ratio mixture) 35 mg / m 2 (hereinafter referred to as FTD) The administration schedule was repeated twice a day for 5 consecutive days followed by 2 days off, and then To investigate the pharmacokinetics of FTD when treatment is repeated with 3 days off per cycle did. Before starting treatment, patients were asked to calculate the CLcr value using the Cockcroft-Gault formula. Renal function was evaluated by dividing the renal function into control (normal, CLcr: ≥ 90 mL / min), mild ( CLcr:60~89mL / min), moderate (CLcr:30~59mL / min) The subjects were divided into groups. Blood samples were taken at 5, 1, 2, 4, 6, 8, 10, and 12 hours to assess plasma FTD and TPI levels. The plasma concentrations were used to determine the pharmacokinetic parameters of FTD and TPI. was calculated, and the results are shown in Table 1.

[0043] [Table 1]

[0044] In FTD / TPI combination drugs, FTD is the active ingredient that exhibits anticancer activity, and TPI is FT D. Thus, FTD plasma concentration after repeated administration The intermediate concentration is most strongly associated with efficacy and safety of FTD / TPI combination drugs. In patients with renal impairment (Cohort 1), the AUC of FTD was significantly lower than in patients with normal renal function. 0-12 is about 1 In patients with moderate renal dysfunction (Cohort 2), the incidence was approximately 51% higher. The AUC of FTD increases with decreased renal function. The need to reduce the dose of the combination drug was suggested. The elimination half-life of FTD was The average time to renal function was 2.40 hours for patients with moderate renal impairment, 3.22 hours for patients with normal renal function, and 2. The half-life of FTD was not significantly longer than that of FTD administered twice daily. The dosing interval was sufficiently short compared to 12 hours, so no change in the dosing interval was required. The efficacy of the FTD / TPI combination drug can be maintained by reducing the dosage to an appropriate level. To determine the appropriate dose for patients with severe renal impairment, oral clotting of FTD was performed on the 12th day after administration. Regression analysis was performed between clearance (CL / F) and creatinine clearance (CLcr). The results are shown in Figure 1.

[0045] As shown in Figure 1, the relationship between the two parameters can be approximated by the following power curve: I did. FTD CL / F (L / hr) = 0.3432 × CLcr (mL / m in) 0.4870

[0046] Using this regression equation, CL / F of FTD at each renal dysfunction level was calculated from CLcr. Furthermore, the ratio of AUC in FTD to that in patients with normal renal function was calculated, and these results are shown in Table 2. In this case, the median CLcr in patients with normal renal function (109 mL / min) was compared with the control ( The ratio was calculated based on a mean of 1.00. g / m 2 , 20 mg / m 2 and 25 mg / m 2 The AUC of FTD when administered at 35 mg / m for patients with normal renal function, patients with mild renal impairment, and patients with moderate renal impairment, respectively. 2 Throw On the other hand, the AUC of FTD· TPI formulation at 35mg / m 2 When administered at 10 mg / kg, the AUC for FTD was 10.1 mg / kg and the AUC for FTD was 10.1 mg / kg. was thought to be more than twice as high as that of patients.

[0047] [Table 2]

[0048] The safety results of this study showed that patients with normal renal function, mild renal impairment, and moderate renal impairment All subjects received 35 mg / m 2 Therefore, FTD / TPI combination drug at 15 mg / m for patients with severe renal dysfunction 2 , 20 mg / m 2 and 25 mg / m 2 The AUC of FTD when administered at 100 mg / kg was at a tolerable level. , 15 mg / m 2 The AUC of FTD when administered was lower than that in patients with normal renal function. On the other hand, the renal function of patients with severe renal impairment is unstable. et al., 25 mg / m 2 The AUC for FTD may be higher than predicted when For these reasons, in patients with severe renal dysfunction (CLcr: 15-29 mL / min), , and FTD / TPI combination drug at 20 mg / m 2 It is most preferred to administer the same in vivo. For patients with severe renal dysfunction, the FTD / TPI combination drug should be administered at a dose of 30-50 mg / kg (FTD equivalent). m 2 / day, especially in terms of FTD equivalent, 2 / Day of the Throw By reducing the dosage, efficacy can be expected while maintaining safety.

Claims

1. Method for treating cancer in patients with creatinine clearance less than 30 mL / min α,α,α-trifluorothymidine (FTD) and 5-chloro-6-[(2-imidazolidinyl) (1H,3H)-pyrimidine-2,4(1H,3H)-dione hydrochloride The blending agent containing the compound in a molar ratio of 1:0.5 is 30 to 50 mg / m2 in terms of FTD. 2 / day orally administering to said patient divided doses two to four times daily.

2. The patient has a creatinine clearance of 15 mL / min or more and 29 mL / min or less. The method for treating cancer according to claim 1 .

3. 40 mg / m2 in terms of FTD 2 The daily dose is divided into two doses and administered orally. The method for treating cancer according to claim 1 or 2.

4. The administration schedule of claims 1 to 5 is oral administration for 5 consecutive days and rest for 2 days per week.

4. A method for treating cancer according to any one of claims 3 to 4.

5. The administration schedule was 5 consecutive days of oral administration, 2 days off, repeated twice, followed by 14 days off. The method for treating cancer according to any one of claims 1 to 4, which is a medicine.

6. The method for treating cancer according to any one of claims 1 to 5, wherein the cancer is digestive tract cancer or breast cancer.

7. The method for treating cancer according to any one of claims 1 to 6, wherein the cancer is colon cancer.

8. A cancer treatment agent for patients with creatinine clearance of less than 30 mL / min. α,α,α-trifluorothymidine (FTD) and 5-chloro-6-[(2-imino pyrrolidin-1-yl)methyl]pyrimidine-2,4(1H,3H)-dione hydrochloride The compounding agent containing the compound at a ratio of 1:0.5 is 30 to 50 mg / m2 in terms of FTD. 2 / Daily use The therapeutic agent is orally administered to said patient in divided doses two to four times daily.

9. The patient has a creatinine clearance of 15 mL / min or more and 29 mL / min or less. The cancer therapeutic agent according to claim 8 .

10. 40 mg / m2 in terms of FTD 2 / day dose is administered orally in two divided doses per day; The cancer therapeutic agent according to claim 8 or 9.

11. The administration schedule is oral administration for 5 consecutive days and rest for 2 days per week.

11. A cancer therapeutic agent according to any one of claims 10 to 19.

12. The administration schedule was 5 consecutive days of oral administration, 2 days off, repeated twice, followed by 14 days off. The cancer therapeutic agent according to any one of claims 8 to 11, which is a medicine.

13. The cancer therapeutic agent according to any one of claims 8 to 12, wherein the cancer is digestive system cancer or breast cancer.

14. The cancer therapeutic agent according to any one of claims 8 to 13, wherein the cancer is colon cancer.

15. A method for preparing a cancer treatment agent for a patient with a creatinine clearance of less than 30 mL / min α,α,α-trifluorothymidine (FTD) and 5-chloro-6-[(2- iminopyrrolidin-1-yl)methyl]pyrimidine-2,4(1H,3H)-dione hydrochloride Use of a compounding agent containing a salt in a molar ratio of 1:0.5, wherein the compounding agent is 30-50 mg / m 2 The patient is orally administered a daily dose of 100 mg / kg / day in divided doses 2 to 4 times daily. To use.

16. The patient has a creatinine clearance of 15 mL / min or more and 29 mL / min or less. The use according to claim 15,

17. 40 mg / m2 in terms of FTD 2 / day dose is administered orally in two divided doses per day; 17. Use according to claim 15 or 16.

18. 15. The administration schedule of claim 15, wherein the administration is oral administration for 5 consecutive days and rest for 2 days per week.

18. The use according to any one of claims 1 to 17.

19. The administration schedule was 5 consecutive days of oral administration, 2 days off, repeated twice, followed by 14 days off. The use according to any one of claims 15 to 18, which is a medicine.

20. The use according to any one of claims 15 to 19, wherein the cancer is gastrointestinal cancer or breast cancer.

21. The use according to any one of claims 15 to 20, wherein the cancer is colon cancer.

22. For use in the treatment of cancer in patients with creatinine clearance less than 30 mL / min α,α,α-trifluorothymidine (FTD) and 5-chloro-6-[(2-methyl- (1H,3H)-pyrimidine-2,4(1H,3H)-dione hydrochloride in a molar ratio of 1:0.5, and the FTD equivalent is 30 to 50 mg / m 2 The combination is orally administered to said patient at a daily dose of 2 to 4 divided doses per day.

23. The patient has a creatinine clearance of 15 mL / min or more and 29 mL / min or less. The combination formulation according to claim 22,

24. 40 mg / m2 in terms of FTD 2 / day dose is administered orally in two divided doses per day; 24. The combination formulation according to claim 22 or 23.

25. 22. The administration schedule of claim 21, wherein the administration is oral administration for 5 consecutive days and rest for 2 days per week.

25. A combination formulation according to any one of claims 1 to 24.

26. The administration schedule was 5 consecutive days of oral administration, 2 days off, repeated twice, followed by 14 days off. The combination formulation according to any one of claims 22 to 25, which is a drug.

27. The combination drug according to any one of claims 22 to 26, wherein the cancer is digestive tract cancer or breast cancer.

28. The combination drug according to any one of claims 22 to 27, wherein the cancer is colon cancer.

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