Title:  Pharmacokinetic modulating chemotherapy

United States Patent:  6,303,583

Assignee:  Kusunoki; Masato (Kobe, JP); Taiho Pharmaceutical Company, Limited (Tokyo, JP)

Filed:  September 21, 1999

PCT NO:  PCT/JP98/05424

102(e) Date:  September 21, 1999

PCT PUB. Date:  April 22, 1999

Foreign Application Priority Data:  Oct 09, 1997[JP]  (9-277312)

A method of treating intestinal cancer characterized by performing an adjuvant therapy comprising continuous injection of 5FU and oral administration of UFT in combination with the injection after surgical resection of a human intestinal cancer.

DISCLOSURE OF THE INVENTION

We have carried out intensive research on dosages and administration schedules so that the basic experiment of Fujii et al. can be practically applied to clinical uses to improve the result of postoperative treatment of intestinal cancer, and consequently found a method of administration which achieves excellent therapeutic results.

The present invention relates to a novel adjuvant therapy to be conducted after surgical resection of intestinal cancer. Stated more specifically, the present invention provides a method of treating intestinal cancer characterized by performing an adjuvant therapy comprising continuous injection of 5FU and oral administration of UFT in combination with the injection after surgical resection of a human intestinal cancer. The term "UFT" refers to an anti-malignant tumor agent comprising a mixture of 1-(tetrahydrofuryl)-5-fluorouracil (brand name: Futraful, common name Tegafur) and uracil in a molar ratio of 1:4. Tegafur is a 5FU derivative corresponding to 5-fluorouracil wherein in a tetrahydrofuryl group is attached to the 1-position thereof and which has its side effect mitigated. Tegafur is given orally or parenterally in the form of suppositories or injections, and releases 5FU to exhibit antitumor activity when metabolized in the liver. On the other hand, UFT is an improved oral antitumor agent of the 5FU type obtained by admixing uracil with Tegafur in a ratio of 4:1, and is widely used in the field of cancer therapies in the U.S., Japan, etc. The therapy of the present invention is applicable to intestinal cancers treated by various surgical operations. The term "intestinal cancers" as used herein refers, for example, to those of the large intestine developing in the cecum, vermiform appendix, ascending colon, transverse colon, descending colon, sigmoid colon, rectum and anal canal, and cancers of the small intestine developing in the duodenum jejunum and ileum.

The therapy of the present invention is a novel adjuvant therapy for patients with an intestinal cancer surgically resected. The therapy is capable of remarkably ameliorating recurrence or metastasis.

The novel adjuvant therapy of the present invention achieves a satisfactory therapeutic result by administering 5FU and UFT to the patient treated by surgical resection, according to the therapeutic schedule of the invention. We named this therapy Pharmacokinetic Modulating Chemotherapy (PMC). The PMC of the invention is performed after surgical resection of a cancer and comprises continuously infusing 5FU intra-arterially or intravenously and orally administering UFT in combination with the infusion. The therapy greatly reduces the incidence of metastasis or local recurrence, leading to survival over a prolonged period.

The intestinal cancer patients to be treated by the therapy of the invention are those developing cancer primarily in the large intestine or small intestine and having the cancerous tissues removed from the primary lesion by surgery. Accordingly, the patients include those having the cancerous tissues removed completely and those having cancer metastasized, for example, to the liver. Continuous infusion is effected by means capable of delivering the drug at a specified rate. Usual drip may be resorted to, while it is desirable to use an external pump permitting adjustment of the rate and duration of infusion. In this case, 5FU is continuously delivered via a catheter adapted for use in surgery and inserted into the blood vessel, by means of a drug infusor attached to one end of the catheter. The catheter may be one widely used in the field of surgery, such as Teflon catheter, polyethylene catheter or the like. The preferred catheter is, for example, 5Fr anthrone P-u catheter (product of Toray Medical Co.). Useful drug infusors are implantable port systems, intravenous infusion pumps and intra-arterial infusion pumps.

Examples of implantable port systems are those usually used insofar as the drug can be continuously delivered intravenously or intra-arterially at a constant rate. For example, MRI port (Bard Access Systems Inc., Salt Lake City, Utah, USA) is desirable. Examples of useful intra-arterial infusion pumps are Watkins chronofusor continuous intra-arterial infusion pump and Sharp continuous intra-arterial infusion pump, MP-22, and Intermate (registered trademark, product of Baxter Healthcare Corporation). Singleday Infusor (product of Baxter Healthcare Corpocation) is desirable as the intravenous infusion pump. 5FU is filled into the implantable port system, and a needle is inserted into the blood vessel in the manner of drip. Alternatively, the drug may be delivered by drip when such infusors are not usable for one reason or another.

The blood vessel to be used for infusion is generally a vein or artery although suitably selectable according to the site of the cancer. Examples of useful veins are the right subclavian vein and cubital vein. Examples of arteries usable are the hepatic artery, gastroduodenal artery, subclavian artery, etc.

It is furthr desirable to perform radiotherapy in order to achieve improved therapeutic results. The radiotherapy is conducted by a common method practiced for treating intestinal cancers. The radiotherapy is conducted prior to, during or after the surgical resection. Preoperative irradiation is especially preferred to ensure wider applicability of surgery and inhibit metastasis or local recurrence.

The method of irradiation to be practiced is one of those usually used for radiotherapy, such as external irradiation and rectal intraluminal brachytherapy. The dose is usually 5 to 70 Gy, preferably 20 to 50 Gy although variable depending on the condition or symptoms. The radiation can be given in a single dose or divided doses.

According to the present invention, an adjuvant therapy is performed which comprises continuous injection of 5FU and oral administration of UFT in combination. More specifically stated, 5FU is continuously injected for a specified period, and UFT is orally given before, during or after the continuous injection.

5FU is used preferably as dissolved in an auxiliary solution for drip, such as saline or a solution of heparin, glucose or fructose. It is especially desirable to deliver 5FU as mixed with 45 ml of saline and 2000 units of heparin using an infusor. 5FU is intra-arterially or intravenously given continuously for 3 to 48 hours, preferably for 6 to 36 hours, more preferably for 12 to 24 hours, once a week as a unit. UFT is orally administered once to four times daily for 3 to 7 days. This dosage regimen is continued for 2 months to 3 years.

The therapy of the present invention is intended to maintain the concentration of 5FU in the blood at a constant level for a prolonged period of time by the continuous infusion of 5FU and the oral administration of UFT. The desired concentration is generally 50 nglm to 400 nglml although variable with the age or symptoms of the patient.

The present invention has achieved remarkable improvements in recurrence rate and prognosis. The improvements in the prognoses of patients are attained especially through a marked reduction of distant recurrences by PMC of the invention. The improvements in prognoses include an improved survival rate, extended survival period, prevention of recurrence and prevention of distant recurrence. It has been found that patients have tolerance for the therapy of the invention, and that 5FU as enhanced by pharmacokinetic modulation is effective for treating tumors.

5FU is given usually at a dose of 100 to 1000 mg/m² /day, preferably about 200 to about 600 mg/m² /day. UFT is given in an amount of up to 3000 mg, preferably about 1000 to about 2800 mg, per week. The daily dose is usually 200 to 600 mg/m², preferably about 200 to about 300 mg/m².

According to the invention, it is possible to intravenously and/or orally give other drugs in combination with the oral administration of UFT. Examples of such other drugs usable are leucovorin (LV), cisplatin (CDDP), irinotecan hydrochloride (CPT-11), mitomycin (MMC), methotrexate (MTX), etc.

The patient having a cancerous lesion surgically removed can be treated by the therapy of the invention at home or as an outpatient without hospitalization. The therapy is lower than conventional therapies in medical cost and therefore very useful also from the viewpoint of medical economy.

Claim 1 of 12 Claims

What is claimed is:

1. A method of treating a human having an intestinal cancer characterized by performing an adjuvant therapy comprising continuous injection of 5-fluorouracil (5FU) for 3 to 48 hours once a week and oral administration of a mixture of 1-(tetrahydrofuryl)-5-fluorouracil and uracil (UFT) one to four times a day for 3 to 7 days per week.

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