Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
1999-09-21
2001-10-16
Wilson, James O. (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C514S049000, C514S051000
Reexamination Certificate
active
06303583
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a novel adjuvant therapy to be performed after the surgical resection of intestinal cancers such as colorectal cancer and cancer of the small intestine. The term “adjuvant therapy” means an auxiliary therapy.
BACKGROUND ART
With the westernization of dietary habit, patients with cancer of the large intestine are increasing in number among Japanese. It is said that cases of colorectal cancer will exceed those of gastric cancer in number in the 21st century, predominating over other malignant tumors along with lung cancer and breast cancer.
Colorectal cancer is treated by surgical resection, which includes endoscopic polypectomy for early colorectal cancer which is an early carcinoma, and abdominoperineal resection of the rectum, abdominosacral resection of the rectum, pull-through operation, low anterior resection, total pelvic exenteration, Hartmann operation and colostomy for progressive cancers. Radical surgery results in a 5-year survival rate of 50 to 60%. The closer the lesion to the rectum, the higher is the rate of recurrence. The site of recurrence is most frequently local. Distant metastases generally occur to the liver and the lung. The rate of such recurrence or metastasis is about 40% for rectal cancer and about 20% for lung cancer. It is empirically known that the recurrence or metastasis is attributable to the presence of a metastasized lesion not detectable macroscopically or to the spread or dissemination of cancer cells by surgical manipulation. Improvements in the oncologic result of large intestinal cancer are dependent not only on early detection but also on how to prevent recurrence or metastasis after surgical resection. For this purpose, it is general practice to conduct adjuvant therapies including (1) chemotherapy, (2) radiotherapy, (3) immunotherapy, (4) thermotherapy, or (5) other treatment. These therapies are performed singly or in combination pre- or post-operatively or during operation. Among these adjuvant therapies, chemotherapy and radiotherapy are widely performed.
Carter summarized 5-fluorouracil (5FU) administration schedules in an introduction to colorectal cancer, including a method wherein a standard loading dose (SLD) of 370 to 500 mg/m
2
bolus (intravenous injection for 5 to 10 min) is given for 5 days, and this dosage regimen is repeated every 4 to 5 weeks. Reportedly, this method achieves effectiveness of 19% (Cancer Treat Rev. 1: 111-129 1974), whereas it is reported that SLD attains effectiveness of 7 to 29% according to research in recent years.
Lokich et al. compared administration of 5FU at a dose of 500 mg/M
2
bolus for 5 days every 5 weeks with CVI (continuous intravenous infusion) of the drug at 300 mg/m
2
/day, reporting that the respective regimens were 7% and 30% in effectiveness, hence a significant difference, but that there was no difference between the resulting survival periods which were 11.2 months and 10.3 months (J. Clin. Oncol. 7: 425-432 1989). Thus, CVI of 5FU over a prolonged period produces an improved effect but still fails to lengthen the survival period.
Various improvements in the dosage regimen of 5FU and research on drugs for use in combination therewith have been made in order to improve such results of treatments. Extensive research has been conducted on therapies comprising CVI of 5FU and use of other anticancer drugs in combination. The drugs to be used in combination with 5FU include Adriamycin, mitomycin C, carmustine, semustine, leucovorin and cisplatin, whereas satisfactory results still remain to be reported.
On the other hand, research has been carried out also on the basis of the therapy comprising CVI of 5FU and use of a multiplicity of drugs in combination with the infusion. Fujii et al. conducted CVI of 5FU in rats implanted with Yoshida sarcoma at a low concentration (20 mg/kg/day) for a prolonged period of time consecutively for 6 days, in combination with oral administration of UFT (to be described later) at a dose of 20 mg/kg once every day, whereby an excellent tumor diminution effect was obtained along with suppressed leukopenia (Jpn. J. Cancer Res. 80, 509-512, 1989).
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 implan
Arent Fox Kintner Plotkin & Kahn PPLC
Kusunoki Masato
Wilson James O.
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