JP2006306775A - Method of curing stomach cancer - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an after-operation auxiliary chemical curative method lowering the recurrence rate of stomach cancer after operation and improving the survival rate. <P>SOLUTION: The curative method comprises administering a drug composition containing tegafur and urasil in a 1:4 molar ratio orally to a patient of stomach cancer with a histological depth of tumor invasion of t2 and a histological degree of lymph node metastasis of n1 to n2, based on the classification of the stages of stomach cancer, in an amount, based on tegafur, of 300-400 mg/m<SP>2</SP>/day according to an administration schedule of five-day continuous administration and two-day suspension, starting from a day within six weeks after operation. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

  The present invention relates to postoperative adjuvant chemotherapy for gastric cancer.

  Treatment methods for gastric cancer include surgical treatment such as endoscopic mucosal resection (EMR), laparoscopic surgery, reduction surgery, routine surgery, and extended surgery; chemotherapy; radiation therapy and the like. In actual treatment, these treatment methods are selected and treated according to the progression of the stage. The stage of progression of gastric cancer, which is a criterion for selecting a treatment method, includes histological depth (t1 to t4), histological lymph node metastasis (n0 to n3), and presence or absence of peritoneal metastasis (p0 to p1). ), Presence / absence of liver metastasis (h0-h1), presence / absence of cancer cells by abdominal cytology (cy0-cy1), and presence / absence of distant metastasis (m0-m1). Among these, reduction surgery or routine surgery (partial gastrectomy) is performed in principle for cases with a histological depth of t1 or more and a histological lymph node metastasis degree of n1 or more.

  However, even with gastric cancer surgical therapy that matches the degree of progression of such stage, the recurrence rate is high, and the remote outcome (5-year survival rate) in the case of surgery alone is 20 to 40% (Non-patent Document 1). Surgery alone is not enough to treat stomach cancer. Therefore, postoperative adjuvant chemotherapy is necessary. However, postoperative adjuvant chemotherapy for gastric cancer has been studied for a long time, but even if adjuvant chemotherapy is performed, the survival rate is not good (Non-patent Document 1) and is statistically useful. There are few established methods (Non-Patent Documents 2 to 4).

On the other hand, tegafur (1- (2-tetrahydrofuryl) -5-fluorouracil) is activated in vivo to release 5-fluorouracil (hereinafter referred to as “5-FU”) which is an active body. It is a prodrug of FU, and is a drug that exhibits an anticancer effect by inhibiting the synthesis of DNA due to the inhibition of thymidylate synthase by 5-FU and the dysfunction of RNA. And the composition which mix | blended the said tegafur and the uracil which has the anti-tumor effect enhancement effect of the said tegafur so that it might become 1: 4 by molar ratio is used as a cancer chemotherapeutic agent. With regard to postoperative adjuvant chemotherapy for gastric cancer of this composition, when this composition is continuously administered daily at 375 mg / m ² / day as a tegafur amount, a significant life-prolonging effect is obtained with this composition alone. It was reported that there was not (Non-patent document 5). Moreover, in addition to mitomycin C, when this composition was administered as a tegafur amount of 600 mg / day continuously every day for 2 years from 2 weeks after surgery, there was a significant life-prolonging effect, but leukopenia: 22 %, GOT increased: 18%, GPT increased: 18%, loss of appetite: 25%, nausea / vomiting: 22%, diarrhea 7%, and the median actual administration period is the target administration period 16.9% (123 days). There is also no report that a significant life-prolonging effect was obtained by administration of this composition alone (Non-patent Document 6).
dovglass J., HO, Gastric Cancer, p145-172 (1988) Nakajima, T. et al, Gastric Cancer, 125-143 (1988) Hermans, J. et al, J. Clin. Oncol. 11: 1441-1447,1993 Wils, J. et al, Ann. Oncol. 5: 69-72, 1994 Tokunaga, T. et al, J. Surg. Oncol. 75: 31-36,2000 Arima, S. et al, Eur. J. Surg. 160: 227-232,1994

  An object of the present invention is to provide a postoperative adjuvant chemotherapy that reduces the recurrence rate after surgery and improves the survival rate for patients whose gastric cancer stage of progression is t1 and n1 or more.

Therefore, as a result of various studies on the target patient, dosage, administration schedule and the like regarding adjuvant chemotherapy after gastric cancer surgery, the present inventor has found that the histological depth is t2 in the stage classification of gastric cancer and the histological lymph node For a gastric cancer patient with a metastasis degree of n1 to n2, a pharmaceutical composition containing tegafur and uracil in a molar ratio of 1: 4 is added as a tegafur amount of 300 to 400 mg / m ² / day, within 6 weeks after the operation, Oral administration with 5 days continuous dosing and 2 days continuous withdrawal administration schedule allows easy administration for a long period of time, low incidence of side effects, remarkably reduced recurrence rate, and long-term survival rate Was found to be significantly improved, and the present invention was completed.

That is, the present invention relates to postoperative chemotherapy for gastric cancer, which has a histological depth of t2 and a histological lymph node metastasis of n1 to n2 in the stage of gastric cancer. A pharmaceutical composition containing tegafur and uracil in a molar ratio of 1: 4 is administered as a tegafur amount of 300 to 400 mg / m ² / day, and administered within 5 weeks of continuous administration for 5 days and 2 days of continuous rest The present invention provides a method for treating gastric cancer, characterized by being orally administered on a schedule.

The present invention also relates to a pharmaceutical composition comprising tegafur and uracil in a molar ratio of 1: 4, and has a histological depth of t2 and a histological lymph node metastasis degree in staging of gastric cancer. Gastric cancer treatment for oral administration of gastric cancer patients who are n1 to n2 as a tegafur amount of 300 to 400 mg / m ² / day, within 6 weeks after surgery, with 5 days continuous dosing and 2 days continuous withdrawal A pharmaceutical composition for use is provided.

  According to the treatment method of the present invention, the long-term survival rate of postoperative gastric cancer patients is significantly improved, and the recurrence rate is also significantly reduced. Moreover, according to the dosage and administration schedule in the treatment method of the present invention, long-term administration can be performed without difficulty, and the incidence of side effects also decreases.

  A stomach cancer patient to be treated in the present invention is a patient having a histological depth of t2 and a histological lymph node metastasis degree of n1 to n2 in the stage classification of gastric cancer. These patients are usually applied patients for reduction surgery or routine surgery, i.e., surgery to remove one to two thirds of the stomach (partial gastrectomy). These histological findings can be judged using the tissue excised in the operation. The classification of these stages is based on the description of the Gastric Cancer Handling Regulations, 13th edition, Japan Gastric Cancer Society, Kanehara Publishing (Tokyo), 1999, and the Japanese Gastric Cancer Association, Gastric Cancer, p10-24 (1998). It is.

  The chemotherapeutic agent used in the present invention is a pharmaceutical composition containing tegafur and uracil in a molar ratio of 1: 4 (Japanese Patent Publication No. 59-53885 and Japanese Patent Laid-Open No. 4-36237). This pharmaceutical composition is sold under the trade name UFT (Head and neck cancer), stomach cancer, colorectal cancer, liver cancer, gallbladder / bile duct cancer, pancreatic cancer, lung cancer, breast cancer, bladder cancer, prostate cancer, cervical cancer. It is used as a therapeutic drug. However, there is no report that the UFT is useful for postoperative adjuvant chemotherapy for gastric cancer patients with the administration schedule of continuous administration for 5 days alone and continuous withdrawal for 2 days.

  The form of the composition is not particularly limited as long as it is a composition for oral administration containing tegafur and uracil. Examples of the composition include tablets, granules, fine granules, powders, capsules, pills, emulsions, suspensions, liquids and the like.

  When forming into a tablet form, for example, lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid and other excipients, water, ethanol, propanol, simple syrup, glucose solution , Starch solution, gelatin solution, binders such as carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone, dry starch, sodium alginate, agar powder, laminaran powder, sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid ester Disintegrants such as sodium lauryl sulfate, stearic acid monoglyceride, starch, lactose, disintegration inhibitors such as sucrose, stearin, cocoa butter, hydrogenated oil, quaternary ammonium base, sodium lauryl sulfate, etc. Uses accelerating agents, humectants such as glycerin and starch, adsorbents such as starch, lactose, kaolin, bentonite and colloidal silicic acid, and lubricants such as purified talc, stearate, boric acid powder and polyethylene glycol. it can. Further, the tablets can be made into tablets with ordinary coatings as necessary, for example, sugar-coated tablets, gelatin-encapsulated tablets, enteric-coated tablets, film-coated tablets, double tablets, and multilayer tablets. In shaping into a pill form, for example, excipients such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, kaolin, talc, gum arabic powder, tragacanth powder, binders such as gelatin, ethanol, laminaran powder, Disintegrants such as Kanteng powder can be used.

  Moreover, it can also be set as the composite preparation which consists of an enteric composition containing tegafur and a gastric composition containing uracil (Unexamined-Japanese-Patent No. 4-36237). Here, the enteric composition containing tegafur is preferably an enteric-coated composition. Examples of enteric coating agents include hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose, and methacrylic acid copolymer. L, methacrylic acid copolymer LD and the like.

  The pharmaceutical composition only needs to contain tegafur and uracil in a molar ratio of 1: 4, and may be a preparation containing these two components, and these two components are different from each other. It may be a combination of shapes (eg, tablets and capsules).

The compositions are administered orally, the dosage is at 300-400 mg / m ² / day as tegafur amount, in particular 360 mg / m ² / day is preferred. When the dose is out of the range of 300 to 400 mg / m ² / day, sufficient effectiveness may not be obtained, or the incidence of side effects may increase. This dose is a daily dose, and the tegafur amount of 300 to 400 mg / m ² may be administered in ² to 4 divided doses, preferably administered in 2 divided daily doses. . In this case, the administration interval may be 4 to 16 hours, and is preferably after breakfast and dinner.

  The administration start time is within 6 weeks after the operation. If it exceeds 6 weeks after the operation, the effectiveness of the therapy of the present invention cannot be sufficiently obtained.

  In the present invention, it is important that the administration schedule for one week is 5 days continuous dosing and 2 days continuous rest. In order to obtain a sufficient therapeutic effect, continuous administration every day is desirable, but continuous administration every day for a long period of time is burdensome for the patient and may increase the incidence of side effects. On the other hand, if a schedule of continuous administration for 5 days and 2-day continuous withdrawal is used, there is less burden on the patient and long-term administration is possible. In addition, side effects are alleviated by having a 2-day continuous withdrawal. Long-term administration is possible by both reducing the burden on the patient and reducing side effects. According to the patient's life cycle, the administration schedule may be administered from Monday to Friday and closed on Saturdays and Sundays.

  The administration period is preferably 10 months or longer, more preferably 16 months or longer. A good therapeutic effect can be obtained by administration for 10 months or longer.

  The postoperative adjuvant chemotherapy for gastric cancer according to the present invention significantly reduces the recurrence rate after surgery and significantly improves the long-term survival rate. In addition to the method of the present invention, doxorubicin, epirubicin, irinotecan hydrochloride, etoposide, docetaxel, paclitaxel, cisplatin, carboplatin, krestin, lentinan, picibanil and the like can be used in combination.

  EXAMPLES Next, although an Example is given and this invention is demonstrated in detail, this invention is not limited to this.

Example 1
(1) Objectives of the study Moderately advanced t2 (invasion of cancer exceeds submucosa in gastric cancer staging, but is intrinsic muscle layer (mp) or serosa (ss)), n1 Capsule containing UGT: tegafur 100 mg, uracil 224 mg for the purpose of preventing recurrence of gastric cancer after curative surgery in cases where n2 (metastasis up to group 2 lymph node) is observed. (Surgical + UFT group: test group), and the life extension effect is examined by a comparative control test with the surgical single group. The primary endpoint is survival and a secondary endpoint is observed for recurrence-free periods.

(2) Subjects of clinical trial (2) -1. Eligibility criteria 1) Case histologically confirmed to be gastric cancer 2) No distant metastasis, dissection greater than D2 (group 1 lymph node and group 2 lymph node), radical cure A or Case 3 who underwent surgery of B (no cancer remnants) 3) histologically determined to be mp-ss in the resected specimen (t2) and histologically has lymph node metastases of n1 or n2 Case 4: PS: Performance status (ECOG scale) after surgery (within 2 weeks before registration) is 0-2 5) Age at registration: 20 years old or older, 75 years old or younger 6) Surgery as prior treatment Cases not receiving treatment other than treatment 7) No serious complications and postoperative (within 2 weeks before registration) test values satisfy the following criteria
WBC ≧ 4,000 / mm ³
PLT ≧ 100,000 / mm ³
GOT ≦ 2.0 × Nu (Nu: Upper limit of facility standard value. Set in the range of 25 to 48 for each facility.)
GPT ≦ 2.0 × Nu (Nu: upper limit of facility standard value. Set in the range of 25-50 for each facility.)
T-Bil ≦ 1.5 × Nu (Nu: Upper limit of facility standard value. Set in the range of 0.9 to 1.3 for each facility.)
BUN ≦ 1.5 × Nu (Nu: Upper limit of facility standard value. Set within the range of 18-23 for each facility.)
Cr ≦ 1.5 × Nu (Nu: Upper limit of facility standard value. Set within the range of 0.8 to 1.3 for each facility.)
8) A case with no mental disorder that interferes with obtaining consent, and who gave written informed consent after explaining the outline of this study to the person.

(2) -2. Cases below the exclusion criteria will be excluded.
1) Cases with simultaneous and metachronous double cancers (Definition of synchrony: cases diagnosed within 6 months after surgery)
2) Cases with serious postoperative complications (complications that do not recover by the registration time within 6 weeks after surgery, such as postoperative infection, suture failure, gastrointestinal bleeding)
3) Japan Clinical Oncolgy Group (JCOG) side effect criteria (Grade) 3 or more cases with a history of severe drug allergy (references on JCOG side effect criteria: Tobinai, K. et al, Jpn. J. Clin. Oncol. 23: 250-257,1993)
4) Pregnant women, lactating women, women who may be pregnant, cases with intention of pregnancy 5) Cases where treatment and follow-up cannot be performed properly due to reasons such as remote location 6) HIV (+), HBs (+ ), HCV (+) cases

(3) Treatment 1) Surgery alone group (control group)
Patients who are assigned to the surgery alone group will be followed up without metastasis until metastasis or recurrence is confirmed. There were 95 control groups.

2) Surgery + UFT group (test group)
Administration of UFT (capsule) starts within 6 weeks after surgery, 360 mg / m ² / day after breakfast and dinner, 5 days (Monday-Friday) of the week, 2 days (Saturday, Sunday) For 16 months. Since UFT is a 100 mg / cap preparation as tegafur, the dosage capsule per body surface area is as follows.
The following doses are administered according to body surface area.
Less than 1.25m ² : 4cap / body / day (Morning 2cap, Evening 2cap)
1.25 m ² or more and less than 1.54 m ² : 5 cap / body / day (morning 3 cap, evening 2 cap)
1.54m ² or more: 6cap / body / day (morning 3cap, evening 3cap)
After 16 months of administration, anticancer therapy is not performed until metastasis or recurrence. The treatment end date is taken as the treatment end date, and if the treatment is stopped due to an adverse event, the treatment end date is taken as the treatment end date. There were 93 test groups.

(4) Results 1) Survival period The period from surgery to death.
The event is death of the original disease and death of other diseases. Surviving cases and cases with unknown survival will be censored when survival is confirmed. The results are shown in FIG.

2) No recurrence period The period from surgery to metastasis / recurrence confirmation.
The event that is the earliest of metastasis / recurrence, death of primary disease, or death of other disease is taken as the event. For all other cases, the date of final confirmation that no metastasis or recurrence has been confirmed will be the time of discontinuation. The results are shown in FIG.

From FIG. 1, the 5-year survival rate is 71.7% for the control group, 84.2% for the test group (the 4-year survival rate is 73.6% for the control group, 86.3% for the test group), log In the -rank test, there was a significant difference in the risk rate p = 0.176.
From FIG. 2, the 5-year recurrence-free survival rate was 68.1% in the control group, the test group: 84.5% (the 4-year recurrence-free survival rate was 68.1% in the control group, 84.5% in the test group). %), And there was a significant difference in the risk rate p = 0.040 in the log-rank test.
From these results, it was found that according to the administration method of the present invention, the long-term survival rate after surgery for gastric cancer patients is improved and the recurrence rate is significantly reduced.
In addition, regarding adverse events (JCOG side effect criteria of grade 2 or higher), in the administration method of the present invention, leukopenia: 17.6%, GOT increase: 5.5%, GPT increase: 7.7%, anorexia : 19.4%, nausea / vomiting: 6.5%, diarrhea 8.6%. On the other hand, in addition to the conventionally known mitomycin C, this composition was administered as a tegafur amount of 600 mg / day for 2 consecutive days every day from 2 weeks after surgery (Non-patent Document 6). %, GOT increase: 18%, GPT increase: 18%, loss of appetite: 25%, nausea / vomiting: 22%, diarrhea 7%. Therefore, the administration method of the present invention was generally low in adverse events as compared with the conventionally known administration methods, and was particularly good with low frequency of GOT increase, GPT increase, nausea / vomiting.
As for medication compliance, in addition to mitomycin C, this composition was administered as a tegafur amount of 600 mg / day for 2 consecutive days every day from 2 weeks after surgery (Non-patent Document 6). Although the median period was 16.9% (123 days) of the target administration period, the median of the actual administration period increased to 69.3% (324 days) of the target administration period in the present administration method. It was. By providing a 2-day withdrawal after 5-day dosing as in the administration method of the present invention, adverse events were reduced, leading to adherence to the treatment schedule, and as a result, contributing to a good survival rate.
As described above, the administration method of the present invention was superior in effect and adverse events as compared with conventional adjuvant chemotherapy after gastric cancer using UFT.

It is a figure which shows a postoperative survival rate. It is a figure which shows the recurrence-free survival rate after an operation.

Claims (5)

Adjuvant chemotherapy after surgery for gastric cancer, with tegafur and uracil 1 for gastric cancer patients with histological depth of t2 and histological lymph node metastasis of n1 to n2 : A pharmaceutical composition containing a molar ratio of 4 is orally administered as a tegafur amount of 300 to 400 mg / m ² / day, within 6 weeks after surgery, on a continuous schedule of 5 days and 2 days of continuous withdrawal A method for treating gastric cancer, comprising: The method according to claim 1, wherein the dosage of the pharmaceutical composition is 360 mg / m ² / day as a tegafur amount.   The method according to claim 1 or 2, wherein the daily dose of the pharmaceutical composition is administered in two divided doses. A gastric cancer composition comprising tegafur and uracil in a molar ratio of 1: 4 and having a histological depth of t2 and a histological lymph node metastasis degree of n1 to n2 in the staging of gastric cancer A pharmaceutical composition for the treatment of gastric cancer, which is orally administered to a patient in a dosage schedule of 300 to 400 mg / m ² / day as a tegafur amount, within 6 weeks after the operation, on a 5-day continuous dosing and 2-day continuous off schedule. The pharmaceutical composition for gastric cancer treatment according to claim 4, wherein the dose is 360 mg / m ² / day as the amount of tegafur.