Effect of intraperitoneal chemotherapy on experimental peritoneal dissemination of gastric cancer

In vitro chemosensitivity test using a collagen-gel method was done on 165 primary gastric cancers. All of 5-FU, CBDCA, CDDP and docetaxel showed a high sensitivity. The effects of per oral (po) administration of TS-1, a combination of po TS-1 and intraperitoneal (ip) administration of CDDP, ip 5-FU and ip docetaxel, were evaluated in athymic mice bearing peritoneal dissemination of a gastric cancer cell line (MKN-45-P that shows a high rate of metastasis to the peritoneal cavity of nude mice). Nude mice were inoculated by ip with 10(7) MKN-45-P cells. No survival benefit was obtained after po administration of TS-1 (12 mg/kg) alone or ip CDDP alone. However, a combination of po TS-1 (8 mg/kg x 10 days, from day 3) and ip CDDP (3.5 mg/kg, day 6 and 13) showed a significant survival improvement than that of po TS-1 or ip CDDP treatment alone. ip administration of 30 mg/kg (3 times/week x 3 weeks) or 15 mg/kg (6 times/week x 3 weeks) of 5-FU significantly improved the survival of mice bearing MKN-45-P. 5-FU concentration of ascites after ip administration of 30 mg/kg of 5-FU was 600-fold higher than po administration of 12 mg/kg of TS-1 at peak level. ip injections of docetaxel of 8 mg/kg, and 2 mg/kg improved the survival of 4 and 1 mice, respectively, and they were tumor-free on day 90. Survival of mice treated with ip injection of CBDCA (100 mg/kg, on day 3, or 50 mg/ kg on day 3 and 10) was significantly better than the control group. These results suggest the potential of po TS-1 + ip CDDP, ip 5-FU, ip docetaxel and ip CBDCA administration for the treatment of peritoneal dissemination of gastric cancer.     

A case of recurrent gastric cancer with peritoneal dissemination successfully treated over 1 year 8 months with combined chemotherapy of paclitaxel and TS-1

We report a case of gastric cancer with peritoneal recurrence that responded to chemotherapy with paclitaxel and TS-1. A 62-year-old woman, who underwent total gastrectomy for advanced gastric cancer 2 years and 6 months ago, was admitted to our hospital with a chief complaint of abdominal distention and intestinal obstruction due to a large amount of ascites. Cytology of ascites revealed peritoneal dissemination, and chemotherapy with bi-weekly paclitaxel (90 mg/body) was begun. Clinical symptoms, including ascites and intestinal obstruction, were improved only after the second administration of paclitaxel. As she was able to take food orally, she was placed on combined chemotherapy consisting of tri-weekly paclitaxel (9 0 mg/body-120 mg/body: day 1) and TS-1 (80 mg/day: day 1-14) and 1 or 2 weeks rest. The patient had no signs or symptoms of peritoneal metastasis or toxicity except for general fatigue and watery eyes 1 year and 8 months after the diagnosis of peritoneal metastasis. Paclitaxel and TS-1 therapy was thought to be an effective chemotherapy against recurrent gastric cancer with peritoneal dissemination.     

A case of gastric cancer with peritoneal recurrence which developed during adjuvant administration of TS-1 showing complete response by weekly docetaxel regimen

A 62-year old man had undergone total gastrectomy for Borrmann type 4 gastric cancer. No peritoneal dissemination was observed at the laparotomy. Pathological examination revealed that the tumor involved the subserosal layer, and that the lymph node metastasis extended to the left gastric nodes. Vascular and lymphatic involvement was also observed. One hundred mg/body of TS-1, an oral 5-fluorouracil (5-FU) anticancer agent, which consisted of tegafur (a prodrug of 5-FU), and two modulators (gimeracil and oteracil potassium) was given from the 16th post-operative day. A course of TS-1 consisted of consecutive administration for 4 weeks followed by 2 weeks rest. The patient complained of abdominal fullness after administration of the second course of TS-1. Computed tomography (CT) revealed massive ascites. The serum carcinoembryonic antigen (CEA) titer was elevated to 13.5 ng/ml. From these findings, the occurrence of peritoneal dissemination was suspected. Weekly docetaxel of 30 mg/m2 (40 mg/body) was given for 3 weeks followed by a week cessation. At the start of the 6th course, the serum CEA was normalized, and CT scan detected the disappearance of ascites without any new lesion. Administration of docetaxel was continued until the 10th course then stopped without relapse of the disease. No dose reduction or postponement of administration were required. The patient has survived without disease one year after cessation of the treatment. Weekly docetaxel is a safe and effective regimen for gastric cancer worth using for a second-line therapy after failure of the 5-FU-based regimen.     

Two cases of advanced and recurrent gastric cancer responding markedly to TS-1/CDDP therapy

Case 1: A 77-year-old woman with advanced gastric cancer and peritoneal dissemination was treated with TS-1/CDDP therapy. TS-1 (100 mg/day) was orally administered for 21 days and CDDP (70 mg/body) was administered intravenously on day 8. After 2 courses reduction in size of the primary carcinoma was observed (PR). The duration of the PR and the survival time were over 1 year and 6 months. Case 2: A 77-year-old woman with recurrent abdominal and liver metastasis from advanced gastric cancer was treated with TS-1/CDDP therapy. TS-1 (100 mg/day) was orally administered for 21 days and CDDP (80 mg/body) was administered intravenously on day 8. The reduction was judged to be CR for the liver metastasis and PR for the abdominal tumor (total judgment: PR). The duration of the PR and the survival time were over 1 year and 5 months. It is suggested that TS-1/CDDP chemotherapy is useful for advanced and recurrent gastric cancer.     

Two cases of gastric cancer with peritoneal dissemination that responded to TS-1 without progression or recurrence for over 3 years

for over 3 years. A 67-year-old woman underwent distal gastrectomy for advanced gastric cancer. Histological examination of several nodules in the posterior gastric wall led to suspicion of peritoneal dissemination. Low-dose FP treatment was performed for only 5 days after surgery. Peritoneal dissemination was diagnosed at the time of surgery for postoperative abdominal hernia 20 months after the gastrectomy. TS-1 was administered postoperatively, and recurrence or progression has not been detected for 3 years 4 months. Another patient, a 68-year-old woman,underwent distal gastrectomy for advanced gastric cancer with multiple lymph node metastasis and peritoneal dissemination. TS-1 was administered after surgery, and no recurrence or progression has been detected for 3 years and 7 months. These cases suggest that TS-1 is a promising treatment for gastric cancer with peritoneal dissemination.     

A case of peritoneal dissemination of gastric cancer successfully treated by irinotecan combined with cisplatin

We report a case of a 59-year-old man with advanced gastric cancer. Distal gastrectomy with lymph node dissection (D1) was performed. Pathological staging was IV (T3N1CY1), and the operation resulted in curability C. The serum CA19-9 level before the operation was 201 U/ml, and it did not normalize 3 months after the operation. Postoperative chemotherapy (TS-1, 100 mg/day) was performed. Because the tumor markers such as CEA and CA19-9 level elevated 5 months after the operation, triweekly docetaxel therapy and TS-1 administration (days 1-14) were performed. We disbontinued this therapy after 2 courses due to adverse reactions, such as leukopenia (grade 4) and liver dysfunction (grade 2). Peritoneal dissemination was diagnosed by the appearance of ascites and thickness of the peritoneum 11 months after the operation. So the patient was treated with a biweekly combination chemotherapy of irinotecan (CPT-11 60 mg/m2) and cisplatin (CDDP 30 mg/m2). Eight courses of this therapy induced partial remission and normalization of the serum CEA level. No major adverse reaction to this therapy was observed. The partial remission and good patient's QOL were achieved during follow-up 7 months after the administration of CPT-11 plus CDDP. This case suggests that patients with recurrent peritoneal dissemination of gastric cancer could benefit from CPT-11 with CDDP combination therapy as a second-line or third-line treatment.     

A resected case of advanced gastric cancer after treatment with low-dosage TS-1

We report a case of advanced gastric cancer that responded well to low-dosage TS-1. A 72-year-old woman was diagnosed as having unresectable advanced gastric cancer with ascites and hydronephrosis in the right kidney. She was treated with chemotherapy using a low-dosage of TS-1 (80 mg/body/day) administered perorally for 4 weeks followed by a drug-free 2 weeks, in six-week cycles. However, she developed weight loss, appetite loss, and stomatitis. We therefore reduced the dosage of TS-1 from 80 mg/body/day to 60 mg/body/day. The ascites and hydronephrosis gradually improved during the following 3 months, whereupon she could undergo total gastrectomy. The postoperative findings showed no ascites and no peritoneal dissemination. The postoperative pathological findings showed that the cancer cells were localized to within the mucosa, and there were no cancer cells in the greater and lesser omentum. Three weeks after the operation, TS-1 was resumed at 60 mg/body/day. However, 3 months later,ascites and metastasis to the abdominal skin developed, and she died 9 months after the operation.     

Id proteins in neural cancer

The effect of intraperitoneal (i.p.) administration of docetaxel was evaluated for preclinical evidence of anticancer activity in athymic mice bearing a gastric cancer cell line, MKN-45-P that shows a high rate of metastasis to the peritoneal cavity of nude mice. Nude mice were inoculated i.p. with 10⁷ MKN-45-P cells. On days 2, 5, 9, 12, 16 and 19 after tumor inoculation, mice were treated with i.p. injection of docetaxel. Treatment doses of docetaxel were 8 mg/kg (N=7), 2 mg/kg (N=7) and 0.5 mg/kg (N=7). Intraperitoneal carcinoembryonic antigen (CEA) levels, animal body weight, mortality and survival were determined. All control mice developed ascites and died within 19–40 days. The median survival time in the control group was 32 days, while those of mice treated with 8, 2 and 0.5 mg/kg were 90, 63 and 49.5 days, respectively. One of seven mice treated with 8 mg/kg of docetaxel died of toxicity on day 12. Four mice were tumor-free on day 90, but two had tumors in the abdomen when autopsied on day 90. One mouse treated with 2 mg/kg was ascertained to be tumor-free on day 90. All seven mice treated with 0.5 mg/kg of docetaxel died of peritoneal dissemination within 71 days. The results suggest the potential of intraperitoneal docetaxel administration for the treatment of peritoneal dissemination of gastric cancer.     

The clinical effect of TS-1 in advanced and recurrent gastric cancer with peritoneal dissemination

Eighteen patients with far advanced and recurrent gastric cancer with peritoneal dissemination were treated with a novel oral anticancer drug, TS-1, and assessed according to clinical effect. TS-1 was administered at a dose of 80-120 mg/day. One course consisted of consecutive administration of TS-1 for 28 days followed by 14 days rest. The 1- and 2-year survival rates and median survival time after administration of TS-1 were 63.2%, 23.7% and 437 days, respectively. Eight patients (44.4%) survived for 1 year or more. Adverse reactions consisted of reduction in hemoglobin level and hyperbilirubinemia at grades 3 and 4, which were observed in 3 patients and 1 patient, respectively. TS-1 is a promising drug for gastric cancer with peritoneal dissemination.     

Unusual survival for more than 2 years with peritoneal metastases of gastric cancer

We report a patient with peritoneal metastases who was successfully treated with a novel oral fluoropyrimidine anticancer drug, TS-1, as first-line chemotherapy. The patient was a 72-year-old man who had undergone curative resection for type 4 gastric cancer with peritoneal dissemination that was located only at the greater omentum. Final findings were P1, T4, N1, and stage IV. Eighteen months after the gastrectomy, his cancer recurred with peritoneal metastases; these were diagnosed by the presence of multiple stenoses of the colon, an abdominal mass, and elevated levels of the serum tumor markers, carcinoembryonic antigen (CEA) and carbohydrate antigen (CA)19-9. He was treated with 100 mg/day of TS-1, given orally, for 28 days, followed by 14 days' rest, as one course. Two courses of the treatment resulted in a marked reduction of the abdominal tumor, without severe toxicity. After 3 courses, barium enema revealed dramatic improvement in the stenoses. Laparoscopy after 11 courses showed neither peritoneal dissemination, nor ascites, and peritoneal lavage cytology was negative. The serum tumor markers were reduced to almost normal levels. Two years after the onset of the peritoneal metastases, the patient is alive without any sign of progressive disease. Our report is the first to demonstrate the advantages of TS-1 as chemotherapy for the treatment of peritoneal metastasis of gastric cancer. Received: August 23, 2001 / Accepted: December 7, 2001     

A case of advanced gastric cancer with peritoneal dissemination effectively treated by combined chemotherapy of paclitaxel (TXL) and TS-1

The patient was a 49-year-old woman. Chemotherapy was conducted combining paclitaxel (TXL) and TS-1 under the diagnosis of non-resectable advanced gastric cancer with peritoneal dissemination. The administration schedule was as follows: 60 mg/m2 of TXL on days 1, 8 and 15 intravenously and 120 mg/day of TS-1/on days 1 5, 8-12, and 15-19 orally. One cycle lasted for 5 weeks. Grade 1 peripheral neuropathy was noted, but no other serious adverse reaction occurred. Ascites fluid was reduced after completion of the 1st cycle, and the therapeutic efficacy was rated as PR. Abdominal fullness was relieved shortly after starting the treatment, making it possible to conduct treatment on an ambulatory basis in the 2nd and subsequent cycles. At present, 6 months after starting chemotherapy, there is no evidence of relapse or adverse reactions that require intervention. Chemotherapy is being continued on an ambulatory basis. Combination of TXL and TS-1 is expected to show good therapeutic efficacy and improve patients' QOL in patients with gastric cancer associated with peritoneal dissemination.     

A case of hepatic metastasis of gastric cancer responding to TS-1, administered for two consecutive weeks and one week rest

We have treated a case of hepatic metastasis of gastric cancer that has responded well to TS-1. The patient was a 68-year-old male, who underwent distal gastrectomy for gastric cancer. After surgery 5'-deoxy-5-fluorouridine (5'-DFUR) 800 mg/day was administered orally for two months. Grade 4 diarrhea appeared, so administration of 5'-DFUR was discontinued. Afterward the patient was followed with no chemotherapy. Liver metastasis (S6, 3 cm in diameter) was found at twelve months after surgery. 5'-DFUR (800 mg/day) was administered orally everyday. Grade 3 diarrhea appeared and metastasis showed NC after four weeks. 5'-DFUR administration was discontinued. Seventeen days later TS-1 (80 mg/day) was administered orally everyday for 2 weeks, followed by 1 week rest, as one course. Two courses of TS-1 administration resulted in a marked reduction of the liver metastasis, for a PR (75% reduction). After 3 courses, the liver metastasis showed CR. The patient is alive without recurrence after 12 courses. This TS-1 administration regimen was effective and tolerable for a patient with liver metastasis from gastric cancer.     

Multicenter phase II study of S-1 and docetaxel combination chemotherapy for advanced or recurrent gastric cancer patients with peritoneal dissemination

Purpose

Peritoneal dissemination is the most frequent and life-threatening mode of metastasis and recurrence in patients with gastric cancer. A multicenter phase II study was designed to evaluate the efficacy and tolerability of S-1 and docetaxel combination chemotherapy regimen for the treatment of advanced or recurrent gastric cancer patients with peritoneal dissemination.

Methods

Nineteen patients with histologically confirmed unresectable or recurrent gastric cancer with peritoneal dissemination were enrolled. Oral S-1 at 80 mg/m²/day was administered twice daily for 2 weeks, followed by 1 drug-free week. Docetaxel infusion at 40 mg/m² was performed on day 1, simultaneous with S-1 administration. The primary endpoints were overall survival (OS) and time to progression (TTP). The secondary endpoints were the response rates and safety status.

Results

Patients received a median of 4 cycles of the S-1 and docetaxel regimen (range 1–43). The disease control rate was 73.7 % (14/19). Median overall survival was 459 days (15.3 months), while median time to progression was 212 days (7.1 months). Neutropenia was the most common type of toxicity (n = 7, 36.8 %).

Conclusions

Combination chemotherapy with S-1 and docetaxel is a tolerable and effective treatment for advanced or recurrent gastric cancer patients with peritoneal dissemination.     

A case of stage IV gastric cancer treated sequentially for over two years by TS-1, paclitaxel, and CPT-11

We report a patient with advanced stage IV gastric cancer treated by chemotherapy for over two years. The patient was a 69-year-old man with paraaortic lymph node metastasis of gastric cancer. He underwent a distal gastrectomy in non-curative resection. After surgery, chemotherapy with TS-1 (100 mg/body/day) was performed. At 7 months after surgery, progression of lymph node metastasis in porta hepatis was recognized, and paclitaxel was administered at a weekly dose of 80 mg/m(2) for 3 weeks followed by one week rest. He remained stable for 12 months under paclitaxel treatment. At 26 months after surgery, progression of lymph node metastasis in porta hepatis was recognized again, and CPT-11 was administered at a bi-weekly dose of 80 mg/m(2). Although the patient died two years seven months after surgery, the chemotherapy with sequential administration of TS-1, paclitaxel and CPT-11 was thought to be effective for advanced gastric cancer.     

A case of recurrent gastric cancer effectively treated by combined chemotherapy of weekly paclitaxel (PTX) and CDDP

The patient was a 63-year-old man who underwent distal gastrectomy for advanced gastric cancer with lymph node metastasis and peritoneal dissemination. One year and eleven months after the operation,an increasing CA 19-9 concentration and metastases to the liver and peritoneum were observed. Oral TS-1 was given, but had to be discontinued because of anorexia and nausea. Chemotherapy consisting of paclitaxel (PTX) and CDDP was performed. PTX (80 mg/body) was administered weekly on day 1, 8 and 15, while CDDP (50 mg/body) was administered weekly on day 1 as one cycle. After two cycles of PTX/CDDP administration,metastases to the liver and peritoneum were not detected. The patient was treated with five courses of PTX/CDDP and survived without recurrence as of this writing. PTX/CDDP was associated with few adverse events in hospital visits, and thought to be an effective chemotherapy against recurrent gastric cancer.     

Three cases of recurrent gastric cancer responding to TS-1 therapy following combination therapy with 5-fluorouracil,mitomycin C and cisplatin

We report three patients with recurrent gastric cancer responding to TS-1 therapy after combination chemotherapy with 5-fluorouracil, mitomycin C and cisplatin. All 3 cases had undergone total gastrectomy with lymphadenectomy for advanced gastric cancer. Postoperative follow-up computed tomography (CT) showed liver metastases (cases 1 and 3), peritoneal dissemination (case 2) and enlargement of paraaortic lymph nodes (case 1) due to cancer recurrence. After 2 to 4 courses of combined treatment with 5-fluorouracil (500-750 mg/body/day, days 1-5, civ), mitomycin C (6-8 mg/body, day 6) and cisplatin (60-80 mg/body, day 7), CT revealed considerable reduction of the metastatic tumors. Subsequently oral administration of TS-1 (80-100 mg/body/day) for 4 weeks was performed. All 3 patients are well without any signs of increase in tumor size.     

A case of metastatic gastric cancer responding to weekly administration of paclitaxel as a second-line therapy

We report a 65-year-old man who underwent distal gastrectomy for advanced and metastatic gastric cancer in June 2000. TS-1 was administered for remnant metastatic lesions as first-line chemotherapy, but a recurrence was found in June 2001. Paclitaxel 80 mg/m2 was then administered weekly in a 1-h infusion on day 1, 8, and 15 as one cycle. After two cycles of paclitaxel administration, the patient was relieved from abdominal pain, and a barium enema revealed marked improvement of the colonic stenosis due to the peritoneal metastasis. There have been few effective chemotherapeutic agents against peritoneal metastasis from gastric cancer to date; however, a weekly paclitaxel regimen is considered to be one of the promising regimens for metastatic and recurrent gastric cancer.     

A case of gastric cancer with metastasis to cervical lymph nodes and pulmonary lymphangitis carcinomatosa responding to neoadjuvant chemotherapy with TS-1 and CDDP

The patient was a 61-year-old man who had gastric cancer with metastasis to cervical lymph nodes and pulmonary lymphangitis carcinomatosa. He received daily oral administration of 120 mg of TS-1 (day 1-21) and systemic administration of 100 mg of CDDP (day 8) as one treatment course. As the metastatic lesions had disappeared after chemotherapy, he underwent total gastrectomy. Histopathological examination of resected regional lymph nodes revealed marked fibrosis and a small amount of scattered cancer cells. Although much peritoneal dissemination was observed macroscopically, histopathological examination of these tumors revealed only fibrosis with no cancer cells. These findings supported the effect of this neoadjuvant chemotherapy. He died of recurrence of the carcinoma 203 days after surgery, without any sign of recurrence of metastasis to cervical lymph nodes or pulmonary lymphangitis carcinomatosa.     

Long survival and effective treatment of unresectable gastric cancer by TS-1 based chemotherapy with a sequential combination

We report a case of peritoneal cancer dissemination and cytological appearance of cancer cells with Type 4 gastric cancer. Treatment with unichemotherapy and combination chemotherapy with TS-1 proved successful. The patient was a 58-year-old female,who complained of abdominal pain. She was diagnosed as unresectable Type 4 gastric cancer, T 3 NxH 0 P 1 CY 1 M 0, Stage IV (cytology: Class V). Thirteen days after surgery, chemotherapy with TS-1 (80 mg/body/day, 4 weeks) at 2-week intervals in 1 course was performed. However, due to side effects with marrow restraint of grade 1, we changed to the following chemotherapy regimen: TS-1 (80 mg/body/day, 2 weeks) at 4-week intervals as 1 course (23 courses in total). After 16 courses, a partial response (PR) was noted. As additional therapy to recover tumor marker (CA19-9) after 21 courses, combination chemotherapy with TS-1 (80 mg/body/day, 2 weeks) and CDDP (25 mg/body/day, day 1, 8, 15 drip infusion) was performed as one course. This chemotherapy was then performed in 3 courses and tumor markers did not deteriorate, so we changed docetaxel (DOC) (50 mg/body/day(day 1)) to CDDP, and tumor markers returned to the normal value. No recurrence and no side effects appeared (hematological or non-hematological) during this combination chemotherapy.     

A case of recurrent gastric cancer tolerant to TS-1 therapy successfully treated by TS-1 combined with docetaxel

We report a case of a 58-year-old man with advanced gastric cancer producing sialyl-Tn antigen (STN). Total gastrectomy with distal pancreatectomy and splenectomy was performed. Pathological staging was IV (T 3 N 2 CY1), and most of the cancer cells were strongly positive for anti-STN antibody on immunohistochemical stainings. Serum STN level before the operation was 2,500 U/ml, and the value significantly decreased to the normal range (< 45 U/ml) 2 months after the operation. Low-dose FP (5-FU+CDDP) followed by TS-1 alone (80 mg/day) had been performed as adjuvant chemotherapy. Jaundice appeared and the serum STN level increased again 22 months after the operation. He was diagnosed with a recurrence in the hilar lymph node of the liver. After implantation of expandable stent in the common bile duct, triweekly docetaxel therapy with TS-1 administration (day 1-14) has been performed. Three courses of this therapy have induced a complete response of the recurrent lymph node and the normalization of the serum STN value. No major adverse reaction to this therapy was observed. A complete response and good patient QOL have been achieved during follow-up 8 months after the administration of TS-1 with docetaxel. This case suggests that patients with recurrent gastric cancer who have undergone prior therapy with TS-1 alone could benefit from TS-1 with docetaxel therapy as a second line.