A case of TS-1 resistant recurrent gastric cancer with lung metastasis responding to TS-1 and irinotecan combination therapy

We report a case of TS-1-resistant recurrent gastric cancer with lung metastasis responding to TS-1 and irinotecan (CPT-11) combination therapy. A 72-year-old man underwent total gastrectomy with pancreaticosplenectomy for advanced gastric cancer on October 18, 2001, and partial hepatectomy for postoperative liver metastasis on August 22, 2002. In March 2004, a chest computed tomography scan revealed metastatic lesions in the bilateral lungs, and he received a single administration of TS-1, resulting in partial response. After 13 courses, this therapy was discontinued due to progressive disease. Then,TS-1 and CPT-11 combination therapy was chosen as the second-line chemotherapy. After 4 courses, a partial response was obtained in lung metastasis, and thereafter has been maintained. He has been treated on an outpatient basis because of no grade 3 or severer adverse reactions. TS-1 and CPT-11 combination therapy could be a promising regimen as the second-line chemotherapy for gastric cancer resistant to TS-1.     

Chemotherapy for gastric cancer

5-FU has been a key chemotherapeutic agent in the treatment of advanced or recurrent gastric cancer. In order to enhance the effect of 5-FU, biochemical modulation or combined chemotherapy has been developed. Although several phase III studies have been reported in 1990's, a standard chemotherapeutic regimen has not been established worldwide. Recently, newly developed anticancer agents such as CPT-11, TS-1, Paclitaxel, or Docetaxel can be clinically used for advanced gastric cancer either single agent or in combination that may further improve the quality of life and prolong the survival of patients with gastric cancer. In Japan, postoperative adjuvant chemotherapy has been actively developed to enhance survival benefit of surgery for patients with gastric cancer. There were a few positive single randomized controlled study showing benefit of adjuvant chemotherapy with a high evidence level. However, all reports of meta-analysis of adjuvant chemotherapy for gastric cancer indicated the survival benefit of adjuvant chemotherapy. At present, a nation-wide randomized controlled study in the postoperative adjuvant setting for gastric cancer using TS-1 (ACTS-GC) is under way that may clarify the effect of postoperative adjuvant chemotherapy in gastric cancer.     

A case of advanced gastric cancer with lymphangitis carcinomatosa after operation of Krukenberg tumor treated by TS-1 plus CPT-11 as third-line chemotherapy

Chemotherapies for recurrent gastric cancer have not yet been established. Here we report a case of type 4 gastric cancer associated with lymphangitis carcinomatosis which became refractory to the previous chemotherapies. The case was a 40-year-old woman. She had been diagnosed with gastric cancer after a Krukenberg tumor operation. Chemotherapies (TS-1 plus CDDP as first-line, and TS-1 plus taxanes as second-line) were performed, and a partial response was achieved. Disease activity has been well controlled until this time. Since recurrence of left pleural effusion and lymphangitis carcinomatosis was recognized, we changed the chemotherapy TS-1 plus CPT-11. Pleural effusion decreased and lymphangitis carcinomatosis improved. The serum CA 19-9 level rose transiently after CPT-11 administration, and tended to fall at the second week of chemotherapy. However, the patient died 2 years 4 months after the onset. TS-1 plus CPT-11 combination chemotherapy would be effective for lymphangitis carcinomatosis and also useful as third-line chemotherapy for recurrent gastric cancer.     

Combination chemotherapy of S-1 +CPT-11 (q 4-5 w) for metastatic gastric cancer

The effectiveness of systemic chemotherapy for metastatic gastric cancer has already been established. However, a standard chemotherapy still remains uncertain. New agents such as S-1, CPT-11 and taxanes are markedly improving the response rates for gastric cancer. Including these new drugs, several randomized phase III trials are ongoing in Japan. In the near future, the candidate for standard regimen to treat gastric cancer will be reported. In this article, we described the current state of S-1 +CPT-11 combination chemotherapy for gastric cancer. Among various CPT-11 based chemotherapy, S-1 +CPT-11 appears to be the most effective and less toxic treatment.     

A case of TS-1 resistant recurrent gastric cancer responding to TS-1 +CPT-11 combination therapy

A 71-year-old man underwent distal partial gastrectomy for gastric cancer. Four years after surgery, the tumor marker was elevated. Examinations by computed tomography (CT) revealed para-aortic lymphnode swelling and hydronephrosis. The patient treated oral administration of TS-1 (120 mg/day). After 3 courses of treatment of TS-1, progressive disease was observed. TS-1+CPT-11 (TS-1 120 mg/day day 1-14, CPT-11 100 mg/day day 1, 15) combination therapy was then chosen as second-line chemotherapy. After 5 courses of combination therapy, the tumor marker was decreased and para-aortic lymphnodes could not be detected by CT. Only grade 2 leukopenia was observed as an adverse event during the therapy. TS-1+CPT-11 combination therapy could be useful as the second-line chemotherapy for cases of TS-1 resistant recurrent gastric cancer.     

Current evidence of irinotecan combination chemotherapy with TS-1 in patients with advanced colorectal cancer

A combination of irinotecan (CPT-11) with continuous intravenous infusions of (infusional) 5-fluorouracil (5-FU) and Leucovorin (LV) is one of the standard treatments for advanced colorectal cancer patients. However, recent concerns about safety and convenience have prompted the development of new oral fluoropyrimidine derivatives and improved regimens. TS-1, the oral fluoropyrimidine widely used in the treatment for gastric cancer, was approved for advanced colorectal cancer. Recently, several phase I/II studies assessed the efficacy and safety of combined treatment with TS-1 plus CPT-11 in patients with advanced colorectal cancer. These results showed that TS-1 plus CPT-11 was very effective. Toxicity was generally mild and manageable on an outpatient basis. Current evidence showed that a combination of CPT-11 plus TS-1 was more convenient and easier to administer than a combination of CPT-11 plus infusional 5-FU and LV. It is essential to prove that the combination of TS-1 plus CPT-11 can replace the combination of infusional 5-FU and LV plus CPT-11 without negatively affecting efficacy and toxicity.     

A case of advanced gastric cancer with long-term survival treated by chemotherapy and surgical cytoreduction

A 74-year-old man was revealed to have type 3 gastric cancer with lymph-node metastasis in the third group (N 3) and liver metastasis (H 1). Since we regarded a curative operation as impossible, we started preoperative chemotherapy using TS-1 plus irinotecan hydrochloride (CPT-11) on the premise that we would perform surgical cytoreduction after the chemotherapy. After two courses of chemotherapy, both the primary lesion and the liver metastasis were reduced in size, and the paraaortic lymph-nodes disappeared. Subsequently, a distal gastrectomy (D 0, curability C) was performed. The patient has been receiving postoperative chemotherapy using TS-1 and paclitaxel as an outpatient for 2.3 years. Although there is not enough evidence to support the benefit of surgical cytoreduction, chemotherapy combined with surgical cytoreduction would improve the survival time without deterioration of quality of life (QOL) in patients with advanced gastric cancer. This combined therapy should be considered as one of the promising strategies for advanced gastric cancer.     

Complete response of recurrent gastric cancer to chemotherapy with TS-1 and CPT-11--a case report

A 58-year-old man with gastric cancer who had undergone distal gastrectomy on February 8, 2001 was revealed to have anorexia, and was diagnosed with a local recurrence in anastomosis by upper GI examination in August 2003. In September 2003, he was given combination chemotherapy with TS-1 50 mg/m2 (days 1-14) and CPT-11 80 mg/m2 (days 1, 8) every 3 weeks. A complete response (CR) was confirmed by endoscopy in December 2003. At present, he has been receiving chemotherapy with only TS-1 50 mg/m2 as a maintenance therapy and continuing CR. However, a trial of combination therapy with TS-1 plus CPT-11 is ongoing, and this combination chemotherapy may well achieve a high response rate. Because the adverse events of this chemotherapy have been mild and tolerable in some of our cases, this regimen is considered very useful.     

A case report of bowel obstruction due to peritonitis carcinomatosa using combined administration with CPT-11 and CDDP

We report here a case of recurrent gastric cancer that responded to third-line chemotherapy with CPT-11 and CDDP. The patient was a 61-year-old man with recurrent gastric cancer, who had administered TS-1 for first-line chemotherapy and paclitaxel for second-line chemotherapy. After such therapy, bowel obstruction was revealed due to peritoneal dissemination. The patient underwent third-line chemotherapy with CPT-11 and CDDP after drainage of gastrointestinal juice by nasogastric tube. The treatment schedule for CPT-11 and CDDP therapy consisted of CPT-11 60 mg/m2 div at day 1, day 15 and CDDP 60 mg/m2 div at day 1. It was repeated every 4 weeks. After first administration, the bowel obstruction was improved, so the treatment was continued for 8 months on an outpatient basis. These findings imply that this treatment can be a useful second-line or third-line chemotherapy for unresectable advanced or recurrent gastric cancer.     

Effectiveness of chemotherapy for outpatients with gastric or colorectal cancer

We retrospectively evaluated the efficacy of chemotherapy regarding symptom control, toxicity and discharge rate in 39 patients with gastric or colorectal cancer. Treatment consisted of TS-1 (n = 16), TS-1 + CPT-11 (n = 8), CDDP + CPT-11 (n = 5), paclitaxel (n = 8) and MTX + 5-FU (n = 4) for gastric cancer and 5-FU + l-leucovirin (n = 6), 5-FU + CPT-11 (n = 5), MMC + CPT-11 (n = 8) and 5-FU protracted continuous infusion (n = 5) for colorectal cancer. The rates of symptom improvement were the following: pain 60% (10/15), general fatigue 56% (5/9) and abdominal fullness 53% (8/15). 87% (34/39) of the patients were discharged from hospital and continued chemotherapy as outpatients grade 3 toxicities were the following: anemia 10.3%, nausea and/or vomiting 7.7%, diarrhea 5.1%. There was no treatment related death. The rates of outpatient based treatment duration improvement were the following: gastric cancer: 47.6%, colorectal cancer: 72%. These data suggest that these treatments for gastric and colorectal cancer are safe and improve the patients' QOL.     

A case of non-curatively resected gastric cancer successfully treated over 17 months with TS-1 and irinotecan combination therapy

We report a case of non-curatively resected gastric cancer successfully treated with TS-1 and irinotecan (CPT-11) combination therapy, resulting in long-term survival of 17 months. A 56-year-old woman underwent noncurative resection with total gastrectomy for advanced gastric cancer with severe lymph node metastasis on June 3, 2004. Postoperatively, She received TS-1 and CPT-11 combination therapy (TS-1 80 mg/m(2) day 1-21, CPT-11 80 mg/m(2) day 1, 15, every 5 weeks). However, due to grade 4 neutropenia, and grade 3 nausea and anorexia in the first course, both doses were reduced. Since then, no grade 3 or severer adverse reactions have been observed. After 5 courses, partial response to lymph node metastasis was obtained, and her quality of life was improved. Thus, TS-1 and CPT-11 combination therapy has been effective for 17 months, suggesting that it is promising for long-term administration and survival to continue it perseveringly.     

A case of gastric cancer presenting with obstructive jaundice and responding to biweekly CPT-11 and CDDP combination administration

A 74-year-old man was suffering from Borrmann type 2 advanced gastric cancer with abdominal lymph node metastases and multiple lung metastases. He started to undergo outpatient treatment with oral administration of TS-1. But pyloric stenosis was found after 6 courses of TS-1 chemotherapy, so he underwent palliative distal gastrectomy. TS-1 chemotherapy was continued afterwards, however obstructive jaundice was found. So combination chemotherapy of CPT-11 60 mg/m(2)and CDDP 30 mg/m(2)biweekly was selected as a second-line therapy after PTCD. As no side effects were found, he could be treated on an outpatient basis by CPT-11 60 mg/body and CDDP 30 mg/body biweekly. Four months has passed since the palliative operation, and the PTCD tube was successfully removed. The abdominal lymph nodes had decreased in size and the patient has maintained good QOL. Thus, combination CPT-11 and CDDP therapy could well be a new candidate for a second-line chemotherapy in outpatients.     

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 randomized phase II clinical trial of tailored CPT-11 + TS-1 vs TS-1 in patients with advanced or recurrent gastric carcinoma as the first-line chemotherapy (JFMC31-0301)

The Japanese Foundation for Multidisciplinary Treatment of Cancer (JFMC) has designed and initiated a randomized Phase II clinical trial planned as a first-line of chemotherapy for advanced or recurrent gastric cancer. The trial focuses on two groups and selecting the better of two regimens. The first group was given tailored CPT-11, adjusting individual optimal dosage using toxicity-based grading as an index in combination with TS-1, and the second group was given standard TS-1 treatment. The aim of this tailored dosage regimen for each individual patient is to continue chemotherapy as long as possible, and eventually, to prolong survival. In this trial, subsidiary pharmacokinetics analysis for the tailored arm is also proposed. We would like to introduce the significance and theory of tailored dosage chemotherapy in this paper.     

Combination chemotherapy for gastric cancer including LV/5-FU

LV (l-LV)/5-FU therapy has been used broadly and is considered to be a standard treatment for large bowel cancer due to an enhancing therapeutic effect of 5-FU. According to recent clinical study reports on large bowel cancer in Europe and the United States, various administration methods of LV/5-FU with a combination of other drugs have been devised. It appeared that 5-FU used together in bolus and continuous infusions have yielded outstanding results. Although the basis of combination therapy for gastric cancer seemed to be LV/5-FU, there were many reports on TS-1 combined with other drugs because the oral medicine TS-1 was domestically available for the past one or two years. Currently, controlled randomized trials of LV/5-FU therapy and TS-1 have been ongoing. However, when patients cannot take oral intakes, LV/5-FU therapy is important. It seems that LV/5-FU therapy in combination with other drugs, in particular, CDDP, CPT-11, paclitaxel, docetaxel, oxaliplatin, and ETP will be given as candidates for the standard treatment of gastric cancer.     

A case of advanced gastric cancer with liver metastasis completely responding to CPT-11+low-dose 5-FU+CDDP chemotherapy

The case was a 54-year-old man with type-3 gastric cancer in the cardia accompanied by multiple liver metastasis. He received combination chemotherapy consisting of CPT-11 (60 mg/body, day 1 and 8)+low-dose 5-FU and CDDP (5-FU 500 mg/body/day and CDDP 5 mg/body/day, day 1-5 and 8-12, continuous infusion) every 3 weeks. The initial 2 courses were administered on an inpatient basis,and further courses as an outpatient. After 7 courses of therapy without severe adverse events, not only primary lesion but also hepatic metastasis disappeared. He has been free from disease for 4 months, and chemotherapy was further continued with TS-1 (100 mg/body, day 1-14)+CPT-11 60 mg/body, day 1, 8), every 3 weeks. CPT-11 in combination with low-dose 5-FU+CDDP can be one of the most effective regimens for unresectable advanced gastric cancer.     

State of the treatment for gastrointestinal cancer

We reviewed the results of chemotherapy for gastrointestinal cancer. In Western countries, FAMTX or ECF is recognized as the standard therapy for gastric cancer. In Japan, no standard chemotherapeutic regimen has been established yet, but FP or MTX/5-FU are often used as a first line chemotherapy. There have been only a few clinical trials of adjuvant chemotherapy for gastric cancer in which this regimen was identified as having a statistically significant effect. For colon cancer, 5-FU plus LV are now used as the standard therapy. Recently, however, it has been shown that 5-FU + LV combined with CPT-11 is more active than 5-FU + LV alone. The efficacy of oral anticancer agents such as UFT + LV, S-1, and capecitabin have also been shown to be equally or more active than i.v. administration of 5-FU and LV, so that the standard therapy for colon cancer will be changed in near future.     

Two cases of advanced and recurrent gastric cancer treated with the combination of chemotherapy and radiation

Recently, new promising anti-tumor agents such as TS-1, taxanes, and CPT-11 have been approved for gastric cancer treatment. These agents showed a better response and may contribute to a patient's survival and quality of life. However, there are cases with advanced and recurrent gastric cancer that are resistive or tolerant to these agents. We report two cases in which the patients had suffered symptomatic local recurrence during the chemotherapy. Consequently, they had been treated with radiotherapy in order to improve their clinical status. We also discuss the significance of radiotherapy in gastric cancer.     

Clinical development of S-1 (TS-1) for advanced gastric cancer

The 5-FU plus cisplatin containing regimen like FP, ECF and DCF, is considered to be the most effective treatment for advanced gastric cancer in the United States, Europe, and Korea. In Japan, oral fluoropyrimidine S-1 (TS-1) is currently considered to be the first candidate as the standard drug for advanced gastric cancer. S-1 based combination therapies with other promising drugs like cisplatin, irinotecan and taxanes, are expected to yield good results. Above all, S-1+CDDP therapy showed a high efficacy and expected to be a standard therapy for advanced gastric cancer. Two large phase III studies, JCOG 9912 5-FU vs S-1 vs CPT-11 +CDDP and S-1 vs S-1+CDDP, are now on going to establish an acceptable frontline standard for patients with AGC. We therefore need to develop new agents and combination chemotherapy regimens to achieve a greater survival benefit in AGC.     

A case of an increase in resectability with preoperative chemotherapy TS-1 combined with CPT-11 for unresectable rectal cancer in downstaging

A 50-year-old woman visited our hospital with a chief complaint of lower abdominal mass. The patient was diagnosed with rectal cancer using colonoscopy and also diagnosed with unresectable rectal cancer because abdominal CT revealed metastases to the liver, lung and lymph node located porta hepatis. The patient was treated with TS-1 combined with CPT-11. The TS-1 (80 mg/m2) was orally administered for 2 weeks and followed by a 2 week interval, and CPT-11 (80 mg/m2) was simultaneously administered biweekly. One cycle of chemotherapy was 28 days. The patient experienced grade 1 leukocytopenia and neutropenia. Abdominal CT revealed partial response after 2 cycles. After 6 cycles, the patient was subjected to curative operation. Pathological efficacy was Grade 1a at lymph node metastasis and Grade 3 at liver metastasis. TS-1 combined with CPT-11 regimen was very feasible and convenient, and obtained a good compliance. So this regimen was promising for unresectable colorectal cancer. In the future, this regimen will be verified in phase III clinical trial and compared with FOLFIRI and FOLFOX regimens.