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.     

CPT-11 combined chemotherapy for metastatic gastric cancer

The effectiveness of chemotherapy for metastatic gastric cancer has been already revealed. But a standard chemotherapy has not been established yet. New agents such as TS-1, CPT-11 and taxanes are improving the response rates and also the survivals for gastric cancer. Including these new drugs, several randomized phase III trials are ongoing in Japan. In the near future, the candidate for standard resume will be sent abroad. In this article, we described the current state of CPT-11 combined chemotherapy for gastric cancer. Among various CPT-11- combined chemotherapy, CPT-11 + TS-1 is the most effective and less toxic treatment.     

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.     

Three successful cases with CPT-11 + CDDP chemotherapy where S-1 failed to respond to recurrent gastric cancer

We report three successful cases with irinotecan (CPT-11 60 mg/m2) + cisplatin (CDDP 30mg/m2) chemotherapy (once in 2 weeks) where S-1 failed to respond to recurrent gastric cancer. Case 1: A total gastrectomy and splenectomy were performed for a cardiac gastric cancer (T3, N2, H0, P0, CY0, por 1, Stage IIIB). An abdominal CT revealed paraortic lymph node metastases 4 months after the surgery. No reductions were noted after S-1 monotherapy. We next treated this patient with CPT-11 + CDDP. An abdominal CT revealed a CRin after 11 courses. Case 2: A total gastrectomy, splenectomy and cholecystectomy were performed for a cardiac gastric cancer (T3, N3, H0, P0, CY1, tub1, Stage IV). After the surgery, we treated this patient with S-1 mono-therapy. However, we finished this treatment for abdominal recurrence. We next treated this patient with CPT-11 + CDDP. An abdominal CT revealed a CR after 24 courses. Case 3: A distal gastrectomy and cholecystectomy were performed for a pyloric gastric cancer (T2, N1, H0, P0, CY0, tub 2, Stage II). An abdominal CT revealed paraortic lymph node metastases 10 months after the surgery. We treated this patient with S-1 + paclitaxel (PTX) chemotherapy. No reductions were noted after 2 courses. We next treated this patient with CPT-11 + CDDP. An abdominal CT revealed a CR after 8 courses.     

Chemotherapy for metastatic disease: review from JCOG trials

The Gastrointestinal Oncology Study Group of Japan Clinical Oncology Group (GIOSG/JCOG) has conducted several clinical trials to establish standard chemotherapy for unresectable or recurrent gastric cancer. From the late 1980s to early 1990s, two phase II studies by JCOG evaluated oral fluoropyrimidines, and others introduced Western chemotherapy regimens. Thereafter, the first phase III study (JCOG9205), comparing 5-fluorouracil (5-FU), 5-FU plus ciplatin (CDDP) (FP), and uracil and tegafur (UFT) plus mitomycin (UFTM), could not show a survival benefit of either FP or UFTM over 5-FU alone. In the late 1990s, new active agents such as irinotecan (CPT-11) and S-1 (new oral fluoropyrimidine) showed promising results in their phase II trials. The latest phase III study (JCOG9912), comparing 5-FU, CPT-11 plus CDDP, and S-1, showed significant noninferiority of S-1 to 5-FU in overall survival, associated with a better response rate and progression-free survival and acceptable toxicities, and concluded that S-1 should be considered for the standard chemotherapy of unresectable or recurrent gastric cancer. Simultaneously, another Japanese phase III trial comparing S-1 with S-1 plus CDDP showed a survival benefit of S-1 plus CDDP. At present, S-1 plus CDDP is recognized as standard chemotherapy for unresectable or recurrent gastric cancer, and new treatment with molecular target agents is under development.     

A case of advanced gastric cancer responding remarkably to neo-adjuvant combination chemotherapy using CPT-11 plus S-1

Adjuvant chemotherapy for advanced gastric cancer has not yet been established. We report a patient with advanced gastric cancer responding remarkably to neo-adjuvant combination chemotherapy consisting of CPT-11 and S-1. The patient was a 69-year-old woman diagnosed with large type 3 advanced gastric cancer with esophageal invasion and having No.3 lymph node metastasis (cT3, cN1, cM0, cStage IIIA), treated with 2 courses of CPT-11 plus S-1 as neo-adjuvant chemotherapy. Computed tomography after neo-adjuvant chemotherapy showed improvement of gastric wall thickness and reduction of lymph node metastasis. Subsequently, she underwent an operation. There was no lymph node swelling,so we performed curative surgery consisting of total gastrectomy, splenectomy, cholecystectomy, and D 2 lymph node dissection. Histological diagnosis was pT2 (MP), pN1, pStage II, and estimation of the histological change by chemotherapy was Grade 2. The course after surgery was good, and she was treated by S-1 after discharge. To date, 8 months after surgery, there is no evidence of recurrence. Combination chemotherapy consisting of CPT-11 plus S-1 can be performed safely as a neo-adjuvant treatment, and may be an effective treatment modality for advanced gastric cancer.     

A case of synchronous double cancer of stomach and lung responding to neoadjuvant chemotherapy

A 66-year-old male was admitted to our hospital because of dyspnea in 2007. Cancerous pleural effusion and gastric cancer was diagnosed, and the chemotherapy consisted of S-1 + DOC was started for Stage IV gastric cancer. In 2009, lung cancer was found. The chemotherapy was changed to CDDP + CPT-11. This chemotherapy was effective for both lung and gastric cancers. Operation was performed for both tumors in 2010, and the pathological diagnosis revealed that gastric cancer was pStage I, Cur A, and the lung cancer was pStage IA, R0. Pathologic histology inspection of both tumors was judged to be effective for the chemotherapy prior to resection.     

A case of advanced gastric cancer which has kept partial response with the fifth-line chemotherapy

We report a case of a 48-year-old male with advanced gastric cancer. A total gastrectomy was performed for cancer of remnant stomach. S-1 was administered for cytological cancer cells detected by abdominal cavity lavage as the first-line chemotherapy. After 2 cycles of S-1, cervical lymph nodes were enlarged, and the patient underwent paclitaxel monotherapy as the second-line chemotherapy. After 8 cycles, Virchow lymph nodes were enlarged. The regression of Virchow lymph nodes were observed with a S-1 /CPT-11 combination therapy as the third-line chemotherapy and DOC/CPT-11 as the fourth-line chemotherapy. We then used a combination chemotherapy of CPT-11 60 mg/m2 and CDDP 30 mg/m2 at day 1 and 15, every 4 weeks as the fifth-line chemotherapy. A partial response was achieved after 2 cycles, and has been continued for 7 months. The hematological toxicities and the non-hematological toxicities of grade 2 or higher were not observed. This regimen may be effective for patients with advanced gastric cancer resistant to prior chemotherapy with several agents.     

Combination therapy with S-1 and irinotecan (CPT-11) for advanced or recurrent gastric cancer

S-1 and irinotecan (CPT-11) are active agents against gastric cancer. Some preclinical studies have demonstrated the theoretical background of combination therapy with S-1 and CPT-11 for gastric cancer. Based on these findings, several phase I/II studies of this combination therapy, which has been proposed as a candidate of standard treatment for advanced or recurrent gastric cancer in Japan, have been conducted. Although there were slight differences in the administration schedules of the combination therapy with S-1 and CPT-11 in these phase II studies, the response rates were more than 50%, and the median survival time (MST) exceeded 1 year. Also, good safety profiles were reported. These results warranted a further, phase III, study to define the efficacy of the combination in improving survival. In a phase III study (GC0301/TOP 002 trial), the response rate, the 1-year survival rate, and the MST in the arm with combination therapy of S-1 and CPT-11 were better than these parameters in the S-1 monotherapy arm. However, at 1.5-year follow-up, the overall survival (OS) in the combination therapy of S-1 and CPT-11 arm did not exceed that in the S-1 monotherapy arm [P = 0.23; hazard ratio (HR), 0.89]. As 22% of the patients were censored, further follow-up is needed to determine the OS with more precision. But, of note, in the SPIRITS trial, combination therapy with S-1 and cisplatin (CDDP) significantly prolonged OS compared to S-1 monotherapy (P = 0.037; HR, 0.77), suggesting that CPT-11 may not be the best partner to use in combination with S-1 at present.     

Combination therapy with S-1 and irinotecan (CPT-11) for advanced or recurrent gastric cancer

S-1 and irinotecan (CPT-11) are active agents against gastric cancer. Some preclinical studies have demonstrated the theoretical background of combination therapy with S-1 and CPT-11 for gastric cancer. Based on these findings, several phase I/II studies of this combination therapy, which has been proposed as a candidate of standard treatment for advanced or recurrent gastric cancer in Japan, have been conducted. Although there were slight differences in the administration schedules of the combination therapy with S-1 and CPT-11 in these phase II studies, the response rates were more than 50%, and the median survival time (MST) exceeded 1 year. Also, good safety profiles were reported. These results warranted a further, phase III, study to define the efficacy of the combination in improving survival. In a phase III study (GC0301/TOP 002 trial), the response rate, the 1-year survival rate, and the MST in the arm with combination therapy of S-1 and CPT-11 were better than these parameters in the S-1 monotherapy arm. However, at 1.5-year follow-up, the overall survival (OS) in the combination therapy of S-1 and CPT-11 arm did not exceed that in the S-1 monotherapy arm [P = 0.23; hazard ratio (HR), 0.89]. As 22% of the patients were censored, further follow-up is needed to determine the OS with more precision. But, of note, in the SPIRITS trial, combination therapy with S-1 and cisplatin (CDDP) significantly prolonged OS compared to S-1 monotherapy (P = 0.037; HR, 0.77), suggesting that CPT-11 may not be the best partner to use in combination with S-1 at present.     

A randomized phase II clinical trial of tailored CPT-11 + S-1 vs S-1 in patients with advanced or recurrent gastric carcinoma as the first line chemotherapy

A randomized phase II clinical trial has been designed and started in the Japanese Foundation for Multidisciplinary Treatment of Cancer (JFMC) to select the better regimen between tailored CPT-11 + S-1 and the standard S-1 treatment for advanced or recurrent gastric cancer as the first line chemotherapy. Selection of the better treatment for general clinical practice in this clinical trial will lead to a more precise assignment of a promising regimen for a future phase III randomized trial, placing continuous 5-FU infusion as the reference arm. In this trial, subsidiary pharmacokinetic analysis for the tailored dose arm is also proposed. In order to continue chemotherapy for a long time and to obtain longer survival, our study design for the tailored therapy could be exploited, especially in the field of general clinical practice.     

A case of advanced gastric cancer with pulmonary carcinomatous lymphangitis and paraaortic lymph node metastases responding to combination chemotherapy of S-1 and irinotecan(CPT-11)

A 70-year-old woman with pulmonary carcinomatous lymphangitis and paraaortic lymphnode metastases due to gastric cancer, was treated by combination chemotherapy of S-1 and irinotecan(CPT-11). After one course of the chemotherapy, pulmonary carcinomatous lymphangitis and paraaortic lymphnode metastases were remarkably improved. Diet intake was improving and cancer pain remarkably declined. Because the origin of gastric cancer was not improved, total gastrectomy, distal pancreatectomy and splenectomy were performed. After surgery, relapse of pulmonary carcinomatous lymphangitis caused death of the patient. The combination chemotherapy of S-1 and CPT-11 was effective for pulmonary carcinomatous lymphangitis and paraaortic lymphnodes metastases due to gastric cancer. However, careful consideration is required since surgery is performed on a patient who had suffered pulmonary carcinomatous lymphangitis.     

A case of S-1-resistant resected advanced gastric cancer with para-aortic lymph node recurrence responding to bi-weekly CPT-11 and CDDP

A 64-year-old man with advanced gastric cancer who underwent a curative total gastrectomy(LM, Less, Type 3, 70×55 mm, por1>tub2>sig, pT3(ss), med, INF b, ly3, v3, pN3b(41/61), pPM0, pDM0, pT3N3bM0, Stage III B)followed by adjuvant chemotherapy(paclitaxel+S-1)a year ago, revealed an increasing level of serum CEA and para-aortic lymphnode (#16b1)recurrence on abdominal CT. He was given chemotherapy with low-dose weekday CDDP+S-1 for the recurrence, after which he failed to respond. Thereafter, he received 2nd-line chemotherapy with bi-weekly CPT-11+CDDP as a S-1- refractory regimen. 3 courses of the regimen reduced the serum CEA level accompanied by grade 3 of anemia. After recovery from the adverse event, another 4 courses at a 20% lower dosage for safety were administered. Complete response to the lymphnode was ensured on the abdominal CT with a reduced serum CEA level into the normal range. The patient has no signs of recurrence and has survived in fair condition for more than 5 years after the surgery. The combination treatment of biweekly CPT-11+CDDP can be a worthwhile regimen for patient with S-1-refractory recurrence of the resected advanced gastric cancer.     

Palliative anti-cancer chemotherapy is safely executable in a hemodialytic patient with unresectable advanced gastric cancer

A 75-year-old man with chronic renal failure was on maintenance hemodialysis.He was admitted to our hospital for advanced gastric cancer with multiple liver metastases (cStage IV).Three courses of tegafur-uracil (300 mg/day daily) plus docetaxel (20 mg/m2, every 3 weeks) as first-line treatment and nine courses of tegafur-uracil (same dose) plus CPT-11 (64 mg/m2, day 1, 15, every 4 weeks) were given without any complications.Docetaxel and CPT-11 were given on days between hemodialyses. No severe adverse effects of more than grade 3 were encountered. The standard regimens in our country for unresectable advanced gastric cancer are the S-1 single or S-1/CDDP combined chemotherapies that have already been evidenced in the JCOG 9912 and SPIRITS trial. However, no standard chemotherapy for patients on hemodialysis has been reported as yet.Therefore, doctors in charge must arrange an individualized regimen for each patient, considering metabolic characteristics of each anti-cancer agent.In this context, our case was considered to be very suggestive, and that is why we report it here in detail.     

Three cases of unresectable advanced gastric cancer treated with S-1 based chemotherapy after surgical bypass

Case 1: The patient underwent gastrojejunostomy [T4 (pancreas), N2, P0, CY0] in April 2004, and then 23 courses of chemotherapy with S-1 + DOC (40 mg/m2/day 1:3 w). Then, the regimen was switched to CPT-11 because of a decreased efficacy of the treatment, and CPT-11 was continued for 10 courses. (The patient was alive for 36 months). Case 2: The patient was treated with S-1 [T4 (pancreas), N3, P0, CY0] after surgical bypass in November 2004. After two courses of chemotherapy with S-1, 9 courses of the second-line chemotherapy with PTX (120 mg/m2/day 1:3 w) were provided. As the disease progressed, 15 courses of CPT-11 (125 mg/m2/day 1: 2 w) were administered (The patient was alive for 29 months). Case 3: The patient was diagnosed as CY1 by staging laparoscopy in August 2005. The second-look laparoscopy revealed CY0 after 5 courses of S-1 + PTX (120 mg/m2/day1: 3 w). Although the second-look laparoscopy revealed CYO, gastrojejunostomy was performed because of P1 and T4 (pancreas). Chemotherapy with S-1 + PTX was continued for 18 courses, followed by OPT-11 (The patient was alive for 20 months). This report describes three cases of gastric cancer treated with S-1 based chemotherapy after surgical bypass, which resulted in the long-term survival and an improvement of the patients' quality of life.     

A case of Stage IV gastric cancer with liver and peritoneal metastases responding completely to tailored S-1/CPT- 11 combination therapy

A 75-year-old man with advanced gastric cancer underwent distal gastrectomy with lymph node dissection(D1)and Roux-en Y reconstruction. Pathological staging was Stage IV (T3N3P1CY1M1), and curability was Cur C. He started adjuvant chemotherapy with oral administration of S-1(100 mg/body weight), but experienced grade 3 anorexia for one month. Abdominal computed tomography(CT)2 months postoperatively showed multiple liver metastases and ascites. We then conducted tailored S-1/CPT-11 as second-line chemotherapy(S-1 80 mg/body weight on days 1-5 and 8-12, CPT-11 60 mg/body weight on days 1 and 8). After 5 courses of this therapy, CT showed that the liver metastases and ascites had disappeared, leading to a complete response(CR). The only adverse event was general grade 1 fatigue. He continues to undergo oral administration of S-1(80 mg/body weight)as maintenance therapy, and maintained CR for 12 months since undergoing chemotherapy. Adverse events in tailored S-1/CPT-11 combination therapy are mild and tolerable, making this regimen a potential therapeutic strategy for patients with advanced or recurrent gastric cancer.     

S-1 in gastric cancer: a comprehensive review

The current basic and clinical studies of S-1 (TS-1^®) were reviewed. S-1 is a novel oral dihydropyrimidine dehydrogenase (DPD) inhibitory fluoropyrimidine (DIF) based on a biochemical modulation of 5-fluorouracil (5-FU); S-1 contains tegafur (FT) and two types of enzyme inhibitor; 5-chloro-2,4-dihydroxypyridine (CDHP) and potassium oxonate (Oxo) in a molar ratio of 1?:?0.4?:?1. In pharmacokinetic studies, S-1 showed high 5-FU concentration in blood for long periods of time. In a combined analysis of two pivotal late phase II studies in gastric cancer, the overall response rate was 44.6% (45/101), and median survival time and 1-year survival rate were 244 days and 37%, respectively. A postmarketing survey was conducted, and in the interim analysis, tolerability and safety profiles were shown in 3294 patients with gastric cancer. The oral dose form and low incidence of adverse reactions permit treatment on an outpatient basis. To evaluate the survival benefit of S-1 in advanced gastric cancer, a phase III study of S-1 vs 5-FU vs cisplatin (CDDP) plus irinotecan (CPT-11) has been conducted. The effect of S-1 in adjuvant chemotherapy is also promising. Currently, a phase III study of surgery alone vs S-1 in patients with curative resection of gastric cancer is in progress. Further therapeutic benefits are expected to be gained by combining S-1 with other chemotherapeutic agents. Several preliminary results of combination phase I/II studies of S-1 with CDDP or CPT-11 have recently been obtained, and phase II studies are in progress. Thus, S-1 is currently the first candidate as the standard anticancer drug for gastric cancer. Further evaluations by well-controlled clinical trials are still needed.     

Present status and prospects for chemotherapy for advanced or recurrent gastric cancer in our hospital

Since S-1 was approved in 1999, the response rate and the disease control rate of the chemotherapy for advanced or recurrent gastric cancer have improved. It is important to perform chemotherapy using key drugs and to plan the chemotherapy for each case. Of the 32 patients in our hospital, the median survival time (MST) was 21 months for chemotherapy in advanced or recurrent gastric cancer during 2003-2006. MST for patients who had up to second- or third-line treatment was longer than for patients with up to first-line treatment. In addition, it there was no difference in prognosis for patients using CPT-11 or taxane at second-line after using S-1 at first-line treatment. The first-line chemotherapy for advanced or recurrent gastric cancer should be decided by the disease condition of each patient and the characteristics of each anti-cancer drug. In addition, the prognosis of patients will improve if second- or third-line chemotherapy can be performed.     

Fifth-line chemotherapy for metastatic gastric cancer--a case responding to modified FOLFOX 6

According to the National Comprehensive Cancer Network (NCCN) clinical practice guideline for gastric cancer (2006, the first edition), 5-FU/Leucovorin (LV), 5-FU-based, cisplatin (CDDP)-based, oxaliplatin (L-OHP)-based, taxane-based, and irinotecan (CPT-11)-based, ECF are recommended. We used modified FOLFOX 6 (mFOLFOX 6) for pretreatment, that is oxaliplatin-based chemotherapy, for a patient who had received 5-FU-based, CDDPbased, taxane-based, and CPT-11-based treatment for an unresectable gastric cancer case responding to mFOLFOX 6. A 73-year-old male admitted to our hospital for treatment of advanced gastric cancer was diagnosed to be inoperable. A combination chemotherapy docetaxel and CDDP and S-1 as first-line treatment, CPT-11 and CDDP as second-line treatment, weekly paclitaxel treatment as third-line treatment, and MTX and 5-FU as fourth-line treatment were performed. He had progressed after 5-FU-based, CDDP-based, taxane-based, and CPT-11-based chemotherapy. There are no effective approved drugs for gastric cancer in Japan. Oxaliplatin was reportedly effective for metastatic gastric cancer, but it is still non-approved in Japan. After receiving an explanation of oxaliplatin-based therapy, he gave informed consent. Oxaliplatin-based therapy for this patient was then evaluated and approved under an institutional review board of Higashi Sapporo Hospital. mFOLFOX 6 used for the oxaliplatin-based therapy. After 2 courses of mFOLFOX 6, he showed a partial response. Oxaliplatin-based treatment was thought to be promising for previously CDDP-treated patients with unresectable gastric cancers.