Combination therapy of a novel oral fluorouracil derivative TS-1 with low-dose cisplatin for recurrent and very advanced gastric cancer

The case reports and clinical trials on combination therapy of a novel oral 5-fluorouracil derivative TS-1 with low-dose cisplatin for gastric cancer were reviewed. In the majority of the case reports, TS-1 was administered at 80-120 mg/body per day for 4 weeks followed by a rest of 2 weeks. However, in several case reports, TS-1 administration was slightly shortened such as 3 weeks administration followed by a rest of 2 weeks. The administration of cisplatin (CDDP) varied: every day, weekly, bi-weekly, and so on; the doses were from 1 to 25 mg/m2. CDDP was mostly given at 5-10 mg/body 5 days per week, mimicking the low-dose FP (5-fluorouracil+ CDDP). In most case reports, combination therapies were undertaken on an inpatient basis due to frequent administration of CDDP, while the weekly or bi-weekly CDDP administration regimens were done on an outpatient basis. The case reports demonstrated high efficacies and few adverse effects of the combination therapy. Several case reports showed unresectable cases could be operated curatively after the combination therapy. There have been three phase I clinical trials, two of which were regimens on an outpatient basis. JFMC 27-9902, an inpatient-basis phase I clinical trial, consisted of TS-1 at 80 mg/m2 every day and CDDP at low-dose for 5 days per a week: the regimen consisted of 4 weeks administration and 2 weeks' rest. The recommended dose of CDDP was determined to be 4 mg/m2 in the JFMC27-9902 regimen. In the modified JFMC27-9902 regimen, CDDP was given twice a week on an outpatient basis. This new phase I/II clinical trial has been under way since 2003 December. In conclusion, TS-1 + low-dose CDDP combination therapy will be done on an outpatient basis in future, and may be examined as a neoadjuvant therapy as well as a conventional form of chemotherapy.     

Combination chemotherapy of S-1/low-dose CDDP/lentinan for advanced gastric cancer

Eight patients with inoperable advanced gastric cancer were treated with combination chemotherapy of S-1, low-dose cisplatin(CDDP)and Lentinan. S-1 80 mg/ m2 was orally administered for 2 weeks followed by 1-week rest, CDDP 15 mg/ m2 and Lentinan 2 mg/body were given intravenously on day 1 and 8. One complete response and four partial responses were observed for an overall response rate of 63%(5 of 8 patients). Only one patient developed over grade 3 toxicity leukocytopenia. Many patients could be maintained by long-term continuous treatment. Since combination chemotherapy of S-1/low-dose CDDP/Lentinan for advanced gastric cancer was very tolerable, it could be used for a long time.     

A case of multiple bone metastasis of gastric carcinoma accompanying DIC successfully controlled with combination of S-1 and low-dose CDDP

The patient was a 50-year-old man who underwent total gastrectomy twelve years ago. Ahigh level of ALP was found in the patient in April 2008. Based on various examinations, the diagnosis of multiple bone metastasis of gastric carcinoma accompanying disseminated intravascular coagulation(DIC)was made. The patient was treated with S-1/CDDP. S-1(80mg/ m / / 2day)was administered for 14 days followed by a 7-day rest period, and a CDDP(20mg/m2)infusion was administered on days 1 and 8. After one course of treatment, the DIC was controlled, and the patient was given a one-year prognosis. The combination of S-1 and low-dose CDDP may be considered effective even for multiple bone metastases of gastric carcinoma with DIC.     

Two patients with StageIV gastric cancer responding to combination therapy with S-1 and low-dose CDDP after reduction surgery

Two patients with advanced gastric cancer who underwent gastrectomy and pathological examination were both diagnosed as having Stage IV gastric cancer with distant lymph-node metastases and peritoneal dissemination, respectively. The patients received S-1 and low-dose CDDP in combination therapy after reduction surgery. Each treatment course consisted of S-1 100 mg/body oral administration for 3 weeks and intravenous administration of CDDP at a dose of 25 mg/m(2) on days 7, 14 and 21. The course repeated after a two-week rest period, and the treatment was repeated every five weeks. After three courses of treatment, both patients received S-1 100 mg/body for 2 weeks on and 2 weeks off as long as possible. They remain alive 15 and 12 months after initial treatment, respectively, without any sign of recurrence. The patients did not experience grade 3 or more adverse events and received this regimen as an outpatient. These results suggest that combination therapy with S-1 and low-dose CDDP is effective against advanced gastric cancer.     

Treatment of S-1 plus weekly CDDP for advanced gastric cancer

We analyzed the clinical efficacy and safety of chemotherapy using S-1 plus weekly CDDP( w-CS therapy) for unresectable gastric cancer. Twenty one patients were treated with this treatment. S-1 80 mg/m2/day was administered for 2 weeks followed by a 1-week rest. CDDP 20 mg/m2 was injected intravenously on day 1 and 8. The overall response rate was 52. 3%. The disease control rate was 85.7%. Grade 3 or 4 major toxicity comprised neutropenia (14.2%), thrombocytopenia (4.7%) and plasma creatinine elevation (4.7%). w-CS therapy is satisfied resulting with efficacy and safety. Thus, future clinical trials and accumulation of futher cases are warranted.     

Weekly chemotherapy with alternating low-dose CPT-11 and low-dose FP against a far advanced pancreatic cancer--a case report

We attempted a new regimen of weekly chemotherapy with alternating low-dose CPT-11 and low-dose FP against a case of far advanced pancreatic cancer with invasion to the super mesentric artery, celiac artery, and left renal vein. CPT-11 was administered at 25 mg/m2/day x 3/week, and CDDP and 5-FU were administered at 7 mg and 350 mg/m2/day x 3/week by intravenous infusion. These regimens were alternated every week. The serum CA19-9 level decreased gradually with a half time of approximately 2 months (from 972 to 126 U/ml). The tumor was reduced more than 50% 4 months after chemotherapy, and continuing decreasing for more than 6 months. There were no adverse effects except mild leukopenia (less than Grade 1). These results suggest that the combination of low-dose chemotherapy with fewer side effects may be effective not only for tumor shrinkage, but also for a prolonged time to progression.     

Three advanced gastric cancer patients successfully treated by combination therapy of paclitaxel and cisplatin

We report 3 gastric cancer patients with peritoneal dissemination who were successfully treated with weekly paclitaxel and cisplatin. The patients were 2 men and 1 woman from 57 to 70 years in age. The histological types were 2 poorly-differentiated adenocarcinomas and 1 moderately-differentiated adenocarcinoma. Intravenous infusion of PTX (80 mg/m(2)) and CDDP (25 mg/m(2)) after short premedication was continued for 3 weeks followed by 1 week rest. Ascites improved only after administration of 1 course in all patients.PTX/CDDP is thought to be an effective chemotherapy showing acceptable toxicity against advanced gastric cancer with ascites.     

A case of unresectable advanced gastric cancer treated with S-1/low-dose CDDP combination chemotherapy through jejunostomy

A 70-year-old woman with unresectable advanced gastric cancer accompanied by peritoneal dissemination underwent jejunostomy, and was treated with S-1 and low-dose CDDP. One course consisted of S-1 (80 mg/day) via an intestinal fistula tube from days 1 to 14. This was followed by 7 days rest, and CDDP (20 mg/day) was administered by 1-hour continuous intravenous infusion on day 1 and 8. She continued to receive this chemotherapy for a total of 14 courses, followed by 3 courses of a weekly paclitaxel regimen. She died 14 months after surgery. All chemotherapy had been conducted in an outpatient setting. We concluded that the administration of S-1, combined with low-dose CDDP (div) through a jejunostomy, can improve the quality of life (QOL) of a patient who has unresectable advanced gastric and is incapable of oral intake. We report this rare case with a review of the literature.     

Continuous infusion of 5-fluorouracil with versus without low-dose, consecutive administration of cisplatin in advanced colorectal cancer. A prospective randomized phase II study

Recently, the treatment of advanced gastric cancer by continuous infusion of 5-fluorouracil (5-FU) with low-dose cisplatin (CDDP) has improved efficacy without severe toxicities. The possible effectiveness of 5-FU+low-dose CDDP for colorectal cancer (CRC) is intriguing. One hundred fifty-five patients with far-advanced CRC including at least one measurable lesion were enrolled in a prospective randomized clinical trial funded by the Japanese Foundation for Multidisciplinary Treatment of Cancer. These patients were assigned to the two arms to assess the value of low-dose CDDP when added to a continuous intravenous infusion of 5-FU at a dose of 300 mg/m(2)/24 hrs in a one-week cycle consisting of 5 days of treatment and 2 days of rest for at least 12 weeks. CD-DP was given intravenously at a dose of 3 mg/m(2) on days 1-5 and days 8-12, and then at a dose of 7 mg/m(2) twice a week. Three patients were excluded from the trial. The response rate in the 5-FU+low-dose CDDP arm (n=75) was significantly higher than that in the 5-FU arm (n=77) (25.3% vs. 11.7%; P = 0.037). There was no significant difference in the median overall survival time between the 5-FU+low-dose CDDP arm and the 5-FU arm (479 and 491 days, respectively). Grades 3/4 toxicities occurred infrequently in both arms. The quality of life was almost the same between the arms. Low-dose CDDP improved the response rate while keeping toxicities within clinically acceptable limits. However, this combined treatment did not confer a survival advantage over treatment with continuous infusion of 5-FU alone for patients with far-advanced CRC; that might be attributable to the short CDDP administration setting of 12 weeks.     

Concurrent chemoradiotherapy with cisplatin and docetaxel for advanced head and neck cancer. A phase I study

BACKGROUND: This phase I study of weekly low-dose administration of cisplatin (CDDP) and docetaxel (DOC) combined with concurrent conventionally fractionated radiotherapy was designed for locoregionally advanced head and neck cancer. PATIENTS AND METHODS: Twelve patients were treated at varying levels of DOC (level 1: 5 mg/m2/week, level 2: 7.5 mg/m2/week, level 3: 10 mg/m2/week) with CDDP constant at 20 mg/m2/week in four cohorts of three patients. Radiation was given at 1.8-2.0 Gy/fraction to a total dose of 60-70.2 Gy. RESULTS: Hematological toxicities, except lymphocytopenia, were minimal. Mucosal toxicities, especially grade 3 mucositis, were common. Dose-limiting toxicity was grade 3 pain, although level 3 did not reach a maximum tolerated dose. No grade 4 toxicities were observed. Complete response rate ranged from 33% to 67% in the various dose levels. CONCLUSION: This concurrent chemoradiotherapy seems to be a promising treatment modality, in which level 3 is the recommended dose for a phase II study.     

A phase I study of weekly docetaxel and cisplatin in advanced non-small cell lung cancer.

This phase I study was designed to determine the maximum tolerated dose (MTD) and toxicity of a weekly docetaxel (TXT) and cisplatin (CDDP) combination regimen in advanced non-small cell lung cancer (NSCLC). Patients with stage IIIB or IV NSCLC who were previously untreated were eligible. Docetaxel, at a starting dose of 20 mg m(-2) per week on days 1, 8 and 15, was combined with a fixed dose of cisplatin 80 mg m(-2) on day 1. Docetaxel was increased in 5 mg m(-2) per week steps. Chemotherapy was given in a 4-weeks cycle. Dose-limiting toxicities (DLTs) were defined as grade 3-4 leukopenia, thrombocytopenia, anemia, fever with grade 4 neutropenia and more than grade 2 non-hematologic toxicity, with the exception of nausea, vomiting, and alopecia. Omission of chemotherapy on day 8 and/or 15 was also considered DLT. Eighteen patients were enrolled in this study. Leukopenia, anemia and fatigue were the DLTs. No grade 4 toxicities were seen in any patients. The overall response rate was 44.4% (95% confidence interval, 21.5-67.4%). The recommended dose of TXT to be combined with CDDP 80 mg m(-2) on day 1 is 35 mg m(-2) per week on days 1, 8 and 15. This is a promising regimen, therefore a multicenter phase II study is now under way.     

A case of unresectable gastric cancer complicated by serious pyloric stenosis in which S-1 administration after gastrojejunostomy proved effective

We report a patient with unresectable gastric cancer who was effectively treated with S-1 after gastrojejunostomy. A 64-year-old man was referred to our hospital for anorexia and epigastric palpable mass. Upper gastrointestinal endoscopy revealed an ulcerous tumor in the antrum of the stomach, and gastric roentgenography showed pyloric stenosis. CT showed simultaneous multiple liver metastases. We performed gastrojejunostomy to allow oral intake. He was treated with daily oral administration of 120-80 mg S-1 for two weeks followed by one week rest as one course. The treatment was repeated for 19 courses until remission was observed. Weekly paclitaxel therapy (80 mg/m(2)/week) was then chosen as second-line chemotherapy. Administration was continued for three weeks with one-week rest. The treatment course was repeated for 6 courses. Bi-weekly administration of CPT-11 (80 mg) and CDDP (30 mg) was chosen as third-line chemotherapy. He died of progressive disease 2 years and 2 months after surgery. During chemotherapy, he maintained a performance status of 0 to 1, and maintained quality of life. This case suggested that the gastrojejunostomy was a useful method for treating unresectable gastric cancer, allowing the possibility of oral intake, and the use of S-1.     

A case of long-term survival of 5 years after operation and chemotherapy for type 4 gastric cancer with peritoneal dissemination

We report a case of long-term survival of 5 years after operation and chemotherapy for type 4 gastric cancer with peritoneal dissemination. A 41-year-old woman underwent total gastrectomy for type 4 gastric cancer with peritoneal dissemination and pancreas invasion. After operation, chemotherapy with S-1 plus PSK therapy, S-1 plus CDDP, and S-1 plus DOC was performed. The regimen of S-1 plus CDDP included S-1 on day 1-5, 8-12, 15-19, 22-26 and 2 weeks rest and PSK daily. After S-1 plus PSK therapy(34th course), peritoneal recurrence caused ileus, so a right hemicolonectomy was performed. Now the patient is undergoing weekly paclitaxel. The S-1 plus PSK therapy is able to prolong time to progression and has fewer adverse effects.     

Determination of platinum in plasma of patients affected by inoperable lung carcinoma treated with radiotherapy and concurrent low-dose continuous infusion ofcis-dichlorodiammine platinum(II)

Platinum microquantities were determined in plasma of patients affected by lung carcinoma during treatment with radiotherapy (RT) and concurrent low-dose continuous infusion ofcis-dichlorodiammineplatinum(II) (CDDP). RT was given at 50 Gy in continuous course; CDDP was continuously infused at 4 mg/m² daily for 100h/week for 5 weeks, and the infusions were separated by 68h of rest. The percentage of free drug versus total drug in plasma was about 3%. It did not vary with therapy duration and was not significantly different from that found in 5-day continuous infusions at much higher daily doses. Never-theless, maximal values of free Pt in plasma were very low and agreed with the low level of CDDP toxicity encountered on the present administration schedule.     

A case of complete response to combination therapy of S-1 and CDDP for Stage IV gastric cancer with Virchow's lymph node and para-aorta lymph node metastasis

The patient was a 53-year-old male with Stage IV gastric cancer with Virchow's lymph node and para-aorta lymph node metastasis. The chemotherapy regimen was given S-1 orally at 80 mg/m(2) day on day 1 to 21 and CDDP intravenously at 60 mg/m(2) day on day 8, repeated for 35 days. After two courses and a reduced regimen with S-1 64 mg/m(2) day plus CDDP 35 mg/m(2) day, the tumor lesion became CR and the serum CEA 575 ng/mL level before therapy decreased to the normal level. The patient received six courses of oral S-1(64 mg/m(2) day)for 28 days followed by a 14- day rest as maintenance therapy. The serum CEA elevated 13 months after the treatment, and the patient received a reduced course and two-course S-1/CDDP therapy. The serum CEA decreased to normal level and the patient has now survived 1 year 5 months without recurrence.     

Clinical development of S-1 plus cisplatin therapy as first-line treatment for advanced gastric cancer

We reviewed the clinical development of S-1 and S-1 plus cisplatin (CDDP) therapy for advanced gastric cancer (AGC). S-1 is an active oral fluoropyrimidine in patients with AGC. Phase I/II clinical trials of S-1 plus CDDP for AGC have yielded high response rates and the agents were well tolerated. On the basis of these phase I/II studies, we performed a randomized phase III study comparing S-1 plus CDDP with S-1 alone in patients with AGC. In the S-1 plus CDDP group, S-1 was given orally, twice daily for 3 consecutive weeks, and 60 mg/m² CDDP was given intravenously on day 8, followed by a 2-week rest period, within a 5-week cycle. In the S-1 alone group, S-1 was given orally, twice daily for 4 consecutive weeks, followed by 2 weeks of rest, within a 6-week cycle. Median overall survival was significantly longer in the S-1 plus CDDP group (13.0 months) than in the S-1 alone group (11.0 months; P = 0.04). Progression-free survival was significantly longer in the S-1 plus CDDP group (median, 6.0 months vs 4.0 months; P < 0.0001) and the response rate was also significantly higher (54.0% vs 31.1%; P = 0.002). There were more grade 3 or 4 adverse events, including leukopenia, neutropenia, anemia, nausea, and anorexia in the S-1 plus CDDP group, but the events were manageable. No treatment-related deaths were observed. As a result of this study, S-1 plus CDDP therapy has become a standard first-line treatment for AGC in Japan.     

Clinical development of S-1 plus cisplatin therapy as first-line treatment for advanced gastric cancer

We reviewed the clinical development of S-1 and S-1 plus cisplatin (CDDP) therapy for advanced gastric cancer (AGC). S-1 is an active oral fluoropyrimidine in patients with AGC. Phase I/II clinical trials of S-1 plus CDDP for AGC have yielded high response rates and the agents were well tolerated. On the basis of these phase I/II studies, we performed a randomized phase III study comparing S-1 plus CDDP with S-1 alone in patients with AGC. In the S-1 plus CDDP group, S-1 was given orally, twice daily for 3 consecutive weeks, and 60 mg/m² CDDP was given intravenously on day 8, followed by a 2-week rest period, within a 5-week cycle. In the S-1 alone group, S-1 was given orally, twice daily for 4 consecutive weeks, followed by 2 weeks of rest, within a 6-week cycle. Median overall survival was significantly longer in the S-1 plus CDDP group (13.0 months) than in the S-1 alone group (11.0 months; P = 0.04). Progression-free survival was significantly longer in the S-1 plus CDDP group (median, 6.0 months vs 4.0 months; P < 0.0001) and the response rate was also significantly higher (54.0% vs 31.1%; P = 0.002). There were more grade 3 or 4 adverse events, including leukopenia, neutropenia, anemia, nausea, and anorexia in the S-1 plus CDDP group, but the events were manageable. No treatment-related deaths were observed. As a result of this study, S-1 plus CDDP therapy has become a standard first-line treatment for AGC in Japan.     

Phase I/II study of S-1 combined with cisplatin in patients with advanced gastric cancer

A dose-escalation study of cisplatin (CDDP) combined with S-1, a new oral dihydropyrimidine dehydrogenase inhibitory fluoropyrimidine, was performed to determine the maximum-tolerated dose (MTD), recommended dose (RD), dose-limiting toxicities (DLTs), and objective response rate (RR) in advanced gastric cancer (AGC). S-1 was given orally at 40 mg m(-2) b.i.d. for 21 consecutive days following a 2-week rest. CDDP was planned to be given intravenously on day 8, at a dose of 60, 70, or 80 mg m(-2) depending on the DLT. Treatment was repeated every 5 weeks, unless disease progression was observed. In the phase I portion, the MTD of CDDP was presumed to be 70 mg m(-2), because 33.3% of patients (2/6) developed DLTs, mainly neutropenia. Therefore, the RD of CDDP was estimated as 60 mg m(-2). In the phase II portion, 19 patients including six patients of the RD phase I portion were evaluated. The median administered courses was four (range: 1-8). The incidences of severe (grades 3-4) haematological and nonhaematological toxicities were 15.8 and 26.3%, respectively, but all were manageable. The RR was 74% (14/19, 95% confidence interval: 54.9-90.6%), and the median survival day was 383. This regimen is considered to be active against AGC with acceptable toxicity.     

Phase II study of combination chemotherapy with S-1 and weekly cisplatin in patients with previously untreated advanced non-small cell lung cancer

We aimed to evaluate the efficacy and safety of combination chemotherapy with S-1 and low-dose weekly cisplatin in patients with advanced non-small cell lung cancer (NSCLC). In this phase II trial, previously untreated patients with stage IIIB/IV NSCLC were treated with oral administration of S-1 at 80 mg/m(2) for 21 days and three consecutive weekly low doses of cisplatin (25 mg/m(2)) followed by a 2-week rest period. Twenty-six patients were eligible for the assessment of efficacy and safety. Six partial responses were observed with an overall response rate of 23.1% (95% confidence interval: 12.3-31.6%). The median survival time and median progression-free survival were 13.4 months and 5.4 months, respectively. Grade 3/4 hematologic toxicities were observed in 9 patients (34.6%), including one grade 4 neutropenia and thrombocytopenia. As for non-hematologic adverse reactions, although grade 3 events were observed in 4 patients (15.3%), no severe renal toxicity or vomiting was found. S-1 and weekly low-dose cisplatin combination chemotherapy in patients with advanced NSCLC showed an acceptable response rate, overall survival time, and toxicity. Because this regimen can be performed in an outpatient setting, it might be an alternative useful and convenient option. Further investigations with a large population are required to confirm our results.     

S-1 combined with weekly paclitaxel in patients with advanced gastric cancer

S-1 Combined with Weekly Paclitaxel in Patients with Advanced Gastric Cancer: Masahiro Gotoh, Shin-ichiro Kawabe and Hiroya Takiuchi (Dept. of Gastroenterology, Osaka Medical College) Summary Both paclitaxel and S-1 have been identified as an effective agent for the treatment of gastric cancer. Furthermore, weekly paclitaxel was found to have a better toxicity profile and to be as effective as an equivalently dosed conventional schedule of delivery every 3 weeks. Osaka Gastrointestinal Cancer Chemotherapy Study Group (OGSG) conducted the phase I/II study of weekly paclitaxel combined with S-1. S-1 was given orally at a fixed dosage of 40 mg/m2 bid for 14 consecutive days, followed by a week rest. Paclitaxel was scheduled to be given intravenously on days 1 and 8. The MTD of paclitaxel was presumed to be 60 mg/m2 because 50.0% of patients (2/4) developed DLTs (mainly grade 3 anorexia). Therefore, the RD of paclitaxel was estimated to be 50 mg/m2. This combination treatment was demonstrated to exhibit a tolerable toxicity profile with a high antitumor activity of 48% (14/29) and MST of 417 days. This regimen is investigated in a randomized phase II trial and may yet become a test arm in future phase III trials.