Predictive value of orotate phosphoribosyltransferase in chemoresistant patients with gastric carcinoma who underwent S-1-based neoadjuvant/adjuvant chemotherapy

S-1, a most effective DPD-inhibitory fluoropyrimidine, used as neoadjuvant/adjuvant chemotherapy has recently been shown to improve clinical outcome in patients with stage II and III advanced stage gastric carcinoma. Orotate phosphoribosyltransferase(OPRTEC 2.4.2.10)is a primary enzyme involved in the first-step phosphorylation process of 5-fluorouracil and is an important enzyme that possibly enables to predict sensitivity to S-1 irrespective of tissue DPD levels. To test the hypothesis that a low OPRT level in gastric carcinoma tissue is an indicator of chemoresistance to S-1-based chemotherapy, the predictive value of OPRT levels in chemoresistance was evaluated in patients with gastric carcinoma undergoing S-1-based-neoadjuvant/adjuvant chemotherapy using survival analyses. A total of 67 patients with advanced-stage gastric carcinoma who underwent S-1-based neoadjuvant/adjuvant chemotherapy were subjected to the study. The OPRT level was determined by an enzyme-linked immunosorbent assay(ELISA)that has recently been developed. Postoperative cumulative survival rates were determined by the Kaplan-Meier method. The patients who underwent S-1-based adjuvant/neoadjuvant chemotherapy(n=67)were divided into 2 groups using various cut-off values to determine the prognostic significance of the OPRT level. The prognostic significance of OPRT levels was analyzed using Cox's proportional hazard model. The P value of the survival rate between the groups of low and high OPRT levels was the lowest(p=0.0018), when 2.0 ng/mg protein was used as a cut-off value for the OPRT level. The 3-year survival rate of Group L and Group H was 0% and 60%, respectively. In particular, there was a significant difference in the survival rates between Group L and Group H in stage III patients(p<0.05 by logrank test). T he survival rate of Group L(OPRT<2.0 ng/mg protein)was significantly lower than that of group H(OPRT> or =2.0 ng/mg protein)(p<0.05 by logrank test). The multivariate analysis using Cox' proportional hazard model indicated that venous invasion of carcinoma(>v2), lymph node metastasis(>5), and low OPRT level (OPRT<2.0 ng/mg protein) were significant prognostic factors in patients who were underwent S-1-based neoadjuvant/adjuvant chemotherapy. These results suggest that patients with a low OPRT level(OPRT<2.0 ng/mg protein)are non-responders to S-1- based adjuvant/neoadjuvant chemotherapy. The determination of OPRT levels in gastric carcinoma tissue enables to predict the response to S-1-based neoadjuvant/adjuvant chemotherapy.     

Evaluation of S-1 for stage IV gastric cancer

To evaluate the efficacy of S-1 for Stage IV gastric cancer, we retrospectively examined 124 patients with Stage IV gastric cancer. We classified patients into two groups based on the presence or absence of S-1 administration: the S-1 therapy group (n= 56) and the non-S-1 therapy group (n=68). Basically, patients received S-1 orally at 40 mg per square meter of body surface area twice daily for 4 weeks, followed by 2 weeks without chemotherapy. When side effects appeared, we tried dose reduction or cut short the administering period according to the dose modification criteria. Major patient characteristics were as follows: gender (male/female: 76/48), and age (median[range]: 63[24-83]). The median S-1 dosage was about 5 courses, and the median of the S-1 total dosage was 10. 08 g, based on the amount of tegafur. The relative dose intensity (RDI) was well maintained (average: 74. 9%). The survival rate in the S-1 therapy group was significantly higher than in the non-S-1 therapy group. The median survival time (MST) was 308 days in the S-1 group and 157 days in the non-S-1 group. In the S-1 therapy group, the MST was 629 days for those receiving 10 g or more, while that of those receiving less than 10 g was 209 days. The MST of patients administered 10 g or more was significantly longer than that of those receiving less than 10 g (p<0. 0001). Therefore, we consider that S-1 therapy improves survival in patients with Stage IV gastric cancer.     

Prediction of clinical outcome of S-1-based chemotherapy for gastric cancer patients

S-1, an oral fluoropyrimidine has been considered to be a key drug in the treatment of advanced gastric cancer in Japan as a standard chemotherapy option. Individual variations in the enzyme activity of the 5-FU metabolic pathway can affect the extent of 5-FU metabolism and affect the efficacy of S-1 based chemotherapy. In this review, the role of genetic factors in affecting the therapeutic efficacy of S-1 is discussed, with special emphasis on enzymes involved in the 5-FU metabolic pathway. The gene expressions of thymidylate synthase, thymidine phosphorylase, and orotate phosphoribosyltransferase, in particular, are discussed in relation to the efficacy of S-1 monotherapy. The predictive values of these candidate genes may, however, be overcome when other drugs are combined with S-1. In gastric cancer patients, pharmacogenetic studies, based on either the pathway approach or a global approach, are promising for identifying both survival benefit and clinical benefit more accurately than studies based on a candidate approach, especially for the new era of S-1 combination therapy as the standard regimen. However, large controlled studies are needed to justify changes in chemotherapeutic strategies; from a “one-size fits all” to a “tailor-made” approach.     

Prediction of clinical outcome of S-1-based chemotherapy for gastric cancer patients

S-1, an oral fluoropyrimidine has been considered to be a key drug in the treatment of advanced gastric cancer in Japan as a standard chemotherapy option. Individual variations in the enzyme activity of the 5-FU metabolic pathway can affect the extent of 5-FU metabolism and affect the efficacy of S-1 based chemotherapy. In this review, the role of genetic factors in affecting the therapeutic efficacy of S-1 is discussed, with special emphasis on enzymes involved in the 5-FU metabolic pathway. The gene expressions of thymidylate synthase, thymidine phosphorylase, and orotate phosphoribosyltransferase, in particular, are discussed in relation to the efficacy of S-1 monotherapy. The predictive values of these candidate genes may, however, be overcome when other drugs are combined with S-1. In gastric cancer patients, pharmacogenetic studies, based on either the pathway approach or a global approach, are promising for identifying both survival benefit and clinical benefit more accurately than studies based on a candidate approach, especially for the new era of S-1 combination therapy as the standard regimen. However, large controlled studies are needed to justify changes in chemotherapeutic strategies; from a “one-size fits all” to a “tailor-made” approach.     

Macroscopic tumor size as an independent prognostic factor for stage II/III gastric cancer patients who underwent D2 gastrectomy followed by adjuvant chemotherapy with S-1

Background  

In patients with stage II/III gastric cancer, tumors often recur even after curative D2 gastrectomy followed by adjuvant S-1 chemotherapy. The objective of this retrospective study was to clarify the prognostic factors in these patients that might be useful for future patients.     

Lentinan prolonged survival in patients with gastric cancer receiving S-1-based chemotherapy

AIM: To examine whether administration of lentinan, purified β-1, 3-glucan, can prolong survival in advanced gastric cancer patients receiving S-1-based chemotherapy.METHODS: Since 2004, 78 patients with metastatic or recurrent gastric cancer have received S-1-based chemotherapy as first-line treatment. Survival, side effects, and the ratio of granulocytes/lymphocytes (G/L ratio) were compared between 2 groups of patients who received chemo-immunotherapy using lentinan and chemotherapy alone.RESULTS: Median overall survival was significantly longer in the former group than in the latter group [689 d (95% CI: 431-2339 d) vs 565 d (95% CI: 323-662 d), P = 0.0406]. In addition, the G/L ratio in patients who received lentinan was maintained around or below 2, which was significantly lower than that in patients who received chemotherapy alone (P < 0.001).CONCLUSION: Chemo-immunotherapy with lentinan offers a significant advantage over S-1-based chemotherapy alone in terms of survival in patients with advanced gastric cancer.     

Challenges in predicting the clinical outcome in S-1-based chemotherapy for gastric cancer patients

S-1 has been considered to be a key drug in the treatment of advanced gastric cancer in Japan as a standard option of chemotherapy. Interindividual variation in the enzymes of the S-1 metabolic pathway can affect the extent of S-1 metabolism and impact the efficacy of S-1-based chemotherapy. In this review, the role of the "candidate" genetic factors affecting the therapeutic efficacy of S-1 is discussed with a special emphasis on polymorphism and gene expressions involved in the S-1 metabolic pathway, including CYP2A6, thymidylate synthase, thymidine phosphorylase, and orotate phosphoribosyltransferase. The predictive values of these candidates might be overcome with drugs combined with S-1. Pharmacogenetic studies based on a "global" approach by DNA microarray are promising to identify gastric cancer patients with both survival benefit and clinical benefit more accurately than those based on the "candidate" approach, especially for S-1 combination therapy. Large and controlled studies are needed to justify changes in the chemotherapeutic strategies, from "one-size fits all" to "tailor-made."     

Two cases of stage IV gastric cancer who underwent total gastrectomy and achieved long-term survival by sequential chemotherapy

We describe two patients, who suffered from Stage IV gastric poorly differentiated adenocarcinoma and underwent palliative total gastrectomy, were treated by sequential chemotherapy and achieved long term-survival. The first patient was a 55-year-old male with peritoneal dissemination. After total gastrectomy, he was treated with methotrexate-5-fluorouracil (MTX/5-FU) sequential therapy for 5 months, S-1 single-agent therapy for 4 years and weekly paclitaxel (PTX) therapy for 9 months. He is being treated with irinotecan (CPT-11) therapy as an outpatient now, and has achieved 5 year 8-month survival. The second patient was a 60-year-old female. We observed unresectable metastases around the pancreas, aorta, and transverse mesocolon. She was treated with S-1 single-agent therapy for 1 year 10 months, MTX/5-FU sequential therapy for 9 months. She is now receiving weekly PTX therapy for 3 months as an outpatient and has achieved 2 year 11-month survival.     

Two cases of stage IV gastric cancer responding to chemotherapy with S-1 or UFT

We report patients with advanced Stage IV gastric cancer responding to chemotherapy with S-1 or UFT. Case 1: The patient was a 59-year-old man with Stage IV gastric cancer because of CY 1. After surgery, chemotherapy with S-1 (100 mg/body/day) was performed for one year and 11 months. At present, 5 years and 5 months after surgery, this patient shows no signs of tumor recurrence. Case 2: The patient was a 68-year-old woman with Stage IV gastric cancer because of P 1. She was treated with 200 mg/day of UFT for one year and 9 months. At present, 5 years after surgery, she shows no signs of tumor recurrence. We considered that the longterm survival of such patients is attributable to chemotherapy with S-1 or UFT. The OPRT activity of the two cases was high, so chemotherapy with S-1 or UFT was thought to be effective for them.     

Three-week combination chemotherapy with S-1 and cisplatin as first-line treatment in patients with advanced gastric cancer: a retrospective study with 159 patients

Background

Doses and schedules of the combination of S-1 and cisplatin for the treatment of advanced gastric cancer (AGC) have not been standardized. We therefore evaluated the efficacy and feasibility of a 3-week schedule of S-1 and cisplatin in patients with AGC, as well as assessing factors prognostic of patient outcomes.

Methods

A total of 159 patients with AGC were treated with S-1 (40?mg/m² bid on days?1–14) and cisplatin (60?mg/m² IV on day?1) between January 2004 and December 2008.

Results

Median follow-up duration was 20.0?months (range, 11.4–48.5?months), during which time 129 patients (81.1%) died. Patients received a median 6 cycles of chemotherapy (range, 1–19 cycles). Among the 59 patients with measurable disease, 1 achieved a complete response (1.7%) and 24 (40.7%) had partial responses, giving an overall response rate of 42.4% (95% CI, 23.0–61.8%). The median progression-free survival (PFS) was 5.8?months (95% CI, 4.8–6.9?months), and the median overall survival (OS) was 11.3?months (95% CI, 9.6–13.0?months). Multivariate analysis showed that initial metastasis, bone metastasis, and liver metastasis were independent prognostic factors for reduced PFS, whereas poor performance status, initial metastasis, and bone metastasis were prognostic for reduced OS. Application of a previous prognostic model showed that observed PFS and OS survival curves for patients in various risk groups differed significantly (P?Conclusions A 3-week regimen of S-1 plus cisplatin was active and well tolerated as first-line treatment in patients with AGC. Disease status and bone metastasis were the most important prognostic factors.     

Retrospective analysis of stage IV advanced gastric cancer treated with S-1 or other chemotherapy

Background We retrospectively analyzed the influence of various clinicopathologic factors on the survival of patients treated with chemotherapy. Methods A retrospective analysis was made of 110 patients with stage IV gastric cancer who were treated from January 1996 to June 2004. Results Median survival time was 429 days for patients treated with S-1 therapy and 236 days for patients without S-1 therapy. A better survival was demonstrated in patients who had good performance status, one metastatic site, or had been given a second-line chemotherapy (P < 0.01). But very few patients (17%; 5/29) with multiple metastatic sites were able to receive the second-line chemotherapy. Conclusion Patients treated with S-1 therapy had a better prognosis than patients without S-1. One metastatic site and being given second-line chemotherapy were other factors for better prognosis. For patients with only one metastatic site, a good prognosis can be obtained by second-line chemotherapy for those refractory to S-1. The prognosis of patients who had more than two metastatic sites remained poor; more effective chemotherapy might improve the survival of such patients if they retain good performance status.     

Gastrectomy and chemotherapy with S-1 for gastric cancer in a patient with acquired immunodeficiency syndrome

Total gastrectomy and chemotherapy with S-1 after surgery were performed in a 50-year-old woman with gastric cancer associated with acquired immunodeficiency syndrome (AIDS). She was given a diagnosis of gastric cancer at the lesser curvature of the body of the stomach, and distal gastrectomy was performed in December 2004. The postoperative course was eventful, with persistent high fever of unknown origin after surgery and infiltrative shadows in the bilateral lung fields showing on CT scan. Polymerase chain reaction (PCR) for pneumocystis carinii on bronchoscopy was positive, serum HIV antibody was positive, HIV-RNA was 2.2 × 10⁵ copies/ml, and the serum CD4 lymphocyte level was 25/mm³ on postoperative day 28. She was given a diagnosis of pneumocystis carinii with AIDS. Pneumocystis carinii and fever improved immediately when ST mixture and highly active antiretroviral therapy (HAART) were performed. After 3 months, the serum CD4 lymphocyte level was elevated to 125/mm³, and she underwent total gastrectomy because cancer cells at the cut end of the resected stomach were positive microscopically. The postoperative course was uneventful, and she underwent adjuvant chemotherapy with S-1 because the serum CD4 lymphocyte level was 568/mm³. S-1 therapy was continued for 2 years (each course consisting of 2 weeks of administration followed by 2 weeks off) while performing HAART and monitoring CD4 lymphocyte levels. No side effects such as decreases in white blood cell counts or CD4 lymphocyte levels were seen during S-1 therapy. She is alive and well without recurrence of gastric cancer 5 years after initial gastrectomy.     

Neoadjuvant chemotherapy with S-1 for scirrhous gastric cancer: a pilot study

We conducted a pilot study using S-1 (TS-1^®), a novel oral derivative of 5-fluorouracil, as neoadjuvant chemotherapy for potentially resectable scirrhous gastric cancer. The neoadjuvant chemotherapy consisted of two courses (each, 4-week administration and 2-week withdrawal) of S-1 at 100–120?mg/body per day. Five patients were enrolled in this pilot study and underwent resection. The response rate for the neoadjuvant chemotherapy was 60% (three partial response [PR]; two stable disease [SD]). Three of the five patients received curative resection; the other two patients received noncurative resection because of localized peritoneal dissemination and positive results on cytological examination of the abdominal washing. No toxicity of grade 3 or more was exhibited during the two courses of chemotherapy. Pathological examination of the resected specimens revealed a marked reduction in the distribution of viable cancer cells in the stomach in the three patients with PR. In one of these patients, pathological findings suggestive of the possibility of disappearance of the cancer cells in the perigastric and paraaortic lymph nodes were noted. Because of the unexpectedly high response to S-1, we consider that the efficacy of S-1 as neoadjuvant chemotherapy for scirrhous gastric cancer should be verified by phase II and III trials.     

S-1-based chemotherapy for unresectable advanced gastric cancer of the elderly or patients with renal dysfunction

Objective: S-1 based therapy is a valued standard chemotherapy regimen for unresectable gastric cancer in Japan. S-1/ CDDP therapy has been highly effective, especially for patients under 75 years old who have good organ function. However, it is the elderly and/or patients with renal dysfunction who make up the majority of the candidates for chemotherapy in general hospitals. These factors make it difficult to apply the results of RCTs to chemotherapy regimens. Aim and methods: To investigate clinical outcomes, the medical records of patients who had received S-1 based chemotherapy for gastric cancer at our hospital from January 2002 to September 2009 were retrospectively reviewed. Results: A total of 78 patients were evaluated for analyses. Among the patients, 23(29%)were the elderly, 8(10%)had renal dysfunction, and 27(35%)were either the elderly or those who had renal dysfunction. S-1/CDDP therapy was provided for 63% of the patients. Regarding the outcomes from therapy, RR was 44%, mPFS was 5. 4 months, and MST was 10. 6 months. Regarding survival benefit for OS, the elderly, the intestinal type, and therapy with S-1 alone were considered to be good factors in multi-variant analysis, but no significant differences were confirmed. Conclusion: In general practice, the elderly and/or patients with renal dysfunction account for 35%, and S-1-based chemotherapy has been proven to be very effective. However, additional effects of CDDP were not shown in this study.     

Feasibility study of alternate-day S-1 as adjuvant chemotherapy for gastric cancer: a randomized controlled trial

Background

The Adjuvant Chemotherapy Trial of S-1 for Gastric Cancer established oral S-1 administration for 1 year as the standard postoperative adjuvant chemotherapy for gastric cancer in Japan. We conducted a multicenter cooperative prospective study comparing daily and alternate-day S-1 administration as postoperative adjuvant therapy for gastric cancer.

Methods

Patients with Stage II or III gastric cancer who underwent curative surgery were randomly assigned to receive standard daily S-1 administration [group A: 80–120 mg/day S-1 depending on body surface area (BSA); days 1–28 every 6 weeks for 1 year] or alternate-day administration (group B: 80–120 mg/day S-1 depending on BSA; alternate days for 15 months). Treatment completion rate was the primary endpoint, and relative dose intensity and safety, overall survival, and relapse-free survival (RFS) were secondary endpoints.

Results

Seventy-three patients were enrolled. The treatment completion rate was 72.2 % in group A and 91.8 % in group B; the relative dose intensity was 67.5 % in group A and 81.2 % in group B; and compliance was better in group B. Digestive system adverse effects were less frequent in group B than in group A. Median follow-up time was 2.8 years; 3-year survival rate was 69.6 % in group A and 87.3 % in group B; and 3-year RFS rate was 76.4 % in group A and 73.1 % in group B.

Conclusions

Our data show improved compliance and fewer adverse effects with alternate-day S-1 administration, which appears to be a more sustainable option for adjuvant chemotherapy for Stage II or III gastric cancer.     

Combination chemotherapy with S-1 plus cisplatin for gastric cancer that recurs after adjuvant chemotherapy with S-1: multi-institutional retrospective analysis

Background

It is unclear whether S-1 plus cisplatin is effective for patients with recurrent gastric cancer after adjuvant S-1 chemotherapy.

Methods

We retrospectively evaluated the efficacy of S-1 plus cisplatin in patients whose gastric cancer recurred after adjuvant S-1 chemotherapy.

Results

In the 52 patients evaluated, the median duration of adjuvant S-1 chemotherapy was 8.1?months, and the median recurrence-free interval (RFI) since the last administration of adjuvant S-1 was 6.4?months. Among the 36 patients with measurable lesions, 7 achieved a complete or partial response, and 13 were evaluated as having stable disease, for an overall response rate of 19.4% and a disease control rate of 55.6%. For all patients, the median progression-free survival (PFS) was 4.8?months, and the median overall survival (OS) was 12.2?months. Compared with patients with an RFI of <6?months (n?=?25), patients with an RFI of ≥6?months (n?=?27) had a significantly higher response rate (5.0 vs. 37.5%, respectively), longer PFS (2.3 vs. 6.2?months, respectively), and longer overall survival (7.3 vs. 16.6?months, respectively). According to a multivariate Cox model including performance status (PS) and reason for discontinuation of adjuvant S-1, an RFI of 6?months was still significantly associated with PFS and OS.

Conclusions

S-1 plus cisplatin is effective for patients with gastric cancer that recurs after adjuvant S-1 chemotherapy, especially for those with an RFI of ≥6?months.     

S-1-based therapy versus S-1 monotherapy in advanced gastric cancer: a meta-analysis

This study aimed to derive a more precise estimate of the prognostic significance of S-1-based therapy over S-1 monotherapy in patients with advanced gastric cancer (AGC), including overall survival (OS) time, progression-free survival (PFS) time, objective response rate (ORR), and adverse events (AEs). Studies stratifying OS, PFS, ORR, and AEs in AGC patients in an S-1-based therapy versus an S-1 monotherapy setting were eligible for analysis by systematic computerized PubMed, Embase and Cochrane Library searches. Data from these studies were pooled using STATA package version 11.0. Six studies that investigated outcomes in a total of 913 AGC cases, of which 443 (48.5 %) received S-1-based therapy and 470 (51.5 %) received S-1 monotherapy, were included in the meta-analysis. Median OS and median PFS were significantly prolonged in AGC patients receiving S-1-based therapy compared with those receiving S-1 monotherapy (hazard ratio [HR] 0.83, 95 % confidence interval [CI] 0.71–0.96, P?=?0.015, and HR 0.69, 95 % CI 0.60–0.80, P?=?0.000, respectively). The ORR favored patients with S-1-based therapy (OR 1.65, 95 % CI 1.34–2.06, P?=?0.000). Higher incidence of grade 3/4 neutropenia was found in patients with S-1-based therapy (P?=?0.000). For the Asian population, S-1-based therapy significantly improved OS and PFS and enhanced ORR in comparison to S-1 monotherapy. The safety profile was poorer in patients with S-1-based therapy, but could be considerable between the S-1-based therapy and S-1 monotherapy group. Our conclusion needs to be confirmed via high-quality trials and the results need to be reproduced in other regions and populations.     

S-1-based versus 5-FU-based chemotherapy as first-line treatment in advanced gastric cancer: a meta-analysis of randomized controlled trials

To compare the efficacy, prognosis, and toxicity of S-1-based with fluorouracil (5-FU)-based chemotherapy in patients with advanced gastric cancer (AGC) as first-line treatment, we performed this meta-analysis of all eligible randomized controlled trials (RCTs). A comprehensive literature search of electronic databases (up to February 20, 2014) was performed. Additionally, abstracts presented at the American Society of Clinical Oncology (ASCO) conferences held between January 2000 and February 2014 were searched to identify relevant trials. Overall response rate (ORR), time to treatment failure (TTF), overall survival (OS), and grade 3 or 4 toxicities were analyzed. Six RCTs with 2,264 patients of AGC were included. Meta-analysis demonstrated that S-1-based therapy was associated with better OS compared with 5-FU-based therapy (hazard ratio (HR)?=?0.80, 95 % confidence interval (CI) 0.80–0.99, P?=?0.03). Pooled estimate has showed the trend of superiority of S-1-based therapy in the aspect of ORR (odds ratio (OR)?=?1.55, 95 % CI 0.87–2.77, P?=?0.14) and TTF (HR?=?0.73, 95 % CI 0.53–1.00, P?=?0.05), but the difference was not significant. The incidence of toxicities of 5-FU-based regimens was significantly higher for thrombocytopenia (OR?=?0.60, 95 % CI 0.42–0.88, P?=?0.008) and stomatitis (OR?=?0.22, 0, 95 % CI 0.05–0.9, P?=?0.03). Based on the published studies, S-1-based therapy was superior to 5-FU-based therapy in OS and safety profile as first-line treatment in AGC. It was prone to improving ORR and TTF, though the difference was not significant. More high-quality randomized controlled trials should be performed to provide more information in comparing these two regimens.     

Complete histological response in gastric cancer stage IV after neoadjuvant chemotherapy including S-1 combined with CDDP--report of a case

A 60-year-old man complaining of black stool, body weight loss, and anemia, was examined and diagnosed with advanced gastric cancer (M, type 3, por 2, cT3, cN3, cH0, cP0, cM0, cStage IV). A poor prognosis was predicted, yet we tried neoadjuvant chemotherapy (NAC) expecting downstaging of the tumor. Considering the efficacy and safety, we chose S-1+CDDP as the NAC regimen. S-1 (120 mg/day) was administered orally for 21 days, followed by CDDP (75 mg/body) div on day 8. Distal partial gastrectomy and lymph node dissection (D2) were performed, with Billroth I reconstruction. Histological examination of the resected stomach and lymph nodes revealed no residual cancer cells, suggesting complete histological remission (grade 3) according to the Japanese classification of gastric carcinoma.