CYP2A6基因多态性对胃癌术后含S-1辅助化疗方案疗效的影响

  目的  S-1（替吉奥）的活性前体为替加氟,主要通过细胞色素P450酶2A6（human cytochrome P450,family 2,subfamily A,polypeptide 6,CYP2A6）代谢为5-FU而发挥细胞毒作用。本研究探讨CYP2A6基因多态性与胃癌术后患者含S-1辅助化疗方案疗效的相关性。  方法  选取2007年11月至2013年5月于郑州市人民医院收治的胃癌患者200例,给予标准给药方案。在CYP2A6基因分析中,选取野生型的CYP2A6*1,突变型的CYP2A6*4、*7、*9、*10等位点进行分析。  结果  200例患者中位随访时间为46.4（12.5~80.1）个月。野生型（W/W）3年无复发生存（relapse free survival,RFS）率为95.9%、突变杂合子（W/V）型为83.1%、突变纯合子（V/V）型为72.5%（P=0.032）。不同基因型之间的3~4级不良反应的差异无统计学意义（P=0.628,P=0.227）。  结论  CYP2A6基因型与含S-1化疗方案的长期疗效有关,突变型患者的3年RFS降低。      

Associations between CYP2A6 polymorphisms and outcomes of adjuvant S-1 chemotherapy in patients with curatively resected gastric cancer

Gastric Cancer - Oral fluoropyrimidine S-1 contains tegafur, which is metabolized to 5-fluorouracil by cytochrome P450 2A6 (CYP2A6). We here examined associations between CYP2A6 polymorphisms and...     

Current status and problem of adjuvant chemotherapy for curatively resected gastric cancer

Randomized controlled trials (RCT) on adjuvant chemotherapy for gastric cancer published in the West and Japan were reviewed. Although several small trials showed positive data, adjuvant chemotherapy for curatively resected gastric cancer has been thought to be ineffective in western countries. Results of Japanese RCTs also have not become evidence of its benefit. Despite this, suggestive data by non-predefined subset analyses of old RCTs have been misread as definitive evidence of benefit because of less understanding of clinical statistics in Japan. As a result most Japanese patients have received postoperative adjuvant chemoimmunotherapy. Recently understanding of clinical trial has spread gradually and well designed RCTs with sufficient sample size have been reported. First of all we have to determine the efficacy of adjuvant chemotherapy by carefully designed RCT using surgery alone arm as control.     

Efficacy of adjuvant chemotherapy using tegafur-based regimen for curatively resected gastric cancer: update of a meta-analysis

A consensus regarding standard adjuvant chemotherapy for curatively resected gastric cancer has not been obtained between Japan and the Western world. In order to evaluate the effect of a tegafur-based regimen (the most frequently used regimen in Japan) compared with a surgery-alone control, a meta-analysis was performed, investigating four clinical trials. After meticulous examination of each trial, trials with improper noncentralized randomization were excluded from the analysis. A total of 1197 patients were enrolled in the four relevant trials determined to be eligible for the meta-analysis (Nakajima 1984; Japan Clinical Oncology Group [JCOG] 8801, JCOG 9206-2, and National Surgical Adjuvant Study of Gastric Cancer [NSASGC], in which a tegafur-based regimen was used for chemotherapy and central randomization was performed. The endpoint was overall survival, and a common hazard ratio was estimated. The 5-year overall survival rates differed among the trials because of differences in the background disease status. But there was no heterogeneity (P = 0.235) of treatment effect. The estimated common hazard ratio was 0.75, with a 95% confidence interval of 0.58–0.98. The treatment effect of the tegafur-based agent was shown to be statistically significant (P = 0.037) compared with surgery-alone therapy (n = 1179). From the results of the above meta-analysis, it is suggested that chemotherapy with a tegafur-based agent after surgery can improve the survival of patients with curatively resected gastric cancer. The Global Advanced/Adjuvant Stomach Tumor Research through International Collaboration (GASTRIC) group is conducting two individual patient data meta-analyses, testing post-operative adjuvant chemotherapy for resect-able gastric cancer and chemotherapy for advanced gastric cancer. It is expected to determine and quantify the role of adjuvant chemotherapy in detail from the GASTRIC.     

Second-line chemotherapy in gastric cancer following S-1 with CPT-11 chemotherapy performed as clinical trial

We previously conducted a phase I/II study of irinotecan (CPT-11) combined with S-1 as first-line chemotherapy for metastatic advanced gastric cancer. In the present study,second-line chemotherapy was given to 32 of 44 patients whose disease became refractory to this first-line treatment. Overall survival time of the patients given second-line chemotherapy was significantly longer than that of patients not given such therapy (444 days vs. 230 days, p = 0.013). The response rate to second-line chemotherapy was 13% (4/32). Survival time of patients who responded to second-line chemotherapy was significantly longer than that of non-responders. Second-line chemotherapy may produce a better clinical response in patients who have progressive disease during first-line chemotherapy. Overall survival time and time to progression after second-line chemotherapy did not significantly differ between patients who received second-line chemotherapy regimens including S-1 and those who received regimens not including S-1.     

A case of curatively resected gastric cancer through an effective response to chemotherapy

The patient is a 66-year-old male who underwent gastrojejunostomy at another hospital with the diagnosis of type 3 unresectable gastric cancer. He was admitted to our hospital for adjuvant chemotherapy. A CT scan revealed both peritoneal dissemination and a large tumor directly invading the pancreas and liver. After 7 courses of combined chemotherapy with 5-FU, Leucovorin, cis-platinum and methotrexate, an effective response, tumor reduction and the disappearance of peritoneal dissemination, was verified by CT scan. Pancreatoduodenectomy with transverse colectomy was carried out and the pathological diagnosis was also curative (pT3, pN1, pP0, HO: stage III A). Although he unfortunately died from peritoneal recurrence after 9 months, he maintained good quality of life after re-operation. We think this case shows the possibility of NAC for patients with far advanced gastric cancer with peritoneal dissemination to improve their prognosis or QOL.     

Adjuvant therapy for resected gastric carcinoma

Despite its continued decline over the past 40 years, gastric carcinoma is a common gastrointestinal cancer and a major health problem around the world. In Asian countries, such as Korea, Japan, Taiwan, and China, it remains one of the leading causes of cancer-related death. Similarly, it is a common malignancy in many South American countries, Eastern European countries, and many countries of the former Soviet Union. In North America, the incidence of gastric carcinoma is low; however, the incidence of proximal gastric carcinoma has risen over the past 15 years. In 2001, approximately 21,700 new cases and 12,800 deaths were estimated in the United States as a result of gastric carcinoma. In the United States, gastric cancer ranks 14th among all cancers in incidence rate and 10th in overall mortality rate. An early detection program has been established in Japan, where nearly 6,000,000 adults are screened annually. This type of mass screening for gastric cancer is not practiced elsewhere, however. Because the risk of relapse remains high for patients after a curative resection, there is a great need for effective adjuvant therapy for patients with gastric carcinoma.     

Development of clinical pathway in S-1 chemotherapy for gastric cancer

We have developed a clinical pathway to enable the safe continuous administration of S-1 (TS-1^®) in ambulatory care for patients with advanced gastric cancer. The S-1 clinical pathway includes a pathway for clinicians, a pathway for patients, and such assist tools as a medication diary, an explanatory document containing instructions relating to patient compliance, a table of associations between adverse reactions and prodromes, and general principles for dose reduction and withdrawal. These pathways and assist tools will improve the patient's perception of adverse reactions, thereby contributing to early discovery and rapid action against adverse events. The S-1 clinical pathway has been used with ten patients. S-1 administration has been continued in seven patients. In four of the seven patients, continued administration on the occurrence of adverse reactions was made possible by the use of appropriate measures such as drug withdrawal or dose reduction. It was confirmed that the S-1 clinical pathway was a useful tool for cancer chemotherapy in ambulatory care.     

Efficacy of adjuvant chemotherapy using oral fluorinated pyrimidines for curatively resected gastric cancer: a meta-analysis of centrally randomized controlled clinical trials in Japan

Adjuvant chemotherapy for gastric cancer has been extensively explored in Japan since the 1950s, and a combination of oral fluorinated pyrimidines (o-FP) and mitomycin C (MMC) has been mainly utilized for adjuvant chemotherapy. However, there is no sufficient evidence for the efficacy of adjuvant therapy. Therefore, we assessed the efficacy of o-FPs over surgery alone (control) by means of a meta-analysis of Japanese centrally randomized controlled clinical trials conducted between 1980 and 2005. For inclusion in this study, studies had to compare adjuvant chemotherapy for curatively resected gastric cancer with surgery alone, mainly targeting o-FP, and central randomization designed to comply with contemporary standards for clinical trials in Japan. For the 4 trials that met the eligibility criteria, the estimated hazard ratio was 0.73 (95%CI=0.60-0.89). Our findings show that in Japan adjuvant chemotherapy using o-FP for long-term maintenance therapy appears to be effective for gastric cancer patients after curative resection.     

Adjuvant chemotherapy for resected non-small-cell lung cancer

Because of the high rate of distant disease recurrence, the 5-year survival of patients who have undergone complete surgical resection of localized non-small-cell lung cancer (NSCLC) is approximately 50%. Initial results from early studies of adjuvant postoperative chemotherapy reported an adverse effect of alkylating agent and older chemotherapy regimens on survival. Cisplatin-based combinations were the first to show a survival advantage. A 1995 meta-analysis of these studies suggested a 13% reduction in the hazard ratio for death (HR = 0.87), leading to a 5% survival benefit at 5 years. Still, these trials involved limited numbers of patients (N = 1,394), and the results failed to reach statistical significance (P = .08). Of the five largest subsequent randomized trials of platinum-based adjuvant therapy, three showed a significant survival advantage. Although it is impossible to determine the reasons for the differing outcomes of these studies, several key features distinguish them, and the data suggest that medically fit patients with resected stage IB or II NSCLC should be offered chemotherapy with a platinum/new drug combination.     

Adjuvant chemotherapy with S-1 for head and neck carcinoma

Combined chemotherapy is considered essential for further improvement of the cure rate of head and neck carcinoma. Chemotherapy in cases of head and neck carcinoma is administered with one of two objectives: as adjuvant therapy to increase the survival rate after radical treatment in the early stage of the disease, and to prolong the survival rate in cases with advanced or recurrent carcinoma. There is, however, no clear answer to the question of how these objectives can be accomplished. In our department, we use S-1 chemotherapy to achieve these goals. Our modified S-1 administration method until 2005 consists of a 3-week drug administration period followed by a 2-week drug-free period (3w-2w), or a 2-week administration period followed by a 2-week drug-free period (2w-2w). We determined the usefulness of the optimum administration method by examining the rate of completion of the treatment, and its safety and therapeutic efficacy. S-1 administration was used in 68 cases of head and neck carcinoma until 2005. As a result, the rate of completion of the treatment and its safety were high. Further randomized controlled trials with a high degree of accuracy are needed to confirm whether or not our treatment method would improve the survival rate/ prolong the duration of survival in these patients.     

S-1抗肿瘤药物在胃癌病人中的临床应用进展

药物治疗在胃癌治疗中具有重要地位.S-1作为一种新型口服抗肿瘤药物具有高效低毒、病人依从性好的优势,合理开展含S-1及S-1单药方案治疗胃癌的临床试验具有重要意义.     

A case of AFP-producing gastric cancer resected after efficient S-1/CDDP combination chemotherapy

A 62-year-old male was diagnosed as AFP-producing gastric cancer with lymph node metastases and multiple liver metastases. He was treated with S-1 and CDDP combination chemotherapy. At the end of the first course, both primary and metastatic lesions were remarkably decreased in size, and the serum AFP level was also decreased. The chemotherapy was effective against the cancer and led to a partial response (PR) according to the RECIST guideline. Following the nine months of PR, the primary lesion which had once nearly disappeared, emerged again. Because distant lymph node metastases and liver metastases were considered to have disappeared, distal gastrectomy with D2 lymphadenectomy was performed. The patient received S-1 monotherapy for 6 months after the operation. At present the patient has achieved progression-free survival for 1 year and 3 months after the operation. Though AFP-producing gastric cancer is known for its poor prognosis, combination treatment such as operation or hepatic arterial infusion chemotherapy may improve the prognosis in patients with advanced AFP-producing gastric cancer when systemic chemotherapy is effective.     

Adjuvant chemotherapy for resected non-small-cell lung cancer: future perspectives for clinical research

Adjuvant chemotherapy for non-small-cell lung carcinoma (NSCLC) is a debated issue in clinical oncology. Although it is considered a standard for resected stage II-IIIA patients according to the available guidelines, many questions are still open. Among them, it should be acknowledged that the treatment for stage IB disease has shown so far a limited (if sizable) efficacy, the role of modern radiotherapies requires to be evaluated in large prospective randomized trials and the relative impact of age and comorbidities should be weighted to assess the reliability of the trials'' evidences in the context of the everyday-practice. In addition, a conclusive evidence of the best partner for cisplatin is currently awaited as well as a deeper investigation of the fading effect of chemotherapy over time. The limited survival benefit since first studies were published and the lack of reliable prognostic and predictive factors beyond pathological stage, strongly call for the identification of bio-molecular markers and classifiers to identify which patients should be treated and which drugs should be used. Given the disappointing results of targeted therapy in this setting have obscured the initial promising perspectives, a biomarker-selection approach may represent the basis of future trials exploring adjuvant treatment for resected NSCLC.     

A modified prognostic score for patients with curatively resected gastric cancer

AIMS AND BACKGROUND: Gastric cancer is the second leading cause of cancer death worldwide; the risk of dying depends on several patient and disease characteristics. An existing prognostic score predicts survival in gastric cancer patients undergoing curative resection based on patient age, tumor site, extent of wall invasion and nodal status, categorized as simply as negative or positive. METHODS: Our aim was to modify the original prognostic score by incorporating information on nodal stage according to the latest TNM classification (number of involved nodes), based on a retrospective series of 610 chemotherapy-naive gastric cancer patients recruited to a surgical clinical trial. We then tested the modified score on an independent series of 136 gastric cancer patients. RESULTS: Nodal stage added significant prognostic information to the nodal status classification (P < 0.001), and was therefore included in the modified score. With the latter, we were able to identify three risk groups with overall five-year survival varying from more than 70% to less than 30%. The prognostic performance of the modified score was better than that achieved with the AJCC-UICC TNM staging. CONCLUSIONS: The modified score, based on established prognostic factors, is proposed as a simple tool for prognostic grouping of gastric cancer patients undergoing curative surgery.     

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.     

Adjuvant chemotherapy with S-1 for advanced head and neck carcinoma

Most cases of head and neck squamous cell carcinoma (HNSCC) are in the advanced stages, resulting in a poor prognosis. To improve the poor outcome, adjuvant chemotherapy is indispensable for advanced cases with a high relapse risk after standard definitive treatments including surgery and/or radiotherapy. To define an adequate administration schedule in adjuvant chemotherapy with S-1, a controlled randomized study in multi-institutes was done. The results showed the 2-week administration followed by 1-week rest was superior to the 4-week administration followed by the 2-week rest in terms of safety and efficacy. In the present paper, some problems of adjuvant chemotherapy were discussed, and the protocol was described in terms of a multi-institutional controlled randomized comparison study of S-1 versus UFT in an adjuvant chemotherapy setting for locally advanced HNSCC.