Postoperative chemotherapy for gastric cancer

INTRODUCTION: Adjuvant chemotherapy for gastric cancer after potentially curative surgery has been under clinical investigation for more than four decades. However, potentially curative resection can be performed in only 30%-50% of patients. The objective of this article is to review briefly the clinical trials available in the current literature using adjuvant cytotoxic chemotherapy in patients with gastric cancer after potentially curative surgical resection. METHODS: Computerized (MEDLINE) and manual searches were performed to identify papers published on this topic between 1965 and 2005. Only articles with an English abstract were reviewed for inclusion; information abstracted included histologic proof of diagnosis, number of patients, dose and modality of treatment, survival duration, and side effects. RESULTS: Forty-three reports were identified. Single-agent chemotherapy was evaluated in four clinical trials, and postoperative combination chemotherapy was evaluated in 33 trials. Furthermore, we identified five meta-analyses. Five-year survival rates ranged from 12%-91.2%, and the median survival durations were 13-60+ months. Adjuvant chemotherapy, when compared with surgery alone, seems to result in longer survival. CONCLUSION: The high rate of recurrence, even in patients undergoing state-of-the art curative resection, suggests that effective adjuvant chemotherapy might indeed be an attractive concept to improve the overall outcome of patients with gastric cancer. However, because there is no standard regimen for postoperative treatment at the moment, patients with R0-resected (no residual tumors) gastric cancer should be offered the opportunity to participate in prospective clinical trials.     

Recent advances in chemotherapy and chemoradiotherapy for gastrointestinal tract cancers: adjuvant chemoradiotherapy for gastric cancer

Chemoradiotherapy (CRT) is one of the effective modalities for the local control of gastric cancer. Advances in CRT as an adjuvant treatment have been made in the West. The INT0116 trial demonstrated that postoperative chemotherapy with 5-fluorouracil (FU) plus leucovorin and concomitant 45-Gy radiation significantly improved the survival of gastric cancer patients who received gastrectomy with D0 or D1 lymph node dissection. As the result of this trial, the standard treatment for curable gastric cancer in the United States has been considered as a combination of surgery and postoperative CRT. The great interest in CRT in the adjuvant setting for gastric cancer has induced oncologists, particularly in the West, to conduct new clinical trials using various kinds of anticancer drugs. However, there is no rationale for adjuvant CRT after D2 dissection. Large-scale randomized controlled trials in Japanese patients have shown significant improvement of overall survival brought about by postoperative adjuvant chemotherapy with S-1. The results of these studies have suggested that even D2 surgery alone brings about much better survival for patients than limited surgery plus adjuvant CRT. Thus, strategies for the postoperative treatment of gastric cancers should be classified according to the degree of surgery.     

Adjuvant and neoadjuvant therapy of gastric cancer: A comparison of three pivotal studies

In the past, the role of adjuvant therapy for gastric cancer was indefinite. However, three large, randomized controlled trials have recently shown the survival benefit of adjuvant therapy over surgery alone: the American INT 0116 trial, with adjuvant chemoradiation therapy; the European MAGIC trial, with perioperative combination chemotherapy; and the Japanese ACTS-GC trial, with adjuvant monotherapy. Because the patient populations and surgical approaches are considerably different among these trials, it is not sensible to simply compare survival rates to determine the best modality. In the time since these pivotal trials, various innovative studies have been planned and launched to evaluate treatment factors including modality (chemotherapy or chemoradiation), timing (before and/or after surgery), and different surgical extent (D1 or D2 lymphadenectomy). Because the East and West have different backgrounds and treatments for localized gastric cancer, each region should design its own clinical trial to determine the best evidence-based treatment regimens.     

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.     

Surgical treatment of pancreatic cancer: the role of adjuvant and multimodal therapies.

Surgical treatment in specialized referral centers has improved the prognosis of resectable pancreatic cancer considerably despite the generally aggressive behavior of this malignancy. At the same time, adjuvant therapy for pancreatic cancer has been shown to be effective in providing a survival benefit. However, some controversy remains over whether to use chemotherapy alone or combined chemoradiation. Few prospective randomized controlled clinical trials (RCTs) on the use of adjuvant chemotherapy and chemoradiation have demonstrated a distinct survival advantage of systemic chemotherapy (5-FU/FA or gemcitabine) following surgical resection. The most notable published trial is the European Study Group for Pancreatic Cancer (ESPAC)-1 trial. In addition, there are several retrospective analyses and two randomized studies on adjuvant radiation and chemoradiation. Some of these suggested increased survival rates using chemoradiation, which was subsequently widely introduced in clinical routine, especially in the United States. RCTs and a recent meta-analysis of these RCTs confirm, however, the superiority of chemotherapy over chemoradiation, except for a subgroup of patients with positive resection margins. Thus, curative surgery followed by adjuvant systemic chemotherapy should be the standard treatment for patients with resectable, locally confined pancreatic cancer. Further RCTs may clarify potential benefits of chemoradiation in the adjuvant treatment setting. Moreover, the best chemotherapy, or a combination thereof, remains to be determined in large-scale randomized trials.     

Efficacy of Adjuvant Chemotherapy Using Oral Fluorinated Pyrimidines for Curatively Resected Gastric Cancer: A Meta-Analysis of Centrally Randomized Controlled Clinical Trials in Japan

Abstract

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 in gastric cancer: a meta-analysis of randomized trials and a comparison with previous meta-analyses

AIMS AND BACKGROUND: Up to now adjuvant chemotherapy after curative resection for gastric cancer (GC) has been considered an experimental approach. The results of existing phase III randomized trials comparing chemotherapy with control after surgery are controversial. Three meta-analyses have been published in recent years. It is likely that each of them presents a theoretical bias, mainly as regards the inclusion criteria of the trials. In this article we re-examine this potential bias, highlighting the differences between the present and past meta-analyses on adjuvant chemotherapy for GC. METHODS: Only randomized controlled clinical trials comparing systemic adjuvant chemotherapy with control after radical resection of GC were eligible. Total mortality was assessed as outcome measure of the treatment effect and a pooled odds ratio was calculated using the Peto-Mantel-Haenszel method. RESULTS: After the selection process 17 papers (18 comparisons) proved eligible for inclusion in the meta-analysis with a total of 3118 patients, of whom 1546 randomized to the treatment arms and 1572 to the control arms; 762 and 871 deaths occurred in the treatment and control arms, respectively. Statistical analysis suggests an absence of significant heterogeneity between the trials and a significant advantage in survival for adjuvant chemotherapy (pooled odds ratio, 0.72, 95% Cl, 0.62-0.84). CONCLUSIONS: Our meta-analysis would seem to indicate that adjuvant chemotherapy results in a significant survival advantage in patients with GC. However, this observation undoubtedly requires confirmation in large randomized controlled trials including cisplatin before adjuvant chemotherapy after curative resection for GC can be proposed for use in clinical practice.     

Adjuvant therapy for noncolorectal cancers.

Cancers of the esophagus, stomach, and pancreas account for 11% of American cancer deaths and have a high case fatality rate. For esophageal cancer, the superiority of chemoradiotherapy rather than radiotherapy alone as a nonsurgical management was reaffirmed by a large pattern-of-care study in the United States. The study of preoperative chemoradiotherapy followed by surgery continues, with the investigation of newer chemotherapeutic agents combined with radiotherapy in an attempt to improve the therapeutic index of therapy. Trials attempting to intensify chemoradiotherapy treatments have included the addition of postoperative chemotherapy, the addition of brachytherapy, and the escalation of radiotherapy dose above the standard dose of 50.4 Gy. Neither brachytherapy nor an increase in external beam radiotherapy dose has been proven to improve local tumor control or patient survival. Adjuvant chemotherapy alone may have an impact on patient survival in one preliminary report, despite the results of earlier trials that failed to show a benefit for adjuvant chemotherapy alone. In the adjuvant treatment of gastric cancer, a meta-analysis of adjuvant chemotherapy trials suggested a survival benefit for adjuvant chemotherapy compared with surgery alone; however, preliminary reports of two large adjuvant chemotherapy trials using cisplatin-based chemotherapy failed to improve survival compared with surgery alone. The large Intergroup Trial 116, comparing surgery alone to surgery followed by postoperative fluorouracil, leucovorin, and radiotherapy, indicated a significant survival benefit for postoperative chemoradiotherapy. Postoperative chemoradiotherapy is the new standard of care for high-risk resected gastric cancer. Ongoing and future trials will address the inclusion of newer chemotherapeutic agents, the use of preoperative chemotherapy and radiotherapy, and the use of intraperitoneal therapy. In the adjuvant treatment of pancreatic cancer, clinical trials continue to evaluate the role of fluorouracil and radiotherapy, the use of preoperative chemoradiotherapy, and the incorporation of new therapeutic agents.     

Neoadjuvant or adjuvant therapy for resectable gastric cancer: a systematic review and practice guideline for North America

Background

Gastric cancer is a global health problem accounting for 10% of all new cancer cases and 12% of all cancer deaths worldwide. Many clinical trials and meta-analyses have explored the value of neoadjuvant or adjuvant chemotherapy and radiation therapy in gastric cancer; however, these studies have produced conflicting results. The purpose of this guidance document was to determine whether patients with resectable gastric cancer should receive neoadjuvant or adjuvant therapy in addition to surgery. Outcomes of interest were overall survival, disease-free survival, and adverse events.

Methods

A systematic review was undertaken to inform recommendations regarding neoadjuvant and adjuvant therapy in resectable gastric cancer in Ontario, Canada. MEDLINE and EMBASE databases, as well as American Society of Clinical Oncology (ASCO) annual meeting proceedings and American Society for Therapeutic Radiology and Oncology (ASTRO) proceedings were systematically searched from 2002 to 2010. Oral fluoropyrimidine trials were excluded owing to the unavailability of these agents in North America.

Results

Overall, 22 randomized controlled trials (RCTs), 13 meta-analyses, and two secondary analyses were included. The systematic review informed the development of a clinical practice guideline with the following recommendations. Postoperative 5-fluorouracil-based chemoradiotherapy based on the Macdonald approach or perioperative ECF (epirubicin, cisplatin, fluorouracil) chemotherapy based on the Cunningham/MAGIC (Medical Research Council Adjuvant Gastric Infusional Chemotherapy) approach are both acceptable standards of care in North America. Choice of treatment should be made on a case-by-case basis. Adjuvant chemotherapy is a reasonable option for those patients for whom the Macdonald and MAGIC protocols are contraindicated. All patients with resectable gastric cancer should undergo a pretreatment multidisciplinary assessment to determine the best plan of care.

Conclusions

Overall survival in patients with resectable gastric cancer is significantly improved with the use of either postoperative chemoradiation (Macdonald approach) or perioperative ECF (MAGIC protocol).     

Role of adjuvant therapy in resected stage II/IIIA non-small-cell lung cancer

The role of adjuvant therapy following complete resection of node-positive (stage II/IIIA) non-small-cell lung cancer remains controversial. Five-year survival rates in pathologic stage II disease range from 30% to 50% and in resected stage IIIA disease from 10% to 30%. The majority of recurrences following surgery are distant metastases. This two-part review, which began in the December 2001 issue, analyzes the role of adjuvant therapy in this setting, using an evidence-based approach and focusing primarily on randomized trials and meta-analyses. The key variables in evaluating these studies are elucidated, ranging from the extent of mediastinal, systemic, and "molecular" staging to the quality of the adjuvant treatments administered. Some of the potential flaws inherent in meta-analyses are reviewed. To date, there is no convincing evidence that any therapy consistently improves survival in the adjuvant setting. Postoperative radiotherapy has been associated with a significant improvement in local control, particularly in patients with pathologic N2 disease. Chemotherapy should be offered to patients on appropriate clinical trials, and active phase III trials are reviewed. Future strategies include novel chemotherapy, methods to reduce toxicity, the emerging role of neoadjuvant therapy, and the promise of new biologic agents.     

Chemotherapy sensitivity and resistance testing: to be “standard” or to be individualized, that is the question

Radical surgery with extended lymph-node dissection is the treatment of first choice and the only curative treatment for locally advanced gastric cancer. While recent combination chemotherapy with S-1 (a combination of tegafur with two biomodulators, gimeracil and oteracil) has achieved high response rates, controversy still remains regarding the significance of adjuvant cancer chemotherapy after surgery. We have been applying chemosensitivity testing in evaluating the appropriate adjuvant cancer chemotherapy for advanced gastric cancer. Our multiple studies have indicated that this chemosensitivity testing would be useful to improve the results of adjuvant chemotherapy, by increasing survivals in the sensitive group. The chemosensitivity testing is approved as “advanced clinical medicine” by the Japanese Ministry of Health, Welfare, and Labor at 11 institutes at present. While complete lymph-node dissection and chemosensitivity test-guided adjuvant chemotherapy has been reported to result in a survival benefit for patients with advanced gastrointestinal cancer, the clinical utility of the testing should be established by means of prospective, randomized clinical trials. Two pivotal clinical trials have been initiated to clarify the utility of chemosensitivity testing in the selection of the appropriate adjuvant cancer chemotherapy for gastric cancer.     

Adjuvant and Neoadjuvant Therapy for Gastric Carcinoma

Despite its declining incidence, gastric cancer remains one of the leading causes of cancer-related death worldwide. The definitive management of localized gastric cancer has been the center of much international controversy over the years; surgery remains the mainstay, with debate centering on the required extent of lymph node resection. The role of adjuvant chemotherapy has been studied for decades, but because trials have been underpowered, it has been difficult to demonstrate a statistically significant benefit. Recently, four large meta-analyses have been published on adjuvant chemotherapy in gastric cancer. The first three have been criticized for their methodology, but the most recent meta-analysis was well conducted and showed a statistically significant benefit in favor of adjuvant chemotherapy. The heterogeneity of chemotherapy schedules included in this meta-analysis, however, makes it difficult to define the current standard. Randomized trials in the metastatic setting have shown that the combinations of epirubicin, cisplatin, and infusional fluorouracil (ECF) and docetaxel, cisplatin, and fluorouracil (TCF) have demonstrated superiority over other regimens. The role of preoperative chemotherapy is currently under investigation, with results from the MAGIC (Medical Research Council Adjuvant Gastric Infusional Chemotherapy) trial demonstrating a significant improvement in resectability, progression-free survival, and overall survival with perioperative therapy in patients with operable gastric cancer. Postoperative chemoradiotherapy has also been adopted as a standard of care in the US following the publication of the results of the Intergroup Study, INT-0116, although there remains debate over the relative benefits of more radical surgery versus the use of radiation with adjuvant treatment. It is clear that adjuvant therapy is now an appropriate addition to surgery, although there are still further questions regarding the optimal protocols.     

A systematic overview of chemotherapy effects in non-small cell lung cancer.

A systematic review of chemotherapy trials in several tumour types was performed by The Swedish Council of Technology Assessment in Health Care (SBU). The procedures for the evaluation of the scientific literature are described separately (Acta Oncol 2001; 40: 155-65). This overview of the literature on chemotherapy for non-small cell lung cancer (NSCLC) is based on 53 scientific publications including six meta-analyses based on 65 prospective randomised trials comprising 15,607 patients and an additional 32 prospective randomised studies including 8,902 patients. The conclusions reached can be summarised into the following points: In stage IIIB-IV disease, published data demonstrate that cisplatin-based chemotherapy confers a modest, median 1.5-3 months, prolongation of survival. The closely related compound carboplatin seems to provide similar effects. Randomised studies indicate symptomatic relief and improvement of indices of quality of life (QoL) for patients who receive platinum-based combination chemotherapy or single drug therapy with more recent compounds. Data supporting the use of chemotherapy are not available for patients in poor general condition (WHO performance status 3 4) and evidence is limited for elderly patients (above 70-75 years). Platinum-based chemotherapy can be recommended for selective use in routine care of advanced NSCLC although patients should be encouraged to participate in controlled clinical trials to further elucidate the role of chemotherapy in advanced disease. In advanced disease, recent data suggest that the newer agents gemcitabine, paclitaxel, irinotecan and vinorelbine, in combination with cisplatin, provide an additional survival benefit compared with earlier cisplatin-based regimens. Furthermore, paclitaxel, docetaxel and vinorelbine as single agents seemingly provide a survival benefit over supportive care alone comparable to that of older cisplatin-based combinations. A standard regimen for advanced disease cannot yet be defined. Until more data are at hand, it is recommended to be platinum-based and preferably combined with one of the newer agents. At progression after platinum-based chemotherapy for advanced disease, limited data indicate a small survival benefit from docetaxel over supportive care alone. Such second-line chemotherapy of advanced disease can be recommended for selected patients but should preferably be confined to controlled clinical trials. In stage III disease, published data show that induction cisplatin-based chemotherapy before radical radiotherapy modestly prolongs long-term survival and lowers the incidence of distant metastases compared with radiotherapy alone. Furthermore, published data show that concurrent chemo- and radiotherapy with cisplatin or carboplatin may enhance local control and long-term survival. Chemotherapy in this setting can be recommended for selected patients but treatment should preferably be given within a controlled clinical trial. In stage IIIAN2 disease, data from pilot studies demonstrate that surgery after induction chemotherapy is feasible. Pathologically complete remissions have been confirmed in 10-20% of treated patients. Two small randomised studies demonstrate a significant survival advantage for induction chemotherapy followed by surgery compared with surgery alone. Induction chemotherapy can be recommended for selected patients but treatment should preferably be given within a controlled clinical trial. The superiority of induction chemotherapy plus surgery compared with combined chemotherapy and radical irradiation has not been proven in a randomised trial but currently such studies are under way. In the adjuvant setting, published data suggest that cisplatin-based chemotherapy after radical surgery may increase five-year survival from around 50% by a further 5% but the confidence interval for this estimate is too wide for firm conclusions. Large-scale prospective randomised trials are under way to resolve this important issue and adjuvant chemotherapy is, thus, not recommended for routine treatment.     

DOS方案辅助化疗对进展期胃癌的临床效果分析

目的 探讨进展期胃癌患者手术前给予多西他赛联合奥沙利铂和替吉奥(DOS)进行辅助化疗的临床疗效.方法 选取实施手术治疗的进展期胃癌患者88例进行回顾性分析,根据治疗方法不同将患者分为化疗组与单纯手术组,每组各44例.其中化疗组患者手术前给予DOS方案进行辅助化疗,单纯手术组患者仅行手术治疗.对比两组患者的手术情况、手术不良反应和远期生存情况.结果 化疗组44例患者中,有1例患者未能完成一个化疗周期,化疗的总有效率为95.35%;化疗组患者的术中出血量、阳性淋巴结数目均明显少于单纯手术组(P﹤0.001);化疗组患者的R0切除率高于单纯手术组(P﹤0.05);化疗组患者的术后2年复发率低于单纯手术组,2年生存率高于单纯手术组,但差异均无统计学意义(P﹥0.05).结论 术前DOS方案辅助化疗治疗进展期胃癌有利于提高肿瘤的手术根治性效果,有利于患者的远期生存获益.     

Efficacy of adjuvant chemotherapy after curative resection for gastric cancer: A meta-analysis of published randomised trials

Background:Several studies have investigated the possible roleof the adjuvant chemotherapy after curative resection for gastric cancerfailing to show a clear indication; previous meta-analyses suggested smallsurvival benefit of adjuvant chemotherapy, but the statistical methods usedwere open to criticisms. Materials and methods:Randomised trials were identified by meansof Medline and CancerLit and by selecting references from relevant articles.Systematic review of all randomised clinical trials of adjuvant chemotherapyfor gastric cancer compared with surgery alone, published before January 2000,were considered. Pooling of data was performed using the fixed effect model.Death for any cause was the study endpoint. The hazard ratio and its95% confidence intervals (95% CI), derived according to themethod of Parmar, were the statistics chosen for summarising the relativebenefit of chemotherapyversuscontrol. Results:Overall 20 articles (21 comparisons) were considered foranalysis. Three studies used single agent chemotherapy, seven combination of5-fluorouracil (5-FU) with anthracyclin, ten combination of 5-FU withoutanthracyclines. Information on 3658 patients, 2180 deaths, was collected.Chemotherapy reduced the risk of death by 18% (hazard ratio 0.82,95% CI: 0.75–0.89, P < 0.001). Association ofAnthracyclines to 5-FU did not show a statistically significant improvementwhen compared with the effect of the other regimens. Conclusions:Chemotherapy produces a small survival benefit inpatients with curatively resected gastric cancer. However, taking into accountthe limitations of literature based meta-analyses, adjuvant chemotherapy isstill to be considered as an investigational approach.     

Efficacy of adjuvant chemotherapy after curative resection for gastric cancer: A meta-analysis of published randomised trials: A study of the GISCAD (Gruppo Italiano per lo Studio dei Carcinomi dell'Apparato Digerente)

Background: Several studies have investigated the possible roleof the adjuvant chemotherapy after curative resection for gastriccancer failing to show a clear indication; previous meta-analysessuggested small survival benefit of adjuvant chemotherapy, butthe statistical methods used were open to criticisms. Materials and methods: Randomised trials were identified bymeans of Medline and CancerLit and by selecting references fromrelevant articles. Systematic review of all randomised clinicaltrials of adjuvant chemotherapy for gastric cancer comparedwith surgery alone, published before January 2000, were considered.Pooling of data was performed using the fixed effect model.Death for any cause was the study endpoint. The hazard ratioand its 95% confidence intervals (95% CI), derived accordingto the method of Parmar, were the statistics chosen for summarisingthe relative benefit of chemotherapy versus control. Results: Overall 20 articles (21 comparisons) were consideredfor analysis. Three studies used single agent chemotherapy,seven combination of 5-fluorouracil (5-FU) with anthracyclin,ten combination of 5-FU without anthracyclines. Informationon 3658 patients, 2180 deaths, was collected. Chemotherapy reduced the risk of death by 18% (hazard ratio0.82, 95% CI: 0.75–0.89, P < 0.001). Association ofAnthracyclines to 5-FU did not show a statistically significantimprovement when compared with the effect of the other regimens. Conclusions: Chemotherapy produces a small survival benefitin patients with curatively resected gastric cancer. However,taking into account the limitations of literature based meta-analyses,adjuvant chemotherapy is still to be considered as an investigationalapproach. adjuvant, chemotherapy, gastric cancer, meta-analysis, randomised clinical trial     

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.     

Adjuvant chemotherapy for gastric cancer in Japan: global and Japanese perspectives

Adjuvant therapy for gastric cancer after surgical resection has been under clinical investigation for decades. However, up until now, consistent and concrete evidence has not been generated either in Japan or other countries in favor of adjuvant therapy in terms of survival compared to surgery alone. Meta-analyses reported from Western countries have shown either no or borderline benefit for chemotherapy after surgical resection of gastric cancer. A recent trial showed significant benefit for chemoradiotherapy. However, Japanese specialists believe that their perspectives are different from those in the West due to the following: (1) gastric cancer incidence is several times higher in Japan; (2) more stringent screening programs are emphasized in Japan, thus baseline conditions of cancer patients are different; (3) specific operative techniques are used; and (4) Japanese surgeons have probably acquired additional experience in gastric cancer resection techniques. From the 1960s to the 1980s first mitomycin (MMC) and, later, a combination of oral fluorinated pyrimidines (o-FP) and MMC showed improved survival benefit in Japan compared to surgery alone. However, in the late 1980s, an expert group re-examined the results of previous trials, questioned them, and suggested fresh trials. Since then, the Japanese Clinical Oncology Group (JCOG) has conducted relevant trials to re-examine the effect of MMC and/or o-FP as adjuvant chemotherapy. The results of trials JCOG 8801 and JCOG 9206 have already been reported, and the accrual of patients for another trial (NSAS-GC trial) has just been completed. A pooled analysis of the two preceding trials showed a borderline survival benefit for o-FP compared to surgery alone. If o-FP treatment shows a 5% difference in survival benefit in the NSAS-GC trial, a meta-analysis of the three trials would probably reveal overall significant results. In conclusion, this therapy could become the standard adjuvant treatment regimen for gastric cancer patients after curative resection in Japan.     

Postoperative chemotherapy in resected gastric cancer: results of a single center experience

Gastric cancer remains a major health problem despite its decline in incidence in Western countries. Although radical surgery represents the primary curative option for gastric cancer patients, most of them relapse and die due to their disease despite an R0 resection. At present the routine use of postoperative adjuvant therapy to reduce disease recurrence is still considered an investigational approach. Out of a total of 275 patients (stage IB through IV M0 AJCC/UICC) who underwent surgery for gastric cancer at our Surgery Unit between 1993 and 2001, 156 were eligible for adjuvant chemotherapy, of whom only 52 accepted to undergo this treatment. This group of patients was retrospectively compared with a control group (1:2) and overall survival was assessed using hazard ratio and Kaplan-Meier estimates. Five-year survival was 40% in the chemotherapy group and 37.8% in the group which underwent surgery alone. Indeed, chemotherapy did not reduce the risk of death (HR 0.87, 95% CI = 0.57-1.34, p=0.54). Serosal involvement and the invasion of more than 6 lymph nodes were the main independent prognostic factors identified by multivariate analysis. The current study did not show a clear advantage of chemotherapy over surgery alone. However, our results can help to define strategies for future clinical trials with the use of new regimens based on more effective and less toxic drugs.     

Adjuvant chemotherapy using S-1 for curatively resected gastric cancer-the nationwide clinical trial

Actually there has been no established adjuvant therapy for curable gastric cancer. Thus it is strongly recommended in the guidelines to actively carry out clinical trials. A large scale clinical trial on adjuvant chemotherapy for gastric cancer using S-1 (ACTS-GC) started in 2001. This was the first large trial having the surgery alone as control after 1980. The target population was Stage II, IIIA, IIIB, and the expected hazard ratio was less than 0.70. Between October 2001 and December 2004, for 3 years and 2 months, 1,056 patients were enrolled. Thus it was proven that we should carry out a pivotal study instead of making meta-analysis in the field of gastric cancer. Certainly, the results of this trial will strongly affect the clinical practice in Japan. If the results are negative, the use of adjuvant chemotherapy in practice and in social insurance might be restricted.