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.     

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.     

Role of adjuvant chemotherapy in patients with resected non-small-cell lung cancer: reappraisal with a meta-analysis of randomized controlled trials.

PURPOSE: The role of adjuvant chemotherapy in patients with resected non-small-cell lung cancer (NSCLC) remains to be defined. This study was aimed at re-evaluating the effectiveness of adjuvant chemotherapy in patients with resected NSCLC, by performing a meta-analysis of relevant trials. METHODS: We performed a literature search to identify trials reported after the publication of a meta-analysis in 1995, comparing patients with NSCLC receiving chemotherapy after surgery with those undergoing surgery alone. The hazard ratio (HR) was estimated to assess the survival advantage of adjuvant chemotherapy. RESULTS: Eleven trials conducted on a total of 5,716 patients were identified by the literature search. In these trials, hazard ratio estimates suggested that adjuvant chemotherapy yielded a survival advantage over surgery alone (HR, 0.872; 95% CI, 0.805 to 0.944; P =.001). In a subset analysis, both cisplatin-based chemotherapy (HR, 0.891; 95% CI, 0.815 to 0.975; P =.012) and single-agent therapy with tegafur and uracil (UFT; HR, 0.799; 95% CI, 0.668 to 0.957; P =.015) were found to yield a significant survival benefit. The toxicities of adjuvant chemotherapy were found to be generally mild. CONCLUSION: This is the first updated meta-analysis demonstrating the importance of cisplatin-based chemotherapy and single-agent UFT therapy as adjuvant chemotherapy in the treatment of resected NSCLC. Although the results must be carefully interpreted because of one limitation (the meta-analysis was performed with abstracted data), they raise critical issues that must be resolved in future studies.     

胃癌术后辅助放化疗与辅助化疗比较的荟萃分析

目的 采用偱证医学荟萃分析的方法比较胃癌术后辅助放化疗与辅助化疗间的疗效差异。方法 计算机检索PubMed、EMbase、Cochrane图书馆、万方、维普、CNKI及中国生物医学等数据库,搜集有关胃癌术后辅助放化疗和辅助化疗比较的临床对照研究资料,汇总数据采用RevMan 5.2.5和Stata 12.0软件进行分析。两组间差异采用优势比(OR)及95%可信区间(95% CI)描述。结果 根据纳入和排除标准,最终纳入12个包括1674例患者的临床对照研究资料。荟萃分析结果显示,与胃癌术后辅助化疗相比,辅助放化疗的3、5年生存率更高(OR=2.96,95% CI= 1.75~5.03,P=0.000;OR=1.45,95% CI=1.06~1.99,P=0.020),辅助放化疗的局部复发率更低(OR=0.50,95% CI=0.34~0.72,P=0.000),但远处转移率两组相似(OR=0.79,95% CI=0.58~1.07,P=0.130)。结论 现有研究结果的荟萃分析显示,与胃癌术后辅助化疗相比,胃癌术后辅助放化疗是一种较为安全和有效的治疗方法。     

Review of comparative studies of postoperative adjuvant chemotherapy after curatively resected colorectal cancer in Japan

Six randomized control studies (RCT) in Japan conducted after 1984 were reviewed. These studies basically investigated postoperative oral administration of 5-FU followed by venous injection of MMC. The efficacy of this treatment compared with a surgery alone group was demonstrated with statistical significance in some papers only in patients with Dukes' B and C cancer. However, there were many mistakes in these studies, including incorrect stratification, incorrect administration of the drugs, and follow-up mistakes. Furthermore, two new types of RCT were introduced. One was studies with prospective stratification of the patients according to predicting factors for recurrence, and the other was those examining continuous arterial infusion of 5-FU for the purpose of suppressing recurrence in the residual liver after curative resections of hepatic metastases.     

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.     

An individual patient data meta-analysis of long supported adjuvant chemotherapy with oral carmofur in patients with curatively resected colorectal cancer

To reappraise the benefits of the long supported chemotherapy with carmofur, a meta-analysis based on individual patient data from the three clinical trials was performed by pooling 614 patients from three trials, there is a statistically significant survival benefit (2p=0.032) and disease-free survival (DFS) benefit (2p=0.021) for carmofur; and a highly significant advantage for carmofur in DFS (2p=0.0004) and in survival (2p=0.004) in Dukes' C patients. This IPD meta-analysis strongly suggested an effect of oral carmofur in a long supported chemotherapy for curatively resected colorectal carcinoma.     

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.     

Update of adjuvant chemotherapy for resected gastric cancer

Gastric cancer is the second cause of cancer that is related to death and the fourth most common cancer, worldwide. Complete resection of cancer is the only curative treatment for gastric cancer. However, even if complete resection is possible, recurrence is frequently observed in Gastric patients. Therefore, adjuvant treatment modality for resectable gastric cancer is needed to increase the survival of patients. This study wants to describe the role of adjuvant chemotherapy for resectable gastric cancer, with updated data of recent studies. Several meta-analysis studies demonstrated a benefit of adjuvant chemotherapy for resectable gastric cancer. Due to the heterogeneity of the population and regimens, there is no consensus regarding the adjuvant chemotherapy. Recently published, well designed phase III studies demonstrated the statistically significance of adjuvant chemotherapy for the resectable gastric cancer, with the extended lymph node dissection. Further phase III trials, to determine the best regimen and schedule of adjuvant chemotherapy, was suggested to use the fluoropyrimidine based regimen as control group.     

Magnitude of benefit of adjuvant chemotherapy for non-small cell lung cancer: meta-analysis of randomized clinical trials

Several randomized trials investigating the benefit of adjuvant chemotherapy after surgery in non-small cell lung cancer (NSCLC) have provided conflicting results. With over 7000 patients included, we analyzed results of 13 reports over the past 10 years in which patients received either platinum-containing chemotherapy or not. The major endpoint was to assess the magnitude of the benefit of adjuvant chemotherapy in terms of the absolute benefit. All phase III randomized trials and meta-analyses published as peer-reviewed papers or as abstracts from 1994 to 2007 were eligible. A literature-based meta-analysis was performed; event-based overall- and disease-free survival (OS/DFS) and Relative Risks (RRs) with 95% confidence intervals (CIs) were derived. Magnitudes of benefit were evaluated with: absolute benefit and the number of patients treated for one patient to benefit. Seven sub-populations were examined. Combined effect estimation was computed with fixed- and random-effect models; a heterogeneity test was also applied. Twelve trials plus an individual patient meta-analysis (7334 patients) were gathered; the trials were designed to determine if cisplatin- or carboplatin-based chemotherapy improves survival over surgery. When data were pooled and plotted, significant differences in favor of chemotherapy were seen in OS in all seven sub-population, with a relative benefit of 7-12% and an absolute benefit ranging from 2.5% to 4.1%. A more significant trend for chemotherapy was found in DFS. No significant heterogeneity was observed for all outcomes and sub-populations. The absolute benefit of adjuvant chemotherapy remains essentially the same regardless of how data are screened. While significant differences are clearly found in this analysis, the small magnitude of benefit seen with this large population, especially when considering the number of patients needed for one to benefit, raises important issues when weighing risks and benefits of treatment for individual patients.     

Cost-effectiveness of adjuvant chemotherapy with uracil-tegafur for curatively resected stage III rectal cancer

Recently, the National Surgical Adjuvant Study of Colorectal Cancer in Japan, a randomised controlled trial of oral uracil-tegafur (UFT) adjuvant therapy for stage III rectal cancer, showed remarkable survival gains, compared with surgery alone. To evaluate value for money of adjuvant UFT therapy, cost-effective analysis was carried out. Cost-effectiveness analysis of adjuvant UFT therapy was carried out from a payer's perspective, compared with surgery alone. Overall survival and relapse-free survival were estimated by Kaplan-Meier method, up to 5.6 years from randomisation. Costs were estimated from trial data during observation. Quality-adjusted life-years (QALYs) were calculated using utility score from literature. Beyond observation period, they were simulated by the Boag model combined with the competing risk model. For 5.6-year observation, 10-year follow-up and over lifetime, adjuvant UFT therapy gained 0.50, 0.96 and 2.28 QALYs, and reduced costs by $2457, $1771 and $1843 per person compared with surgery alone, respectively (3% discount rate for both effect and costs). Cost-effectiveness acceptability and net monetary benefit analyses showed the robustness of these results. Economic evaluation of adjuvant UFT therapy showed that this therapy is cost saving and can be considered as a cost-effective treatment universally accepted for wide use in Japan.     

Clinical effectiveness of neoadjuvant chemotherapy in advanced gastric cancer: An updated meta-analysis of randomized controlled trials

Aims

To assess the efficacy and safety of neoadjuvant chemotherapy (NAC) for advanced gastric cancer (AGC).

Methods

By searching electronic databases (PubMed, Embase, Cochrane Library) and ASCO proceedings from 1990 to 2012, all randomized controlled trials (RCTs) which compared the effect of NAC-combined surgery versus surgery alone in AGC were included. All calculations and statistical tests were performed using RevMan 5.0 software.

Results

12 RCTs with a total of 1820 patients were included. All patients had locally advanced but resectable gastric cancer and received NAC. NAC can slightly improve the survival rate (OR = 1.32, 95% confidence interval (CI): 1.07–1.64, P = 0.01), with little or no significant benefits in subgroup analyses between either different population or regimens. NAC can significantly improve the 3-year progression-free survival (PFS) (OR: 1.85, 95% CI: 1.39–2.46, p < 0.0001), tumor down-staging rate (OR: 1.71, 95% CI: 1.26, 2.33, p = 0.0006) and R0 resection rate (OR: 1.38, 95% CI: 1.08–1.78, P = 0.01) of patients with AGC. There was no difference between the two arms, in terms of relapse rates (OR: 1.03, 95% CI: 0.60–1.78, p = 0.92), operative complications (OR: 1.20, 95% CI: 0.90–1.58, p = 0.21), perioperative mortality (OR: 1.14, 95% CI: 0.64–2.05, p = 0.65) and grade 3/4 adverse effects: gastrointestinal problem (OR: 0.57, 95% CI: 0.25–1.30, p = 0.18), leukopenia (OR: 0.88, 95% CI: 0.41–1.91, p = 0.75), thrombocytopenia (OR: 1.27, 95% CI: 0.27–5.93, p = 0.76).

Conclusion

NAC is effective and safe. However, further prospective multi-national and multi-center RCTs are still needed in order to investigate the long-term oncological and functional outcomes to define the clinical benefits of NAC and the most effective strategies for AGC.     

Comparative effectiveness of adjuvant treatments for resected gastric cancer: a network meta-analysis

Background

Different adjuvant treatments are available for patients with gastric cancer, but conventional meta-analyses performing direct comparisons between two alternative treatments did not have enough power to compare all the adjuvant treatments. Thus, we did a network meta-analysis summarizing the direct and indirect comparisons to identify the optimum treatment.

Methods

We systematically searched for RCTs of adjuvant treatments for gastric cancer comparing two or more of the following treatments: surgery alone, radiotherapy with fluoropyrimidine, S-1-based regimens, and XELOX. The treatments offering available indirect evidence to investigate the comparative effectiveness of adjuvant treatments mentioned above were also included. Then we performed a Bayesian network meta-analysis to summarize the direct and indirect comparisons. We estimated hazard ratios with 95% credible intervals (CrI) for OS and DFS.

Results

11 eligible RCTs (5620 patients) were included in the network meta-analysis. Radiotherapy with fluorouracil (5-FU/RT), S-1-based regimens, and XELOX significantly improved OS as compared with surgery alone [(HR?=?0.75 with 95% CrI: 0.63–0.89), (HR?=?0.63 with 95% CrI: 0.52–0.76), and (HR?=?0.66 with 95% CrI: 0.51–0.85), respectively]. No treatment was clearly superior to others; however, S-1-based regimes and XELOX showed a statistically non-significant trend to better survival as compared with 5-FU/RT.

Conclusions

S-1-based chemotherapy and XELOX are likely to be the most effective adjuvant treatments for patients with resected gastric cancer. 5-FU alone provided little survival benefits as compared with surgery alone. Further clinical trials may be required to investigate S-1-based and XELOX-based adjuvant treatment strategies.

     

A systematic meta-analysis of randomized controlled trials of adjuvant chemotherapy for localized resectable soft-tissue sarcoma

BACKGROUND: The use of adjuvant chemotherapy to treat adults with localized resectable soft-tissue sarcoma remains controversial. The objective of this systematic review was to update the 1997 meta-analysis of randomized controlled trials (RCTs) to reassess the efficacy of doxorubicin-based chemotherapy with respect to recurrence and survival. METHODS: A comprehensive literature search was performed to identify RCTs of adjuvant chemotherapy for adult patients diagnosed with localized resectable soft-tissue sarcoma. Two reviewers independently assessed eligibility and quality of the studies using a modified version of the Detsky Quality Scale. The outcome measures were local, distant, and overall recurrence and survival calculated through the fixed effect or random effect model. RESULTS: Four new eligible trials were identified allowing for a total of 18 trials representing 1953 patients to be included in the analysis. The odds ratios (OR) for local recurrence was 0.73 (95% confidence interval [CI] 0.56-0.94; P = .02) in favor of chemotherapy. For distant and overall recurrence the OR was 0.67 (95% CI 0.56-0.82; P = .0001) in favor of chemotherapy. In terms of survival, doxorubicin alone had an OR of 0.84 (95% CI, 0.68-1.03; P = .09), which as not statistically significant. However, the OR for doxorubicin combined with ifosfamide was 0.56 (95% CI, 0.36-0.85; P = .01) in favor of chemotherapy. CONCLUSIONS: This updated meta-analysis confirms the marginal efficacy of chemotherapy in localized resectable soft-tissue sarcoma with respect to local recurrence, distant recurrence, overall recurrence, and overall survival. These benefits are further improved with the addition of ifosfamide to doxorubicin-based regimens, but must be weighed against associated toxicities.     

Survival benefit of chemotherapy in metastatic colorectal cancer: a meta-analysis of randomized controlled trials

To estimate the magnitude of benefit of chemotherapy in prolonging survival for patients with metastatic colorectal cancer, a meta-analysis of randomized controlled trial was performed. A systematic search was performed to identify randomized trials comparing chemotherapy with observation or supportive care alone. Trials were assessed for quality of reporting, publication bias and heterogeneity. Relative risks for outcomes from published data were pooled using a random-effects model. Seven trials with 614 patients were included. All trials used fluoropyrimidine-based chemotherapy, through a variety of routes and schedules, including intravenous, intra-portal and hepatic arterial infusion. Compared with the 'no-chemotherapy' arm, chemotherapy significantly reduced 1-year mortality (risk ratio 0.69; 95% confidence interval (CI) 0.60-0.81, P < 0.00001). The mortality at 2 years was not significantly different (risk ratio 0.93; 95% CI 0.87-1.00, P = 0.053). Between-trial comparisons demonstrated benefit with a variety of routes and schedules. Chemotherapy significantly prolongs 1-year survival for patients with metastatic colorectal cancer, and should be offered to those with good performance status.     

Registration for a large-scale randomized controlled trial of postsurgical adjuvant chemotherapy for lung cancer in Japan

Background. The reliability of results obtained from clinical trials depends on the study design and its implementation, but there are few reports on implementation. We aimed to describe one component of implementation, registration problems, as observed in a large-scale randomized trial of postsurgical adjuvant chemotherapy for lung cancer whose subjects were enrolled during the period from 1994 to 1997. Methods. The trial adopted central registration through telephone or facsimile entry at a randomization center. Unexpected entry processes were counted prospectively, with the reason noted. The time from the start of speaking on the telephone to entry completion was measured automatically by a computer system. Results. The office registered 999 of 1054 patient reports after checking eligibility criteria. Reasons for failure to meet the criteria were: age (22 patients), late entry – more than 6 weeks after surgery (10 patients), histology (8 patients), entry from hospitals for which the contract for trial participation had not been completed (5 patients), and other (10 patients). Among the 999 registered cases (807 telephone entries and 192 facsimile entries), 50 cases (5.0%) showed a lack of information on eligibility criteria on the first call: 17 made by telephone (2.1%) and 33 by facsimile (17.2%). The average time for registration by telephone was 2 min 51 s among the 766 registrations completed without problems on the first call. The busiest hours for the entry calls were 9:00 to 10:00 and 15:30 to 17:00. There was no difference in the number of entry calls among the days from Monday to Friday. Conclusion. Actual registration of a large-scale cancer trial in Japan was documented, which provided useful information for both the trial centers and the doctors engaging in clinical trials. Received: January 5, 1997 / Accepted: January 11, 1999     

Postoperative adjuvant chemotherapy of gastric cancer: scrutiny into the clinical evidence based on quality assessment of medical literature of randomized controlled trials

The aim of this study was to scrutinize the evidence of adjuvant chemotherapy of gastric cancer by assessing the quality of the medical literature of randomized controlled trials (RCTs). A quality assessment (QA) scoring system was devised with the three parameters—control of bias, quality of report, and quality of design—which consisted 19 items. We searched for all the publications of the RCTs, from 1969 to 2007, with surgery-only arm, and their associated meta-analyses to score. Among the 26 RCTs, quality of three articles were graded as (2+), 10 articles as (1+), and 13 articles as (−). Recently published studies had overall better quality of report, but not necessarily better quality of design. Three studies demonstrating a positive survival benefit of adjuvant chemotherapy had a grade (1+). Hierarchical clustering revealed that the 26 articles were grouped into three major branches associated with study quality and a multi-institutional setting. We also obtained a statistically significant set of ten items (P < 0.001) that could differentiate articles of good (1–2+) and low quality (−) through supervised two-way hierarchical clustering. Finally, the level of recommendation for adjuvant chemotherapy in gastric cancer was to be a “B” according to the Scottish Intercollegiate Guidelines Network (SIGN) System. QA of medical literature should be an essential consideration for medical-related decision-making and the formation of evidence-based guidelines. Multidisciplinary discussion to develop and refine trial design is important for procuring better quality of RCTs of adjuvant chemotherapy of gastric cancer.