An updated meta-analysis of adjuvant chemotherapy after curative resection for gastric cancer

Objectives

To investigate whether and how much gastric cancer patients after curative resection could benefit from chemotherapy.

Patients and methods

Meta-analysis was conducted with all the qualified clinical randomized trials which compared adjuvant chemotherapy with surgery alone. The database includes MEDLINE, EMBase and CBM disc, and the censor data were up to November 2007. Primary outcomes were relative risk (RR) on death and disease-free survival (DFS); secondary outcomes include RR of adverse reactions of the two arms. Sub-group analysis and sensitivity analysis were also performed. All the calculations and statistical tests were done with the RevMan 4.2.8 software.

Results

Finally, 23 trials which included 4919 patients (2441 in the adjuvant chemotherapy arm, 2478 in the observation arm) achieved all the criteria. Among them, 19 studies reported the survival rate at the end of follow-up, 60.6% alive among 2286 patients in the adjuvant chemotherapy arm, 53.4% alive among 2313 patients in the observation arm, with the RR on death of 0.85 (95%CI: 0.80–0.90). Eight studies reported the DFS, and the observation arm had a shorter DFS (RR: 0.88, 95%CI: 0.77–0.99). Grade 3/4 of myelosuppression and GI toxicity occurred more frequently in the treatment arm. Nine studies reported the recurrence rate and suggested that the treatment arm had a lower recurrence rate (RR: 0.78, 95%CI: 0.71∼0.86).

Conclusions

Statistically, adjuvant chemotherapy could improve the survival rate and disease-free survival rate in gastric cancer after curative resection and reduce the relapse rate. However, the clinical benefits of adjuvant chemotherapy still need to be improved. Additionally, post-operative chemotherapy could be tolerated.     

Randomized trial of adjuvant chemotherapy versus control after curative resection for gastric cancer: 5-year follow-up

Adjuvant chemotherapy of gastric cancer after curative resection is still subject to discussion. In this study 137 patients with gastric adenocarcinoma, all with positive nodes, were randomized after curative resection so that 69 received epidoxorubicin (EPI), leucovorin (LV) and 5-fluorouracil (5-FU) on days 1-3 every 3 weeks for 7 months, whereas the remaining 68 did not. After a follow-up period of 5 years, 21 of the 69 treated patients (30%) and nine controls (13%) were still alive; median survival time was 18 months for the controls and 31 months for the patients treated with adjuvant chemotherapy (P< 0.01).     

胃癌辅助化疗的研究进展

胃癌一直是肿瘤死亡的主要原因,手术根治性切除是治愈的唯一手段。胃癌辅助化疗是在根治性手术后减少局部和远处复发的方法。许多Ⅲ期临床研究试图证实辅助治疗的疗效,但至今仍没有确立标准的治疗方案。本文就辅助治疗在胃癌中的进展作一总结。     

Expression of thymidylate synthase in gastric cancer patients treated with 5-fluorouracil and doxorubicin-based adjuvant chemotherapy after curative resection

We evaluated the expression of thymidylate synthase (TS) in locally advanced gastric cancer patients treated with adjuvant chemotherapy after curative resection and investigated the association between TS expression and clinicopathologic characteristics including prognosis of the patients. TS expression was evaluated by immunohistochemical staining using TS106 monoclonal antibody in 103 locally advanced gastric cancer patients (stage IB-IV) who underwent 5-fluorouracil (5-FU) and doxorubicin-based adjuvant chemotherapy after curative resection. 65 patients (63%) had primary tumours with high TS expression (> or = 25% of tumour cells positive), and 38 patients (37%) demonstrated low TS expression (< 25% of tumour cells positive or no staining). High TS expression was associated with male gender (P = 0.002), poorly differentiated histology (P = 0.015), and mixed type in Lauren's classification (P = 0.027). There were no statistically significant differences in 4-year disease-free survival (60.0% vs. 57.2%, P = 0.548) and overall survival (59.6% vs. 59.3%, P = 0.792) between high-TS group and low-TS group. In conclusion, although high TS expression was associated with poorly differentiated histology and mixed type in Lauren's classification, it did not predict poor disease-free and overall survival in gastric cancer patients treated with 5-FU and doxorubicin-based adjuvant chemotherapy after curative resection. Further prospective studies including the evaluation of other biological markers associated with the resistance to 5-FU and doxorubicin are necessary.     

Helicobacter pylori infection as an independent prognostic factor for locally advanced gastric cancer patients treated with adjuvant chemotherapy after curative resection

A few studies reported the association between negative Helicobacter pylori infection and poor clinical outcome in resected gastric cancer patients. We investigated the H. pylori infection status and its association with the clinical outcome in 274 locally advanced gastric cancer patients (American Joint Committee on Cancer stage IB: 25, II: 82, IIIA: 80, IIIB: 39 and IV: 48) who underwent adjuvant chemotherapy after curative resection (≥ D2 dissection). H. pylori infection status in hematoxylin and eosin stained corporal and antral mucosa of non-tumor tissue was graded according to the updated Sydney System and categorized as H. pylori negative (normal or mild infection) and H. pylori positive (moderate or marked infection). Eighty-one patients received 5-fluorouracil (5-FU) and doxorubicin-based chemotherapy, while 193 patients underwent 5-FU, mitomycin-C and polysaccharide-K chemotherapy. The median follow-up duration of survivors was 144 (120-184) months. In univariate analysis, patients with H. pylori negative status (108 patients) demonstrated significantly poor 10-year overall survival (OS) compared to those with H. pylori-positive status (166 patients; 21.3% vs. 71.1%, p < 0.0001). H. pylori negative status was associated with poor outcome in all stages except stage IIIB. In multivariate analysis, H. pylori-negative status was the most significant independent prognostic factor of poor OS (hazard ratio: 3.45, 95% confidence interval: 2.43-4.89, p < 0.0001) followed by old age (>54 years, p < 0.0001), advanced stage (stage III or IV, p = 0.001), and Borrmann type IV (p = 0.027). H. pylori infection status seems to have strong prognostic significance in locally advanced gastric cancer. H. pylori-negative patients may need careful follow-up after curative resection.     

Dose intensity of mitomycin C in adjuvant cancer chemotherapy for patients with gastric cancer

Using a cohort of macroscopic curative resections of gastric cancer at stages II, III, and IV, a randomized controlled trial was performed to elucidate the dose efficacy of intensive adjuvant cancer chemotherapy with mitomycin C. Between June 1983 and December 1986, 336 patients with gastric cancer from 31 institutes were enrolled in the study. The cohort was stratified randomly by the telephone method into two arms. Group A received 20 mg and 10 mg of mitomycin C per body intravenously (IV) on postoperative days 0 and 1, respectively, and then tegafur at 600 mg/body daily perorally (PO) from postoperative week 2 for 1 year. Group B also received 0.2 mg of mitomycin C per kg IV at 3, 6, 9, and 12 months after surgery. The background factors in groups A and B were essentially identical, and the adverse effects were tolerable in both groups. The total administered doses of mitomycin C were significantly higher in group B than in group A, according to the protocol. Although no significant differences were observed in the actuarial overall survival rates between groups A and B at stages II, III, and IV, favorable survival was observed in group B, which received histologically absolute curative resection. This dose-intensive adjuvant cancer chemotherapy would be useful for gastric cancer patients treated by histologically curative surgery. © 1994 Wiley-Liss, Inc.     

可切除胃癌术后辅助化疗现状

世界范围内,胃癌发病率和死亡率占所有癌症的第2位.在中国胃癌占发病和死亡的第1位.5年生存率低.手术是惟一可根治的方法.术后辅助化疗在提高生存率方面的作用尚有争议.本文综述胃癌根治术后辅助化疗方面的现状.     

Adjuvant chemotherapy vs radiotherapy in high-risk endometrial carcinoma: results of a randomised trial

Patients with high-risk endometrial carcinoma (stage IcG3, IIG3 with myometrial invasion >50%, and III) receive adjuvant therapy after surgery but it is not clear whether radiotherapy (RT) or chemotherapy (CT) is better. We randomly assigned 345 patients with high-risk endometrial carcinoma to adjuvant CT (cisplatin (50 mg m(-2)), doxorubicin (45 mg m(-2)), cyclophosphamide (600 mg m(-2)) every 28 days for five cycles, or external RT (45-50 Gy on a 5 days week(-1) schedule). The primary end points were overall and progression-free survival. After a median follow-up of 95.5 months women in the CT group as compared with the RT group, had a no significant hazard ratio (HR) for death of 0.95 (95% confidence interval (CI), 0.66-1.36; P = 0.77) and a nonsignificant HR for event of 0.88 (95% CI, 0.63-1.23; P = 0.45). The 3, 5 and 7-year overall survivals were 78, 69 and 62% in the RT group and 76, 66 and 62% in the CT group. The 3, 5 and 7-year progression-free survivals were, respectively, 69, 63 and 56 and 68, 63 and 60%. Radiotherapy delayed local relapses and CT delayed metastases but these trends did not achieve statistical significance. Overall, both treatments were well tolerated. This trial failed to show any improvement in survival of patients treated with CT or the standard adjuvant radiation therapy. Randomised trials of pelvic RT combined with adjuvant cytotoxic therapy compared with RT alone are eagerly awaited.     

胃差分化腺癌根治术后辅助化疗的临床研究

目的:观察和比较HELF方案和HELF/HPLF交替方案对胃差分化腺癌(低分化腺癌、粘液腺癌、印戒细胞癌)根治术后患者无病生存期(DFS)、总生存期(OS)的影响。方法:经组织学证实为低分化腺癌、粘液腺癌及印戒细胞癌的Ⅱ~Ⅲ期胃癌根治术后患者,随机分配至A组(单独HELF方案化疗)或B组(HELF/HPLF方案交替化疗),术后3~5周开始化疗,化疗4~6周期。结果:共入组80例患者,72例可按要求随访及评价不良反应,A组、B组各36例。全组患者共随访7~98月,A组与B组中位随访期差异无统计学意义(30月vs.33月,P=0.383)。A组患者的DFS为4~97月(中位值20月),B组为5~98月(中位值39月),两组差异有统计学意义(P=0.025)。A组的OS为10~97月(中位值28月),B组为7~98月(中位值48月),以B组生存时间更长(P=0.042)。主要不良反应为骨髓抑制及消化道反应,多为Ⅰ~Ⅱ度。结论:HELF方案与HPLF方案交替用于差分化胃腺癌根治术后的辅助治疗,在推迟肿瘤复发转移及延长生存期方面可能优于单用HELF方案。     

胃癌术后辅助化疗前患者贫血发生情况的调查

目的探讨胃癌术后辅助化疗前患者贫血发生的危险因素、临床特点和发病规律。方法回顾性分析近1年住院接受辅助化疗胃癌患者的临床资料。统计贫血的发生率及贫血的发病程度,从单因素、多因素两个层面针对年龄、性别、临床分期、手术方式、病理组织类型、血清白蛋白水平等诸方面对贫血发生发展的影响进行分析。结果232例胃癌术后辅助化疗前患者,贫血发生率53．5％。单因素,分析：年龄≥60岁的贫血构成比显著高于年龄〈60岁的患者（P〈0．05）;女性患者贫血构成比显著高于男性患者（P〈0．05）;Ⅲ、Ⅳ期患者的贫血构成比明显高于Ⅰ、Ⅱ期患者（P〈0．05）;不同手术方式贫血发生率差异存在统计学意义（P〈0．05）;血清白蛋白水平低于35g／L的患者贫血发生率明显高于不低于35g／L的患者（P〈0．05）。Logistic多因素逐步回归分析表明年龄[比数比（OR）26．422,95％可信区间（CI）5．716～122．129]、血清白蛋白（OR4．987,95％CI1．840～13．514）、病理分期（OR4．590,95％CI1．488。14．163）、手术方式（OR9．440,95％CI2．313～38．535）是胃癌术后辅助化疗前患者合并贫血的独立危险因素。结论胃癌术后辅助化疗前贫血的发生与年龄、血清白蛋白、手术方式、分期等因素有相关性。高龄、营养不良、全胃切除、中晚期患者更易发生贫血。     

Current status of neoadjuvant and adjuvant chemotherapy for muscle-invasive bladder cancer

Muscle-invasive transitional cell carcinoma occurs in approximately 30% of patients and is associated with a high risk of distant metastasis. Radical local therapy in the form of cystectomy or radiotherapy is curative in a portion of patients. Systemic therapy to treat occult micrometastasis at the time of local control is necessary to improve outcomes. Neoadjuvant chemotherapy is associated with a 5–6% improvement in overall survival at 5 years, and adjuvant chemotherapy may achieve similar results, although this remains unproven. Operative complications are not increased with neoadjuvant therapy. Perioperative treatment strategies remain underutilized, and many patients are not offered treatment to reduce the risk of relapse. Neoadjuvant strategies are a potent tool for research and should be employed to test new agents for the treatment of transitional cell carcinoma.     

An individual patient data meta-analysis of adjuvant therapy with uracil-tegafur (UFT) in patients with curatively resected rectal cancer

Uracil-Tegafur (UFT), an oral fluorinated pyrimidine chemotherapeutic agent, has been used for adjuvant chemotherapy in curatively resected colorectal cancer patients. Past trials and meta-analyses indicate that it is somewhat effective in extending survival of patients with rectal cancer. The objective of this study was to perform a reappraisal of randomised clinical trials conducted in this field. We designed an individual patient-based meta-analysis of relevant clinical trials to examine the benefit of UFT for curatively resected rectal cancer in terms of overall survival (OS), disease-free survival (DFS), and local relapse-free survival (LRFS). We analysed individual patient data of five adjuvant therapy randomised clinical trials for rectal cancer, which met the predetermined inclusion criteria. These five trials had a combined total of 2091 patients, UFT as adjuvant chemotherapy compared to surgery-alone, 5-year follow-up, intention-to-treat-based analytic strategy, and similar endpoints (OS and DFS). In a pooled analysis, UFT had significant advantage over surgery-alone in terms of both OS (hazard ratio, 0.82; 95% confidence interval (CI), 0.70-0.97; P=0.02) and DFS (hazard ratio, 0.73; 95%CI, 0.63-0.84; P<0.0001). This individual patient-based meta-analysis demonstrated that oral UFT significantly improves both OS and DFS in patients with curatively resected rectal cancer.     

Phase III randomised trial of doxorubicin-based chemotherapy compared with platinum-based chemotherapy in small-cell lung cancer

This randomised trial compared platinum-based to anthracycline-based chemotherapy in patients with small-cell lung cancer (limited or extensive stage) and 相似文献   

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     

Expression of multidrug resistance-associated protein1,P-glycoprotein,and thymidylate synthase in gastric cancer patients treated with 5-fluorouracil and doxorubicin-based adjuvant chemotherapy after curative resection

Both 5-fluorouracil and doxorubicin are commonly used agents in chemotherapy of gastric cancer in adjuvant setting as well as metastatic disease. In a variety of malignancies, high expression of multidrug resistance-associated protein1 and P-glycoprotein has been associated with resistance to doxorubicin, whereas 5-fluorouracil resistance has correlated with the level of thymidylate synthase expression. We evaluated the expression of multidrug resistance-associated protein1, P-glycoprotein, and thymidylate synthase using immunohistochemistry in 103 locally advanced gastric cancer patients (stage IB-IV) who underwent 5-fluorouracil and doxorubicin-based adjuvant chemotherapy after curative resection and investigated the association between their expression and clinicopathologic characteristics including prognosis of the patients. While high expression (> or =5% of tumour cells positive) of multidrug resistance-associated protein1 and P-glycoprotein was observed in 70 patients (68%) and 42 patients (41%), respectively, 65 patients (63%) had primary tumours with high expression (> or =25% of tumour cells positive) of thymidylate synthase. There was a significant association between multidrug resistance-associated protein1 and P-glycoprotein expression (P<0.0001) as well as P-glycoprotein and thymidylate synthase expression (P<0.0001). High multidrug resistance-associated protein1 and P-glycoprotein expressions were associated with well and moderately differentiated histology (P<0.0001 and P=0.03, respectively) and intestinal type (P<0.0001 and P=0.009, respectively). High multidrug resistance-associated protein1 expression correlated with lymph node metastasis (P=0.037), advanced stage (P=0.015), and older age (P=0.021). Five-year disease-free survival and overall survival of total patients were 55.2% and 56.2%, respectively, with a median follow-up of 68 months. There were no significant differences in disease-free survival and overall survival according to the expression of multidrug resistance-associated protein1 (P=0.902 and P=0.975, respectively), P-glycoprotein (P=0.987 and P=0.955, respectively), and thymidylate synthase (P=0.604 and P=0.802, respectively). Concurrent high expression of these proteins (high multidrug resistance-associated protein1/P-glycoprotein, high multidrug resistance-associated protein1/thymidylate synthase, high P-glycoprotein/thymidylate synthase) did not correlate with disease-free survival or overall survival. Even high expression of all three proteins was not associated with poor disease-free survival (P=0.919) and overall survival (P=0.852). In conclusion, high expression of multidrug resistance-associated protein1, P-glycoprotein, and thymidylate synthase did not predict poor prognosis of gastric cancer patients treated with 5-fluorouracil and doxorubicin-based adjuvant chemotherapy. A larger study including patients treated with surgical resection alone would be necessary.     

以草酸铂为主方案用于结直肠癌术后辅助化疗的疗效分析

目的 探讨草酸铂为主方案用于大肠癌术后辅助化疗的临床价值.方法 71例Ⅱ期(24%)和Ⅲ期(76%)结直肠癌患者,根治术后接受草酸铂/5-FU/CF方案辅助化疗.治疗结束后每3个月一次全面复查肿瘤情况.观察无病生存期及2年无病生存率.结果 经过2年以上的随访,本组病人总的2年无病生存率为69%,其中Ⅱ期和Ⅲ期2年无病生存率分别为87%和63%.化疗期间主要的不良反应为Ⅰ～Ⅱ度外周神经毒性,中性粒细胞减少及腹泻,Ⅲ-Ⅳ度毒性反应少见.结论 草酸铂联合5-FU/CF方案,疗效显著,且耐受性好,是大肠癌术后辅助化疗的理想选择.     

Characteristics and outcomes of patients with advanced non-small-cell lung cancer who declined to participate in randomised clinical chemotherapy trials

There are inadequate data on the outcomes of patients who declined to participate in randomised clinical trials as compared with those of participants. We retrospectively reviewed the patient characteristics and treatment outcomes of both participants and non-participants in the two randomised trials for chemotherapy-naive advanced non-small-cell lung cancer. Trial 1 compared four platinum-based combination regimens. Trial 2 compared two sequences of carboplatin plus paclitaxel and gefitinib therapies. Nineteen of 119 (16%) and 153 (37%) patients declined to participate in Trials 1 and 2, respectively. Among the background patient characteristics, the only variable associated with trial participation or declining was the patients'' attending physicians (P<0.001). Important differences were not observed in the clinical outcomes between participants and non-participants, for whom the response rates were 30.6 vs 34.2% and the median survival times were 489 vs 461 days, respectively. The hazard ratio for overall survival, adjusted for other confounding variables, was 0.965 (95% confidence interval: 0.73–1.28). In conclusion, there was no evidence to suggest any difference in the characteristics and clinical outcomes between participants and non-participants. Trial designs and the doctor–patient relationship may have an impact on the patient accrual to randomised trials.     

Adjuvant chemotherapy after curative resection for gastric cancer in non-Asian patients: revisiting a meta-analysis of randomised trials

The aim of this study was to assess whether adjuvant chemotherapy after curative resection of gastric cancer increases survival rates. Data sources: MEDLINE (1966–1999), CancerLit (1983–1999), bibliographies, personal reprint files, and review articles were searched for relevant articles. Studies had to be randomised controlled trials of adjuvant chemotherapy versus observation following curative resection of stomach cancer that took place in non-Asian countries. Two reviewers independently evaluated the trials for eligibility, quality assessment and data abstraction. 13 trials met the eligibility criteria. The odds ratio for death in the treated group was 0.80 (95% confidence interval (CI) 0.66–0.97), corresponding to a relative risk of 0.94 (95% CI 0.89–1.00). Subgroup analyses showed a trend towards a larger magnitude of the effect when analysis was restricted to trials in which at least 2/3 of patients had node-positive disease. Our results suggest that adjuvant chemotherapy may produce a small survival benefit of borderline statistical significance in patients with curatively resected gastric carcinoma. Continued trials to find and confirm an effective adjuvant strategy are warranted.     

Cumulative total S-1 dose in adjuvant chemotherapy affects the long-term outcome following curative gastrectomy for gastric cancer

A recent JCOG1104, OPAS-1 trial revealed the significance of S-1 duration. However, the significance of cumulative total S-1 dose (CTSD) remains unclear. In this study, we designed to evaluate the prognostic effect of CTSD on adjuvant chemotherapy after curative gastrectomy. We retrospectively analyzed 77 consecutive pStage II and III gastric cancer (GC) patients, who underwent curative gastrectomy followed by adjuvant S-1 chemotherapy from 2008 through 2014. CTSD of 20000 mg was the upper-limit of cut-off value to stratify the prognosis (5-year relapse free survival (RFS); CTSD < 20000 mg vs. CTSD ≥ 20000 mg: 51.9% vs. 85.1%, P = 0.004). Compared patients with CTSD more than 20000 mg, those with CTSD less than 20000 mg had a significantly higher rate of preoperative anemia (P = 0.041), low nutrition (P = 0.008) and open gastrectomy (P = 0.012). Multivariate Cox’s proportional hazards model for RFS proved that CTSD less than 20000 mg was an independent prognostic factor [P = 0.031, HR 3.32 (95% CI: 1.11-11.1)] although S-1 intensity and duration were not independent prognostic factors. The cumulative total S-1 dose more than 20000 mg might contribute to better prognosis.     

Efficacy of surgery after successful chemotherapy for advanced gastric cancer

Background We evaluated the efficacy of surgical resection after successful chemotherapies in patients with advanced gastric cancer. Methods Eighteen surgical patients who had had successful chemotherapies were selected after a review of 218 case records. Results The 18 patients were grouped by their pretreatment status: 8 patients with distant lymph node metastases (N4 group), 7 with a small amount of ascites (P group), and 3 with both factors (N4+P group). Good responses were achieved in all of the 11 patients with node metastases, including 4 patients with a complete response. Ascites in 7 of 10 patients disappeared. Two of 18 patients (11%) achieved curability A resections, while 8 patients (44%) achieved curability B and 8 (44%) achieved curability C resections. Pathologic complete responses were documented in 2 patients of the N4 group. The median survival time of the 18 patients was 14 months, with a 1-year survival rate of 61%. Six patients have survived more than 2 years, and 3 more than 5 years to date. The 8 N4-group patients who had surgery showed significantly better survival than 19 similar patients who had distant metastases and responded to chemotherapy but did not have surgery. A similar comparison of the P-group patients found no significant difference in survival associated with surgery. Conclusions Surgery after chemotherapy might be beneficial for patients with distant lymph node metastases, but not effective for those with peritoneal dissemination.