A systematic overview of chemotherapy effects in gastric 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 in the treatment of gastric cancer is based on 153 scientific papers including one meta-analysis, 18 reviews, 60 randomised studies and 57 prospective studies. The trials consist of 12,367 patients. The conclusions reached can be summarized into the following points: A meta-analysis of 21 randomised adjuvant studies revealed a statistically significant survival benefit. The Odds Ratio (OR) is 0.84 (95% confidence interval, 95% CI, 0.74-0.96). However, by analysing Western world and Asian studies separately, a statistically significant difference can be noticed; the Western world studies showed an OR of 0.96 (95% CI 0.83-1.12) and the Asian an OR of 0.58 (95% CI 0.44-0.76). The cause of this difference is not apparent. There is not sufficient evidence to recommend adjuvant chemotherapy as routine treatment in the Western world. Preoperative chemotherapy given to patients with non-resectable tumours or locally advanced potentially resectable tumours has achieved resectability rates of 40-100% and potentially curative resections in 37-80%. One out of two randomised studies showed a significant survival benefit, but reported data are not convincing. Experimental data in favour of preoperative therapy has not yet been confirmed in randomised clinical studies. Therapy is only justified in controlled clinical trials. Published studies on the use of intraperitoneal chemotherapy are few and not conclusive regarding the efficiency and safety. This method of drug administration is, accordingly, justified only in controlled clinical trials. In advanced gastric cancer, phase II studies have indicated better response rates using drug combinations than using single drug regimens, differences that have not, however, been convincingly demonstrated in randomised studies. No firm conclusions can be drawn regarding the superiority for any of the studied drug combinations with respect to response or survival gain. A statistically significant survival benefit has been shown in trials comparing drug combinations with a best supportive care arm in the treatment of advanced gastric cancer. However, the number of included patients is small. The median survival benefit in advanced disease is in the range of three to nine months. The use of chemotherapy in advanced gastric cancer is justified in selected patients, e.g. in younger patients in good performance status, low tumour burden and no other serious medical condition after adequate information of potential gains and risks. The influence of chemotherapy on quality of life in advanced gastric cancer has been reported in only a few studies. It appears that about 50% of the patients have a clinically relevant relief of tumour-related symptoms and thereby improved quality of life. In one study, quality-adjusted survival was estimated to a median of six months in the treated patients compared with two months in the controls. The quality of the literature addressing chemotherapy for gastric cancer is frequently poor with few properly designed randomised trials. In a number of randomised multi-centre adjuvant studies the inclusions rates are remarkably low, which reduces the scientific value of the studies.     

Alternating chemotherapy in advanced gastric cancer

Summary A phase II study with an alternating chemotherapeutic scheme, in advanced gastric cancer was conducted. Twentytwo patients were treated with cisplatin and mitomycin C on day 1 and BCNU and doxorubicin on day 28. Tegafur p.o. was given daily from the start to the end of chemotherapy. This scheme was repeated every four weeks. Response rate was 25% (2 complete and 3 partial). However, remissions were short lived, and median survival for the entire group was 7 months. Haematological and gastrointestinal toxicities were severe. In conclusion, the low response rate and the high toxicity of this regimen preclude its use for the treatment of gastric cancer.     

Hypertensive chemotherapy of advanced gastric cancer

Hypertensive chemotherapy of advanced gastric cancer is reported in this paper. The blood pressure of the patient was first elevated by intravenous angiotensin II, then mitomycin C was given for two consecutive days at doses of 20 mg and 10 mg. Out of 20 cases, it was effective in 11 (55%), especially for those with Borrmann III and IV types and poorly differentiated adenocarcinoma which recurred after subtotal gastrectomy. The side effect of this treatment was not marked and the response satisfactory Therefore, it may easily be accepted as the treatment for advanced gastric cancer.     

晚期胃癌化疗进展

随着细胞毒药物和分子靶点药物的研发,晚期胃癌患者姑息化疗取得一定进展。患者中位生存期可接近1年。本文主要介绍新药多西紫杉醇、紫杉醇、奥沙利铂、伊立替康、卡培他滨、S1及靶向药物在晚期胃癌治疗中的作用以及局部晚期胃癌的化疗策略,尤其重点介绍Ⅲ期临床试验研究结果。提出一些新联合方案,如含多西他赛的DCF方案、含奥沙利铂的EOX和FLO方案、含卡培他滨的EOX和顺铂＋希罗达方案、含伊立替康的ILF方案、含S1的S1＋DDP方案,可以作为一线治疗晚期胃癌的新的参考方案。而靶向药物在晚期胃癌治疗中结论尚不明确,其有效性、安全性和最终收益有待进一步的研究;新辅助化疗可作为局部晚期胃癌治疗的选择。     

Evolving chemotherapy for advanced gastric cancer

Gastric cancer is the fourth most commonly diagnosed cancer and is the second leading cause of cancer death worldwide. More than 50% of patients undergo surgery, but even after a curative resection, 60% of patients relapse locally or with distant metastases. Despite the fact that many advances have occurred in the management of gastric cancer, it continues to carry a poor prognosis, amplifying the importance of palliative chemotherapy. When compared with best supportive care alone, combination chemotherapy yields a significant advantage in the management of advanced gastric cancer. However, no single regimen has emerged or been accepted as clearly superior over another. Numerous phase II studies have demonstrated promising results with newer agents including irinotecan, docetaxel, capecitabine, S-1, and oxaliplatin. Recently reported phase III results with these agents now demonstrate positive developments in the treatment options for patients with advanced gastric cancer.     

晚期胃癌化疗策略进展

胃癌是死亡率最高的肿瘤之一。对于晚期胃癌,化疗仍是其主要的治疗手段。但是目前为止尚无标准方案。根据临床研究的进展,我们应该进一步优化化疗策略。单药化疗有效率低,不推荐用于常规化疗,但由于毒性较小,仍适用于体质状况差、无法耐受强烈化疗的患者,同时可尝试用于强烈化疗间歇期的维持治疗。两药联合化疗有效率明显高于单药化疗,同时毒副反应发生率低于三药联合,适用于大多数患者。三药联合化疗毒性反应强烈,但近期有效率最高,适用于体质较好或希望获得高有效率的患者。很多分子靶向药物已经在临床研究和应用中显示出良好的效果和治疗前景,但仍需在临床研究和实践中进一步调整和优化。     

Second-line chemotherapy for advanced gastric cancer in Korea

Stomach cancer is still one of the most prevalent malignancies and is the main cause of cancer deaths worldwide. The outcome for patients with metastasis, as well as for those with tumor recurrence, is dismal, with median survival time not greater than a year. Patients with unresectable locally advanced or metastatic lesions have been treated with systemic chemotherapy, and several randomized studies have demonstrated the benefit of chemotherapy compared with best supportive care. Recently, randomized phase III trials have presented a benefit of second-line chemotherapy compared with supportive care alone. However, it is not known at present which drug is the most effective in this setting. In Korea, the practice of offering second-line treatment to patients with advanced gastric cancer (AGC) is common, and many prospective clinical trials investigating clinical outcomes of second-line chemotherapy have been reported. Therefore, to define the potential role of second-line chemotherapy and to help to select an effective regimen, we review the published Korean prospective data concerning the use of chemotherapy in the second-line setting for the treatment of AGC. No phase III trials but 20 phase II trials were identified. The benefit of second-line chemotherapy in AGC has indirect evidence considering prolongation of progression-free survival (PFS) and improvement of the response rate. Taxanes, irinotecan, and oxaliplatin have been studied much and might be promising drugs considering cross-resistance to a 5-fluorouracil and cisplatin combination (FP). A large, prospective, multicenter, randomized phase III study is warranted to select the most effective second-line chemotherapeutic agents.     

Adjuvant chemotherapy after surgery in advanced gastric cancer

Two hundred and fifty-four patients with advanced gastric cancer underwent radical surgery and ftorafur (FT) or 5-fluorouracil (5-FU) was orally administered as the adjuvant chemotherapy (ACT). Recurrence after ACT were analyzed by the quantification method II. As a result, it was found that: 1) ACT over 2 years could lower the recurrence rate, and careful follow-up is still necessary up to 4 years, and 2) after the remission induction therapy with mitomycin C and/or 5-FU and cytarabine, 12 mg/kg/day of FT for the first year and 8 mg for the second year are advisable.     

Recent advances in chemotherapy for advanced gastric cancer

Although medical treatment has been shown to improve quality of life and prolong survival, no significant progress has been made in the treatment of advanced gastric cancer (AGC) within the last two decades. Thus, the choice of optimum standard first-line chemotherapy regimen for AGC remains debatable, and most responses to chemotherapy are partial and of short duration, with a median survival of approximately 7-11 mo and survival at 2 years rarely more than 10%. Recently, remarkable progress in tumor biology has led to the development of new agents that target critical aspects of oncogenic pathways. For AGC, several molecular targeting agents are now under evaluation in international randomized studies, and trastuzumab, an anti-HER2 monoclonal antibody, has shown antitumor activity against HER-2 positive AGC. However, this benefit is limited to only about 20% of patients with AGC (patients with HER-2 positive AGC). Therefore, there remains a critical need for both the development of more effective agents and the identification of predictive and prognostic molecular markers to select those patients who will benefit most from specific chemotherapeutic regimens and targeted therapies.     

Palliative chemotherapy for advanced gastric cancer.

BACKGROUND: More than two-thirds of patients diagnosed with gastric cancer will have unresectable disease. They present a difficult problem to clinicians as to whether to choose a strictly supportive approach or expose patients to the side-effects of a potentially ineffective treatment. The objective of this article is to review the clinical trials utilizing cytotoxic chemotherapy in patients with advanced gastric cancer. METHODS: A computerized (Medline) search was carried out to identify papers published on this topic between 1966 and 2003. Only articles with an English abstract were reviewed, and studies only presented in abstract form were not included in the analysis. RESULTS: A total of 101 trials were subsequently identified. Four randomized trials compared palliative chemotherapy with best supportive care in 174 patients with advanced gastric cancer. Effectiveness and side-effects were evaluated in 73 phase II studies and 24 randomized phase III trials. CONCLUSION: Analysis of results shows chemotherapy to be superior to best supportive care alone. Combination chemotherapy compared with monochemotherapy is associated with significantly higher overall (complete plus partial) response rates but nevertheless results in similar survival. ECF (epirubicin, cisplatin and 5-fluorouracil) currently represents one of the most effective regimens for advanced gastric cancer, whereas among the newer combinations, irinotecan- or taxane-based regimens have also given promising results. In patients with a poor performance status, consideration could be given to leucovorin-modulated 5-fluorouracil alone. Prognosis for the majority of patients, however, remains poor, as increases in survival were moderate at best.     

Does chemotherapy improve survival in advanced breast cancer? A statistical overview.

The relative efficacies of cytotoxic chemotherapy regimens in the treatment of advanced breast cancer are generally assessed by comparing response rates in randomised trials. Treatment attempts to prolong survival but trials rarely demonstrate a statistically significant survival advantage: it has been argued that chemotherapy does not prolong survival. The correlation between response rates and survival has been examined by reviewing 79 comparisons between arms with unequal response rates in 50 published trials of chemotherapy in advanced breast cancer. In 73% of comparisons the group with the higher response rate also demonstrated the longer median survival (P less than 0.001). Weighted linear regression showed a statistically significant relationship between relative response rates and survival (P less than 0.001). The number of patients in a comparison did not influence this relationship.     

紫杉醇联合化疗方案治疗晚期胃癌31例临床观察

目的 评价含紫杉醇（Paclitaxel）化疗方案治疗晚期胃癌的临床疗效和毒性反应。方法 用含紫杉醇联合化疗方案治疗晚期胃癌31例,包括Paclitaxel＋5．FU＋CF 18例,Taxol＋DDP 13例。结果 可评价疗效者29例,完全缓解（CR）1例（3.2％）,部分缓解（PR）12例（38．7％）,稳定（SD）13例（41．9％）,进展（PD）3例（9．7％）,总有效率（CR＋PR）为41．9％。中位肿瘤进展期5．6个月,中位生存期9．8个月。主要副反应为白细胞减少27例（87．1％）,脱发25例（80．7％）,肌肉关节痛23例（74．2％）等,无治疗相关性死亡。结论 以紫杉醇为主的联合化疗方案治疗晚期胃癌有效,临床缓解率较高,明显减轻病人痛苦,提高生存质量,毒副反应可耐受。     

进展期胃癌新辅助化疗的临床疗效观察

目的 评价进展期胃癌新辅助化疗的疗效及对预后的影响.方法 回顾性分析45例确诊进展期胃癌患者通过新辅助化疗后再行手术治疗的疗效及预后,并与60例同期收治的未经新辅助化疗的胃癌手术患者进行对照.结果 新辅助化疗组临床有效率RR(CR+ PR)为68.9％ (31/45),其中CR 6.7％(3例),PR62.2％ (28例),SD 28.9％(13例),PD 2.2％(1例),术后1例在病理水平达到完全缓解(pCR),缓解率为2.2％ (1/45).不良反应主要为Ⅰ及Ⅱ度白细胞减少、恶心、脱发、呕吐及黏膜炎,其中Ⅲ及Ⅳ级的白细胞减少及胃肠道反应6例(13.3％),无严重感染和死亡病例.新辅助化疗组手术根治性切除率为84.4％,对照组的手术根治性切除率为66.7％,两者差异有统计学意义(P＜0.05).与对照组比较,新辅助化疗组的术后生存期明显延长(P＜0.05),且两组术后并发症无明显差异.结论 手术切除较为困难或根治率低的局部晚期胃癌患者,术前配合新辅助化疗,可显著提高胃癌切除率,并且最终可明显提高胃癌患者的术后生存期.     

Future perspectives of chemotherapy for advanced gastric cancer

According to the results of two recent randomized studies of treatment for metastatic gastric cancer in Japan, S-1 could replace infusional 5-fluorouracil and S-1 plus cisplatin showed a significant survival advantage over S-1 monotherapy, with a favorable toxicity profile. However, no globally accepted standards have been established yet and we have to wait for the results of other ongoing international studies, including studies of S-1 and its combinations, to achieve such standards. There are two major approaches to achieve further progress in the treatment of advanced gastric cancer. The first is to optimize the use of conventional cytotoxic agents (regimens) in the continuum of treatment for this disease. Several randomized studies of such regimens as second-line treatments are being planned in Japan, for which definitions of eligibility criteria and primary endpoints should be fully discussed in the design of the protocols. The second approach is to incorporate new active agents, particularly molecular targeting agents. Several molecular targeting agents that have shown survival advantages in patients with other tumor types are now under investigation for the treatment of gastric cancer in international randomized studies, including Japan and Korea. The next generation of targeting agents is also being evaluated in early clinical studies. Biological research has become essential for developing new targeting agents. For such biological studies, the tumor tissues of gastric cancer are easily obtainable via endoscopy, and such studies may constitute new frontiers in biological therapy. We expect that these studies will provide not only further clinical advantages but that they will also lead to tailored medicine.     

Future perspectives of chemotherapy for advanced gastric cancer

According to the results of two recent randomized studies of treatment for metastatic gastric cancer in Japan, S-1 could replace infusional 5-fluorouracil and S-1 plus cisplatin showed a significant survival advantage over S-1 monotherapy, with a favorable toxicity profile. However, no globally accepted standards have been established yet and we have to wait for the results of other ongoing international studies, including studies of S-1 and its combinations, to achieve such standards. There are two major approaches to achieve further progress in the treatment of advanced gastric cancer. The first is to optimize the use of conventional cytotoxic agents (regimens) in the continuum of treatment for this disease. Several randomized studies of such regimens as second-line treatments are being planned in Japan, for which definitions of eligibility criteria and primary endpoints should be fully discussed in the design of the protocols. The second approach is to incorporate new active agents, particularly molecular targeting agents. Several molecular targeting agents that have shown survival advantages in patients with other tumor types are now under investigation for the treatment of gastric cancer in international randomized studies, including Japan and Korea. The next generation of targeting agents is also being evaluated in early clinical studies. Biological research has become essential for developing new targeting agents. For such biological studies, the tumor tissues of gastric cancer are easily obtainable via endoscopy, and such studies may constitute new frontiers in biological therapy. We expect that these studies will provide not only further clinical advantages but that they will also lead to tailored medicine.     

Latest progress on chemotherapy for advanced gastric cancer

Although recent phase II studies have demonstrated high antitumor activity in the treatment of advanced gastric cancer, no significant survival benefit has been clearly demonstrated yet, when compared with 5-FU alone. More recently, a number of new agents including irinotecan and S-1 have demonstrated significant activity against gastric cancer as single agent or in combination with other chemotherapeutic agents. A phase III trial of 5-FU alone versus irinotecan plus cisplatin versus S-1 alone in advanced gastric cancer patients will be initiated in Japan Clinical Oncology Group (JCOG) within a few months. These new regimens have a potential becoming a new standard chemotherapy for the treatment of gastric cancer. The patients with peritoneal dissemination has usually not yet evaluated and explored from clinical study because of risk of toxicity and having no measurable disease. A next randomized phase III trial comparing 5-FU alone with sequential methotrexate and 5-fluorouracil in patients with peritoneal metastasis will be initiated in JCOG next year. The development of molecular biology has demonstrated the molecular mechanisms of chemoresistance or chemosensitivity, as well as a number of molecular targets against cancer cells. To date, many molecular targeted agents are being evaluated in various stages of clinical testing. These advances may provide a possibility of tailor made treatment.     

Second-line chemotherapy for patients with advanced gastric cancer

The first choice for treating patients with metastatic gastric cancer is chemotherapy, and combination therapy with fluorouracil, platinum, and trastuzumab has been established as the standard first-line chemotherapy. For further improvement of treatment outcomes, it is important to develop second- and third-line chemotherapy. In the first decade of this century, irinotecan and taxanes, cytotoxic agents, and various molecular targeted agents began to be developed as second-line therapy. Treatment with paclitaxcel weekly in combination with ramucirumab targeting vascular endothelial growth factor receptor 2 has become the first choice for second-line therapy. Immune checkpoint inhibitors are now being developed, and the current treatment strategies for advanced gastric cancer may undergo major changes in the future. This review summarizes the transitions and future prospects of clinical developments for second-line therapy in patients with advanced gastric cancer.