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Review
, 8 (8), CD004064

Chemotherapy for Advanced Gastric Cancer

Affiliations
Review

Chemotherapy for Advanced Gastric Cancer

Anna Dorothea Wagner et al. Cochrane Database Syst Rev.

Abstract

Background: Gastric cancer is the fifth most common cancer worldwide. In "Western" countries, most people are either diagnosed at an advanced stage, or develop a relapse after surgery with curative intent. In people with advanced disease, significant benefits from targeted therapies are currently limited to HER-2 positive disease treated with trastuzumab, in combination with chemotherapy, in first-line. In second-line, ramucirumab, alone or in combination with paclitaxel, demonstrated significant survival benefits. Thus, systemic chemotherapy remains the mainstay of treatment for advanced gastric cancer. Uncertainty remains regarding the choice of the regimen.

Objectives: To assess the efficacy of chemotherapy versus best supportive care (BSC), combination versus single-agent chemotherapy and different chemotherapy combinations in advanced gastric cancer.

Search methods: We searched the Cochrane Central Register of Controlled Trials, MEDLINE and Embase up to June 2016, reference lists of studies, and contacted pharmaceutical companies and experts to identify randomised controlled trials (RCTs).

Selection criteria: We considered only RCTs on systemic, intravenous or oral chemotherapy versus BSC, combination versus single-agent chemotherapy and different chemotherapy regimens in advanced gastric cancer.

Data collection and analysis: Two review authors independently identified studies and extracted data. A third investigator was consulted in case of disagreements. We contacted study authors to obtain missing information.

Main results: We included 64 RCTs, of which 60 RCTs (11,698 participants) provided data for the meta-analysis of overall survival. We found chemotherapy extends overall survival (OS) by approximately 6.7 months more than BSC (hazard ratio (HR) 0.3, 95% confidence intervals (CI) 0.24 to 0.55, 184 participants, three studies, moderate-quality evidence). Combination chemotherapy extends OS slightly (by an additional month) versus single-agent chemotherapy (HR 0.84, 95% CI 0.79 to 0.89, 4447 participants, 23 studies, moderate-quality evidence), which is partly counterbalanced by increased toxicity. The benefit of epirubicin in three-drug combinations, in which cisplatin is replaced by oxaliplatin and 5-FU is replaced by capecitabine is unknown.Irinotecan extends OS slightly (by an additional 1.6 months) versus non-irinotecan-containing regimens (HR 0.87, 95% CI 0.80 to 0.95, 2135 participants, 10 studies, high-quality evidence).Docetaxel extends OS slightly (just over one month) compared to non-docetaxel-containing regimens (HR 0.86, 95% CI 0.78 to 0.95, 2001 participants, eight studies, high-quality evidence). However, due to subgroup analyses, we are uncertain whether docetaxel-containing combinations (docetaxel added to a single-agent or two-drug combination) extends OS due to moderate-quality evidence (HR 0.80, 95% CI 0.71 to 0.91, 1466 participants, four studies, moderate-quality evidence). When another chemotherapy was replaced by docetaxel, there is probably little or no difference in OS (HR 1.05; 0.87 to 1.27, 479 participants, three studies, moderate-quality evidence). We found there is probably little or no difference in OS when comparing capecitabine versus 5-FU-containing regimens (HR 0.94, 95% CI 0.79 to 1.11, 732 participants, five studies, moderate-quality evidence) .Oxaliplatin may extend (by less than one month) OS versus cisplatin-containing regimens (HR 0.81, 95% CI 0.67 to 0.98, 1105 participants, five studies, low-quality evidence). We are uncertain whether taxane-platinum combinations with (versus without) fluoropyrimidines extend OS due to very low-quality evidence (HR 0.86, 95% CI 0.71 to 1.06, 482 participants, three studies, very low-quality evidence). S-1 regimens improve OS slightly (by less than an additional month) versus 5-FU-containing regimens (HR 0.91, 95% CI 0.83 to 1.00, 1793 participants, four studies, high-quality evidence), however since S-1 is used in different doses and schedules between Asian and non-Asian population, the applicability of this finding to individual populations is uncertain.

Authors' conclusions: Chemotherapy improves survival (by an additional 6.7 months) in comparison to BSC, and combination chemotherapy improves survival (by an additional month) compared to single-agent 5-FU. Testing all patients for HER-2 status may help to identify patients with HER-2-positive tumours, for whom, in the absence of contraindications, trastuzumab in combination with capecitabine or 5-FU in combination with cisplatin has been shown to be beneficial. For HER-2 negative people, all different two-and three-drug combinations including irinotecan, docetaxel, oxaliplatin or oral 5-FU prodrugs are valid treatment options for advanced gastric cancer, and consideration of the side effects of each regimen is essential in the treatment decision. Irinotecan-containing combinations and docetaxel-containing combinations (in which docetaxel was added to a single-agent or two-drug (platinum/5-FUcombination) show significant survival benefits in the comparisons studied above. Furthermore, docetaxel-containing three-drug regimens have increased response rates, but the advantages of the docetaxel-containing three-drug combinations (DCF, FLO-T) are counterbalanced by increased toxicity. Additionally, oxaliplatin-containing regimens demonstrated a benefit in OS as compared to the same regimen containing cisplatin, and there is a modest survival improvement of S-1 compared to 5-FU-containing regimens.Whether the survival benefit for three-drug combinations including cisplatin, 5-FU, and epirubicin as compared to the same regimen without epirubicin is still valid when second-line therapy is routinely administered and when cisplatin is replaced by oxaliplatin and 5-FU by capecitabine is questionable. Furthermore, the magnitude of the observed survival benefits for the three-drug regimens is not large enough to be clinically meaningful as defined recently by the American Society for Clinical Oncology (Ellis 2014). In contrast to the comparisons in which a survival benefit was observed by adding a third drug to a two-drug regimen at the cost of increased toxicity, the comparison of regimens in which another chemotherapy was replaced by irinotecan was associated with a survival benefit (of borderline statistical significance), but without increased toxicity. For this reason irinotecan/5-FU-containing combinations are an attractive option for first-line treatment. Although they need to be interpreted with caution, subgroup analyses of one study suggest that elderly people have a greater benefit form oxaliplatin, as compared to cisplatin-based regimens, and that people with locally advanced disease or younger than 65 years might benefit more from a three-drug regimen including 5-FU, docetaxel, and oxaliplatin as compared to a two-drug combination of 5-FU and oxaliplatin, a hypothesis that needs further confirmation. For people with good performance status, the benefit of second-line chemotherapy has been established in several RCTs.

Conflict of interest statement

ADW: has received consulting fees from Eli Lilly, Celgene, MerckKG/Phizer, MSD, TAIHO and Roche pharmaceuticals for consultancy work over the past three years, travel and accomodation support from Janssen and support from Merck Serono to conduct a clinical trial of targeted treatment for gastric cancer, which is beyond the scope of this review. The overall number of consultancy agreements per year is low (usually less than five advisory boards/year, with fees of between 500 and 1500 Euro per event). All funds were paid to her institution in accordance with their guidelines. A portion of the money that the institution receives is transferred to ADW and represents a trivial percentage of her salary. NLXS: none known. MM: has received consulting fees from Eli Lilly, Onyx, Roche, Nordic, Amgen, MSD, Merck Serono, Pfizer and BMS. He has received payment for lectures from Falk, Nordic, Amgen, mci, MSD, Merck Serono, Pfizer and BMS. His institution has received funds for independent research grants from Merck, Amgen, BMS, Taiho, Roche, AIO, MSD, and the EORTC. WG: none known. WPY: has received payment from Eli Lilly for service on speaker bureaus and travelling/accommodation for conferences from BMS and Taiho, unrelated to this review. BCT: has received a payment from Boehringer Ingelheim for providing a lecture, and royalties from Wiley‐Blackwell from a publication. Her institution has received funds from the Health Science Authority (Singapore) for statistical consultancy. JH: none known. SU: none known.

Figures

Figure 1
Figure 1
Study flow diagram: review update
Figure 2
Figure 2
'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study.
Figure 3
Figure 3
'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Analysis 1.1
Analysis 1.1
Comparison 1 Chemotherapy versus best supportive care, Outcome 1 Overall survival.
Analysis 1.2
Analysis 1.2
Comparison 1 Chemotherapy versus best supportive care, Outcome 2 Time to progression.
Analysis 2.1
Analysis 2.1
Comparison 2 Combination versus single‐agent chemotherapy, Outcome 1 Overall survival.
Analysis 2.2
Analysis 2.2
Comparison 2 Combination versus single‐agent chemotherapy, Outcome 2 Tumour response.
Analysis 2.3
Analysis 2.3
Comparison 2 Combination versus single‐agent chemotherapy, Outcome 3 Time to progression.
Analysis 2.4
Analysis 2.4
Comparison 2 Combination versus single‐agent chemotherapy, Outcome 4 Treatment‐related death.
Analysis 3.1
Analysis 3.1
Comparison 3 5‐FU/cisplatin/anthracycline combinations versus 5‐FU/cisplatin combinations (without anthracyclines), Outcome 1 Overall survival.
Analysis 3.2
Analysis 3.2
Comparison 3 5‐FU/cisplatin/anthracycline combinations versus 5‐FU/cisplatin combinations (without anthracyclines), Outcome 2 Tumour response.
Analysis 3.3
Analysis 3.3
Comparison 3 5‐FU/cisplatin/anthracycline combinations versus 5‐FU/cisplatin combinations (without anthracyclines), Outcome 3 Time to progression.
Analysis 4.1
Analysis 4.1
Comparison 4 5‐FU/cisplatin/anthracycline combinations versus 5‐FU/anthracycline combinations (without cisplatin), Outcome 1 Overall survival.
Analysis 5.1
Analysis 5.1
Comparison 5 Chemotherapy with irinotecan versus non‐irinotecan‐containing regimes, Outcome 1 Overall survival.
Analysis 5.2
Analysis 5.2
Comparison 5 Chemotherapy with irinotecan versus non‐irinotecan‐containing regimes, Outcome 2 Tumour response.
Analysis 5.3
Analysis 5.3
Comparison 5 Chemotherapy with irinotecan versus non‐irinotecan‐containing regimes, Outcome 3 Progression‐free survival.
Analysis 5.4
Analysis 5.4
Comparison 5 Chemotherapy with irinotecan versus non‐irinotecan‐containing regimes, Outcome 4 Treatment‐related death.
Analysis 5.5
Analysis 5.5
Comparison 5 Chemotherapy with irinotecan versus non‐irinotecan‐containing regimes, Outcome 5 Treatment discontinuation due to toxicity.
Analysis 6.1
Analysis 6.1
Comparison 6 Chemotherapy with docetaxel versus non‐docetaxel‐containing regimes, Outcome 1 Overall survival.
Analysis 6.2
Analysis 6.2
Comparison 6 Chemotherapy with docetaxel versus non‐docetaxel‐containing regimes, Outcome 2 Tumour response.
Analysis 6.3
Analysis 6.3
Comparison 6 Chemotherapy with docetaxel versus non‐docetaxel‐containing regimes, Outcome 3 Time to progression.
Analysis 6.4
Analysis 6.4
Comparison 6 Chemotherapy with docetaxel versus non‐docetaxel‐containing regimes, Outcome 4 Progression‐free survival.
Analysis 6.5
Analysis 6.5
Comparison 6 Chemotherapy with docetaxel versus non‐docetaxel‐containing regimes, Outcome 5 Treatment‐related death.
Analysis 6.6
Analysis 6.6
Comparison 6 Chemotherapy with docetaxel versus non‐docetaxel‐containing regimes, Outcome 6 Treatment discontinuation due to toxicity.
Analysis 7.1
Analysis 7.1
Comparison 7 Chemotherapy with capecitabine versus 5‐FU‐containing regimes, Outcome 1 Overall Survival.
Analysis 7.2
Analysis 7.2
Comparison 7 Chemotherapy with capecitabine versus 5‐FU‐containing regimes, Outcome 2 Tumour response.
Analysis 7.3
Analysis 7.3
Comparison 7 Chemotherapy with capecitabine versus 5‐FU‐containing regimes, Outcome 3 Time to progression.
Analysis 7.4
Analysis 7.4
Comparison 7 Chemotherapy with capecitabine versus 5‐FU‐containing regimes, Outcome 4 Progression‐free survival.
Analysis 7.5
Analysis 7.5
Comparison 7 Chemotherapy with capecitabine versus 5‐FU‐containing regimes, Outcome 5 Treatment‐related death.
Analysis 7.6
Analysis 7.6
Comparison 7 Chemotherapy with capecitabine versus 5‐FU‐containing regimes, Outcome 6 Treatment discontinuation due to toxicity.
Analysis 8.1
Analysis 8.1
Comparison 8 Chemotherapy with oxaliplatin versus the same regime including cisplatin, Outcome 1 Overall Survival.
Analysis 8.2
Analysis 8.2
Comparison 8 Chemotherapy with oxaliplatin versus the same regime including cisplatin, Outcome 2 Tumour response.
Analysis 8.3
Analysis 8.3
Comparison 8 Chemotherapy with oxaliplatin versus the same regime including cisplatin, Outcome 3 Progression‐free survival.
Analysis 8.4
Analysis 8.4
Comparison 8 Chemotherapy with oxaliplatin versus the same regime including cisplatin, Outcome 4 Treatment‐related death.
Analysis 8.5
Analysis 8.5
Comparison 8 Chemotherapy with oxaliplatin versus the same regime including cisplatin, Outcome 5 Treatment discontinuation due to toxicity.
Analysis 9.1
Analysis 9.1
Comparison 9 Taxane‐platinum‐fluoropyrimidine combinations versus taxane‐platinum (without fluoropyrimidine), Outcome 1 Overall survival.
Analysis 9.2
Analysis 9.2
Comparison 9 Taxane‐platinum‐fluoropyrimidine combinations versus taxane‐platinum (without fluoropyrimidine), Outcome 2 Tumour response.
Analysis 9.3
Analysis 9.3
Comparison 9 Taxane‐platinum‐fluoropyrimidine combinations versus taxane‐platinum (without fluoropyrimidine), Outcome 3 Progression‐free survival.
Analysis 9.4
Analysis 9.4
Comparison 9 Taxane‐platinum‐fluoropyrimidine combinations versus taxane‐platinum (without fluoropyrimidine), Outcome 4 Treatment‐related death.
Analysis 9.5
Analysis 9.5
Comparison 9 Taxane‐platinum‐fluoropyrimidine combinations versus taxane‐platinum (without fluoropyrimidine), Outcome 5 Treatment discontinuation due to toxicity.
Analysis 10.1
Analysis 10.1
Comparison 10 S‐1 versus 5‐FU‐containing regimes, Outcome 1 Overall Survival.
Analysis 10.2
Analysis 10.2
Comparison 10 S‐1 versus 5‐FU‐containing regimes, Outcome 2 Tumour response.
Analysis 10.3
Analysis 10.3
Comparison 10 S‐1 versus 5‐FU‐containing regimes, Outcome 3 Progression‐free survival.
Analysis 10.4
Analysis 10.4
Comparison 10 S‐1 versus 5‐FU‐containing regimes, Outcome 4 Time‐to treatment failure.
Analysis 10.5
Analysis 10.5
Comparison 10 S‐1 versus 5‐FU‐containing regimes, Outcome 5 Treatment‐related deaths.
Analysis 10.6
Analysis 10.6
Comparison 10 S‐1 versus 5‐FU‐containing regimes, Outcome 6 Treatment discontinuation due to toxicity.

Update of

  • Chemotherapy for advanced gastric cancer.
    Wagner AD, Unverzagt S, Grothe W, Kleber G, Grothey A, Haerting J, Fleig WE. Wagner AD, et al. Cochrane Database Syst Rev. 2010 Mar 17;(3):CD004064. doi: 10.1002/14651858.CD004064.pub3. Cochrane Database Syst Rev. 2010. PMID: 20238327 Updated. Review.

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