Palliative chemotherapy and targeted therapies for esophageal and gastroesophageal junction cancer

Vincent T Janmaat; Ewout W Steyerberg; Ate van der Gaast; Ron HJ Mathijssen; Marco J Bruno; Maikel P Peppelenbosch; Ernst J Kuipers; Manon CW Spaander

doi:10.1002/14651858.CD004063.pub4

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Figure 1

Study flow diagram: review update

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Figure 2

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

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Figure 3

Forest plot of the main analysis: chemotherapy or targeted therapy agent(s) plus control arm versus control arm, outcome: 1.1 Overall survival.

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Figure 4

Funnel plot of the main comparison: chemotherapy or targeted therapy agent(s) plus control arm versus control arm, outcome: 1.1 Overall survival.

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Figure 5

Forest plot of the main analysis: chemotherapy or targeted therapy agent(s) plus control arm versus control arm, outcome: 1.2 Progression free survival.

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Figure 6

Forest plot of subcomparison 1: chemotherapy or targeted therapy agent(s) plus BSC versus BSC, outcome 4.1: overall survival.

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Figure 7

Forest plot of subcomparison 1: chemotherapy or targeted therapy agent(s) plus BSC versus BSC, outcome 4.1: progression free survival.

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Analysis 1.1

Comparison 1 Main analysis: chemotherapy or targeted therapy agent(s) plus control intervention versus control intervention alone, Outcome 1 Overall survival.

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Analysis 1.2

Comparison 1 Main analysis: chemotherapy or targeted therapy agent(s) plus control intervention versus control intervention alone, Outcome 2 Progression‐free survival.

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Analysis 2.1

Comparison 2 Sensitivity analysis: studies that also included participants with gastric cancer, Outcome 1 Overall survival.

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Analysis 3.1

Comparison 3 Sensitivity analysis: effect of intervention on participants with GE‐junction cancer versus effect of intervention on participants with gastric cancer, Outcome 1 Overall survival, GE‐junction cancer outcomes.

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Analysis 3.2

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Analysis 4.1

Comparison 4 Subcomparison 1: chemotherapy or targeted therapy plus BSC versus BSC, Outcome 1 Overall survival.

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Analysis 4.2

Comparison 4 Subcomparison 1: chemotherapy or targeted therapy plus BSC versus BSC, Outcome 2 Progression‐free survival.

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Analysis 5.1

Comparison 5 Subcomparison 2: studies with participants receiving second‐line therapy, Outcome 1 Overall survival.

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Analysis 5.2

Comparison 5 Subcomparison 2: studies with participants receiving second‐line therapy, Outcome 2 Progression‐free survival.

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Analysis 6.1

Comparison 6 Subgroup analysis 4a: EGFR‐targeting agent plus control intervention versus control intervention alone, Outcome 1 Overall survival.

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Analysis 6.2

Comparison 6 Subgroup analysis 4a: EGFR‐targeting agent plus control intervention versus control intervention alone, Outcome 2 Progression‐free survival.

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Analysis 7.1

Comparison 7 Subgroup analysis 4b: cetuximab plus control intervention versus control intervention alone, Outcome 1 Overall survival.

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Analysis 7.2

Comparison 7 Subgroup analysis 4b: cetuximab plus control intervention versus control intervention alone, Outcome 2 Progression‐free survival.

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Analysis 8.1

Comparison 8 Subgroup analysis 4c: ramucirumab plus control intervention versus control intervention alone, Outcome 1 Overall survival.

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Analysis 8.2

Comparison 8 Subgroup analysis 4c: ramucirumab plus control intervention versus control intervention alone, Outcome 2 Progression‐free survival.

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Analysis 9.1

Comparison 9 Subcomparison 5: chemotherapy or targeted therapy agent(s) plus control intervention versus control intervention alone in participants with AC of the esophagus, Outcome 1 Overall survival.

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Analysis 9.2

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Analysis 10.1

Comparison 10 Subcomparison 6: chemotherapy or targeted therapy agent(s) plus control arm versus control arm in participants with SCC of the esophagus, Outcome 1 Overall survival.

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Analysis 10.2

Comparison 10 Subcomparison 6: chemotherapy or targeted therapy agent(s) plus control arm versus control arm in participants with SCC of the esophagus, Outcome 2 Progression‐free survival.

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Summary of findings for the main comparison. Summary of findings table: chemotherapy or targeted therapy agent(s) plus control intervention versus control intervention alone for palliative treatment of esophageal and GE‐junction carcinoma

Chemotherapy or targeted therapy agent(s) plus control intervention versus control intervention alone for palliative treatment of esophageal and GE‐junction carcinoma
Patient or population: palliative participants with esophageal and GE‐junction carcinoma Setting: hospital Intervention: chemotherapy or targeted therapy agent(s) plus control intervention Comparison: control intervention
Outcome	Relative effect (95% CI)	No. of participants (studies)	Quality of the evidence (GRADE)	Comments
Overall survival	HR 0.75 (0.68 to 0.84) Median OS 6.7 months in the chemotherapy or targeted therapy agent(s) + control arm versus 5.7 months in the control arm	1347 participants (11 RCTs)	⊕⊕⊕⊕ High	Quality not downgraded. Although participant populations and agents used differ between studies, there is low imprecision and low inconsistency. Cochrane's Q test for heterogeneity showed almost no heterogeneity (I² = 5%, P = 0.50)
Progression‐free survival	HR 0.64 (0.45 to 0.92)	883 participants (5 RCTs)	⊕⊕⊕⊝ Moderate^a	Cochrane's Q test for heterogeneity showed considerable heterogeneity (I² = 79%, P < 0.001)
Toxicity	Palliative chemotherapy and/or targeted therapy appear to increase the frequency of treatment‐related toxicity of at least grade 3. However, treatment‐related deaths did not occur more frequently.	For 3296 participants with esophageal, GE‐junction, and gastric cancer (9 RCTs) information was provided on toxicity according to WHO or NCI‐CTC guidelines. For at least 1189 participants with esophageal and GE‐junction cancer from these trials, toxicity was reported.	⊕⊝⊝⊝ Very low^b	Small sample size of studies reporting toxicity for the esophageal and GE‐junction cancer subgroup separately, for both arms, and with validated methods. Heterogeneity in the relative frequency of toxicities due to palliative chemotherapy and/or targeted therapy.
Quality of life	Quality of life was measured with validated methods in 5 studies included in this analysis. Although the 5 studies were not representative of all the studies in this analysis, as 4 tested a targeted agent, the quality of life reported improved in the arms with the additional agent.	For 1870 participants with esophageal, GE‐junction, and gastric cancer (5 RCTs), information was provided on quality of life. For at least 823 participants with esophageal and GE‐junction cancer, quality of life was reported.	⊕⊝⊝⊝ Very low^c	Small sample size of studies reporting data for the esophageal and GE‐junction cancer subgroup separately whilst using validated methods
CI: confidence interval; GE: gastroesophageal; HR: hazard ratio; NCI‐CTC: National Cancer Institute Common Toxicity Criteria; OS: overall survival; RCT: randomized controlled trial; WHO: World Health Organization.
GRADE Working Group grades of evidence High quality: further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: we are very uncertain about the estimate.
^aDowngraded by one level due to inconsistency. ^bDowngraded by three levels due to small sample size of studies reporting toxicity for the esophageal and GE‐junction cancer subgroup separately, for both arms, and with validated methods. Additionally, some studies in general, or for specific toxicities, reported no difference in toxicity, which indicates possible inconsistency. ^cDowngraded by three levels due to lack of studies reporting data for the esophageal and GE‐junction cancer subgroup separately whilst using validated methods.

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Summary of findings 2. Summary of findings table (sensitivity analysis): interventions esophageal and GE‐junction carcinoma versus gastric carcinoma

Sensitivity analysis: chemotherapy or targeted therapy agent(s) plus control intervention versus control intervention alone for palliating esophageal and GE‐junction carcinoma versus gastric carcinoma
Patient or population: palliative participants with esophageal and GE‐junction carcinoma or gastric carcinoma Setting: hospital Intervention: chemotherapy or targeted therapy agent(s) plus control arm Comparison: control arm
Comparison	Outcome	Relative effect (95% CI)	No. of participants (studies)	Quality of the evidence (GRADE)	Comments
Studies with gastric cancer participants in addition to eligible participants	Overall survival	HR 0.94 (0.83 to 1.05)	1755 participants (8 RCTs)	It should not be judged independently as it is not meant to be an exhaustive summary of either esophageal, GE‐junction, or gastric cancer participant data.	Cochrane's Q test for heterogeneity showed considerable heterogeneity (I² = 54%, P = 0.03).
Sensitivity analysis, meta‐regression analysis, first part	Overall survival	HR 0.75 (0.68 to 0.84) versus HR 0.94 (0.83 to 1.05), P = 0.004 (treatment has a significantly different effect)	1347 participants (11 RCTs) versus 1755 participants (8 RCTs)	⊕⊝⊝⊝ Very low^a	Cochrane's Q test for heterogeneity showed almost no heterogeneity (I² = 5%, P = 0.50) in the arm with esophageal and GE‐junction cancer participants. Cochrane's Q test for heterogeneity showed considerable heterogeneity (I² = 54%, P = 0.03) in the arm that included also gastric cancer participants.
Sensitivity analysis, only esophageal and GE‐junction cancer participants	Overall survival	HR 0.66 (0.54 to 0.81)	538 participants (5 RCTs)	It should not be judged independently as it is not meant to be an exhaustive summary of either esophageal and GE‐junction participant data.	Cochrane's Q test for heterogeneity showed no heterogeneity (I² = 0%, P = 0.56). This meta‐analysis was not meant to be exhaustive with regard to the effect of chemotherapy or targeted therapy in people with esophageal and GE‐junction cancer.
Sensitivity analysis, only gastric cancer participants	Overall survival	HR 0.89 (0.76 to 1.04)	2093 participants (5 RCTs)	It should not be judged independently as it is not meant to be an exhaustive summary of gastric cancer participant data.	Cochrane's Q test for heterogeneity showed heterogeneity (I² = 52%, P = 0.08). This meta‐analysis was not meant to be exhaustive with regard to the effect of chemotherapy or targeted therapy in people with gastric cancer.
Sensitivity analysis, meta‐regression analysis, second part	Overall survival	HR 0.66 (0.54 to 0.81) versus HR 0.89 (0.76 to 1.04), P = 0.03 (treatment has a significantly different effect)	538 participants (5 RCTs) versus 2093 participants (5 RCTs)	⊕⊕⊕⊝ Moderate^b	Cochrane's Q test for heterogeneity showed no heterogeneity (I² = 0%, P = 0.56) in the arm with only GE‐junction cancer participants and heterogeneity (I² = 52%, P = 0.08) in the arm with only gastric cancer participants. This result applies only to GE‐junction versus gastric cancer.
CI: confidence interval; GE: gastroesophageal; HR: hazard ratio; OS: overall survival; RCT: randomized controlled trial.
GRADE Working Group grades of evidence High quality: further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: we are very uncertain about the estimate.
^aDowngraded by three levels due to inconsistency in the group of studies with gastric cancer participants besides eligible participants. Additionally, quality was downgraded because the interventions in both groups of studies were not similar, making the comparison indirect. ^bDowngraded by one level due to small sample size (for a meta‐regression analysis) and inconsistency of the arm of the meta‐regression analysis that contains gastric cancer participants.

Summary of findings 2. Summary of findings table (sensitivity analysis): interventions esophageal and GE‐junction carcinoma versus gastric carcinoma

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Summary of findings 3. Summary of findings table (subcomparison 1): chemotherapy or targeted therapy plus best supportive care (BSC) versus BSC for palliative treatment of esophageal and GE‐junction carcinoma

Subcomparison 1: chemotherapy or targeted therapy plus best supportive care (BSC) versus BSC for palliative treatment of esophageal and GE‐junction carcinoma
Patient or population: palliative participants with esophageal and GE‐junction carcinoma Setting: hospital Intervention: chemotherapy or targeted therapy plus BSC Comparison: BSC
Outcomes	Relative effect (95% CI)	No. of participants (studies)	Quality of the evidence (GRADE)	Comments
Overall survival	HR 0.81 (0.71 to 0.92) Median OS 4.7 months in the chemotherapy or targeted therapy arm versus 4.2 months in the BSC arm	750 (5 RCTs)	⊕⊕⊕⊕ High	Quality not downgraded. Participant populations and agents used differ between studies. However, there is low imprecision and low inconsistency. Cochrane's Q test for heterogeneity showed almost no heterogeneity (I² = 0%, P = 0.57), indicating that results of the studies were consistent.
Progression‐free survival	HR 0.58 (0.28 to 1.18)	540 (2 RCTs)	⊕⊝⊝⊝ Very low^a	95% CI includes benefit and harm. Cochrane's Q test for heterogeneity showed considerable heterogeneity (I² = 85%, P = 0.01).
Toxicity	Palliative chemotherapy and/or targeted therapy appear to increase the frequency of treatment‐related toxicity of at least grade 3. However, treatment‐related deaths did not occur more frequently.	For 972 participants with esophageal, GE‐junction, and gastric cancer (3 RCTs) information was provided on toxicity according to WHO or NCI‐CTC guidelines. For at least 632 participants with esophageal and GE‐junction cancer from these trials, toxicity was reported.	⊕⊝⊝⊝ Very low^b	3/5 studies reported on toxicities with validated methods. 1/3 studies reporting on toxicity, reported it for the esophageal and GE‐junction cancer subgroup separately, for both arms and with validated methods.
Quality of life	On average, the quality of life reported improved in the arms with the additional agent.	For 1129 participants with esophageal, GE‐junction, and gastric cancer (4 RCTs) information was provided on quality of life. For at least 789 participants with esophageal and GE‐junction cancer, quality of life was reported.	⊕⊝⊝⊝ Very low^c	4/5 studies reported on quality of life. 2/4 studies reported quality of life separately for the esophageal and GE‐junction cancer subgroup.
BSC: best supportive care; CI: confidence interval; GE: gastroesophageal; HR: hazard ratio; NCI‐CTC: National Cancer Institute Common Toxicity Criteria; OS: overall survival; RCT: randomized controlled trial; WHO: World Health Organization.
GRADE Working Group grades of evidence High quality: further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: we are very uncertain about the estimate.
^aDowngraded by three levels due to very serious imprecision (small sample size, 95% CI includes appreciable benefit and harm) and serious inconsistency. ^bDowngraded by three levels due to non‐validated methods used and failure to report toxicities specifically for esophageal and GE‐junction cancer patient group. ^cDowngraded by three levels because not all studies reported on quality of life, and not all studies reported quality of life specifically for esophageal and GE‐junction cancer patients.

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Summary of findings 4. Summary of findings table (subcomparison 2): second‐line chemotherapy or targeted therapy agent(s) plus control intervention versus control intervention alone for palliative treatment of esophageal and GE‐junction carcinoma

Subcomparison 2: second‐line chemotherapy or targeted therapy agent(s) plus control intervention versus control intervention alone for palliative treatment of esophageal and GE‐junction carcinoma
Patient or population: palliative participants with esophageal and GE‐junction carcinoma previously treated with chemotherapy Setting: hospital Intervention: chemotherapy or targeted therapy agent(s) plus control arm Comparison: control arm
Outcomes	Relative effect (95% CI)	No. of participants (studies)	Quality of the evidence (GRADE)	Comments
Overall survival	HR 0.71 (0.54 to 0.94) Median OS 5.1 months in the chemotherapy or targeted therapy arm versus 4.4 months in the BSC arm	769 participants (4 RCTs)	⊕⊕⊕⊝ Moderate^a	2 studies investigated the same agent. Cochrane's Q test for heterogeneity showed considerable heterogeneity (I² = 57%, P = 0.07)
Progression‐free survival	HR 0.51 (0.29 to 0.90)	677 participants (3 RCTs)	⊕⊕⊝⊝ Low^b	2 studies investigated the same agent. Cochrane's Q test for heterogeneity showed considerable heterogeneity (I² = 86%, P < 0.001)
Toxicity	Palliative chemotherapy and/or targeted therapy appear to increase the frequency of treatment‐related toxicity of at least grade 3. However, treatment‐related deaths did not occur more frequently.	For 1638 participants with esophageal, GE‐junction, and gastric cancer (4 RCTs) information was provided on toxicity according to WHO or NCI‐CTC guidelines. For at least 769 participants with esophageal and GE‐junction cancer from these trials toxicity was reported.	⊕⊝⊝⊝ Very low^c	1/4 studies reported toxicity for the esophageal and GE‐junction cancer subgroup separately, for both arms, and with validated methods.
Quality of life	On average, the quality of life reported improved in the arms with the additional agent.	For 1638 participants with esophageal, GE‐junction, and gastric cancer (4 RCTs) information was provided on quality of life. For at least 769 participants with esophageal and GE‐junction cancer, quality of life was reported.	⊕⊝⊝⊝ Very low^d	1/4 studies reported quality of life separately for the esophageal and GE‐junction cancer subgroup.
CI: confidence interval; GE: gastroesophageal; HR: hazard ratio; NCI‐CTC: National Cancer Institute Common Toxicity Criteria; OS: overall survival; RCT: randomized controlled trial; WHO: World Health Organization.
GRADE Working Group grades of evidence High quality: further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: we are very uncertain about the estimate.
^aDowngraded by one level due to small sample size and inconsistency. ^bDowngraded by two levels due to small sample size and inconsistency. ^cDowngraded by three levels due to the use of non‐validated methods and failure to report toxicities specifically for esophageal and GE‐junction cancer patient group. ^dDowngraded by three levels because not all studies reported on quality of life, and not all studies reported quality of life specifically for esophageal and GE‐junction cancer patients.

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Summary of findings 5. Summary of findings table (subcomparison 3): chemotherapy agent(s) plus control intervention versus control intervention alone for palliative treatment of esophageal and GE‐junction carcinoma

Subcomparison 3: chemotherapy agent(s) plus control intervention versus control intervention alone for palliative treatment of esophageal and GE‐junction carcinoma
Patient or population: palliative participants with esophageal and GE‐junction carcinoma Setting: hospital Intervention: chemotherapy agent(s) plus control arm Comparison: control arm
Outcome	Relative effect (95% CI)	No. of participants (studies)	Quality of the evidence (GRADE)	Comments
Overall survival	HR 0.73 (0.63 to 0.85) Median OS 6.9 months in the chemotherapy + control arm versus 5.8 months in the control arm.	358 participants (5 RCTs)	⊕⊕⊕⊝ Moderate^a	There is low imprecision and low inconsistency. Cochrane's Q test for heterogeneity showed low heterogeneity (I² = 0%, P = 0.50).
Progression‐free survival	No data on progression‐free survival was available for this comparison.
Toxicity	Palliative chemotherapy and/or targeted therapy appear to increase the frequency of treatment‐related toxicity of at least grade 3. However, treatment‐related deaths did not occur more frequently.	For 1638 participants with esophageal, GE‐junction, and gastric cancer (4 RCTs) information was provided on toxicity according to WHO or NCI‐CTC guidelines. For at least 769 participants with esophageal and GE‐junction cancer from these trials toxicity was reported.	⊕⊝⊝⊝ Very low^b	1/4 studies reported toxicity for the esophageal and GE‐junction cancer subgroup separately, for both arms, and with validated methods.
Quality of life	On average, the quality of life reported improved in the arms with the additional agent.	For 450 participants with esophageal and GE‐junction cancer, quality of life was reported.	⊕⊝⊝⊝ Very low^c	4/5 studies reported on quality of life. 1/4 studies reported quality of life separately for the esophageal and GE‐junction cancer subgroup.
CI: confidence interval; GE: gastroesophageal; HR: hazard ratio; NCI‐CTC: National Cancer Institute Common Toxicity Criteria; OS: overall survival; RCT: randomized controlled trial; WHO: World Health Organization.
GRADE Working Group grades of evidence High quality: further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: we are very uncertain about the estimate.
^aDowngraded by one level due to small sample size. ^bDowngraded by three levels due to the use of non‐validated methods and failure to report toxicities specifically for esophageal and GE‐junction cancer patient group. ^cDowngraded by three levels because not all studies reported on quality of life, and not all studies reported quality of life specifically for esophageal and GE‐junction cancer patients.

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Summary of findings 6. Summary of findings table (subcomparison 4): targeted therapy agent plus control intervention versus control intervention alone for palliative treatment of esophageal and GE‐junction carcinoma

Subcomparison 4: targeted therapy agent plus control intervention versus control intervention alone for palliative treatment of esophageal and GE‐junction carcinoma
Patient or population: palliative participants with esophageal and GE‐junction carcinoma Setting: hospital Intervention: targeted therapy agent plus control arm Comparison: control arm
Outcome	Comparison	Relative effect (95% CI)	No. of participants (studies)	Quality of the evidence (GRADE)	Comments
Overall survival	Subcomparison 4, targeted therapy	HR 0.75 (0.63 to 0.90) Median OS 6.7 months in the targeted therapy agent(s) + control arm versus 5.7 months in the control arm	989 participants (6 RCTs)	⊕⊕⊕⊕ High	Quality not downgraded. Participant populations and agents used differ between studies. However, there is low imprecision and low inconsistency. Cochrane's Q test for heterogeneity showed low heterogeneity (I² = 24%, P = 0.25).
	Subcomparison 4a, EGFR‐targeting agents	HR 0.86 (95% CI 0.73 to 1.01)	655 participants (3 RCTs)	⊕⊕⊕⊝ Moderate^a	Cochrane's Q test for heterogeneity showed low heterogeneity (I² = 0%, P = 0.56).
	Subcomparison 4b, cetuximab	HR 0.76 (95% CI 0.55 to 1.04)	206 participants (2 RCTs)	⊕⊕⊝⊝ Low^b	95% CI includes benefit and harm. Cochrane's Q test for heterogeneity showed low heterogeneity (I² = 0%, P = 0.58).
	Subcomparison 4c, ramucirumab	HR 0.62 (0.43 to 0.88)	228 participants (2 RCTs)	⊕⊕⊕⊝ Moderate^a	Cochrane's Q test for heterogeneity showed low heterogeneity (I² = 28%, P = 0.24).
Progression‐free survival	Subcomparison 4, targeted therapy	HR 0.64 (0.45 to 0.92)	883 participants (5 RCTs)	⊕⊕⊕⊝ Moderate^c	Cochrane's Q test for heterogeneity showed low heterogeneity (I² = 79%, P < 0.001).
	Subcomparison 4a, EGFR‐targeting agents	HR 0.85 (0.73 to 1.00)	655 participants (3 RCTs)	⊕⊕⊝⊝ Low^b	95% CI includes benefit and lack of effect. Cochrane's Q test for heterogeneity showed low heterogeneity (I² = 2%, P = 0.36).
	Subcomparison 4b, cetuximab	HR 0.90 (0.59 to 1.37)	206 participants (2 RCTs)	⊕⊝⊝⊝ Very low^d	95% CI includes benefit and harm. Cochrane's Q test for heterogeneity showed a moderate amount of heterogeneity (I² = 53%, P = 0.14). One of the two studies was not blinded and did not use an independent review board.
	Subcomparison 4c, ramucirumab	HR 0.39 (0.28 to 0.54)	228 participants (2 RCTs)	⊕⊕⊕⊝ Moderate^a	Cochrane's Q test for heterogeneity showed low heterogeneity (I² = 0%, P = 0.99).
Toxicity	Subcomparison 4, targeted therapy	Palliative chemotherapy and/or targeted therapy appear to increase the frequency of treatment‐related toxicity of at least grade 3. However, treatment‐related deaths did not occur more frequently.	For 3020 participants with esophageal, GE‐junction, and gastric cancer (6 RCTs) information was provided on toxicity according to WHO or NCI‐CTC guidelines. For at least 990 participants with esophageal and GE‐junction cancer from these trials toxicity was reported.	⊕⊝⊝⊝ Very low^e	2/6 studies reported toxicity for the esophageal and GE‐junction cancer subgroup separately, for both arms and with validated methods.
Quality of life	Subcomparison 4, targeted therapy	On average, the quality of life reported improved in the arms with the additional agent.	For 2054 participants with esophageal, GE‐junction, and gastric cancer (4 RCTs) information was provided on quality of life. For at least 784 participants with esophageal and GE‐junction cancer, quality of life was reported.	⊕⊝⊝⊝ Very low^f	4/6 studies reported on quality of life. 1/4 studies reported quality of life separately for the esophageal and GE‐junction cancer subgroup.
CI: confidence interval; EGFR: epidermal growth factor receptor; GE: gastroesophageal; HR: hazard ratio; NCI‐CTC: National Cancer Institute Common Toxicity Criteria; OS: overall survival; RCT: randomized controlled trial; WHO: World Health Organization.
GRADE Working Group grades of evidence High quality: further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: we are very uncertain about the estimate.
^aDowngraded by one level due to small sample size. ^bDowngraded by two levels due to small sample size and imprecision. ^cDowngraded by one level due to inconsistency. ^dDowngraded by three levels due to small sample size and imprecision. ^eDowngraded by three levels due to use of non‐validated methods and failure to report toxicities specifically for esophageal and GE‐junction cancer patient group. ^fDowngraded by three levels because not all studies reported on quality of life, and not all studies reported quality of life specifically for esophageal and GE‐junction cancer patients.

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Summary of findings 7. Summary of findings table (subcomparison 5): chemotherapy or targeted therapy agent(s) plus control intervention versus control intervention alone in participants with AC of the esophagus

Subcomparison 5: chemotherapy or targeted therapy agent(s) plus control intervention versus control intervention alone in participants with AC of the esophagus
Patient or population: palliative participants with AC of the esophagus Setting: hospital Intervention: chemotherapy or targeted therapy plus BSC Comparison: BSC
Outcomes	Relative effect (95% CI)	No. of participants (studies)	Quality of the evidence (GRADE)	Comments
Overall survival	HR 0.66 (0.54 to 0.81) Median OS 7.1 months in the chemotherapy or targeted therapy arm versus 6.0 months in the BSC arm	538 (5 RCTs)	⊕⊕⊕⊕ High	Quality not downgraded. Participant populations and agents used differ between studies. However, there is low imprecision and low inconsistency. Cochrane's Q test for heterogeneity showed almost no heterogeneity (I² = 0%, P = 0.55), indicating that results of the studies were consistent.
Progression‐free survival	HR 0.62 (0.38 to 1.00)	713 (4 RCTs)	⊕⊝⊝⊝ Very low^a	95% CI includes benefit and no effect. Cochrane's Q test for heterogeneity showed considerable heterogeneity (I² = 84%, P < 0.001).
Toxicity	Palliative chemotherapy and/or targeted therapy appear to increase the frequency of treatment‐related toxicity of at least grade 3. However, treatment‐related deaths did not occur more frequently.	For 2676 participants with esophageal, GE‐junction, and gastric cancer (5 RCTs) information was provided on toxicity according to WHO or NCI‐CTC guidelines. For at least 570 participants with esophageal and GE‐junction cancer from these trials, toxicity was reported.	⊕⊝⊝⊝ Very low^b	0/5 studies reported toxicity for the esophageal and GE‐junction cancer subgroup separately, for both arms, and with validated methods.
Quality of life	On average, the quality of life reported improved in the arms with the additional agent.	For 1772 participants with esophageal, GE‐junction, and gastric cancer (4 RCTs) information was provided on quality of life. For at least 426 participants with esophageal and GE‐junction cancer, quality of life was reported.	⊕⊝⊝⊝ Very low^c	4/5 studies reported on quality of life. 0/4 studies reported quality of life separately for the esophageal and GE‐junction cancer subgroup.
AC: adenocarcinoma; BSC: best supportive care; CI: confidence interval; HR: hazard ratio; NCI‐CTC: National Cancer Institute Common Toxicity Criteria; OS: overall survival; RCT: randomized controlled trial; WHO: World Health Organization.
GRADE Working Group grades of evidence High quality: further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: we are very uncertain about the estimate.
^a Downgraded three levels due to very serious imprecision (95% CI includes appreciable benefit and no effect) and serious inconsistency. ^bDowngraded by three levels due to use of non validated methods and failure to report toxicities, specifically for esophageal and GE‐junction cancer patient group. ^cDowngraded by three levels because not all studies reported on quality of life, and not all studies reported quality of life specifically for esophageal and GE‐junction cancer patients.

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Summary of findings 8. Summary of findings table (subcomparison 6): chemotherapy or targeted therapy agent(s) plus control intervention versus control intervention alone in participants with SCC of the esophagus

Subcomparison 6: chemotherapy or targeted therapy agent(s) plus control intervention versus control intervention alone in participants with SCC of the esophagus
Patient or population: palliative participants with SCC of the esophagus Setting: hospital Intervention: chemotherapy or targeted therapy plus BSC Comparison: BSC
Outcomes	Relative effect (95% CI)	No. of participants (studies)	Quality of the evidence (GRADE)	Comments
Overall survival	HR 0.76 (95% CI 0.65 to 0.90) Median OS 8.0 months in the chemotherapy or targeted therapy arm versus 6.5 months in the BSC arm.	268 (4 RCTs)	⊕⊕⊕⊕ High	Quality not downgraded. Participant populations and agents used differ between studies. However, there is low imprecision and low inconsistency. Cochrane's Q test for heterogeneity showed almost no heterogeneity (I² = 0%, P = 0.95), indicating that results of the studies were consistent.
Progression‐free survival	HR 0.72 (95% CI 0.55 to 0.96)	168 (2 RCTs)	⊕⊝⊝⊝ Very low^a	Cochrane's Q test for heterogeneity showed significant heterogeneity (I² = 0%, P = 0.97), indicating that results of the 2 studies were not consistent. One of the 2 studies was not blinded and did not use an independent review board.
Toxicity	Palliative chemotherapy and/or targeted therapy appear to increase the frequency of treatment‐related toxicity of at least grade 3. However, treatment‐related deaths did not occur more frequently.	For 150 participants with esophageal and GE‐junction cancer (2 RCTs) information was provided on toxicity according to WHO or NCI‐CTC guidelines.	⊕⊝⊝⊝ Very low^b	2/4 studies reported on toxicities with validated methods. 2/2 studies reporting toxicity for the esophageal and GE‐junction cancer subgroup separately, for both arms, and with validated methods.
Quality of life	On average, the quality of life reported improved in the arms with the additional agent.	For 156 participants with esophageal and GE‐junction cancer (1 RCT) information was provided on quality of life.	⊕⊝⊝⊝ Very low^c	1/4 studies reported on quality of life.
BSC: best supportive care; CI: confidence interval; GE: gastro‐esophageal; HR: hazard ratio; NCI‐CTC: National Cancer Institute Common Toxicity Criteria; OS: overall survival; RCT: randomized controlled trial; SCC: squamous cell carcinoma; WHO: World Health Organization.
GRADE Working Group grades of evidence High quality: further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: we are very uncertain about the estimate.
^aDowngraded by two levels due to small sample size, and one level due lack of blinding or use of an independent review board. ^bDowngraded by three levels due to use of non‐validated methods and failure to report toxicities specifically for esophageal and GE‐junction cancer patient group. ^cDowngraded by three levels because not all studies reported on quality of life, and not all studies reported quality of life specifically for esophageal and GE‐junction cancer patients.

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Comparison 1. Main analysis: chemotherapy or targeted therapy agent(s) plus control intervention versus control intervention alone

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Overall survival Show forest plot	11	1347	Hazard Ratio (Random, 95% CI)	0.75 [0.68, 0.84]

1.1 Subcomparison 3: chemotherapeutic agent(s) plus control intervention versus control intervention alone	5	358	Hazard Ratio (Random, 95% CI)	0.73 [0.63, 0.85]
1.2 Subcomparison 4: targeted therapy agent plus control intervention versus control intervention alone	6	989	Hazard Ratio (Random, 95% CI)	0.75 [0.63, 0.90]
2 Progression‐free survival Show forest plot	5		Hazard Ratio (Random, 95% CI)	Subtotals only

2.1 Subcomparison 4: targeted therapy agent plus control intervention versus control intervention alone	5	883	Hazard Ratio (Random, 95% CI)	0.64 [0.45, 0.92]

Comparison 1. Main analysis: chemotherapy or targeted therapy agent(s) plus control intervention versus control intervention alone

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Comparison 2. Sensitivity analysis: studies that also included participants with gastric cancer

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Overall survival Show forest plot	8	1755	Hazard Ratio (Random, 95% CI)	0.94 [0.83, 1.05]

Comparison 2. Sensitivity analysis: studies that also included participants with gastric cancer

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Comparison 3. Sensitivity analysis: effect of intervention on participants with GE‐junction cancer versus effect of intervention on participants with gastric cancer

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Overall survival, GE‐junction cancer outcomes Show forest plot	5	538	Hazard Ratio (Random, 95% CI)	0.66 [0.54, 0.81]

2 Overall survival, gastric cancer outcomes Show forest plot	5	2093	Hazard Ratio (Random, 95% CI)	0.89 [0.76, 1.04]

Comparison 3. Sensitivity analysis: effect of intervention on participants with GE‐junction cancer versus effect of intervention on participants with gastric cancer

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Comparison 4. Subcomparison 1: chemotherapy or targeted therapy plus BSC versus BSC

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Overall survival Show forest plot	5	750	Hazard Ratio (Random, 95% CI)	0.81 [0.71, 0.92]

2 Progression‐free survival Show forest plot	2	540	Hazard Ratio (Random, 95% CI)	0.58 [0.28, 1.18]

Comparison 4. Subcomparison 1: chemotherapy or targeted therapy plus BSC versus BSC

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Comparison 5. Subcomparison 2: studies with participants receiving second‐line therapy

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Overall survival Show forest plot	4	769	Hazard Ratio (Random, 95% CI)	0.71 [0.54, 0.94]

2 Progression‐free survival Show forest plot	3	677	Hazard Ratio (Random, 95% CI)	0.51 [0.29, 0.90]

Comparison 5. Subcomparison 2: studies with participants receiving second‐line therapy

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Comparison 6. Subgroup analysis 4a: EGFR‐targeting agent plus control intervention versus control intervention alone

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Overall survival Show forest plot	3	655	Hazard Ratio (Random, 95% CI)	0.86 [0.73, 1.01]

2 Progression‐free survival Show forest plot	3	655	Hazard Ratio (Random, 95% CI)	0.85 [0.73, 1.00]

Comparison 6. Subgroup analysis 4a: EGFR‐targeting agent plus control intervention versus control intervention alone

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Comparison 7. Subgroup analysis 4b: cetuximab plus control intervention versus control intervention alone

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Overall survival Show forest plot	2	206	Hazard Ratio (Random, 95% CI)	0.76 [0.55, 1.04]

2 Progression‐free survival Show forest plot	2	206	Hazard Ratio (Random, 95% CI)	0.90 [0.59, 1.37]

Comparison 7. Subgroup analysis 4b: cetuximab plus control intervention versus control intervention alone

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Comparison 8. Subgroup analysis 4c: ramucirumab plus control intervention versus control intervention alone

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Overall survival Show forest plot	2	228	Hazard Ratio (Random, 95% CI)	0.62 [0.43, 0.88]

2 Progression‐free survival Show forest plot	2	228	Hazard Ratio (Random, 95% CI)	0.39 [0.28, 0.54]

Comparison 8. Subgroup analysis 4c: ramucirumab plus control intervention versus control intervention alone

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Comparison 9. Subcomparison 5: chemotherapy or targeted therapy agent(s) plus control intervention versus control intervention alone in participants with AC of the esophagus

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Overall survival Show forest plot	5	538	Hazard Ratio (Random, 95% CI)	0.66 [0.54, 0.81]

2 Progression‐free survival Show forest plot	4	713	Hazard Ratio (Random, 95% CI)	0.62 [0.38, 1.00]

Comparison 9. Subcomparison 5: chemotherapy or targeted therapy agent(s) plus control intervention versus control intervention alone in participants with AC of the esophagus

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Comparison 10. Subcomparison 6: chemotherapy or targeted therapy agent(s) plus control arm versus control arm in participants with SCC of the esophagus

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Overall survival Show forest plot	4	268	Hazard Ratio (Random, 95% CI)	0.76 [0.65, 0.90]

2 Progression‐free survival Show forest plot	2	168	Hazard Ratio (Random, 95% CI)	0.72 [0.55, 0.96]

Comparison 10. Subcomparison 6: chemotherapy or targeted therapy agent(s) plus control arm versus control arm in participants with SCC of the esophagus

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