Non‐surgical versus surgical treatment for oesophageal cancer

Lawrence MJ Best; Muntzer Mughal; Kurinchi Selvan Gurusamy

doi:10.1002/14651858.CD011498.pub2

Tratamiento no quirúrgico versus tratamiento quirúrgico para el cáncer esofágico

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Referencias

References to studies included in this review

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References to other published versions of this review

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estudios excluidos
otras referencias

Best LMJ, Gurusamy KS. Surgical versus non‐surgical treatment for oesophageal cancer. Cochrane Database of Systematic Reviews 2015, Issue 1. [DOI: 10.1002/14651858.CD011498]

Characteristics of studies

Characteristics of included studies [ordered by study ID]

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estudios excluidos

Badwe 1999

Methods	Randomised controlled trial (RCT)
Participants	Country: India Number randomised: 99 Postrandomisation exclusions: 12 (12%) Number analysed: 87 Average age: 52 years Females: 26 (26%) Inclusion criteria Histological confirmation of squamous cell carcinoma of the oesophagus affecting the infra‐aortic thoracic region. Exclusion criteria Karnofsky performance status < 70 and age > 65 years. Inoperability due to metastases or presence of supraclavicular lymphadenopathy. Presence of local disease signalled by presence of thoracic backache at rest. Sinus/fistula presence, more than 20 degrees of axis deviation, or length of greater than 10 cm. Tracheal and bronchial involvement. Insufficient pulmonary function for thoracotomy. Stenotic primary tumour and total obstruction. Neoadjuvant chemotherapy.
Interventions	Participants were randomly assigned to 2 groups Group 1: radiotherapy (N = 43) Further details: 50 gray of external radiation in 28 fractions followed by an external boost of 15 gray in 8 fractions or intraluminal radiotherapy of 15 gray with a 200 centigray/hour dose rate at 1 cm off axis Group 2: oesophagectomy (N = 44) Further details: standard Ivor‐Lewis procedure
Outcomes	Outcomes reported were short‐term mortality and long‐term mortality
Cancer stage/histology	Not reported/squamous cell carcinoma
Tumour location	Infra‐aortic
American Society of Anaesthesiologists (ASA) physical status score	Not reported
Notes	We attempted to contact the study authors in February 2015 Reasons for postrandomisation exclusions: 2 participants from the surgery arm due to direct spread to the bronchus, 10 participants from the radiotherapy arm as 7 received radiotherapy at other treatment centres and 3 did not take any treatment Participants were followed‐up for a maximum of 3 years
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: "randomised by closed envelope method". Comment: further details were unavailable.
Allocation concealment (selection bias)	Unclear risk	Quote: "randomised by closed envelope method". Comment: further details were unavailable.
Blinding of participants and personnel (performance bias) All outcomes	High risk	Comment: it was impossible to blind the participants and healthcare providers.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Comment: this information was unavailable.
Incomplete outcome data (attrition bias) All outcomes	High risk	Comment: there was an imbalance in postrandomisation exclusions.
Selective reporting (reporting bias)	High risk	Comment: treatment‐related complications were not reported.
Source of funding	Unclear risk	Comment: this information was unavailable.
Other bias	Low risk	Comment: there was no other source of bias.

Bedenne 2007

Methods	RCT
Participants	Country: France Number randomised: 259 Postrandomisation exclusions: 0 (0%) Number analysed: 259 Average age: 58 years Females: 17 (6.7%) Inclusion criteria Resectable T₃N_0‐1M₀ (International Union Against Cancer criteria) epidermoid or adenocarcinoma of the thoracic oesophagus. Clinical and biological eligibility for surgery or chemoradiation. Participants responding to induction chemoradiation. Exclusion criteria Tumour within 18 cm from the dental ridge or infiltrating the gastric cardia. Tracheobronchial involvement. Visceral metastases or supraclavicular nodes. Weight loss > 15%. Symptomatic coronary heart disease. Cirrhosis Child‐Pugh B or C. Respiratory insufficiency.
Interventions	Participants were randomly assigned to 2 groups Group 1: chemoradiotherapy (N = 130) Further details: external radiotherapy of 15 gray over 4 days and fluorouracil (FU) 800 mg/m² daily and cisplatin 15mg/m² daily for 5 days (x 3 cycles with a 2 week interval between cycles) Group 2: oesophagectomy (N = 129) Further details: different methods of oesophagectomy as required. Preoperative chemoradiotherapy was administered
Outcomes	Outcomes reported were short‐term mortality, long‐term mortality, recurrence, length of hospital stay, short‐term health‐related quality of life, and medium‐term health‐related quality of life.
Cancer stage/histology	T₃N_0‐1M₀/squamous cell carcinoma or adenocarcinoma
Tumour location	Thoracic oesophagus
American Society of Anaesthesiologists (ASA) physical status score	Not reported
Notes	We attempted to contact the study authors in February 2015 Both groups received external radiotherapy (30 gray over 10 days with a 2 week interval between day 5 and day 6) and fluorouracil (FU) 800 mg/m² daily and cisplatin 15 mg/m² daily for 5 days (x 2 cycles with a 2 week interval between cycles) prior to randomisation Participants were followed up starting at 4 months after starting the treatment (in the surgical arm, 2 months after resection, in the non‐surgical arm, 3 weeks after the end of chemotherapy). Follow‐up was carried out every 3 months for 2 years and then every 6 months thereafter Median follow‐up: 4 years
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Randomly assigned by telephone at the FFCD Data Center through a minimization program".
Allocation concealment (selection bias)	Low risk	Quote: "Randomly assigned by telephone at the FFCD Data Center through a minimization program".
Blinding of participants and personnel (performance bias) All outcomes	High risk	Comment: it was impossible to blind the participants and healthcare providers.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Comment: this information was unavailable.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Comment: there were no postrandomisation exclusions.
Selective reporting (reporting bias)	High risk	Comment: treatment‐related complications were not reported.
Source of funding	Low risk	Quote: "Supported by grants from the Ligue Nationale Contre le Cancer, the Fonds de Recherche de la Société Nationale Francaise de Gastroentérologie, the Programme Hospitalier pour la Recher‐ che Clinique, and the Association pour la Recherche Contre le Cancer".
Other bias	Low risk	Comment: there was no other source of bias.

Blazeby 2014

Methods	RCT
Participants	Country: UK Sample size: 5 Postrandomisation exclusions: 0 (0%) Number analysed: 5 Average age: not reported Females: not reported Inclusion criteria Histologically confirmed oesophageal squamous cell carcinoma. Aged ≥ 18 years. Sufficient performance status and fitness to undergo surgery or definitive chemoradiotherapy. Tumour staged between T₂N₀M₀ and T₄N₁M₀ (where the T4 tumour involved the diaphragmatic crura or mediastinal pleura only), and a total primary tumour and node length of < 10 cm. Exclusion criteria Concomitant or past malignancy within 5 years (except for basal cell carcinoma or squamous cell carcinoma of the skin or in situ carcinoma of the cervix). Tumour within 2 cm of cricopharyngeus. Tumour including 42 cm of gastric wall or previous treatment that compromised the ability to deliver definitive chemoradiotherapy or surgery.
Interventions	Participants were randomly assigned to 2 groups Group 1: chemoradiotherapy (N = 2) Further details: chemotherapy was given for a total of 84 days (including induction therapy) of 21 days cycles of either cisplatin 80 mg/m² by intravenous infusion on days 1 and 5 followed by fluorouracil 1 g/m² per day intravenous infusion for 4 days or cisplatin 80 mg/m² by intravenous infusion on day 1 and capecitabine 625 mg/m² orally twice daily continuously and radiotherapy total 50 gray in 25 fractions Group 2: oesophagectomy (N = 3) Further details: different methods of oesophagectomy as required
Outcomes	The trial did not report any of the outcomes of interest
Cancer stage/histology	T_2‐4N_0‐1M₀/Squamous cell carcinoma
Tumour location	Any part of the oesophagus up to 2 cm away from the cricopharyngeus
American Society of Anaesthesiologists (ASA) physical status score	Not reported
Notes	We attempted to contact the study authors in February 2015 Both groups received induction chemotherapy given as 21 days of either cisplatin 80 mg/m² by intravenous infusion on days 1 and 5 followed by fluorouracil 1 g/m² per day intravenous infusion for 4 days or cisplatin 80 mg/m² by intravenous infusion on day 1 and capecitabine 625 mg/m² orally twice daily continuously
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "When eligible patients consented to randomisation, treatment allocation was determined by an automated randomisation web‐based system".
Allocation concealment (selection bias)	Low risk	Quote: "When eligible patients consented to randomisation, treatment allocation was determined by an automated randomisation web‐based system".
Blinding of participants and personnel (performance bias) All outcomes	High risk	Comment: it was impossible to blind the participants and healthcare providers.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Comment: this information was unavailable.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Comment: there were no postrandomisation exclusions.
Selective reporting (reporting bias)	High risk	Comment: mortality and complications were not reported.
Source of funding	Low risk	Quote: "This article summarises independent research funded by the National Institute for Health Research (NIHR) under its Research for Patient Benefit (RfPB) Program (Grant reference PB‐PG‐0807– 14131)".
Other bias	Low risk	Comment: there was no other source of bias.

Carstens 2007

Methods	RCT
Participants	Country: Norway and Sweden Number randomised: 91 Postrandomisation exclusions: 0 (0%) Number analysed: 91 Average age: not reported Females: not reported Inclusion criteria Participants with resectable oesophageal squamous cell carcinoma or adenocarcinoma. Exclusion criteria Not reported.
Interventions	Participants were randomly assigned to 2 groups Group 1: chemoradiotherapy (N = 46) Further details: external radiotherapy total of 64 gray given in 32 fractions over 9 weeks and three 3‐weekly cycles of cisplatin 100 mg/m² on day 1 and 5‐fluorouracil chemotherapy 750 mg/m²/day from day 1 to 5 Group 2: oesophagectomy (N = 45) Further details: Ivor‐Lewis procedure
Outcomes	Outcomes reported were: short‐term mortality and long‐term mortality
Cancer stage/histology	Not reported/squamous cell carcinoma or adenocarcinoma
Tumour location	Not specified
American Society of Anaesthesiologists (ASA) physical status score	Not reported
Notes	We attempted to contact the study authors in February 2015, and the authors replied in March 2015 The trial authors did not specify the follow‐up period but reported 4 year follow‐up results.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: this information was unavailable.
Allocation concealment (selection bias)	Low risk	Comment: participants were centrally allocated (information retrieved directly from the trial author).
Blinding of participants and personnel (performance bias) All outcomes	High risk	Comment: it was impossible to blind the participants and healthcare providers.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Comment: this information was unavailable.
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Comment: this information was unavailable.
Selective reporting (reporting bias)	High risk	Comment: treatment‐related complications were not reported.
Source of funding	Unclear risk	Comment: this information was unavailable.
Other bias	Low risk	Comment: there was no other source of bias.

Chiu 2005

Methods	RCT
Participants	Country: China Number randomised: 81 Postrandomisation exclusions: 1 (1.2%) Number analysed: 80 Average age: 62 years Females: 14 (17.3%) Inclusion criteria Mid‐ or lower‐thoracic oesophageal cancers that were confirmed on histology to be a squamous cell carcinoma deemed to be resectable. Exclusion criteria Participants who had distant metastasis to solid visceral organs or local invasion into trachea, descending aorta, or recurrent laryngeal nerve. Participants > 75 years or who had a serious premorbid condition or a poor physical status that compromised a thoracotomy. Participants with compromised cardiac function or creatinine clearance less than 50 mL/min were ineligible.
Interventions	Participants were randomly assigned to 2 groups Group 1: chemoradiotherapy (N = 36) Further details: external radiotherapy total of 50 to 60 gray given in 25 to 30 fractions over 5 to 6 weeks and two 3‐weekly cycles of cisplatin 60 mg/m² on day 1 and day 22 and 5‐fluorouracil chemotherapy 200 mg/m²/day from day 1 to day 42 Group 2: oesophagectomy (N = 44) Further details: 2‐ or 3‐stage oesophagectomy
Outcomes	Outcomes reported were short‐term mortality, long‐term mortality, short‐term adverse events, short‐term serious adverse events, long‐term recurrence, and length of hospital stay
Cancer stage/histology	Not reported (must be deemed resectable and have no metastases)/squamous cell carcinoma
Tumour location	Mid‐ or lower‐thorax
American Society of Anaesthesiologists (ASA) physical status score	Not reported
Notes	We attempted to contact the study authors in February 2015 Reason for postrandomisation drop‐out: initially deemed resectable but later considered unresectable Patients were followed up at 6 to 8 week intervals in the 1st year and at 3‐month intervals thereafter Median follow‐up: 1.5 years
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: this information was unavailable.
Allocation concealment (selection bias)	Unclear risk	Comment: this information was unavailable.
Blinding of participants and personnel (performance bias) All outcomes	High risk	Comment: it was impossible to blind the participants and healthcare providers.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Comment: this information was unavailable.
Incomplete outcome data (attrition bias) All outcomes	High risk	Comment: there was an imbalance in postrandomisation exclusions.
Selective reporting (reporting bias)	Low risk	Comment: the trial reported all important outcomes.
Source of funding	Low risk	Quote: "This study was supported by the Research Grant Council (RGC) of Hong Kong Special Administrative Region, China".
Other bias	Low risk	Comment: there was no other source of bias.

Fok 1994

Methods	RCT
Participants	Country: China Number randomised: 156 Postrandomisation exclusions: 0 (0%) Number analysed: 156 Average age: 55 years Females: not reported Inclusion criteria Potentially curable middle third oesophageal carcinoma < 5 cm in length on barium swallow. No clinical evidence of extensive local infiltration or metastases. Clinically fit to undergo surgery. Exclusion criteria None specified.
Interventions	Participants were randomly assigned to 4 groups Group 1: radiotherapy (N = 35): Further details: 43 to 53 gray over 4 to 5 weeks Group 2: oesophagectomy with neoadjuvant radiotherapy (N = 40) Group 3: oesophagectomy with adjuvant radiotherapy (N = 42) Group 4: oesophagectomy without radiotherapy (N = 39)
Outcomes	Outcomes reported were long‐term mortality only
Cancer stage/histology	Not reported ('potentially curable')/squamous cell carcinoma
Tumour location	Middle third of the oesophagus
American Society of Anaesthesiologists (ASA) physical status score	Not reported
Notes	We attempted to contact the study authors in February 2015 Long‐term follow‐up with partial data were available at 10 years, however details were not specified
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: this information was unavailable.
Allocation concealment (selection bias)	Unclear risk	Comment: this information was unavailable.
Blinding of participants and personnel (performance bias) All outcomes	High risk	Comment: it was impossible to blind the participants and healthcare providers.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Comment: this information was unavailable.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Comment: there were no postrandomisation exclusions.
Selective reporting (reporting bias)	High risk	Comment: treatment‐related complications were not reported.
Source of funding	Unclear risk	Comment: this information was unavailable.
Other bias	Low risk	Comment: there was no other source of bias.

Stahl 2005

Methods	RCT
Participants	Country: Germany Number randomised: 172 Postrandomisation exclusions: 0 (0%) Number analysed: 172 Average age: 57 years Females: 34 (19.8%) Inclusion criteria Histologically proven squamous cell carcinoma of the upper and mid third of the oesophagus. Untreated participants ≤ 70 years old. Locally advanced disease (e.g. T_3‐4, N_0‐1, M₀) according to computed tomography (CT) scan and endoscopic ultrasound (EUS). Good general condition (World Health Organization (WHO) performance status grade of 0 to 1). Normal liver, renal, and bone marrow function. Written informed consent. Exclusion criteria Participants with infiltration of the tracheobronchial tree.
Interventions	Participants were randomly assigned to 2 groups Group 1: chemoradiotherapy (N = 86) Further details: additional external radiotherapy with 2 x 1.5 gray/day for a total dose of at least 20 gray Group 2: oesophagectomy (N = 86)
Outcomes	Outcomes reported were short‐term mortality and long‐term mortality
Cancer stage/histology	T3‐4 N0‐1 M0/squamous cell carcinoma
Tumour location	Upper and mid third of the oesophagus
American Society of Anaesthesiologists (ASA) physical status score	Not reported (WHO performance status grade of 0 to 1)
Notes	We attempted to contact the study authors in February 2015 Both groups received external radiotherapy with 2 x 1.5 gray/day for a total dose of 40 gray and chemotherapy (bolus fluorouracil 500 mg/m², leucovorin 300 mg/m², etoposide 100 mg/m², and cisplatin 30 mg/m² on days 1 to 3 every 3 weeks) and cisplatin 50 mg/m² on days 2 to 8 and etoposide 80 mg/m² on days 3 to 5 concomitant with radiotherapy Participants were seen for the first follow‐up 8 to 12 weeks after the end of treatment and, thereafter, every 3 months up to 2 years. Afterwards, follow‐up was planned every 6 months up to 5 years Median follow‐up: 6 years
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Allocation to treatment groups was performed...using a computerized randomization program".
Allocation concealment (selection bias)	Low risk	Quote: "Allocation to treatment groups was performed...using a computerized randomization program".
Blinding of participants and personnel (performance bias) All outcomes	High risk	Quote: "This was an unblinded, prospectively randomized phase III trial".
Blinding of outcome assessment (detection bias) All outcomes	High risk	Quote: "This was an unblinded, prospectively randomized phase III trial".
Incomplete outcome data (attrition bias) All outcomes	Low risk	Comment: there were no postrandomisation exclusions.
Selective reporting (reporting bias)	High risk	Comment: treatment related complications were not reported.
Source of funding	Low risk	Quote: "Supported by the Stiftung Deutsche Krebshilfe (German Cancer Aid)".
Other bias	Low risk	Comment: there was no other source of bias.

Sun 2006

Methods	RCT
Participants	Country: China Number randomised: 269 Postrandomisation exclusions: 0 (0%) Number analysed: 269 Average age: 56 years Females: 67 (24.9%) Inclusion criteria Resectable oesophageal cancer in the chest. No history of other cancers. Exclusion criteria None specified.
Interventions	Participants were randomly assigned to 2 groups Group 1: radiotherapy (N = 134) Further details: external radiotherapy conventionally fractionated at 1.8 to 2.0 Gray/day for the 1st two thirds of treatment course to a dose of about 50 to 50.4 gray followed by late course accelerated hyperfractionated radiotherapy, twice daily at 1.5 gray per fraction (with a minimal interval of 6 hours between fractions) to a dose of 18 to 21 gray. The total dose whole radiotherapy was 68.4 to 71.0 gray Group 2: oesophagectomy (N = 135) Further details: abdominothoracic approach
Outcomes	Outcomes reported were long‐term mortality and long‐term recurrence
Cancer stage/histology	Not reported
Tumour location	Upper, middle, and lower oesophagus
American Society of Anaesthesiologists (ASA) physical status score	Not reported
Notes	We attempted to contact the study authors in February 2015 Median follow‐up: 4.8 years
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: this information was unavailable.
Allocation concealment (selection bias)	Unclear risk	Comment: this information was unavailable.
Blinding of participants and personnel (performance bias) All outcomes	High risk	Comment: it was impossible to blind the participants and healthcare providers.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Comment: this information was unavailable.
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Comment: this information was unavailable.
Selective reporting (reporting bias)	High risk	Comment: treatment‐related complications were not reported.
Source of funding	Unclear risk	Comment: this information was unavailable.
Other bias	Low risk	Comment: there was no other source of bias.

Abbreviations: RCT: randomised controlled trial; TNM = tumour stage, nodal stage, and metastasis; WHO: World Health Organization.

Characteristics of excluded studies [ordered by study ID]

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estudios incluidos

Study	Reason for exclusion
Desai 1987	Participants were not randomised.
Earlam 1991	The trial was stopped due to poor recruitment in May 1988 16 months after the start because only 31 participants had been entered. No randomised data was generated.
Hainsworth 2007	The protocol for this trial was changed so allocation was not randomised.
Ilson 2007	This was not a randomised controlled trial. However, we retrieved and screened the full‐text article as this was unclear based on the title alone.
Nozaki 2014	This trial is expected to be completed in 2018 and the current report (a conference abstract) includes details of the safety of surgery in participants randomised to the surgical arm. The report included non‐randomised participants undergoing surgery as well.

Data and analyses

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Comparison 1. Surgical versus non‐surgical treatment of oesophageal cancer

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Short‐term mortality Show forest plot	5	689	Risk Ratio (M‐H, Random, 95% CI)	0.39 [0.11, 1.35]
Open in figure viewer Analysis 1.1 Comparison 1 Surgical versus non‐surgical treatment of oesophageal cancer, Outcome 1 Short‐term mortality.
2 Long‐term mortality (binary) Show forest plot	3	511	Risk Ratio (M‐H, Fixed, 95% CI)	1.03 [0.92, 1.14]
Open in figure viewer Analysis 1.2 Comparison 1 Surgical versus non‐surgical treatment of oesophageal cancer, Outcome 2 Long‐term mortality (binary).
3 Long‐term mortality (time‐to‐event) Show forest plot	7	1114	Hazard Ratio (Fixed, 95% CI)	1.09 [0.97, 1.22]
Open in figure viewer Analysis 1.3 Comparison 1 Surgical versus non‐surgical treatment of oesophageal cancer, Outcome 3 Long‐term mortality (time‐to‐event).
4 Proportion with a serious adverse event within 3 months Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
Open in figure viewer Analysis 1.4 Comparison 1 Surgical versus non‐surgical treatment of oesophageal cancer, Outcome 4 Proportion with a serious adverse event within 3 months.
5 Short‐term health‐related quality of life Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only
Open in figure viewer Analysis 1.5 Comparison 1 Surgical versus non‐surgical treatment of oesophageal cancer, Outcome 5 Short‐term health‐related quality of life.
6 Medium‐term health‐related quality of life Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
Open in figure viewer Analysis 1.6 Comparison 1 Surgical versus non‐surgical treatment of oesophageal cancer, Outcome 6 Medium‐term health‐related quality of life.
7 Long‐term recurrence (binary) Show forest plot	2	339	Risk Ratio (M‐H, Fixed, 95% CI)	1.05 [0.87, 1.28]
Open in figure viewer Analysis 1.7 Comparison 1 Surgical versus non‐surgical treatment of oesophageal cancer, Outcome 7 Long‐term recurrence (binary).
8 Long‐term recurrence (time‐to‐event) Show forest plot	2	349	Hazard Ratio (Fixed, 95% CI)	0.96 [0.80, 1.16]
Open in figure viewer Analysis 1.8 Comparison 1 Surgical versus non‐surgical treatment of oesophageal cancer, Outcome 8 Long‐term recurrence (time‐to‐event).
9 Local recurrence (binary) Show forest plot	3	449	Risk Ratio (M‐H, Fixed, 95% CI)	0.89 [0.70, 1.12]
Open in figure viewer Analysis 1.9 Comparison 1 Surgical versus non‐surgical treatment of oesophageal cancer, Outcome 9 Local recurrence (binary).
10 Proportion with any adverse event within 3 months Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
Open in figure viewer Analysis 1.10 Comparison 1 Surgical versus non‐surgical treatment of oesophageal cancer, Outcome 10 Proportion with any adverse event within 3 months.
11 Length of hospital stay (days) Show forest plot	2		Mean Difference (IV, Fixed, 95% CI)	Subtotals only
Open in figure viewer Analysis 1.11 Comparison 1 Surgical versus non‐surgical treatment of oesophageal cancer, Outcome 11 Length of hospital stay (days).
12 Dysphagia at maximal follow‐up Show forest plot	1	139	Risk Ratio (M‐H, Fixed, 95% CI)	1.48 [1.01, 2.19]
Open in figure viewer Analysis 1.12 Comparison 1 Surgical versus non‐surgical treatment of oesophageal cancer, Outcome 12 Dysphagia at maximal follow‐up.
13 Long‐term mortality (time‐to‐event): stratified by treatment Show forest plot	7	1114	Hazard Ratio (Fixed, 95% CI)	1.09 [0.97, 1.22]
Open in figure viewer Analysis 1.13 Comparison 1 Surgical versus non‐surgical treatment of oesophageal cancer, Outcome 13 Long‐term mortality (time‐to‐event): stratified by treatment.
13.1 Chemoradiotherapy	4	602	Hazard Ratio (Fixed, 95% CI)	0.88 [0.76, 1.03]
13.2 Radiotherapy	3	512	Hazard Ratio (Fixed, 95% CI)	1.39 [1.18, 1.64]
14 Long‐term mortality (binary): definitive chemoradiotherapy versus surgery with neoadjuvant chemotherapy Show forest plot	2	431	Risk Ratio (M‐H, Fixed, 95% CI)	1.04 [0.93, 1.16]
Open in figure viewer Analysis 1.14 Comparison 1 Surgical versus non‐surgical treatment of oesophageal cancer, Outcome 14 Long‐term mortality (binary): definitive chemoradiotherapy versus surgery with neoadjuvant chemotherapy.
15 Long‐term mortality (time‐to‐event): definitive chemoradiotherapy versus surgery with neoadjuvant chemotherapy or chemoradiotherapy Show forest plot	2	431	Hazard Ratio (Fixed, 95% CI)	0.99 [0.78, 1.26]
Open in figure viewer Analysis 1.15 Comparison 1 Surgical versus non‐surgical treatment of oesophageal cancer, Outcome 15 Long‐term mortality (time‐to‐event): definitive chemoradiotherapy versus surgery with neoadjuvant chemotherapy or chemoradiotherapy.

Figure 1

Study flow diagram.

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Figure 2

'Risk of bias' graph: review authors' judgements about each 'Risk of bias' item presented as percentages across all included studies.

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Figure 3

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

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Analysis 1.1

Comparison 1 Surgical versus non‐surgical treatment of oesophageal cancer, Outcome 1 Short‐term mortality.

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Analysis 1.2

Comparison 1 Surgical versus non‐surgical treatment of oesophageal cancer, Outcome 2 Long‐term mortality (binary).

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Analysis 1.3

Comparison 1 Surgical versus non‐surgical treatment of oesophageal cancer, Outcome 3 Long‐term mortality (time‐to‐event).

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Analysis 1.4

Comparison 1 Surgical versus non‐surgical treatment of oesophageal cancer, Outcome 4 Proportion with a serious adverse event within 3 months.

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Analysis 1.5

Comparison 1 Surgical versus non‐surgical treatment of oesophageal cancer, Outcome 5 Short‐term health‐related quality of life.

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Analysis 1.6

Comparison 1 Surgical versus non‐surgical treatment of oesophageal cancer, Outcome 6 Medium‐term health‐related quality of life.

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Analysis 1.7

Comparison 1 Surgical versus non‐surgical treatment of oesophageal cancer, Outcome 7 Long‐term recurrence (binary).

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Analysis 1.8

Comparison 1 Surgical versus non‐surgical treatment of oesophageal cancer, Outcome 8 Long‐term recurrence (time‐to‐event).

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Analysis 1.9

Comparison 1 Surgical versus non‐surgical treatment of oesophageal cancer, Outcome 9 Local recurrence (binary).

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Analysis 1.10

Comparison 1 Surgical versus non‐surgical treatment of oesophageal cancer, Outcome 10 Proportion with any adverse event within 3 months.

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Analysis 1.11

Comparison 1 Surgical versus non‐surgical treatment of oesophageal cancer, Outcome 11 Length of hospital stay (days).

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Analysis 1.12

Comparison 1 Surgical versus non‐surgical treatment of oesophageal cancer, Outcome 12 Dysphagia at maximal follow‐up.

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Analysis 1.13

Comparison 1 Surgical versus non‐surgical treatment of oesophageal cancer, Outcome 13 Long‐term mortality (time‐to‐event): stratified by treatment.

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Analysis 1.14

Comparison 1 Surgical versus non‐surgical treatment of oesophageal cancer, Outcome 14 Long‐term mortality (binary): definitive chemoradiotherapy versus surgery with neoadjuvant chemotherapy.

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Analysis 1.15

Comparison 1 Surgical versus non‐surgical treatment of oesophageal cancer, Outcome 15 Long‐term mortality (time‐to‐event): definitive chemoradiotherapy versus surgery with neoadjuvant chemotherapy or chemoradiotherapy.

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Summary of findings for the main comparison. Non‐surgical versus surgical treatment of oesophageal cancer (primary outcomes)

Non‐surgical versus surgical treatment of oesophageal cancer
Patient or population: people with oesophageal cancer Settings: secondary or tertiary care Intervention: non‐surgical treatment Comparison: surgical treatment
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	Number of participants (studies)	Quality of the evidence (GRADE)
	Assumed risk	Corresponding risk
	Surgical treatment	Non‐surgical treatment
Short‐term mortality All‐cause mortality either in‐hospital or within 3 months	78 per 1000¹	30 per 1000 (9 to 105)	RR 0.39 (0.11 to 1.35)	689 (5 studies)	⊕⊝⊝⊝ very low^2,3
Long‐term mortality (binary outcome) All‐cause mortality for the duration of follow‐up	691 per 1000¹	712 per 1000 (636 to 788)	RR 1.03 (0.92 to 1.14)	511 (3 studies)	⊕⊕⊝⊝ low²
Long‐term mortality (time‐to‐event outcome): chemoradiotherapy versus surgery All‐cause mortality for the duration of follow‐up	349 per 1000¹	314 per 1000 (278 to 357)	HR 0.88 (0.76 to 1.03)	602 (4 studies)	⊕⊕⊝⊝ low²
Long‐term mortality (time‐to‐event outcome): radiotherapy versus surgery All‐cause mortality for the duration of follow‐up	350 per 1000¹	451 per 1000 (398 to 507)	HR 1.39 (1.18 to 1.64)	512 (3 studies)	⊕⊝⊝⊝ very low^2,3
Long‐term mortality (binary): definitive chemoradiotherapy versus surgery with neoadjuvant chemotherapy All‐cause mortality for the duration of follow‐up	740 per 1000	769 per 1000 (688 to 858)	RR 1.04 (0.93 to 1.16)	431 (2 studies)	⊕⊝⊝⊝ low²
Long‐term mortality (time‐to‐event): definitive chemoradiotherapy versus surgery with neoadjuvant chemotherapy or chemoradiotherapy All‐cause mortality for the duration of follow‐up	349 per 1000	346 per 1000 (284 to 418)	HR 0.99 (0.78 to 1.26)	431 (2 studies)	⊕⊝⊝⊝ very low^2,4
Proportion with a serious adverse event within 3 months Serious adverse event within 3 months as defined by ICH‐GCP International Conference on Harmonisation ‐ Good Clinical Practice guideline (ICH‐GCP 1996) or reasonable variations thereof	273 per 1000¹	166 per 1000 (68 to 401)	RR 0.61 (0.25 to 1.47)	80 (1 study)	⊕⊝⊝⊝ very low^2,4
Short‐term health‐related quality of life Any validated scale	The mean short‐term health‐related quality of life in the control groups was 7.52	The mean short‐term health‐related quality of life in the intervention groups was 0.93 higher (0.24 to 1.62 higher)	‐	165 (1 study)	⊕⊝⊝⊝ very low^2,5
Medium‐term health‐related quality of life Any validated scale	The mean medium‐term health‐related quality of life in the control groups was 8.76	The mean medium‐term health‐related quality of life in the intervention groups was 0.95 lower (2.1 lower to 0.2 higher)	‐	62 (1 study)	⊕⊝⊝⊝ very low^2,5
The basis for the assumed risk* is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; RR: risk ratio; HR: hazard ratio.
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.
¹The basis for control risk is the event rate across all studies (i.e. the sum of all events in the surgical group across all studies reporting the outcome divided by the sum of all people in the surgical group in the trials reporting the outcome) for all outcomes except long‐term mortality (time‐to‐event) where a control group risk of 0.35 was used (based on similar control group risks at 2 years in a number of trials included in this analysis) and long‐term recurrence (time‐to‐event) where a control group risk of 0.4 was used (based on similar control group risk at 2 year in a trial included for this analysis). ²Downgraded two levels due to significant bias within the trials. ³Downgraded two levels due to inconsistency in the results across the studies. ⁴Downgraded one level due to wide CIs (overlaps 1 and 0.75 or 1.25). ⁵Downgraded one level due to wide CIs (overlaps 0 and 0.25 and −0.25).

Summary of findings for the main comparison. Non‐surgical versus surgical treatment of oesophageal cancer (primary outcomes)

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Summary of findings 2. Non‐surgical versus surgical treatment of oesophageal cancer (secondary outcomes)

Non‐surgical versus surgical treatment of oesophageal cancer
Patient or population: people with oesophageal cancer Settings: secondary or tertiary care Intervention: non‐surgical treatment Comparison: surgical treatment
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	Number of participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Surgical treatment	Non‐surgical treatment
Long‐term recurrence (binary outcome) Local recurrence, surgical wound recurrence, or distal metastases	526 per 1000¹	552 per 1000 (458 to 673)	RR 1.05 (0.87 to 1.28)	339 (2 studies)	⊕⊝⊝⊝ very low^2,3	‐
Long‐term recurrence (time‐to‐event outcome) Local recurrence, surgical wound recurrence, or distal metastases	508 per 1000¹	494 per 1000 (433 to 561)	HR 0.96 (0.8 to 1.16)	349 (2 studies)	⊕⊕⊝⊝ low²	‐
Local recurrence (binary)	381 per 1000	339 per 1000 (267 to 427)	RR 0.89 (0.70 to 1.12)	449 (3 studies)	⊕⊝⊝⊝ very low^2,3,4	‐
Proportion with any adverse event within 3 months Any adverse event within 3 months of any severity	386 per 1000¹	668 per 1000 (429 to 1000)	RR 1.73 (1.11 to 2.67)	80 (1 study)	⊕⊝⊝⊝ very low^2,4	‐
Length of hospital stay (days) Including the index admission for oesophagectomy (the hospital admission during which the oesophagectomy is performed) and any surgical complication‐related readmissions	See comment	See comment	Not estimable	342 (2 studies)	⊕⊝⊝⊝ very low^2,5	Significant heterogeneity present (I² statistic = 93%, P = 0.0001) making meta‐analysis inappropriate. The mean hospital stay was 16 days shorter (3 days shorter to 29 days shorter) in non‐surgical treatment than surgical treatment in 1 trial (Bedenne 2007) and 14 days longer (5 days longer to 23 days longer) in non‐surgical treatment than surgical treatment in another trial (Chiu 2005).
Dysphagia at maximal follow‐up	367 per 1000	543 per 1000 (370 to 803)	RR 1.48 (1.01 to 2.19)	139 (1 study)	⊕⊝⊝⊝ very low^2,4	‐
The basis for the assumed risk* is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; RR: risk ratio; HR: hazard ratio.
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.
¹The basis for control risk is the event rate across all studies (i.e. the sum of all events in the surgical group across all studies reporting the outcome divided by the sum of all people in the surgical group in the trials reporting the outcome). ²Downgraded two levels due to significant bias within the trials. ³Downgraded one level due to inconsistency in the results across the studies. ⁴Downgraded one level due to wide CIs (overlaps 1 and 0.75 or 1.25). ⁵Downgraded one level due to wide CIs (overlaps 0 and 0.25 and −0.25).

Summary of findings 2. Non‐surgical versus surgical treatment of oesophageal cancer (secondary outcomes)

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Comparison 1. Surgical versus non‐surgical treatment of oesophageal cancer

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Short‐term mortality Show forest plot	5	689	Risk Ratio (M‐H, Random, 95% CI)	0.39 [0.11, 1.35]

2 Long‐term mortality (binary) Show forest plot	3	511	Risk Ratio (M‐H, Fixed, 95% CI)	1.03 [0.92, 1.14]

3 Long‐term mortality (time‐to‐event) Show forest plot	7	1114	Hazard Ratio (Fixed, 95% CI)	1.09 [0.97, 1.22]

4 Proportion with a serious adverse event within 3 months Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

5 Short‐term health‐related quality of life Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

6 Medium‐term health‐related quality of life Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

7 Long‐term recurrence (binary) Show forest plot	2	339	Risk Ratio (M‐H, Fixed, 95% CI)	1.05 [0.87, 1.28]

8 Long‐term recurrence (time‐to‐event) Show forest plot	2	349	Hazard Ratio (Fixed, 95% CI)	0.96 [0.80, 1.16]

9 Local recurrence (binary) Show forest plot	3	449	Risk Ratio (M‐H, Fixed, 95% CI)	0.89 [0.70, 1.12]

10 Proportion with any adverse event within 3 months Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

11 Length of hospital stay (days) Show forest plot	2		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

12 Dysphagia at maximal follow‐up Show forest plot	1	139	Risk Ratio (M‐H, Fixed, 95% CI)	1.48 [1.01, 2.19]

13 Long‐term mortality (time‐to‐event): stratified by treatment Show forest plot	7	1114	Hazard Ratio (Fixed, 95% CI)	1.09 [0.97, 1.22]

13.1 Chemoradiotherapy	4	602	Hazard Ratio (Fixed, 95% CI)	0.88 [0.76, 1.03]
13.2 Radiotherapy	3	512	Hazard Ratio (Fixed, 95% CI)	1.39 [1.18, 1.64]
14 Long‐term mortality (binary): definitive chemoradiotherapy versus surgery with neoadjuvant chemotherapy Show forest plot	2	431	Risk Ratio (M‐H, Fixed, 95% CI)	1.04 [0.93, 1.16]

15 Long‐term mortality (time‐to‐event): definitive chemoradiotherapy versus surgery with neoadjuvant chemotherapy or chemoradiotherapy Show forest plot	2	431	Hazard Ratio (Fixed, 95% CI)	0.99 [0.78, 1.26]

Comparison 1. Surgical versus non‐surgical treatment of oesophageal cancer

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Referencias

References to studies included in this review

Badwe 1999 {published data only}

Bedenne 2007 {published data only}

Blazeby 2014 {published data only}

Carstens 2007 {published and unpublished data}

Chiu 2005 {published data only}

Fok 1994 {published data only}

Stahl 2005 {published data only}

Sun 2006 {published data only}

References to studies excluded from this review

Desai 1987 {published data only}

Earlam 1991 {published data only}

Hainsworth 2007 {published data only}

Ilson 2007 {published data only}

Nozaki 2014 {published data only}

Additional references

Ajani 2011

AJCC Cancer Staging Manual 2010

ASA 2014

Berry 2014

CONSORT 2010

Cuschieri 1992

Demets 1987

DerSimonian 1986

Egger 1997

FDA 2006

Goh 2015

Higgins 2011

IARC 2014

ICH‐GCP 1996

Ishihara 2008

Luketich 2000

McKeown 1976

MHRA 2013

Migliore 2007

Orringer 1978

Parmar 1998

Pennathur 2013

Pöttgen 2012

Review Manager 2014 [Computer program]

Rice 2010

Sjoquist 2011

SPIRIT 2013

Spitzer 1981

Stahl 2013

Sun 2014

van Hagen 2012

Yamamoto 2013

Yamashita 2008

References to other published versions of this review

Best 2015

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Characteristics of excluded studies [ordered by study ID]

Data and analyses

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