Abstract
Background
The existing randomized evidence has failed to conclusively demonstrate the benefit or otherwise of preoperative radiotherapy in treating patients with potentially resectable esophageal carcinoma.
Objectives
This meta‐analysis aimed to assess whether there is benefit from adding radiotherapy prior to surgery and whether or not any pre‐defined patient subgroups benefit more or less from preoperative radiotherapy
Search methods
MEDLINE and CancerLit searches were supplemented by information from trial registers and by hand searching relevant meeting proceedings and by discussion with relevant trialists, organisations and industry. The search strategy was run again in MEDLINE, EMBASE and the Cochrane Library on 30th April 2000; in MEDLINE, EMBASE, CancerLit and The Cochrane Library on August 2002 and August 2003; on MEDLINE, EMBASE and the Cochrane Library, on July 2004 and 2005, June 2006 and September 2008. No new relevant trials were identified on any of these occasions.
Selection criteria
Trials were eligible for inclusion in this meta‐analysis provided they randomized patients with potentially resectable carcinoma of the esophagus (of any histological type) to receive radiotherapy or no radiotherapy prior to surgery. Trials must have used a randomization method which precluded prior knowledge of treatment assignment and completed accrual by December 1993, to ensure sufficient follow‐up by the time of the first analysis (September 1995).
Data collection and analysis
A quantitative meta‐analysis using updated data from individual patients from all properly randomized trials (published or unpublished) comprising 1147 patients (971 deaths) from five randomized trials. This approach was used to assess whether preoperative radiotherapy improves overall survival and whether it is differentially effective in patients defined by age, sex and tumour location.
Main results
With a median follow‐up of 9 years, in a group patients with mostly squamous carcinomas, the hazard ratio (HR) of 0.89 (95% CI 0.78‐1.01) suggests an overall reduction in the risk of death of 11% and an absolute survival benefit of 3% at 2 years and 4% at 5 years. This result is not conventionally statistically significant (p=0.062). No clear differences in the size of the effect by sex, age or tumor location were apparent.
Authors' conclusions
Based on existing trials, there was no clear evidence that preoperative radiotherapy improves the survival of patients with potentially resectable esophageal cancer. These results indicate that if such preoperative radiotherapy regimens do improve survival, then the effect is likely to be modest with an absolute improvement in survival of around 3 to 4%. Trials or a meta‐analysis of around 2000 patients (90% power, 5% significance level) would be needed to reliably detect such an improvement (from 15 to 20%).
Keywords: Humans; Esophageal Neoplasms; Esophageal Neoplasms/radiotherapy; Esophageal Neoplasms/surgery; Preoperative Care; Radiotherapy, Adjuvant; Randomized Controlled Trials as Topic
Plain language summary
Preoperative radiotherapy for esophageal carcinoma (cancer of the gullet)
If the tumour has not spread, surgery is usually the standard treatment for cancer of the esophagus (the tube between the throat and stomach). Surgery to remove the cancer can help people to live longer, but the prognosis is still very poor. Trials have tried using radiotherapy (x‐ray treatment) before the operation. It was hoped that this would make the tumour smaller, less likely to spread and let people live longer. However, the review of trials found no clear evidence that radiotherapy before surgery for cancer of the esophagus increases a patient's chances of survival.
Background
Most patients with esophageal carcinoma have loco‐regional or more advanced disease at diagnosis, with overall 5‐year survival of approximately 10% (Boring 1993). Surgical resection is standard therapy for patients with localized tumours (DeMeester 1988) and while their prognosis is better, it is still poor (15%). One reason being that loco‐regional recurrences are frequent even after intended curative resection. Following the results of numerous uncontrolled historical studies (reviewed in Gignoux 1988) there has been interest in the use of preoperative radiotherapy as a possible means of reducing local spread, thereby, improving survival. By downstaging the tumor, it may also increase resectability and perhaps alleviate symptoms.
Five prospective randomized controlled trials have investigated the effects of preoperative radiotherapy. Although pathological responses were reported in four of these trials (Arnott 1992; Gignoux 1988; Launois 1981; Wang 1989) resectability did not appear to be substantially affected and a conventionally significant survival benefit was detected in only the most recent (Nygaard 1992). All but one of these trials involved fewer than 250 patients, and they were therefore, too small to detect moderate treatment effects. However, combining the results of these trials quantitatively in a meta‐analysis of updated individual patient data, increases the statistical power to detect such differences and is the most reliable and unbiased way to evaluate the evidence (Parmar 1996) from these trials.
Such a meta‐analysis was therefore suggested by the Medical Research Council (MRC) Oesophageal Cancer Working Party, initiated by the MRC Cancer Trials Office, Cambridge, which became part of the MRC Clinical Trials Unit, and was carried out on behalf of the Oesophageal Cancer Collaborative Group (OCCG). Data was collated, checked and analysed by the MRC CTO. The collaborative group met in September 1995 to discuss the preliminary results. This review was first published by OCCG in the International Journal of Radiation Oncology Biology Physics (OCCG 1998) and is reproduced with their permission.
Objectives
The existing randomized evidence has failed to conclusively demonstrate the benefit or otherwise of preoperative radiotherapy in treating patients with potentially resectable esophageal carcinoma. This meta‐analysis aimed to assess whether there is benefit from adding radiotherapy prior to surgery. It also investigated whether any pre‐defined patient subgroup would benefit more or less from preoperative radiotherapy.
Methods
Criteria for considering studies for this review
Types of studies
Trials (published or unpublished) were eligible for inclusion in this meta‐analysis provided they randomized patients with potentially resectable carcinoma of the esophagus (of any histological type) to receive radiotherapy or no radiotherapy prior to surgery. Trials must have used a randomization method, which precluded prior knowledge of the treatment assignment and completed accrual.
Types of participants
Individuals with potentially resectable carcinoma of the esophagus (of any histological type). Individual data from all randomized patients were included in the meta‐analysis. Where possible data were obtained for individuals who had been excluded from the original trial analyses and they were included in the meta‐analysis.
Types of interventions
Trials that compared radiotherapy prior to surgery with surgery alone.
Types of outcome measures
Survival
Search methods for identification of studies
Trials were identified by computerized searching of MEDLINE and CANCERLIT, using a modification of the optimal search strategy for identifying randomized controlled trials developed by the Cochrane Collaboration (Dickersin 1995), and EMBASE and by examining the reference lists of trial publications, review articles, and books. Trial investigators collaborating in the meta‐analysis and trial registers (United Kingdom Coordinating Committee on Cancer Research Register of Cancer Clinical Trials, Physicians Data Query Clinical Protocols and the Cochrane Controlled Trials Register) were also consulted to help identify unpublished and other published trials. The search strategy was run again in MEDLINE, EMBASE and the Cochrane Library on 30th April 2000; in MEDLINE, EMBASE, CancerLit and The Cochrane Library on August 2002 and August 2003; on MEDLINE, EMBASE and the Cochrane Library, on July 2004 and 2005, June 2006 and September 2008. No new relevant trials were identified on any of these occasions.
Data collection and analysis
This review is based on individual patient data obtained directly from the responsible trialist or data centre. The methods used were prespecified in a protocol.
For all eligible trials, information on the following were requested: sex; date of birth or age; tumor location; disease stage; histology; extent of resection; date of randomization; allocated treatment; survival status and updated information on date of death or last follow up. Such information was sought also for patients who had been excluded from the investigators' own analysis, to prevent the potential bias of patient exclusions. No quality of life data were available. Following transfer, each trial dataset was checked thoroughly to ensure both the accuracy of the meta‐analysis database and the quality of randomization and follow‐up. Queries were resolved by, and the final database entries verified by, the responsible trial investigator or data manager.
The role of preoperative radiotherapy was investigated in four trials (Arnott 1992; Gignoux 1988; Launois 1981; Wang 1989) and a fifth trial (Nygaard 1992) used a factorial design to examine the role of preoperative radiotherapy whilst controlling for the effect of chemotherapy. For this reason, the latter trial was split into two allowing separation of preoperative radiotherapy only 'trials' and preoperative radiotherapy plus chemotherapy 'trials' in the meta‐analysis.
All analyses were carried out on an intention‐to‐treat basis. Survival analyses were stratified by trial and the logrank expected number of deaths and variance used to calculate individual and an overall pooled hazard ratio (HR) using the fixed effects model (Yusuf 1985). Thus the time to death for individual patients was used within trials to calculate HRs representing the overall risk of dying on treatment (preoperative radiotherapy) as compared to control (no preoperative radiotherapy). A simple (non‐stratified) Kaplan‐Meier curve was also generated (Kaplan 1958). Baseline survival at two and five years, as derived from the survival curve, together with the overall HR was used to calculate the absolute effect of treatment (Freedman 1982). To investigate the effect of preoperative radiotherapy within pre‐specified subgroups, similar stratified analyses were performed.
Chi square tests for heterogeneity were used to test for gross statistical heterogeneity over all trials (heterogeneity chi square) and between subgroups (interaction chi square). These tests are aimed primarily at detecting quantitative differences (differences in size rather than direction), because there was no a priori reason to expect qualitative differences. Where subgroups had a natural order (e.g. categories of increasing age) the chi square test for trend (trend chi square) was used.
Results
Description of studies
At the time of analysis (1995), 8 potentially eligible trials were identified. Of these, 5 were eligible for inclusion in the meta‐analysis. One was excluded, because it compared preoperative chemoradiotherapy plus surgery with surgery alone (Le Prise 1994). The eligibility of two remaining trials (one published (Zhang 1988) and one with no known publication details) could not be assessed fully and it was not clear that they were actually randomized controlled trials. It proved impossible to establish adequate communication with the trial investigators. Updated searches (to Sepetember 2008) did not uncover any new eligible trials, but rather two further trials comparing preoperative chemoradiotherapy plus surgery with surgery alone (de Pree 1995; Urba 1995).
The meta‐analysis is based on five trials including 1147 patients (Table of included studies). This represents 98.5% of patients from all known randomised trials, because data were not available for 17 patients in one (Launois 1981) of the five trials. All trials included patients with potentially resectable cancer of the thoracic esophagus and with the exception of one (Arnott 1992), restricted entry to patients with squamous carcinoma. Trials included both men and women of most age groups. In general, the majority of patients in the meta‐analysis were men (78%), younger than 65 years (80%) with squamous carcinomas (86%) of the middle or lower third (74%) of the thoracic esophagus. The total planned dose of radiotherapy ranged from 20‐40 Gy given in 10‐20 fractions over a period of one to four weeks, with the delay from the end of radiotherapy to surgery ranging from less than eight days to four weeks. In all trials, the overall rates of resection and complete resection were broadly similar in the treatment and control arms.
Risk of bias in included studies
Trials must have used a randomization method, which precluded prior knowledge of treatment assignment and completed accrual. Following transfer, each trial dataset was checked thoroughly to ensure both the accuracy of the meta‐analysis database and the quality of randomisation and follow‐up. Queries were resolved by, and the final database entries verified by, the responsible trial investigator or data manager.
Effects of interventions
The overall hazard ratio of 0.89, although not conventionally significant (chi square=3.48, df=1, p=0.06), suggests a moderate benefit from preoperative radiotherapy (Figure 1). It should be noted, however, that the meta‐analysis had only about 75% power to detect such an effect. This effect represents an 11% reduction in the risk of death and an absolute benefit of 4% (95% CI 0 to 9%) at two years and 3% (95% CI 0 to 8%) at five years, improving survival from approximately 30 to 34% and 15 to 18% respectively (Figure 2). There was no evidence that this result varied when chemotherapy was used in conjunction with radiotherapy (interaction chi square=1.49, df=1, p=0.22), but there was some borderline evidence of a difference in effect across the trials (heterogeneity chi square=10.37, df=5, p=0.06). This seems to be mainly because of the extreme result of the Scandinavian trial (Nygaard 1992). Removing this trial reduces the overall heterogeneity (heterogeneity chi square=4.557, df=3, p=0.21), while keeping the results comparable (HR=0.96, p=0.53).
1.
Forest plot of comparison: 1 Preoperative radiotherapy (with or without chemotherapy) versus (with or without chemotherapy) surgery, outcome: 1.1 Survival.
2.
Simple (non‐stratified) survival curves of preoperative radiotherapy (with or without chemotherapy) versus (with or without chemotherapy) surgery.
Pre‐defined subgroups of patients were analysed to determine whether the size of the effect of preoperative radiotherapy varied across these groups. Only two trials had information on clinical staging and most patients (89%) had squamous carcinomas. Thus analyses by clinical stage and tumour histology were uninformative. Data on sex and age were available for at least 99% of patients, but on tumor location for only 80%, because one trial (Gignoux 1988) used a different method of classification. Based on these data, there was little evidence to suggest that any patient group, specified by sex (interaction chi square=3.15, df=1, p=0.08), age (trend chi square=0.76, df=1, p=0.38) or tumor location (interaction chi square=1.32, df=1, p=0.25), benefited more or less from preoperative radiotherapy (Figure 3).
3.
Effect of preoperative radiotherapy (with or without chemotherapy) versus (with or without chemotherapy) surgery by sex, age and tumor location. Sex: interaction chisquare=3.15, df=1, p=0.08; Age: Sex: trend chisquare=0.76, df=1, p=0.38; tumor location: intercation chisquare= 1.31, df=1, p=0.25.
Discussion
This meta‐analysis was based on five trials comparing preoperative radiotherapy with no preoperative radiotherapy. It included 1147 patients representing 98.5% of patients from all confirmed eligible randomized trials. Most of the survival data for these trials were updated for the meta‐analysis, many years after the publication of the results and up to 20 years after recruitment had stopped. Therefore, currently, the meta‐analysis provides the most comprehensive and reliable assessment of the effect of preoperative radiotherapy in potentially resectable esophageal cancer. Based on this existing evidence, there is a suggestion that preoperative radiotherapy may offer a modest benefit to patients, reducing the risk of death by 11% and improving absolute survival at two years, from 30 to 34% and at five years, from 15 to 18%. This effect was consistent irrespective of patient age and sex and the location of the tumour in the thoracic esophagus.
As a major aim of preoperative radiotherapy is to downstage the tumor and increase resectability, optimal results may rely on selecting appropriate patients. This will largely depend on accurate clinical staging. The rate of resection in the control arm varied between trials, which may suggest that clinical staging and so patient selection was also variable. Since these trials were performed, there have been two major changes in the staging of esophageal cancer, with international consensus (AJC 1988; UICC 1987). In addition, the advent of new diagnostic techniques, in particular endoscopic ultrasonography, seems to offer the potential for more accurate clinical staging (Thompson 1994). It is possible, therefore, that with modern staging approaches, those patients most likely to benefit from preoperative treatment will be identified. Perhaps in these patients, any effect of preoperative radiotherapy on the rate of resection and survival will be easier to detect.
It is also possible that in these trials the radiotherapy dose was insufficient (particularly Arnott 1992; Gignoux 1988; Nygaard 1992) or the delay between radiotherapy and surgery was too short to allow the inflammatory response to subside and tumor shrinkage to take place. Alternatively, it may have been that surgery was carried out too late, allowing fibrosis to occur. Indeed, based on a simple analysis, the expected improvement in resectability was not evident in these studies. If more detailed and informative analysis of the rates of resection become available in the future, the information will be incorporated into this review. Over time, the methods for administration of radiotherapy have changed and perhaps larger total doses to the tumor site or the same doses in a shorter time scale might be more effective.
Authors' conclusions
Implications for practice.
This meta‐analysis suggests that preoperative radiotherapy, as given in these trials, may provide a small survival advantage for patients with potentially resectable cancer of the esophagus and, moreover, there is no clear evidence to suggest that this therapy is detrimental, at least for survival. However, any small benefit of preoperative radiotherapy could be offset by the increased morbidity, cost, and duration of treatment associated with giving radiotherapy preoperatively. Therefore, preoperative radiotherapy cannot currently be routinely recommended outside of controlled clinical trials.
Implications for research.
The subsequent research focus has been combined preoperative chemotherapy and preoperative radiotherapy and chemotherapy (Ajani 1995), but this meta‐analysis has failed to demonstrate conclusively that preoperative radiotherapy improves survival. Therefore, if more effective means of loco‐regional control using preoperative radiotherapy with surgery can be found, the potential of additional systemic therapy could be assessed. Perhaps then trials of newer radiotherapy regimens followed by a longer (or shorter) delay to surgery, in carefully selected patients could reveal more substantial survival benefits. These would need to be considered alongside any changes in patient‐reported quality of life. However, any such trials (or indeed a meta‐analysis) would need to be substantially larger than those in the current meta‐analysis. To reliably detect an absolute survival benefit of 5% would require 2000 patients and of 10% would require 600 patients (both 90% power, 5% significance). Such large trials would almost certainly necessitate large‐scale international collaboration.
What's new
| Date | Event | Description |
|---|---|---|
| 13 February 2012 | Amended | Contact details updated. |
| 31 March 2009 | Review declared as stable | Searches, tables and figures last updated March 2009. Declared stable and no future updates planned. |
History
Review first published: Issue 3, 2000
| Date | Event | Description |
|---|---|---|
| 5 October 2010 | Amended | Contact details updated. |
| 30 October 2008 | Amended | Converted to new review format. |
Acknowledgements
We would like to thank all those patients who took part in the trials and contributed to this research. The meta‐analysis would not have been possible without their help or without the collaborating institutions who kindly supplied their trial data.
Appendices
Appendix 1. Search Strategy for MEDLINE and CANCERLIT (modified for Probase software)
1 PT=RANDOMIZED‐CONTROLLED‐TRIAL 2 RANDOMIZED‐CONTROLLED‐TRIALS.DE 3 RANDOM‐ALLOCATION.DE 4 DOUBLE‐BLIND‐METHOD.DE. 5 SINGLE‐BLIND‐METHOD.DE. 6 1 OR 2 OR 3 OR 4 OR 5 7 PT=CLINICAL‐TRIAL 8 CLINICAL‐TRIALS#.DE. 9 CLIN$ WITH TRIAL$).AB,TI. 10 ((SINGL$ OR DOUBL$ OR TREBL$ OR TRIPL$) WITH (BLIND$ OR MASK$)).AB,TI. 11 PLACEBO$.DE. 12 PLACEBO$.AB,TI. 13 RANDOM$.AB,TI. 14 RESEARCH‐DESIGN.DE. 15 6 OR 7 OR 8 OR 9 OR 10 OR 11 OR 12 OR 13 OR 14 16 CARCINOMA#.DE. 17 ESOPHAGEAL‐NEOPLASMS.DE. 18 16 and 17 19 (ESOPHAG$ ADJ CARCINOMA$).AB,TI. 20 (ESOPHAG$ ADJ CANCER$).AB,TI. 21 (ESOPHAG$ ADJ NEOPLASM$).AB,TI. 22 (OESOPHAG$ ADJ CARCIMOMA$).AB,TI. 23 (OESOPHAG$ ADJ CANCER$).AB,TI. 24 (OESOPHAG$ ADJ NEOPLASM$).AB,TI. 25 18 OR 19 OR 20 OR 21 OR 22 OR 23 OR 24 26 Radiotherapy.DE. 27 QS Neoplasms WITH RT 28 26 or 27 29 15 and 25 and 28
Please note: Format shown is for Knight‐Ridder Probase version 1.1 $ is a truncation symbol # denotes an exploded term
Data and analyses
Comparison 1. Preoperative radiotherapy (with or without chemotherapy) versus (with or without chemotherapy) surgery.
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
|---|---|---|---|---|
| 1 Survival | 6 | 1147 | Hazard Ratio (95% CI) | 0.89 [0.78, 1.01] |
| 1.1 Preoperative RT only 'trials' | 5 | 1038 | Hazard Ratio (95% CI) | 0.91 [0.80, 1.04] |
| 1.2 Preoperative RT + CT 'trials' | 1 | 109 | Hazard Ratio (95% CI) | 0.70 [0.47, 1.04] |
1.1. Analysis.
Comparison 1 Preoperative radiotherapy (with or without chemotherapy) versus (with or without chemotherapy) surgery, Outcome 1 Survival.
Characteristics of studies
Characteristics of included studies [ordered by study ID]
Arnott 1992.
| Methods | RCT, 1979‐1983 | |
| Participants | 176 patients with potentially resectable squamous cell or adenocarcinoma | |
| Interventions | Surgery with or without prior radiotherapy* *20Gy in 10 fractions over 14 days. 21 days delay to surgery | |
| Outcomes | Survival | |
| Notes | 84% resections, 76% complete resections on treatment 75% resections, 72% complete resections on control | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Allocation concealment? | Low risk | A ‐ Adequate |
Gignoux 1988.
| Methods | RCT, 1976‐1982 | |
| Participants | 229 patients with potentially resectable squamous cell carcinoma | |
| Interventions | Surgery with or without prior radiotherapy* *33Gy in 10 fractions over 28 days. <8 days delay to surgery | |
| Outcomes | Survival | |
| Notes | 68% resections, 43% complete resections on treatment 78% resections, 55% complete resections on control | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Allocation concealment? | Low risk | A ‐ Adequate |
Launois 1981.
| Methods | RCT, 1973‐1976 | |
| Participants | 107 patients with potentially resectable squamous cell carcinoma | |
| Interventions | Surgery with or without prior radiotherapy* *40Gy in ? fractions over 8‐12 days. <8 days delay to surgery | |
| Outcomes | Survival | |
| Notes | 89% resections, 74% complete resections on treatment 89% resections, 78% complete resections on control | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Allocation concealment? | Low risk | A ‐ Adequate |
Nygaard 1992 (a).
| Methods | RCT, 1983‐1988 | |
| Participants | 108 patient with potentially resectable squamous cell carcinoma | |
| Interventions | Surgery with or without prior radiotherapy* *35Gy in 20 fractions over 28 days. 21 days delay to surgery | |
| Outcomes | Survival | |
| Notes | 46% resections, 34% complete resections on treatment 62% resections, 32% complete resections on control | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Allocation concealment? | Low risk | A ‐ Adequate |
Nygaard 1992 (b).
| Methods | RCT, 1983‐1988 | |
| Participants | 109 patients with potentiall resectable squamous cell carcinoma | |
| Interventions | Surgery with or without prior chemotherapy and radiotherapy* *35Gy in 20 fractions over 28 days. 21 days delay to surgery | |
| Outcomes | Survival | |
| Notes | 62% resections, 53% complete resections on treatment 55% resections, 41% complete resections on control | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Allocation concealment? | Low risk | A ‐ Adequate |
Wang 1989.
| Methods | RCT, 1977‐1988 | |
| Participants | 418 patients with potentially resectable squamous cell carcinoma | |
| Interventions | Surgery with or without radiotherapy* *40Gy in 10 fractions over 12 day. 14‐28 days delay to surgery | |
| Outcomes | Survival | |
| Notes | 90% resections, 74% complete resections on treatment 86% resections, 65% complete resections on control | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Allocation concealment? | Low risk | A ‐ Adequate |
Characteristics of excluded studies [ordered by study ID]
| Study | Reason for exclusion |
|---|---|
| de Pree 1995 | Compared preoperative chemoradiotherapy plus surgery with surgery alone |
| Le Prise 1994 | Compared preoperative chemoradiotherapy plus surgery with surgery alone |
| Urba 1995 | Compared preoperative chemoradiotherapy plus surgery with surgery alone |
| Zhang 1988 | Eligibility uncertain: Unsure that it was RCT |
Contributions of authors
All reviewers participated in the design, execution, and analysis of the review and twice commented on the overall intellectual content.
Sources of support
Internal sources
Medical Research Council, UK.
External sources
No sources of support supplied
Declarations of interest
There is no known conflict of interest.
Stable (no update expected for reasons given in 'What's new')
References
References to studies included in this review
Arnott 1992 {published and unpublished data}
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OCCG 1998
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