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ORIGINAL ARTICLES |
From the Division of Surgical Oncology (IGK, KF, DF, ASL) and the Division of Biostatistics (GRW), Sylvester Cancer Center, University of Miami, Miami, Florida.
Correspondence: Address correspondence and reprint requests to: Dido Franceschi, MD, University of Miami School of Medicine, Sylvester Comprehensive Cancer Center, Division of Surgical Oncology (310T), 1475 NW 12th Avenue, Room 3550, Miami, FL 33136; Fax: 305-243-4907; E-mail: dfrances{at}med.miami.edu
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONAPPENDIX A: STUDIES RELEVANT...APPENDIX B: PROSPECTIVE...REFERENCES |
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Methods: A meta-analysis was performed to determine the effect of preoperative treatment on survival of patients with resectable esophageal cancer and the effect of preoperative treatment on patient mortality. A standard variance-based method was used to derive summary estimates of the absolute difference in both 2-year survival and treatment-related mortality.
Results: Eleven randomized trials involving 2311 patients were analyzed. Preoperative chemotherapy improved 2-year survival compared with surgery alone: the absolute difference was 4.4% (95% confidence interval [CI], .3%–8.5%). Marginal evidence of heterogeneity was eliminated by restricting attention to the four most recent studies, which increased the estimate to 6.3% (95% CI, 1.8%–10.7%). For combined chemoradiotherapy, the increase was 6.4% (nonsignificant; 95% CI, -1.2%–14.0%). Treatment-related mortality increased by 1.7% with neoadjuvant chemotherapy (95% CI, -.9%—4.3%) and by 3.4% with chemoradiotherapy (95% CI, -.1%–7.3%), compared with surgery alone.
Conclusions: There seems to be a modest survival advantage for patients who receive neoadjuvant chemotherapy followed by surgery, as compared with surgery alone. There is an apparent increase in treatment-related mortality, mainly for patients who receive neoadjuvant chemoradiotherapy.
Key Words: Esophageal cancer • Meta-analysis • Chemotherapy • Radiotherapy • Neoadjuvant • Survival
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONAPPENDIX A: STUDIES RELEVANT...APPENDIX B: PROSPECTIVE...REFERENCES |
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Radiotherapy alone has been shown to decrease the size of the tumor and alleviate dysphagia in cases of locally advanced neoplasms.5,6 However, in the neoadjuvant setting, no clear effect on survival has been demonstrated.7
Administration of chemotherapy before surgery in patients with resectable cancer of the esophagus has the potential advantage of selecting patients who would benefit from postoperative chemotherapy and potentially treats subclinical micrometastases, which should thereby reduce the rates of systemic failure. It is unclear, however, whether this approach will materially improve patient survival. Several clinical studies using preoperative chemotherapy alone or in combination with radiotherapy have attempted to answer this question. In most of these studies, the results in the treatment groups are compared with those in historical controls.8,9 Recently, a number of randomized phase III trials addressing the effect of neoadjuvant chemotherapy on patient outcome have been published. With the exception of one study (1A), a relatively small number of patients have been included in each trial, and there is no general agreement on the effect of the treatment on patient survival.
We therefore used meta-analysis to synthesize the results of the published randomized trials and thereby estimate the survival effect of preoperative chemotherapy with or without radiotherapy, as compared with surgery alone, for patients with resectable cancer of the esophagus. We also examined the effect of neoadjuvant therapy on overall treatment-related mortality.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONAPPENDIX A: STUDIES RELEVANT...APPENDIX B: PROSPECTIVE...REFERENCES |
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Study Selection
The following inclusion criteria were used to identify studies for the analysis: (1) published studies, (2) clear statement in the Materials and Methods section that eligible patients were randomly assigned to treatment and control arms, (3) administration of chemotherapy alone or in combination with radiotherapy before surgery in the treatment arm, (4) inclusion of patients who received surgery alone in the control arm, (5) pathologic diagnosis of invasive squamous cell carcinoma or invasive adenocarcinoma of the esophagus or the gastroesophageal junction, (6) potentially resectable tumor, and (7) patient survival as outcome measure. Eleven studies met the selection criteria and were used in our analyses (Appendix A). Characteristics of these studies are listed in Table 1.
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Estimation of Treatment Effect
Treatment effect was measured as the absolute percentage difference in survival at 2 years: the percentage of patients on the treatment arm surviving 2 years minus the percentage of patients surviving 2 years on the control arm. All results are stated in absolute terms. We chose this absolute measure rather than the odds ratio because of its direct clinical interpretation.
The study-specific estimates of 2-year survival were obtained from the reported Kaplan-Meier and actuarial estimates in six studies (1A, 3A–7A). For the remaining studies, they were either estimated from the survival plot (8A–10A) or calculated by the life-table method from detailed information in the text and tables (11A, 12A). In study 4A, we observed a discrepancy in the plotted value for the treatment arm, and we therefore based our analysis on the number reported in the text. Except for study 1A, which reported a 95% confidence interval (CI) for the difference in survival at 2 years, an additional parameter was needed to estimate the SE of the 2-year survival difference: namely, the number of patients at risk at 2 years.10 This was reported directly (6A, 7A, 12A), determined from text details (3A, 11A), or determined from Kaplan-Meier plots (9A). For studies 4A, 5A, 8A, and 10A, the SE was calculated by using information about the duration of patient follow-up.11 For most of the identified studies, we were also able to extract estimates of 3-year survival. These became the basis for a limited analysis of the difference in 3-year survival after first restricting attention to studies for which we could adequately determine the precision of the 3-year estimates.
Estimation of Treatment-Related Mortality
We defined treatment-related mortality as the proportion of deaths occurring during preoperative treatment or after surgery because of complications of surgery. This measure was reported directly in two studies (6A, 7A) and was readily computed from details in the text for all others.
Statistical Analysis
The meta-analysis for all measures of interest—survival at 2 and 3 years and treatment-related mortality—was conducted according to standard methods for deriving a variance-based summary estimate.12 Studies were grouped according to treatment type (chemotherapy vs. chemoradiotherapy), and the measures of interest were tested for homogeneity within these groups. Where there was evidence of heterogeneity, we derived summary estimates for homogeneous subgroups of studies by removing outliers or by making further distinctions among the treatment regimens used. Because it is reasonable to assume a fixed treatment effect from similar therapies, we derived all of our summary estimates according to the method of fixed effects. We note, finally, that adjustment was made where necessary for the positive correlation between the two estimates from study 3A, which are comparisons against a common control arm.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONAPPENDIX A: STUDIES RELEVANT...APPENDIX B: PROSPECTIVE...REFERENCES |
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We noted a discrepancy between our inferred estimate of 2-year survival on treatment for study 11A and that study’s reported results at 3 years. Using an alternative rate of 31% instead of our derived life-table estimate (21%) reduced the heterogeneity of the seven chemotherapy studies (P = .13) but had little effect on our summary estimate: 4.7% with the revised value versus 4.4% as reported previously.
Five of the 11 eligible studies (3A, 4A, 8A, 10A, and 12A) investigated a combined chemoradiotherapy treatment arm and enrolled a total of 669 patients. Two-year survival in these studies ranged from 23% to 46% with chemoradiotherapy versus 13% to 41% with surgery only; the difference ranged from -6% to 11%. The summary estimate of treatment effect indicated a gain of 6.4% (95% CI, -1.2%–14.0%) in 2-year survival for patients receiving neoadjuvant chemoradiotherapy, with no evidence of heterogeneity (P = .86). Given the similarity of our summary estimates for the four most recent chemotherapy studies (6.3%) and all five of the studies that combined chemotherapy with radiotherapy (6.4%), we used this set of nine investigations to examine the question of whether treatment effect differs by histology. Five of these studies (3A, group 4; 5A; 7A; 8A; and 12A) enrolled a total of 697 patients with squamous cell carcinoma and resulted in a summary estimate for the difference in 2-year survival of 6.1% (95% CI, -1.4%–13.7%), with no evidence of heterogeneity (P = .75). Most patients in each of the remaining studies were diagnosed with adenocarcinoma: 100% in study 4A, 52% in study 6A, 75% in study 10A, and 67% in study 1A. For this group of studies, which enrolled a total of 1482 patients, the summary estimate of the difference in 2-year survival was 6.4% (95% CI, 1.9%–10.8%), with no evidence of heterogeneity (P = .23). Thus, we did not find evidence to suggest that disease histology is associated with variations in the effect of neoadjuvant treatment on 2-year survival.
Survival at 3 Years
Many of the 3-year survival rates reported in the studies we reviewed were based on a small number of patients who remained at risk beyond the last observed death. We derived a summary estimate of the difference in 3-year survival after first excluding studies for which we could not determine the precision of the reported 3-year survival estimates. Using the reported Kaplan-Meier estimates from three studies (6A, 7A, and 10A), along with life-table estimates derived from suitable information in two others (1A, 12A), we found that 3-year survival ranged from 23% to 44% with neoadjuvant therapy and from 14% to 41% with surgery alone. Differences (treatment minus control) ranged from -3% to 16%. The summary estimate indicated a treatment advantage of 5.1% at 3 years (95% CI, .2%–10.0%), and heterogeneity was not significant (P = .15).
We note that our summary estimate of 5.1%, based on 5 investigations, contrasts with results from four of the studies excluded on the basis of having fewer than 20 patients (total) at risk after 3 years. Specifically, studies 4A and 9A reported 3-year survival rates that indicated that neoadjuvant therapy offers an advantage of as much as 26% and 20%, respectively, whereas studies 3A (group 2) and 11A reported 3-year survival rates that were 6% and 5% lower in the treatment arm than in the control arm.
Treatment-Related Mortality
For the 11 studies, we reviewed a total of 119 treatment-related deaths that occurred among 1184 patients who received neoadjuvant treatment as compared with 81 such deaths among 1127 patients who received surgery alone. Mortality ranged from 2% to 17% in the treatment arm of individual studies and from 0% to 15% in the control arm. Figure 3 displays the results of our meta-analysis of treatment-related mortality, and Fig. 4 shows a plot of the individual study estimates.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONAPPENDIX A: STUDIES RELEVANT...APPENDIX B: PROSPECTIVE...REFERENCES |
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Although an attempt was made to obtain individual patient data, this was not possible for most of the studies, so we conducted a meta-analysis based on summary estimates. We derived separate estimates for the effect of chemotherapy alone and for combined chemoradiotherapy; however, the studies we reviewed included more than twice as many patients given chemotherapy as the number given a combination of chemotherapy and radiotherapy. Thus, our summary estimates had less precision for ascertaining the effect of neoadjuvant chemoradiotherapy.
Radiotherapy alone as a neoadjuvant treatment has been compared with surgery alone in a number of randomized clinical trials.13–16 All studies except one16 exclusively enrolled patients with squamous cell carcinoma. None of these studies showed a statistically significant difference in survival between the treatment groups. There was some evidence, however, that preoperative radiotherapy may reduce the incidence of local failure.15,17 A meta-analysis of the effect of preoperative radiotherapy without chemotherapy versus surgery alone for squamous cell carcinoma and adenocarcinoma of the esophagus was performed by the Esophageal Cancer Collaborative Group.18 This analysis used individual patient data from all previously reported studies. With a mean follow-up period of 9 years, the analysis demonstrated a modest benefit of 4% (95% CI, 0%–9%) at 5 years for patients who received preoperative radiotherapy compared with patients who received surgery alone. No other randomized trials studying the effects of preoperative radiotherapy alone have been published since this comprehensive meta-analysis.
Historical control studies addressing the effect of neoadjuvant chemotherapy on patient survival have produced more favorable results than prospective randomized trials. In a study by Orringer,19 43 patients were included in a prospective series of cis-platinum–based preoperative chemotherapy. The 2-year survival for this group was 60%, which compared favorably to the 32% 2-year survival of a large retrospective series of 417 patients from the same institution. Several other nonrandomized studies have shown a clear benefit for the treatment group.17,20 There are several reasons why the results of historical control studies may be misleading. In the case of cancer of the esophagus, the control group is usually composed of patients who received their treatment two or three decades ago, when the epidemiology of the disease was different and when diagnostic modalities were not as accurate as they are today. As a result, the effect of selection bias and stage migration is likely to be significant.21
In this meta-analysis, there was evidence from a set of 7 randomized trials (1683 patients) that preoperative chemotherapy improves 2-year survival by a modest amount: approximately 4 additional surviving patients at 2 years for every 100 treated. This result narrowly attained statistical significance. Further investigation to address heterogeneity resulted in a statistically significant finding of approximately 6 additional surviving patients per 100, which is an estimate based on the 4 most recent studies (1510 patients). Consideration of 5 studies (669 patients) in which chemotherapy was combined with radiotherapy resulted in an estimate of 6.4% improvement in 2-year survival, which was not statistically significant and did not raise concerns about heterogeneity among the studies that used combined therapy.
Because a number of the studies included in this article have reported survival results at 3 years, an attempt was made to obtain a summary estimate of 3-year survival based on five studies for which the precision of this end point could be determined adequately. According to this analysis, there was a treatment advantage of 5.1% at 3 years (preoperative treatment vs. control), which is comparable with the summary estimate at 2 years. Thus, consideration of the 3-year survival as an alternative end point did not substantially change the summary estimates.
A number of studies analyzed in this article used older regimens at doses that are no longer used. This remark applies mainly to the studies completed before 1994. Similarly, the doses of radiotherapy in some of the studies are considered suboptimal by today’s standards (8A). Although there was no way to conduct a meaningful statistical analysis based on the specific type and dosing of the preoperative treatment, we point out the fact that newer studies (1A and 7A) using higher doses have shown results favoring preoperative treatment. In our analysis, the summary estimates for studies published after 1994 that used 5-fluorouracil and cisplatin and more adequate doses of chemotherapy showed a 6.3% improvement of 2-year survival. It is also likely that the addition of newer chemotherapeutic agents, such as taxanes, may further improve outcome.
Whether there is any difference in the patterns of failure between patients who receive preoperative treatment and those who are treated with surgery alone is a matter of debate. In study 6A, patients who received preoperative chemotherapy had a 9% less incidence of distant metastasis compared with patients who received surgery alone. Two studies (5A and 12A) demonstrated a better local control rate in the preoperative treatment group. This difference may offer a disease-free survival benefit in patients who receive preoperative treatment (12A).
The rate of response to preoperative treatment and its significance to overall survival is another matter that deserves particular attention. Studies 4A, 5A, 6A, 8A, 9A, and 12A reported rates of complete pathologic response ranging from 2.5% to 26% in the treatment group. The higher rates of response were shown in trials that used a combination of chemotherapy and radiotherapy (8A, 4A, and 12A). In these studies, responders had longer survival than nonresponders. A recent phase II trial demonstrated a 28% complete pathologic response rate for patients with adenocarcinoma of the esophagus who received preoperative chemotherapy with radiotherapy.22 This study reported a 91% 2-year survival rate. The results of earlier nonrandomized trials concur.23–25
Examining the effect of neoadjuvant treatment on each histological type separately is an issue we tried to address by grouping the studies according to the histology of the disease. This was possible because of the similarity of our summary estimates for the four more recent chemotherapy studies and the five studies that used chemotherapy in combination with radiotherapy, which formed a homogeneous set of nine studies. The resulting analysis found no evidence of variation in 2-year survival based on disease histology.
This meta-analysis also found an increase of 1.7% in treatment-related mortality with neoadjuvant chemotherapy; this increase was marginally significant (P = .06). When studies using chemoradiotherapy were analyzed, the mortality increase was 3.4%, but the finding was not statistically significant.
Nonrandomized trials have also reported high complication rates in patients who receive chemoradiotherapy before surgery. In a phase II multicenter trial conducted by the Eastern Cooperative Oncology Group,26 the overall mortality reached 16%. In this study, however, the relatively high postoperative mortality rate was attributed to the lack of experience of the centers rather than to the effects of preoperative treatment: five of six postoperative deaths occurred in centers that entered only one or two patients onto the study.
Although studies have shown that neoadjuvant treatment may downstage the tumor and induce complete pathologic response, only four of the trials we analyzed reported separate survival data on patients who responded to treatment. Although it was not possible to perform a separate analysis, the results suggest that neoadjuvant therapy may offer a survival benefit in this group of patients. It is likely that any such improvement would be greater for patients with a complete pathologic response. The results of other phase III randomized trials that are currently still active may contribute to a better understanding of the role of neoadjuvant treatment for resectable cancer of the esophagus and help to identify patient subgroups who would benefit.
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APPENDIX A: STUDIES RELEVANT FOR META-ANALYSIS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONAPPENDIX A: STUDIES RELEVANT...APPENDIX B: PROSPECTIVE...REFERENCES |
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2A. Schlag PM. Randomized trial of preoperative chemotherapy for squamous cell cancer of the esophagus. Arch Surg 1992;127:1446–50.
3A. Nygaard K, Hagen S, Hansen HS, et al. Preoperative radiotherapy prolongs survival in operable esophageal carcinoma: a randomized, multicenter study of preoperative radiotherapy and chemotherapy. The second Scandinavian trial in esophageal cancer. World J Surg 1992;16:1104–10.
4A. Walsh TN, Noonan N, Hollywood D, et al. A comparison of multimodal therapy and surgery for esophageal adenocarcinoma. N Engl J Med 1996;335:462–7.
5A. Law S, Fok M, Chow S, et al. Preoperative chemotherapy versus surgical therapy alone for squamous cell carcinoma of the esophagus: a prospective randomized trial. J Thorac Cardiovasc Surg 1997;114:210–7.
6A. Kelsen DP, Ginsberg R, Pajak TF, et al. Chemotherapy followed by surgery compared with surgery alone for localized esophageal cancer. N Engl J Med 1998;339:1979–84.
7A. Ancona E, Ruol A, Santi S, et al. Only pathologic complete response to neoadjuvant chemotherapy improves significantly the long-term survival of patients with resectable esophageal squamous cell carcinoma. Cancer 2001;91:2165–74.
8A. Le Prise E, Ettiene P, Meunier B, et al. A randomized study of chemotherapy, radiation therapy and surgery versus surgery for localized squamous cell carcinoma of the esophagus. Cancer 1994;73:1779–84.
9A. Roth JA, Pass HI, Flanagan MM, et al. Randomized clinical trial of preoperative and postoperative adjuvant chemotherapy with cisplatin, vindesine and bleomycin for carcinoma of the esophagus. J Thorac Cardiovasc Surg 1988;96:242–8.
10A. Urba SG, Orringer MB, Turrisi A, et al. Randomized trial of preoperative chemoradiation versus surgery alone in patients with locoregional esophageal carcinoma. J Clin Oncol 2001;19:305–13.
11A. Maipang T, Vasinanukorn P, Petpichetchian C, et al. Induction chemotherapy in the treatment of patients with carcinoma of the esophagus. J Surg Oncol 1994;56:191–7.
12A. Bosset JF, Gignoux M, Triboulet JP, et al. Chemoradiotherapy followed by surgery compared with surgery alone in squamous-cell cancer of the esophagus. N Engl J Med 1997;337:161–7.
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APPENDIX B: PROSPECTIVE RANDOMIZED TRIALS REPORTED AS ABSTRACTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONAPPENDIX A: STUDIES RELEVANT...APPENDIX B: PROSPECTIVE...REFERENCES |
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2B. Urba S, Orringer M, Turisi A, et al. A randomized trial comparing surgery to preoperative concomitant chemo-radiation plus surgery in patients with resectable esophageal cancer: update analysis (abstract). Proc Am Soc Clin Oncol 1997;16:277.
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ACKNOWLEDGMENTS |
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The authors thank Isildinha M. Reis for consulting with us about statistical methods and James J. Schlesselman for a statistical review of the manuscript.
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FOOTNOTES |
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Received for publication March 20, 2002. Accepted for publication April 18, 2003.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONAPPENDIX A: STUDIES RELEVANT...APPENDIX B: PROSPECTIVE...REFERENCES |
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