Endoscopic ultrasonography is an independent predictive factor of prognosis in locally advanced esophageal cancer. Results from the randomized FFCD 9102 study from the Fédération Francophone de Cancérologie Digestive. Early surgery for failure after chemoradiation in operable thoracic oesophageal cancer. Analysis of the non-randomised patients in FFCD 9102 phase III trial: Chemoradiation followed by surgery versus chemoradiation alone. Chemoradiotherapy of locally advanced esophageal cancer: long-term follow-up of a prospective randomized trial (RTOG 85-01). Radiation Therapy Oncology Group. INT 0123 (Radiation Therapy Oncology Group 94-05) phase III trial of combined-modality therapy for esophageal cancer: high-dose versus standard-dose radiation therapy. Preoperative chemoradiotherapy for esophageal or junctional cancer. Long-term efficacy of perioperative chemoradiotherapy on esophageal squamous cell carcinoma. Three-Field Lymph Node Dissection for Squamous Cell and Adenocarcinoma of the Esophagus Chemoradiotherapy followed by surgery compared with surgery alone in squamous-cell cancer of the esophagus. A Phase II Study of Paclitaxel, Carboplatin, and Radiation with or without Surgery for Esophageal Cancer A comparison of multimodal therapy and surgery for esophageal adenocarcinoma. Quantitative Synthesis in Systematic Reviews Chemoradiation with and without surgery in patients with locally advanced squamous cell carcinoma of the esophagus. Transhiatal esophagectomy: clinical experience and refinements. Extended transthoracic resection compared with limited transhiatal resection for adenocarcinoma of the esophagus. A comparative longitudinal quality of life study using the Spitzer quality of life index in a randomized multicenter phase III trial (FFCD 9102): chemoradiation followed by surgery compared with chemoradiation alone in locally advanced squamous resectable thoracic esophageal cancer. Toxicity criteria of the Radiation Therapy Oncology Group (RTOG) and the European Organization for Research and Treatment of Cancer (EORTC) Randomized trial of preoperative chemoradiation versus surgery alone in patients with locoregional esophageal carcinoma. Chemotherapy followed by surgery compared with surgery alone for localized esophageal cancer. Chemoradiation followed by surgery compared with chemoradiation alone in squamous cancer of the esophagus: FFCD 9102. Phase III trial of protracted compared with split-course chemoradiation for esophageal carcinoma: Federation Francophone de Cancerologie Digestive 9102.
BACKGROUND No multivariate study has assessed the independent prognostic role of  endoscopic ultrasonography ( EUS )  in esophageal cancer , even when considering computed tomography ( CT ) . OBJECTIVE To evaluate the prognostic value of  EUS  in esophageal cancer before exclusive or preoperative radiochemotherapy . METHODS From 1993 to 1999 , the FFCD 9102 study enrolled 444 patients who had cancer of the thoracic esophagus , stages T3 - 4 , N0 - 1 and M0 on CT . The patients received two sessions of chemotherapy in addition to radiotherapy .  The 259 patients with objective response and no contraindications for further treatment were r and omized to undergo surgery or to continue with radiochemotherapy . EUS was performed in 174 patients enrolled in the trial ( mean age : 59 years ) . Tumor characteristics and lymph node status were prospect ively recorded . A Cox statistical model was used to identify any predictive prognostic factors among the clinical , EUS and CT data . RESULTS In the multivariate analysis , three factors were associated with a poor prognosis : inability to ingest solid food ( OR : 1.98 ; P=0.0008 ) ; more than three neoplastic subdiaphragmatic lymph nodes ( LN ) on EUS ( OR : 2.41 ; P<0.0045 ) and age>65 ( OR : 1.53 ; P<0.056 ) . Their prognostic value persisted after adjustment for type of treatment given . Two- and five- year survival rates were 21.5 and 10.5 % , respectively , in the presence of three neoplastic subdiaphragmatic LN , and 43 and 30 % , respectively , in all other cases . CONCLUSION Degree of dysphagia , age and presence of neoplastic subdiaphragmatic LN on EUS were independently predictive of the prognosis for locally advanced esophageal cancer . EUS results should be taken into account in future trials BACKGROUND Two r and omised trials concerning thoracic oesophageal cancer concluded that for squamous cell carcinoma , chemoradiation alone leads to the same overall survival ( OS ) as chemoradiation followed by surgery . One of these trials , FFCD 9102 , r and omised only fit , compliant and operable responders to induction chemoradiation between continuation of chemoradiation and surgery . In the present analysis , the outcome in the patients not eligible for r and omisation was calculated to determine if attempt of surgery should be recommended . METHODS Eligible patients had operable T3-N0/N1-M0 thoracic oesophageal cancer . After initial  chemoradiation  , patients with no clinical response , or with contraindication to follow any attributed treatment , were not r and omised . OS was studied first in the whole population of not r and omised patients , and then specifically in clinical non-responders . The impact of surgery on OS was studied in these two population s. FINDINGS Of the 451 registered patients in the trial , 192 were not r and omised . Among them , 111 were clinical non-responders . Median OS was significantly shorter for non-r and omised patients ( 11.5 months ) than for r and omised patients ( 18.9 months ; p=0.0024 ) . However , for the 112 non-r and omised patients who underwent surgery , median OS was not different from that in r and omised patients : 17.3 versus 18.9 months ( p=0.58 ) . Concerning clinical non-responders , median OS was longer for those who underwent surgery compared to non-operated patients : 17.0 versus 5.5 months ( hazard ratio (HR)=0.39 [ 0.25 - 0.61 ] ; p<0.0001 ) , and again was not different from that in responding , r and omised patients ( p=0.40 ) . INTERPRETATION In patients with locally advanced thoracic oesophageal cancer , overall survival did not differ between responders to induction chemoradiation and patients having surgery after clinical failure of chemoradiation . Surgery should therefore be considered in those patients who are still operable CONTEXT Carcinoma of the esophagus traditionally has been treated by surgery or radiation therapy ( RT ) , but 5-year overall survival rates have been only 5 % to 10 % . We previously reported results of a study conducted from January 1986 to April 1990 of combined chemotherapy and RT vs RT alone when an interim analysis revealed significant benefit for combined therapy . OBJECTIVE To report the long-term outcomes of a previously reported trial design ed to determine if adding chemotherapy during RT improves the survival rate of patients with esophageal carcinoma . DESIGN R and omized controlled trial conducted 1985 to 1990 with follow-up of at least 5 years , followed by a prospect i ve cohort study conducted between May 1990 and April 1991 . SETTING Multi-institution participation , ranging from tertiary academic referral centers to general community practice s. PATIENTS Patients had squamous cell or adenocarcinoma of the esophagus , T1 - 3 N0 - 1 M0 , adequate renal and bone marrow reserve , and a Karnofsky score of at least 50 . Interventions Combined modality therapy ( n = 134 ) : 50 Gy in 25 fractions over 5 weeks , plus cisplatin intravenously on the first day of weeks 1 , 5 , 8 , and 11 , and fluorouracil , 1 g/m2 per day by continuous infusion on the first 4 days of weeks 1 , 5 , 8 , and 11 . In the r and omized study , combined therapy was compared with RT only ( n = 62 ) : 64 Gy in 32 fractions over 6.4 weeks . MAIN OUTCOME MEASURES Overall survival , patterns of failure , and toxic effects . RESULTS Combined therapy significantly increased overall survival compared with RT alone . In the r and omized part of the trial , at 5 years of follow-up the overall survival for combined therapy was 26 % ( 95 % confidence interval [ CI ] , 15%-37 % ) compared with 0 % following RT . In the succeeding nonr and omized part , combined therapy produced a 5-year overall survival of 14 % ( 95 % CI , 6%-23 % ) . Persistence of disease ( despite therapy ) was the most common mode of treatment failure ; however , it was less common in the groups receiving combined therapy ( 34/130 [ 26 % ] ) than in the group treated with RT only ( 23/62 [ 37 % ] ) . Severe acute toxic effects also were greater in the combined therapy groups . There were no significant differences in severe late toxic effects between the groups . However , chemotherapy could be administered as planned in only 89 ( 68 % ) of 130 patients ( 10 % had life-threatening toxic effects with combined therapy vs 2 % in the RT only group ) . CONCLUSION Combined therapy increases the survival of patients who have squamous cell or adenocarcinoma of the esophagus , T1 - 3 N0 - 1 M0 , compared with RT alone PURPOSE To compare the local/regional control , survival , and toxicity of combined-modality therapy using high-dose ( 64.8 Gy ) versus st and ard-dose ( 50.4 Gy ) radiation therapy for the treatment of patients with esophageal cancer . PATIENTS AND METHODS A total of 236 patients with clinical stage T1 to T4 , N0/1 , M0 squamous cell carcinoma or adenocarcinoma selected for a nonsurgical approach , after stratification by weight loss , primary tumor size , and histology , were r and omized to receive combined-modality therapy consisting of four monthly cycles of fluorouracil ( 5-FU ) ( 1,000 mg/m(2)/24 hours for 4 days ) and cisplatin ( 75 mg/m(2 ) bolus day 1 ) with concurrent 64.8 Gy versus the same chemotherapy schedule but with concurrent 50.4 Gy . The trial was stopped after an interim analysis . The median follow-up was 16.4 months for all patients and 29.5 months for patients still alive . RESULTS For the 218 eligible patients , there was no significant difference in median survival ( 13.0 v 18.1 months ) , 2-year survival ( 31 % v 40 % ) , or local/regional failure and local/regional persistence of disease ( 56 % v 52 % ) between the high-dose and st and ard-dose arms . Although 11 treatment-related deaths occurred in the high-dose arm compared with two in the st and ard-dose arm , seven of the 11 deaths occurred in patients who had received 50.4 Gy or less . CONCLUSION The higher radiation dose did not increase survival or local/regional control . Although there was a higher treatment-related mortality rate in the patients assigned to the high-dose radiation arm , it did not seem to be related to the higher radiation dose . The st and ard radiation dose for patients treated with concurrent 5-FU and cisplatin chemotherapy is 50.4 Gy BACKGROUND The role of neoadjuvant chemoradiotherapy in the treatment of patients with esophageal or esophagogastric-junction cancer is not well established . We compared chemoradiotherapy followed by surgery with surgery alone in this patient population . METHODS We r and omly assigned patients with resectable tumors to receive surgery alone or weekly administration of carboplatin ( doses titrated to achieve an area under the curve of 2 mg per milliliter per minute ) and paclitaxel ( 50 mg per square meter of body-surface area ) for 5 weeks and concurrent radiotherapy ( 41.4 Gy in 23 fractions , 5 days per week ) , followed by surgery . RESULTS From March 2004 through December 2008 , we enrolled 368 patients , 366 of whom were included in the analysis : 275 ( 75 % ) had adenocarcinoma , 84 ( 23 % ) had squamous-cell carcinoma , and 7 ( 2 % ) had large-cell undifferentiated carcinoma . Of the 366 patients , 178 were r and omly assigned to chemoradiotherapy followed by surgery  , and 188 to surgery alone . The most common major hematologic toxic effects in the chemoradiotherapy-surgery group were leukopenia ( 6 % ) and neutropenia ( 2 % ) ; the most common major nonhematologic toxic effects were anorexia ( 5 % ) and fatigue ( 3 % ) . Complete resection with no tumor within 1 mm of the resection margins ( R0 ) was achieved in 92 % of patients in the chemoradiotherapy-surgery group versus 69 % in the surgery group ( P<0.001 ) . A pathological complete response was achieved in 47 of 161 patients ( 29 % ) who underwent resection after chemoradiotherapy . Postoperative complications were similar in the two treatment groups , and in-hospital mortality was 4 % in both . Median overall survival was 49.4 months in the chemoradiotherapy-surgery group versus 24.0 months in the surgery group . Overall survival was significantly better in the chemoradiotherapy-surgery group ( hazard ratio , 0.657 ; 95 % confidence interval , 0.495 to 0.871 ; P=0.003 ) . CONCLUSIONS Preoperative chemoradiotherapy improved survival among patients with potentially curable esophageal or esophagogastric-junction cancer . The regimen was associated with acceptable adverse-event rates . ( Funded by the Dutch Cancer Foundation [ KWF Kankerbestrijding ] ; Netherl and s Trial Register number , NTR487 . ) AIM To investigate the role of perioperative chemoradiotherapy ( CRT ) in the treatment of locally advanced thoracic esophageal squamous cell carcinoma ( ESCC ) . METHODS Using preoperative computed tomography (CT)-based staging criteria , 238 patients with ESCC ( stage II-III ) were enrolled in this prospect i ve study between January 1997 and June 2004 . With informed consent , patients were r and omized into 3 groups : preoperative CRT ( 80 cases ) , postoperative CRT ( 78 cases ) and surgery alone ( S ) ( 80 cases ) . The 1- , 3- , 5- and 10-year survival were followed up . Progression-free survival ( PFS ) was chosen as the primary endpoint by treatment arm measured from study entry until documented progression of disease or death from any cause . The secondary endpoint was overall survival ( OS ) determined as the time ( in months ) between the date of therapy and the date of death . Other objectives were surgical and adjuvant therapy complications . RESULTS With median follow-up of 45 mo for all the enrolled patients , significant differences in the 1- , 3- , 5- , 10-year OS ( 91.3 % , 63.5 % , 43.5 % , 24.5 % vs 91 % , 62.8 % , 42.3 % , 24.4 % vs 87.5 % , 51.3 % , 33.8 % , 12.5 % , P = 0.0176 ) and PFS ( 89.3 % , 61.3 % , 37.5 % , 18.1 % vs 89.1 % , 61.1 % , 37.2 % , 17.8 % vs 84.5 % , 49.3 % , 25.9 % , 6.2 % , P = 0.0151 ) were detected among the 3 arms . There were no significant differences in OS and PFS between the preoperative CRT and postoperative CRT arm ( P > 0.05 ) . For the patients who had radical resection , significant differences in median PFS ( 48 mo vs 61 mo vs 39.5 mo , P = 0.0331 ) and median OS ( 56.5 mo vs 72 mo vs 41.5 mo , P = 0.0153 ) were detected among the 3 arms , but there were no significant differences in OS and PFS between the preoperative CRT and postoperative CRT arm ( P > 0.05 ) . The local recurrence rates in the preoperative CRT , postoperative CRT group and S group were 11.3 % , 14.1 % and 35 % , respectively ( P < 0.05 ) . No significant differences were detected among the 3 groups when comparing complications but tended to be in favor of the postoperative CRT and S groups ( P > 0.05 ) . Toxicities of CRT in the preoperative or postoperative CRT arms were mostly moderate , and could be quickly alleviated by adequate therapy . CONCLUSION Rational application of preoperative or postoperative CRT can provide a benefit in PFS and OS in patients with locally advanced ESCC Objective To determine the prevalence of occult cervical nodal metastases in patients with squamous cell cancer and adenocarcinoma of the esophagus , and to determine the impact of esophagectomy with three-field lymph node dissection on survival and recurrence rates . Summary Background Data Although esophagectomy with three-field lymph node dissection is commonly practice d in Japan , its role in the surgical management of esophageal cancer in the United States , especially in patients with esophageal adenocarcinoma , is essentially unknown . Methods This is a prospect i ve observational study of esophagectomy with three-field lymphadenectomy .  Eighty patients underwent resection between August 1994 and April 2001 . Clinicopathological information and follow-up data were collected on all patients until death or June 2001 . Results Hospital mortality and morbidity rates were 5 % and 46 % , respectively . Metastases to the recurrent laryngeal and /or deep cervical nodes occurred in 36 % of patients irrespective of cell type ( adenocarcinoma 37 % , squamous 34 % ) or location within the esophagus ( lower third 32 % , middle third 60 % ) . Overall 5-year and disease-free survival rates were 51 % and 46 % , respectively . Sixty-nine percent presented with nodal metastases . The 5-year survival rate for node-negative patients was 88 % ; that for those with nodal metastases was 33 % . The 5-year survival rate in patients with positive cervical nodes was 25 % ( squamous 40 % , adenocarcinoma 15 % ) . Conclusions Esophagectomy with three-field lymph node dissection can be performed with a low mortality and reasonable morbidity . Unsuspected metastases to the recurrent laryngeal and /or cervical nodes are present in 36 % of patients regardless of cell type or location within the esophagus . Thirty percent of patients were upstaged , mainly from stage III to stage IV . An overall 5-year survival rate of 51 % suggests a true survival benefit beyond that achieved solely on the basis of stage migration BACKGROUND We conducted a multicenter , r and omized trial to compare preoperative chemoradiotherapy followed by surgery with surgery alone in patients with stage I and II squamous-cell cancer of the esophagus . METHODS The preoperative combined therapy consisted of two one-week courses ; each involved radiotherapy , in a dose of 18.5 Gy delivered in five fractions of 3.7 Gy each , and 80 mg of cisplatin per square meter of body-surface area , administered 0 to 2 days before the first day of radiotherapy . The surgical plan included one-stage en bloc esophagectomy and proximal gastrectomy by the abdominal and right thoracic routes , to be performed immediately after r and omization in the group assigned to surgery alone and two to four weeks after the completion of preoperative chemoradiotherapy in the group assigned to combined therapy . RESULTS A total of 297 patients entered the study ; 11 were found to be ineligible , and 4 were lost to follow-up . Of the remaining 282 , 139 were assigned to surgery alone and 143 to combined therapy . After a median follow-up of 55.2 months , no significant difference in overall survival was observed ; the median survival was 18.6 months for both groups . As compared with the group treated with surgery alone , the group treated preoperatively had longer disease-free survival ( P=0.003 ) , a longer interval free of local disease ( P=0.01 ) , a lower rate of cancer-related deaths ( P=0.002 ) , and a higher frequency of curative resection ( P=0.017 ) . However , there were more postoperative deaths ( P=0.012 ) in the group treated preoperatively with chemoradiotherapy . Three prognostic factors were found to influence survival in a multivariate analysis : the disease stage , based on computed tomography ; the location of the tumor ; and whether the surgical resection was curative . CONCLUSIONS In patients with squamous-cell esophageal cancer , preoperative chemoradiotherapy did not improve overall survival , but it did prolong disease-free survival and survival free of local disease Background : Cisplatin-based chemoradiotherapy ( CRT ) has been a st and ard treatment for patients with locally advanced esophageal cancer . However , cisplatin is associated with significant toxicity . We conducted a phase II clinical trial of concurrent paclitaxel , carboplatin , and radiation with or without surgery as an alternative to the st and ard cisplatin-based CRT for localized and metastatic esophageal cancer . Methods : Fifty patients with esophageal cancer were enrolled : 16 patients with stage II , eight patients with stage III , and 26 patients with stage IV disease . Two thirds ( 67 % ) of patients had adenocarcinoma and one third ( 33 % ) with squamous histology . Patients with resectable disease were treated with paclitaxel 30 mg/m2 , twice weekly for 10 doses , carboplatin AUC ( area under the curve ) 1.5 weekly for five doses ; and concurrent radiation , 1.8 Gy/day , for a total of 45 Gy , followed by esophagectomy . Without surgery , patients received an additional dose each of paclitaxel and carboplatin with concurrent radiation for a total of 50.4 Gy , followed by two consolidation cycles of paclitaxel ( 200 mg/m2 ) and carboplatin ( AUC 6 ) . Results : During CRT , common stage III/IV toxicities included nausea/emesis ( 19 % ) , esophagitis ( 9 % ) , and neutropenia ( 4 % ) . For consolidation chemotherapy , neutropenia ( 23 % ) , neuropathy ( 8 % ) and nausea/emesis ( 4 % ) were the most common stage III/IV side effects . After CRT , 26 % had a complete response , 17 % had a partial response , and 41 % had stable disease . Ninety-one percent of patients had clinical improvement of dysphagia . With a median follow-up of 32 months , the median survival was 12 months for patients with metastatic disease , 44 months for localized disease treated with esophagectomy , and > 44 months for localized disease treated with definitive CRT . Conclusions : The regimen of paclitaxel , carboplatin , and radiation with or without surgery is well tolerated with promising efficacy for patients with esophageal cancer BACKGROUND Uncontrolled studies suggest that a combination of chemotherapy and radiotherapy improves the survival of patients with esophageal adenocarcinoma . We conducted a prospect i ve , r and omized trial comparing surgery alone with combined chemotherapy , radiotherapy , and surgery . METHODS Patients assigned to multimodal therapy received two courses of chemotherapy in weeks 1 and 6 ( fluorouracil , 15 mg per kilogram of body weight daily for five days , and cisplatin , 75 mg per square meter of body-surface area on day 7 ) and a course of radiotherapy ( 40 Gy , administered in 15 fractions over a three-week period , beginning concurrently with the first course of chemotherapy ) , followed by surgery . The patients assigned to surgery had no preoperative therapy . RESULTS Of the 58 patients assigned to multimodal therapy and the 55 assigned to surgery  , 10 and 1 , respectively , were withdrawn for protocol violations . At the time of surgery , 23 of 55 patients ( 42 percent ) treated with preoperative multimodal therapy who could be evaluated had positive nodes or metastases , as compared with 45 of the 55 patients ( 82 percent ) who underwent surgery alone ( P<0.001 ) . Thirteen of the 52 patients ( 25 percent ) who underwent surgery after multimodal therapy had complete responses as determined pathologically . The median survival of patients assigned to multimodal therapy was 16 months , as compared with 11 months for those assigned to surgery alone ( P=0.01 ) . At one , two , and three years , 52 , 37 , and 32 percent , respectively , of patients assigned to multimodal therapy were alive , as compared with 44 , 26 , and 6 percent of those assigned to surgery , with the survival advantage favoring multimodal therapy reaching significance at three years ( P=0.01 ) . CONCLUSIONS Multimodal treatment is superior to surgery alone for patients with resectable adenocarcinoma of the esophagus A quantitative systematic review , or meta- analysis , uses statistical methods to combine the results of multiple studies . Meta-analyses have been done for systematic review s of therapeutic trials , diagnostic test evaluations , and epidemiologic studies . Although the statistical methods involved may at first appear to be mathematically complex , their purpose is simple : They are trying to answer four basic questions . Are the results of the different studies similar ? To the extent that they are similar , what is the best overall estimate ? How precise and robust is this estimate ? Finally , can dissimilarities be explained ? This article provides some guidance in underst and ing the key technical aspects of the quantitative approach to these questions . We have avoided using equations and statistical notations ; interested readers will find implementations of the described methods in the listed references . We focus here on the quantitative synthesis of reports of r and omized , controlled , therapeutic trials because far more meta-analyses on therapeutic studies than on other types of studies have been published . For practical reasons , we present a stepwise description of the tasks that are performed when statistical methods are used to combine data . These tasks are 1 ) deciding whether to combine data and defining what to combine , 2 ) evaluating the statistical heterogeneity of the data , 3 ) estimating a common effect , 4 ) exploring and explaining heterogeneity , 5 ) assessing the potential for bias , and 6 ) presenting the results . Deciding Whether To Combine Data and Defining What To Combine By the time one performs a quantitative synthesis , certain decisions should already have been made about the formulation of the question and the selection of included studies . These topics were discussed in two previous articles in this series [ 1 , 2 ] . Statistical tests can not compensate for lack of common sense , clinical acumen , and biological plausibility in the design of the protocol of a meta- analysis . Thus , a reader of a systematic review should always address these issues before evaluating the statistical methods that have been used and the results that have been generated . Combining poor- quality data , overly biased data , or data that do not make sense can easily produce unreliable results . The data to be combined in a meta- analysis are usually either binary or continuous . Binary data involve a yes/no categorization ( for example , death or survival ) . Continuous data take a range of values ( for example , change in diastolic blood pressure after antihypertensive treatment , measured in mm Hg ) . When one is comparing groups of patients , binary data can be summarized by using several measures of treatment effect that were discussed earlier in this series [ 3 ] . These measures include the risk ratio ; the odds ratio ; the risk difference ; and , when study duration is important , the incidence rate . Another useful clinical measure , the number needed to treat ( NNT ) , is derived from the inverse of the risk difference [ 3 ] . Treatment effect measures , such as the risk ratio and the odds ratio , provide an estimate of the relative efficacy of an intervention , whereas the risk difference describes the intervention 's absolute benefit . The various measures of treatment effect offer complementary information , and all should be examined [ 4 ] . Continuous data can be summarized by the raw mean difference between the treatment and control groups when the treatment effect is measured on the same scale ( for example , diastolic blood pressure in mm Hg ) , by the st and ardized mean difference when different scales are used to measure the same treatment effect ( for example , different pain scales being combined ) , or by the correlation coefficients between two continuous variables [ 5 ] . The st and ardized mean difference , also called the effect size , is obtained by dividing the difference between the mean in the treatment group and the mean in the control group by the SD in the control group . Evaluating the Statistical Heterogeneity of the Data This step is intended to answer the question , Are the results of the different studies similar ( homogeneous ) ? It is important to answer this question before combining any data . To do this , one must calculate the magnitude of the statistical diversity ( heterogeneity ) of the treatment effect that exists among the different sets of data . Statistical diversity can be thought of as attributable to one or both of two causes . First , study results can differ because of r and om sampling error . Even if the true effect is the same in each study , the results of different studies would be expected to vary r and omly around the true common fixed effect . This diversity is called the within- study variance . Second , each study may have been drawn from a different population , depending on the particular patients chosen and the interventions and conditions unique to the study . Therefore , even if each study enrolled a large patient sample , the treatment effect would be expected to differ . These differences , called r and om effects , describe the between- study variation with regard to an overall mean of the effects of all of the studies that could be undertaken . The test most commonly used to assess the statistical significance of between- study heterogeneity is based on the chi-square distribution [ 6 ] . It provides a measure of the sum of the squared differences between the results observed and the results expected in each study , under the assumption that each study estimates the same common treatment effect . A large total deviation indicates that a single common treatment effect is unlikely . Any pooled estimate calculated must account for the between- study heterogeneity . In practice , this test has low sensitivity for detecting heterogeneity , and it has been suggested that a liberal significance level , such as 0.1 , should be used [ 6 ] . Estimating a Common Effect The questions that this step tries to answers are , 1 ) To the extent that data are similar , what is their best common point estimate of a therapeutic effect , and 2 ) how precise is this estimate ? The mathematical process involved in this step generally involves combining ( pooling ) the results of different studies into an overall estimate . Compared with the results of individual studies , pooled results can increase statistical power and lead to more precise estimates of treatment effect . Each study is given a weight according to the precision of its results . The rationale is that studies with narrow CIs should be weighted more heavily than studies with greater uncertainty . The precision is generally expressed by the inverse of the variance of the estimate of each study . The variance has two components : the variance of the individual study and the variance between different studies . When the between- study variance is found to be or assumed to be zero , each study is simply weighted by the inverse of its own variance , which is a function of the study size and the number of events in the study . This approach characterizes a fixed-effects model , as exemplified by the Mantel-Haenszel method [ 7 , 8 ] or the Peto method [ 9 ] for dichotomous data . The Peto method has been particularly popular in the past . It has the advantage of simple calculation ; however , although it is appropriate in most cases , it may introduce large biases if the data are unbalanced [ 10 , 11 ] . On the other h and , r and om-effects models also add the between- study variance to the within- study variance of each individual study when the pooled mean of the r and om effects is calculated . The r and om-effects model most commonly used for dichotomous data is the DerSimonian and Laird estimate of the between- study variance [ 12 ] . Fixed- and r and om-effects models for continuous data have also been described [ 13 ] . Pooled results are generally reported as a point estimate and CI , typically a 95 % CI . Other quantitative techniques for combining data , such as the Confidence Profile Method [ 14 ] , use Bayesian methods to calculate posterior probability distributions for effects of interest . Bayesian statistics are based on the principle that each observation or set of observations should be viewed in conjunction with a prior probability describing the prior knowledge about the phenomenon of interest [ 15 ] . The new observations alter this prior probability to generate a posterior probability . Traditional meta- analysis assumes that nothing is known about the magnitude of the treatment effect before r and omized trials are performed . In Bayesian terms , the prior probability distribution is noninformative . Bayesian approaches may also allow the incorporation of indirect evidence in generating prior distributions [ 14 ] and may be particularly helpful in situations in which few data from r and omized studies exist [ 16 ] . Bayesian analyses may also be used to account for the uncertainty introduced by estimating the between- study variance in the r and om-effects model , leading to more appropriate estimates and predictions of treatment efficacy [ 17 ] . Exploring and Explaining Heterogeneity The next important issue is whether the common estimate obtained in the previous step is robust . Sensitivity analyses determine whether the common estimate is influenced by changes in the assumptions and in the protocol for combining the data . A comparison of the results of fixed- and r and om-effects models is one such sensitivity analysis [ 18 ] . Generally , the r and om-effects model produces wider CIs than does the fixed-effects model , and the level of statistical significance may therefore be different depending on the model used . The pooled point estimate per se is less likely to be affected , although exceptions are possible [ 19 ] . Other sensitivity analyses may include the examination of the residuals and the chi-square components [ 13 ] and assessment of the effect of deleting each study in turn . Statistically significant results that depend on a single study may require further exploration . Cumulative Meta- Analysis PURPOSE Combined chemoradiotherapy with and without surgery are widely accepted alternatives for the curative treatment of patients with locally advanced esophageal cancer . The value of adding surgery to chemotherapy and radiotherapy is unknown . PATIENTS AND METHODS Patients with locally advanced squamous cell carcinoma ( SCC ) of the esophagus were r and omly allocated to either induction chemotherapy followed by chemoradiotherapy ( 40 Gy ) followed by surgery ( arm A ) , or the same induction chemotherapy followed by chemoradiotherapy ( at least 65 Gy ) without surgery ( arm B ) . Primary outcome was overall survival time . RESULTS The median observation time was 6 years . The analysis of 172 eligible , r and omized patients ( 86 patients per arm ) showed overall survival to be equivalent between the two treatment groups ( log-rank test for equivalence , P < .05 ) . Local progression-free survival was better in the surgery group ( 2-year progression-free survival , 64.3 % ; 95 % CI , 52.1 % to 76.5 % ) than in the chemoradiotherapy group ( 2-year progression-free survival , 40.7 % ; 95 % CI , 28.9 % to 52.5 % ; hazard ratio [ HR ] for arm B v arm A , 2.1 ; 95 % CI , 1.3 to 3.5 ; P = .003 ) . Treatment-related mortality was significantly increased in the surgery group than in the chemoradiotherapy group ( 12.8 % v 3.5 % , respectively ; P = .03 ) . Cox regression analysis revealed clinical tumor response to induction chemotherapy to be the single independent prognostic factor for overall survival ( HR , 0.30 ; 95 % CI , 0.19 to 0.47 ; P < .0001 ) . CONCLUSION Adding surgery to chemoradiotherapy improves local tumor control but does not increase survival of patients with locally advanced esophageal SCC . Tumor response to induction chemotherapy identifies a favorable prognostic group within these high-risk patients , regardless of the treatment group OBJECTIVE To review the authors ' clinical experience with  transhiatal esophagectomy ( THE )  and the refinements in this procedure that have evolved . BACKGROUND Increased use of THE during the past two decades has generated controversy about the merits and safety of this approach compared with transthoracic esophageal resection . The authors ' large THE experience provides a valuable basis for benchmarking data regarding the procedure . METHODS The results of THE were analyzed retrospectively using the authors ' prospect ively established esophageal resection data base and follow-up information on these patients . RESULTS From 1976 to 1998 , THE was performed in 1085 patients , 26 % with benign disease and 74 % with cancer . The procedure was possible in 98.6 % of cases . Stomach was the esophageal substitute in 96 % . The hospital mortality rate was 4 % . Blood loss averaged 689 cc . Major complications were anastomotic leak ( 13 % ) , atelectasis/pneumonia ( 2 % ) , intrathoracic hemorrhage , recurrent laryngeal nerve paralysis , chylothorax , and tracheal laceration ( < 1 % each ) . Actuarial survival of patients with carcinoma equaled or exceeded that reported after transthoracic esophagectomy .  Late functional results were good or excellent in 70 % . With preoperative pulmonary and physical conditioning , a side-to-side stapled cervical esophagogastric anastomosis ( <3 % incidence of leak ) , and postoperative epidural anesthesia , the need for an intensive care unit stay has been eliminated and the length of stay reduced to 7 days . CONCLUSION THE is possible in most patients requiring esophageal resection and can be performed with greater safety and fewer complications than the traditional transthoracic approaches BACKGROUND Controversy exists about the best surgical treatment for esophageal carcinoma . METHODS We r and omly assigned 220 patients with adenocarcinoma of the mid-to-distal esophagus or adenocarcinoma of the gastric cardia involving the distal esophagus either to transhiatal esophagectomy or to transthoracic esophagectomy with extended en bloc lymphadenectomy . Principal end points were overall survival and disease-free survival . Early morbidity and mortality , the number of quality -adjusted life-years gained , and cost effectiveness were also determined . RESULTS A total of 106 patients were assigned to undergo transhiatal esophagectomy , and 114 to undergo transthoracic esophagectomy .  Demographic characteristics and characteristics of the tumor were similar in the two groups . Perioperative morbidity was higher after transthoracic esophagectomy , but there was no significant difference in in-hospital mortality ( P=0.45 ) . After a median follow-up of 4.7 years , 142 patients had died--74 ( 70 percent ) after transhiatal resection and 68 ( 60 percent ) after transthoracic resection ( P=0.12 ) . Although the difference in survival was not statistically significant , there was a trend toward a survival benefit with the extended approach at five years : disease-free survival was 27 percent in the transhiatal-esophagectomy group , as compared with 39 percent in the transthoracic-esophagectomy group ( 95 percent confidence interval for the difference , -1 to 24 percent [ the negative value indicates better survival with transhiatal resection ] ) , whereas overall survival was 29 percent as compared with 39 percent ( 95 percent confidence interval for the difference , -3 to 23 percent ) . CONCLUSIONS Transhiatal esophagectomy was associated with lower morbidity than transthoracic esophagectomy with extended en bloc lymphadenectomy . Although median overall , disease-free , and quality -adjusted survival did not differ statistically between the groups , there was a trend toward improved long-term survival at five years with the extended transthoracic approach BACKGROUND The aim of the study was to compare the longitudinal quality of life ( QoL ) between chemoradiation with or without surgery in patients with locally advanced squamous resectable esophageal cancer included in a r and omized multicenter phase III trial ( FFCD 9102 ) . MATERIAL S AND METHODS All patients with locally advanced resectable ( T3 - 4 N0 - 1 M0 ) epidermoid or gl and ular esophageal cancer ( n = 451 ) received induction chemoradiation .  Responders ( n = 259 ) were r and omized between surgery ( arm A ) and continuation of chemoradiation ( arm B ) . The Spitzer QoL Index was scored ( 0 - 10 ) at inclusion and at each follow-up , every 3 months during 2 years . QoL at baseline and longitudinal changes were respectively compared with univariate ANOVA and mixed-model analysis of variance for repeated measurements . The time interval between the follow-up was assessed and the same analyses were performed among survivors with 2 years of follow-up . RESULTS The squamous histology was predominant in both arms . The mean QoL score decreased between baseline and the first follow-up and between the first and the second follow-ups . QoL scores at the first follow-up were comparatively worse in arm A than in arm B ( 7.52 versus 8.45 , P < 0.01 ) , whereas the longitudinal QoL study showed no difference between treatments ( adjusted P = 0.26 ) . Furthermore , the longitudinal QoL was not different ( adjusted P = 0.23 ) among survivors with 2 years of follow-up . CONCLUSIONS Among patients responding to induction chemoradiation , surgery and continuation of chemoradiation had the same impact on QoL in patients with locally advanced , resectable esophageal cancer although a significantly greater decrease in the Spitzer Index was observed in the postoperative period The therapeutic use of ionizing radiations is predicated on sparing normal tissue effects while attempting to achieve lethal effects on tumor cells . From quite early in the history of radiation therapy , it was apparent that there were striking differences in effects in the panoply of normal tissues . Although there was early appreciation of some late effects in normal tissues , often not predicted by acute reactions , only in recent years has there been full documentation of the slow and progressive increase in severity of late damage . Pathophysiological mechanisms of acute and late radiation effects are better understood today ( 2 ) , but interactions of other modalities with radiation therapy require constant monitoring to recognize and mitigate untoward sequelae . The work of Stone ( 3 ) is a classic example of unanticipated late effects , which result ed from irradiation with ‘ fast neutrons .  Acute reactions were moderate and tolerable , but the late sequelae were so marked that there was little interest in pursuing therapy with fast neutrons for nearly three decades . The Late Morbidity Scoring Criteria were developed as a joint effort between physicians with renewed interests in  fast neutron therapy  and  Radiation Therapy Oncology Group ( RTOG ) staff . In the late 1970s the Neutron/Particle Committee was one of several modality committees of the RTOG . Recognizing the results of Stone , this committee , led by Lawrence Davis worked with RTOG staff to establish criteria and scoring for possible late effects from fast neutron radiation therapy . Investigators from the European Organization for Research and Treatment of Cancer ( EORTC ) , led by William Duncan of the Western General Hospital of Edinburgh , wished to have common toxicity criteria in anticipation of joint studies . RTOG Protocol 7929 , an international registry of patients treated with heavy particles , was started in 1980 . At the annual meetings of the international participants in particle studies , there were attempts to monitor interobserver variations in scoring effects in normal tissues and to seek consistency in reporting toxicity , but no publications document these efforts . The first prospect i ve trial to use the Late Morbidity Scoring Criteria was RTOG Protocol 8001 , a study of fast neutron therapy for malignant tumors arising in salivary gl and s. Although the RTOG began to use these criteria in reporting  toxicity  in patients enrolled in all studies from 198 1 ( beginning with RTOG Protocol 8 115 ) , the criteria only became a published part of protocol s in 1983 . At that time , statistical methods began to be used , which presented time-adjusted estimates of late effects , the rationale for which was described by Cox ( 1 ) . It is now considered st and ard to represent cumulative probabilities of late effects with methods similar to those for estimating local control and survival . The Acute Radiation Morbidity Scoring Criteria were developed in 1985 as complimentary to the Late Effects Scoring Criteria . The National Cancer Institute promulgated st and ard toxicity criteria in 1990 , but late effects were not considered . An abbreviated version of the RTOG/EORTC toxicity criteria was published by Winchester and Cox in 1992 as part of the St and ard for Breast Conservation Treatment . The current RTOG Acute  Radiation Morbidity Scoring Criteria are presented in Table 1 . The RTOG/EORTC Late Radiation Morbidity Scoring Scheme is detailed in Table 2 . In both tables , 0 means an absence of radiation effects and 5 means the effects led to death . The PURPOSE A pilot study of 43 patients with potentially resectable esophageal carcinoma treated with an intensive regimen of preoperative chemoradiation with cisplatin , fluorouracil , and vinblastine before surgery showed a median survival of 29 months in comparison with the 12-month median survival of 100 historical controls treated with surgery alone at the same institution . We design ed a r and omized trial to compare survival for patients treated with this preoperative chemoradiation regimen versus surgery alone . MATERIAL S AND METHODS One hundred patients with esophageal carcinoma were r and omized to receive either surgery alone ( arm I ) or preoperative chemoradiation ( arm II ) with cisplatin 20 mg/m2/d on days 1 through 5 and 17 through 21 , fluorouracil 300 mg/m2/d on days 1 through 21 , and vinblastine 1 mg/m2/d on days 1 through 4 and 17 through 20 . Radiotherapy consisted of 1.5-Gy fractions twice daily , Monday through Friday over 21 days , to a total dose of 45 Gy . Transhiatal esophagectomy with a cervical esophagogastric anastomosis was performed on approximately day 42 . RESULTS At median follow-up of 8.2 years , there is no significant difference in survival between the treatment arms . Median survival is 17.6 months in arm I and 16.9 months in arm II . Survival at 3 years was 16 % in arm I and 30 % in arm II ( P = .15 ) . This study was statistically powered to detect a relatively large increase in median survival from 1 year to 2.2 years , with at least 80 % power . CONCLUSION This r and omized trial of preoperative chemoradiation versus surgery alone for patients with potentially resectable esophageal carcinoma did not demonstrate a statistically significant survival difference BACKGROUND We performed a multi-institutional r and omized trial comparing preoperative chemotherapy followed by surgery with surgery alone for patients with local and operable esophageal cancer . METHODS Preoperative chemotherapy for patients r and omly assigned to the chemotherapy group included three cycles of cisplatin and fluorouracil . Surgery was performed two to four weeks after the completion of the third cycle ; patients also received two additional cycles of chemotherapy after the operation . Patients r and omly assigned to the immediate-surgery group underwent the same surgical procedure . The main end point was overall survival . RESULTS Of the 440 eligible patients with adequate data , 213 were assigned to receive preoperative chemotherapy and 227 to undergo immediate surgery .  After a median possible study time of 55.4 months , there were no significant differences between the two groups in median survival : 14.9 months for the patients who received preoperative chemotherapy and 16.1 months for those who underwent immediate surgery ( P=0.53 ) . At one year , the survival rate was 59 percent for those who received chemotherapy and 60 percent for those who had surgery alone ; at two years , survival was 35 percent and 37 percent , respectively . The toxic effects of chemotherapy were tolerable , and the addition of chemotherapy did not appear to increase the morbidity or mortality associated with surgery . There were no differences in survival between patients with squamous-cell carcinoma and those with adenocarcinoma .  Weight loss was a significant predictor of poor outcome ( P=0.03 ) . With the addition of chemotherapy , there was no change in the rate of recurrence at locoregional or distant sites . CONCLUSIONS Preoperative chemotherapy with a combination of cisplatin and fluorouracil did not improve overall survival among patients with epidermoid cancer or adenocarcinoma of the esophagus PURPOSE Uncontrolled studies suggest that chemoradiation has similar efficacy as surgery for esophageal cancer . Therefore , a r and omized trial was carried out to compare , in responders only , chemoradiation alone with chemoradiation followed by surgery in patients with locally advanced tumors . PATIENTS AND METHODS Eligible patients had operable T3N0 - 1M0 thoracic esophageal cancer . Patients received two cycles of fluorouracil ( FU ) and cisplatin ( days 1 to 5 and 22 to 26 ) and either conventional ( 46 Gy in 4.5 weeks ) or split-course ( 15 Gy , days 1 to 5 and 22 to 26 ) concomitant radiotherapy .  Patients with response and no contraindication to either treatment were r and omly assigned to surgery ( arm A ) or continuation of chemoradiation ( arm B ; three cycles of FU/cisplatin and either conventional [ 20 Gy ] or split-course [ 15 Gy ] radiotherapy ) . Chemoradiation was considered equivalent to surgery if the difference in 2-year survival rate was less than 10 % . RESULTS Of 444 eligible patients , 259 were r and omly assigned ; 230 patients ( 88.8 % ) had epidermoid cancer , and 29 ( 11.2 % ) had gl and ular carcinoma .  Two-year survival rate was 34 % in arm A versus 40 % in arm B ( hazard ratio for arm B v arm A = 0.90 ; adjusted P = .44 ) . Median survival time was 17.7 months in arm A compared with 19.3 months in arm B. Two-year local control rate was 66.4 % in arm A compared with 57.0 % in arm B , and stents were less required in the surgery arm ( 5 % in arm A v 32 % in arm B ; P < .001 ) . The 3-month mortality rate was 9.3 % in arm A compared with 0.8 % in arm B ( P = .002 ) . Cumulative hospital stay was 68 days in arm A compared with 52 days in arm B ( P = .02 ) . CONCLUSION Our data suggest that , in patients with locally advanced thoracic esophageal cancers , especially epidermoid , who respond to chemoradiation , there is no benefit for the addition of surgery after chemoradiation compared with the continuation of additional chemoradiation PURPOSE Chemoradiotherapy ( CRT ) is an alternative to surgery for resectable locally advanced esophageal carcinoma ( RLA-EC ) . We investigated the heterogeneity of the treatment benefits across subgroups of patients , defined according to the radiation scheme . PATIENTS AND METHODS Between February 1993 and December 2000 , 451 patients were enrolled . The following two schemes were allowed : protracted radiotherapy ( P-RT ) , which scheduled 46 Gy over 4.5 weeks or split-course radiotherapy ( SC-RT ) with two 1-week courses of 15 Gy . Two courses of cisplatin and fluorouracil were delivered concomitantly . In case of exclusive CRT , a further course of 20 Gy over 2 weeks in the P-RT group and one 1-week course of 15 Gy in the SC-RT group were delivered with three courses of chemotherapy . SC-RT and P-RT were administered to 285 patients ( 64 % ) and 161 patients ( 36 % ) , respectively . RESULTS For P-RT versus SC-RT , the response rate to induction CRT was 67 % v 68 % , respectively ( P = .09 ) , and 2-year local relapse-free survival rate was 76.7 % v 56.8 % , respectively ( P = .002 ) . Shorter tumor length and P-RT were associated with better local control in multivariate analysis ( P = .002 for both ) . After a median follow-up time of 47.4 months , 2-year overall survival rate was 37.1 % for P-RT compared with 30.5 % for SC-RT ( P = .25 ) . Independent prognostic factors on survival were tumor diameter ( P = .02 ) , weight loss of 10 % or less ( P = .05 ) , and response to induction CRT ( P = .002 ) . CONCLUSION Patients with RLA-EC treated with P-RT had better local control than patients treated with SC-RT . Response to induction CRT is a determinant prognostic factor on survival
The outcome of patients with esophageal cancer is generally poor .
Although multimodal therapy is st and ard , there is conflicting evidence regarding the addition of esophagectomy to chemoradiotherapy .
OBJECTIVES To compare the effectiveness and safety of chemoradiotherapy plus surgery with that of chemoradiotherapy alone in people with nonmetastatic esophageal carcinoma .