The Roles of Neoadjuvant Radiotherapy and Lymphadenectomy in the Treatment of Esophageal Adenocarcinoma

Transcription

1 Ann Surg Oncol (2010) 17: DOI /s ORIGINAL ARTICLE THORACIC ONCOLOGY The Roles of Neoadjuvant Radiotherapy and Lymphadenectomy in the Treatment of Esophageal Adenocarcinoma Naveenraj Solomon, MD 1, Ying Zhuge, MD 1, Michael Cheung, MD 1, Dido Franceschi, MD 1, and Leonidas G. Koniaris, MD 1,2 1 DeWitt Daughtry Family Department of Surgery, University of Miami Miller School of Medicine, Miami, FL; 2 Alan Livingstone Chair in Surgical Oncology, University of Miami School of Medicine, Miami, FL ABSTRACT Objective. Using a population-based registry, we evaluated the impact of neoadjuvant radiotherapy and lymphadenectomy on survival of patients undergoing curative-intent surgery for esophageal adenocarcinoma (EAC). Methods. Surveillance, Epidemiology, and End Results (SEER) data for patients with esophageal adenocarcinoma from 1988 to 2005 were queried. Patients undergoing curative operations were included. Treatment was stratified between no radiotherapy, neoadjuvant versus adjuvant radiotherapy, and adequate (C18 lymph nodes) versus inadequate (\18 lymph nodes) lymphadenectomy. Univariate and multivariate analysis were performed to determine survival (MST) and cause-specific survival (CSS). Results. Overall, 4,224 patients underwent surgical extirpation with curative intent for EAC in the study period. MST and CSS for the entire cohort were 25 and 31 months, respectively. Multivariate analysis showed age \65 years, well-differentiated tumor, local disease, negative lymph node status, adequate lymphadenectomy, and neoadjuvant radiotherapy to be independent predictors of improved survival. In node-positive patients, the greatest survival benefit was seen in patients who received both neoadjuvant radiotherapy and adequate lymphadenectomy (MST = 32 months, CSS = 34 months). The lymph node ratio (LNR) for adequately dissected patients treated with neoadjuvant radiotherapy was 0.17, which is \0.2, the established LNR cutoff that is an independent predictor of Ó Society of Surgical Oncology 2009 First Received: 9 July 2009; Published Online: 2 December 2009 L. G. Koniaris, MD lkoniaris@med.miami.edu improved survival. The survival benefit of neoadjuvant treatment is additive to that of adequate lymphadenectomy. Conclusion. There is a cooperative survival benefit for neoadjuvant radiation and adequate lymphadenectomy in patients with node-positive EAC. Both are independent predictors of improved survival. Patients who have clinically node-positive disease should undergo both neoadjuvant radiation and adequate lymphadenectomy to ensure optimal outcome. Cancer of the esophagus ranks as the seventh most common cause of cancer-related death in the USA. 1 In 2008, it is estimated that 16,470 new cases of esophageal cancer will be diagnosed, with 14,280 deaths due to this malignancy. 1 Thirty years ago, squamous cell carcinoma (SCC) was the most common histology. In the past two decades, adenocarcinoma has become the most common among Caucasian patients in the USA and other industrialized countries. 2 8 SCC remains the majority histology of esophageal tumors diagnosed in African-Americans (AA) patients. 2,4,5,7 Surgery is the mainstay of therapy and the only chance of cure for most patients. Due to the high incidence of mortality, even following surgical extirpation, neoadjuvant treatments have been increasingly utilized to improve the rate of cure and optimize palliation. Though recent retrospective and prospective studies demonstrate modest benefit for neoadjuvant chemoradiation, debate still exists regarding the use of radiotherapy due to its unavoidable morbidity The benefit and extent of lymphadenectomy for these patients are also under contention. Retrospective trials have shown that lymph node ratio [0.20, C4 positive lymph nodes, and failure to examine at least 18 lymph nodes are all predictors of poor survival. 12,13 The relationship

2 792 N. Solomon et al. between neoadjuvant radiation and degree of lymphadenectomy remains undefined, since population-based studies evaluating lymphadenectomy and lymph node ratio generally exclude patients undergoing neoadjuvant radiation due to its tumor downstaging effects. The aim of this study is to determine the interaction between neoadjuvant radiation and extent of lymphadenectomy and their effects on long-term survival in these patients. MATERIALS AND METHODS The Surveillance, Epidemiology, and End Results (SEER) program April 2008 release was used to identify all incident cases of esophageal adenocarcinomas diagnosed from 1988 to 2005 using the International Classification of Diseases (ICD) for oncology-morphology codes 8140, 8142, 8144, 8145, 8200, 8210, 8211, 8240, 8244, 8246, 8247, 8255, 8260, , 8310, and Only percentages based on available data are given for each variable. Patients with missing data were excluded from each respective univariate and multivariate analysis. Historical staging codes, i.e., local, regional, and distant staging, were used to categorize patients, since American Joint Committee on Cancer (AJCC) staging is not available for all patients prior to Localized disease is defined as invasive malignancy confined to the organ of origin. Regional disease is defined as a malignant neoplasm that (1) has extended beyond the limits of the organ of origin directly into surrounding organs or tissues, (2) involves regional lymph nodes by way of the lymphatic system, or (3) has both regional extension and involvement of regional lymph nodes. Distant disease is disease that has spread to other parts of the body by either direct extension or discontinuous metastasis to other organs or lymph nodes. Patients included in this study are those who had undergone surgical interventions, including procedure codes 30 and above, i.e., partial esophagectomy and en bloc esophagectomy for curative resections. Forty-nine patients were coded as surgery not otherwise specified (NOS), which accounted for 1.1% of the entire cohort. Although chemotherapeutic intervention is not collected in the SEER dataset, radiotherapy and timing of surgery are available. In patients who received neoadjuvant radiation for their esophageal adenocarcinoma, it is assumed that neoadjuvant chemotherapy was given concurrently due to the lack of supporting literature for using neoadjuvant radiation alone. 15,16 Statistical analysis was performed with SPSS Statistical Package version 15.0 (SPSS Inc., Chicago, IL). Correlations between categorical variables were made using the chi-square test. A P value of less than 0.05 was considered statistically significant. A further distinction was drawn at 0.01 and to identify highly significant differences. All statistical tests were two-sided. Median, overall, and disease-specific survivals were calculated using Kaplan Meier method. Survival was calculated from time of initial diagnosis to date of last contact or date of death. The effects of demographic, clinical, pathologic, and treatment variables on survival were examined by utilizing the log-rank test for categorical values. A multivariate analysis using the Cox proportional-hazards model was used to further test prognostic factors found to be significant on univariate analysis. Specifically, age, gender, race, ethnicity, tumor grade, primary tumor site, surgical resection, and radiation were included in the multivariate analysis. RESULTS Patient Demographics and Tumor Characteristics Over the 17-year study period, 4,224 patients with surgically treated esophageal adenocarcinoma (EAC) were identified. Patient demographics and tumor characteristics are summarized in Table 1. Mean age at diagnosis was 64 years old. Most patients were male (88.9%, n = 3,757), between 41 and 65 years of age (52.8%, n = 2,229), Caucasian (96.7%, n = 4,085), and non-hispanic (95%, n = 4,014). The majority of patients had regional disease (51.3%, n = 2,168) located in the lower esophagus (85.9%, n = 3,360). There were 1,819 patients (43.1%) with nodenegative disease, 1,652 (39.1%) patients with node-positive disease, and 753 (17.8%) patients with unknown nodal status. Based on previous studies that defined an adequate node dissection to be at least 18 lymph nodes, most patients had inadequate lymph node dissection (82.1%, n = 3,469). 17,18 The majority of patients did not receive any radiotherapy (55.8%, n = 2,357), 1,230 (29%) patients received neoadjuvant radiation, and 622 (14.7%) patients received adjuvant radiation. Median survival times (MST) and cause-specific survival (CSS) of the entire cohort, including subset analysis, are presented in Table 1. MST and CSS for the entire study population were 25 and 31 months, respectively. There was no significant difference in MST and CSS between males and females, African Americans (AA) and Caucasians, and Hispanics and non-hispanics. Significantly higher MST and CSS were observed for patients younger than 65 years old (P \ 0.001). Patients with local and regional disease had significantly longer survival than those with distant disease (P \ 0.001). Those with well- and moderately differentiated tumors had significantly longer survival than those with poorly and undifferentiated tumors (P \ 0.001). Patients with tumors located in the upper third of the

3 Neoadjuvant RT and Lymphadenectomy for EAC 793 TABLE 1 Patient demographics, tumor characteristics, and survival n % of total Median survival time Cause-specific survival 90-Day survival Months P Months P % P Mean age at diagnosis = 63.8 years Entire cohort 4, Gender Male 3, Female Age (years) \ \ \ \ , [65 1, Race White 4, Black Unknown Ethnicity Hispanic Non-Hispanic 4, Unknown Tumor stage Local 1, \0.001 ND \ \0.001 Regional 2, Distant Tumor grade Well differentiated \0.001 ND \ \0.001 Moderately differentiated 1, Poorly differentiated 1, Undifferentiated Unknown Site (esophagus) Upper Middle Lower 3, Overlapping Nos Lymph nodes Negative 1, \ \ \0.001 Positive 1, Unknown Inadequate dissection 3, Adequate dissection Unknown Treatment No radiation 2, \ \ \0.001 Neoadjuvant Radiation 1, Adjuvant radiation Unknown

4 794 N. Solomon et al. esophagus had longer MST and CSS than those with tumors found in the middle and lower portions (P = and 0.029, respectively). Patients with negative lymph nodes had significantly better survival than those with positive lymph nodes (P \ 0.001). Furthermore, patients who had adequate lymphadenectomy had significantly longer MST and CSS than those who had inadequate lymphadenectomy (P = and 0.011, respectively). Finally, patients who received neoadjuvant radiotherapy had significantly longer survival than those who received adjuvant radiation (P \ 0.001). In fact, those who received neoadjuvant radiation had similar survival rates to those who did not need radiation therapy. Ninety-day mortality was evaluated for patients who underwent radiotherapy and those who did not, and was found to be not significantly different. Also, 90-day mortality was not significantly different between patients who received no radiotherapy and those who received neoadjuvant radiotherapy treatment. Effect of Radiotherapy and Adequacy of Lymphadenectomy on Survival The effects of radiotherapy on subsets of patients based on nodal status as well as adequacy of lymphadenectomy are summarized in Table 2. For patients with node-negative disease upon pathologic examination, the highest MST and CSS were seen when no radiation treatment was given and adequate dissection was performed. Both MST and CSS were not yet reached (ND) for these patients. When these patients were compared with other node-negative patients who received no radiation but inadequate dissection, MST and CSS were significantly higher for the former group (MST = ND vs. 63 months, P \ 0.001; CSS = ND vs. 129 months, P \ 0.001). In node-negative patients, regardless of adequacy of lymphadenectomy, use of neoadjuvant radiotherapy predicted significantly worse outcome when compared with patients who did not need radiation (P = for inadequate lymphadenectomy group, P = for adequate lymphadenectomy group), which is likely a reflection of disease burden at diagnosis, and subsequent tumor downstaging effects of neoadjuvant radiotherapy. For patients with node-positive disease, lack of radiotherapy and inadequate resection predicted the worst MST and CSS (11 months and 13 months, respectively; Table 2. Figure 1 presents frequency curves for node-positive patients depending on radiotherapy, showing that survival depended on adequacy of lymphadenectomy. Of the nodepositive patients, 315 patients had adequate lymph node dissection while 1,219 patients did not. Node-positive patients who received adequate lymphadenectomy had longer survival than those who did not (P = 0.021, Fig. 1a). In those patients who received no radiotherapy, adequate lymph node dissection significantly improved survival (MST = 15 vs. 11 months in those with inadequate lymphadenectomy, P = 0.002; Table 2, Fig. 1b). Similarly, in node-positive patients who received neoadjuvant radiotherapy, adequate lymph node dissection significantly prolonged survival (32 vs. 19 months, P = 0.036; Table 2, Fig. 1c). MST and CSS were significantly improved in patients who received neoadjuvant radiotherapy, regardless of adequacy of lymph node dissection (P \ for inadequate lymphadenectomy group, P = for adequate lymphadenectomy group). Patients with the greatest survival benefit in the setting of positive nodal disease were those who received both neoadjuvant radiotherapy and adequate lymphadenectomy (MST = 32 months and CSS = 34 months). Multivariate Analysis Multivariate analysis using the Cox regression method is shown in Table 3. Gender, race, ethnicity, and location in the esophagus did not significantly affect survival. On the other hand, patients older than 65 years had significantly worse survival than those younger than 65 years, with an overall hazard ratio (OHR) of 1.681, confidence interval (CI) of , and P \ Tumors that were moderately, poorly, and undifferentiated had significantly worse outcome than those that were well differentiated (OHR 1.238, 1.706, and 1.863, respectively; P = 0.025, \0.001, and \0.001, respectively). Similarly, regional and distant diseases were independent predictors of poorer survival (OHR and respectively; P \ 0.001). Positive lymph node status independently predicted worse outcome (OHR 1.748, CI , P \ 0.001), whereas adequate lymphadenectomy was a positive predictor of outcome (OHR 0.722, CI , P \ 0.001). Finally, neoadjuvant radiotherapy was an independent predictor of improved outcome (OHR 0.835, CI , P \ 0.001). Further subset analyses by stratifying patients by nodal status (Table 4) showed complete lymphadenectomy and neoadjuvant radiation to be independent predictors of survival for both node-positive and node-negative disease. For node-negative disease, performing an adequate node dissection was protective (OHR 0.570, CI , P \ 0.001), but receiving neoadjuvant and adjuvant radiation could be harmful (OHR 1.214, CI , P = and OHR 1.383, CI , P = 0.012, respectively). This again highlights the tumor downstaging effects of radiotherapy, which can cause misclassification of patients who are node positive prior to radiotherapy but who are subsequently downstaged to the node-negative group after radiotherapy. For node-positive disease, adequate lymph node dissection was also protective (OHR 0.800, CI

5 Neoadjuvant RT and Lymphadenectomy for EAC 795 TABLE 2 MST and CSS for radiation treatment and lymph node dissection Median survival time P Cause-specific survival P Node-negative disease No radiation Inadequate node dissection 63 Ref 129 Ref Adequate node dissection ND \0.001 ND \0.001 Neoadjuvant radiation Inadequate node dissection 41 Ref 63 Ref Adequate node dissection ND Adjuvant radiation Inadequate node dissection 32 Ref 46 Ref Adequate node dissection Inadequate node dissection No radiation 63 Ref 129 Ref Neoadjuvant radiation Adjuvant radiation Adequate node dissection No radiation ND Ref ND Ref Neoadjuvant radiation ND Adjuvant radiation Node-positive disease No radiation Inadequate node dissection 11 Ref 13 Ref Adequate node dissection Neoadjuvant radiation Inadequate node dissection 19 Ref 21 Ref Adequate node dissection Adjuvant radiation Inadequate node dissection 17 Ref 18 Ref Adequate node dissection Inadequate node dissection No radiation 11 Ref 13 Ref Neoadjuvant radiation 19 \ \0.001 Adjuvant radiation 17 \ \0.001 Adequate node dissection No radiation 15 Ref 18 Ref Neoadjuvant radiation Adjuvant radiation ND not yet reached , P = 0.003), as were neoadjuvant radiotherapy (OHR 0.552, CI , P \ 0.001) and adjuvant radiation (OHR 0.697, CI , P \ 0.001). This data is confirmed in the CSS analyses (Table 4). Effect of Radiotherapy on Lymph Node Ratio In this analysis, patients were defined as having had adequate lymphadenectomy if 18 or more lymph nodes (LN) were examined. 18,19 The number of positive LN and lymph node ratios (LRN = number of positive LN/total number of LN examined) are compared in Table 5. Most patients in the study received inadequate lymphadenectomy, with an average of 8.72 LN removed. The mean number of positive LN in this group was In patients who received neoadjuvant radiation, the mean number of positive nodes was The LNR for the inadequate lymphadenectomy was 0.44 for patients who did not receive radiation, 0.33 for those who received neoadjuvant radiotherapy, and 0.42 for those who received adjuvant radiotherapy.

6 796 N. Solomon et al. (a) Whole Group 400 Inadeqate Ly mphadenectomy Median Survival: 14 months 200 Adeqate Lymphadenectomy Median Survival: 17 months Mean = 3.57 Std. dev. = 3.04 N = 1,219 LN ratio = Mean = 7.87 Std. dev. = 7.8 N = 315 LN ratio = Numbe r of Positive Nodes p = Numbe r of Positive Nodes (b) No Radiation Group 200 Inadeqate Ly mphadenectomy Median Survival: 11 months 200 Adeqate Lymphadenectomy Median Survival: 15 months 1 Mean = 3.82 Std. dev. = N = 652 LN ratio = Mean = 8.47 Std. dev. = N = 185 LN ratio = Number of Positive Nodes p = Number of Positive Nodes (c) Neoadjuvant Radiation Group 200 Inadeqate Nodes/Neoadjuvant Median Survival: 19 months 200 Adeqate Nodes/Neoadjuvant Median Survival: 32 months 1 Mean = 2.81 Std. dev. = 2.45 N = 279 LN ratio = Mean = 4.79 Std. dev. = N = 47 LN ratio = Number of Positive Nodes p = Numbe r of Positive Nodes (d) Adjuvant Radiation Group Inadeqate Node/Adjuvant Median Survival: 17 months Adeqate Node/Adjuvant Median Survival: 17 months 75 Mean = 3.72 Std. dev. = N = 283 LN ratio = Mean = 8.37 Std. dev. = N = 82 LN ratio = Numbe r of Positive Nodes p = Number of Positive Nodes FIG. 1 Frequency curves comparing inadequate versus adequate lymphadenectomy. Each graph shows the breakdown for the whole group (a), no radiation group (b), neoadjuvant radiation group (c), and adjuvant radiation group (d). Mean number of positive LN is used to calculate the LNR (mean number of positive nodes/mean number of nodes examined) for each group. The survival and P value are shown in Table 2. Note that the number of positive nodes is lower in the group that received neoadjuvant radiation group than in the group that received no radiation

7 Neoadjuvant RT and Lymphadenectomy for EAC 797 TABLE 3 Multivariate analysis of survival Overall survival Cause-specific survival HR 95% CI P HR 95% CI P Sex Male Reference group Reference group Female Age (years) \40 Reference group Reference group [ \ Race White Reference group Reference group Black Ethnicity Non-Hispanic Reference group Reference group Hispanic Tumor grade Well differentiated Reference group Reference group Moderately differentiated Poorly differentiated \ \0.001 Undifferentiated \ \0.001 Tumor stage Local Reference group Reference group Regional \ \0.001 Distant \ \0.001 Site (esophagus) Upper Reference group Reference group Middle Lower Overlapping Nos Lymph nodes Negative Reference group Reference group Positive \ \0.001 Inadequate nodes Reference group Reference group Adequate nodes \ \0.001 Treatment No radiation Reference group Reference group Neoadjuvant radiation \ Adjuvant radiation Patients who received adequate LN dissection had an average of LN removed, with a mean of 7.87 positive nodes. The mean number of positive nodes was again lower for patients who received neoadjuvant radiation (4.79). The LNR for the adequately dissected group was 0.31 for patients who received no radiation, 0.17 for those treated with neoadjuvant radiotherapy, and 0.35 for those who received adjuvant radiotherapy. In both groups, the lower LNR in patients who received neoadjuvant radiotherapy can be attributed to the tumor downstaging effects of radiation. Interaction of Radiotherapy and Adequate Lymphadenectomy Figure 2 shows Kaplan Meier curves that are used to examine whether or not radiotherapy can be used as replacement therapy for inadequate lymphadenectomy.

8 798 N. Solomon et al. TABLE 4 Multivariate analysis for nodal disease Overall survival Cause-specific survival HR 95% CI P HR 95 % CI P Node-negative disease Inadequate dissection Reference group Reference group Adequate dissection \ \0.001 No radiation Reference group Reference group Neoadjuvant radiation \0.001 Adjuvant radiation Node-positive disease Inadequate dissection Reference group Reference group Adequate dissection No radiation Reference group Reference group Neoadjuvant radiation \ \0.001 Adjuvant radiation \ \0.001 TABLE 5 Radiotherapy and lymph node ratio Node-positive patients who received neoadjuvant radiation and inadequate node dissection were compared with nodepositive patients who received no radiation and adequate node dissection. There was a statistically significant difference in MST between the two groups (19 vs. 15 months, P = 0.010) but no difference in CSS (21 vs. 18 months, P = 0.059). However, for CSS, the curves show a trend toward significance. The lack of significant P value could be attributed to insufficient power for the analysis. It is likely that the survival benefit of neoadjuvant treatment is additive to that of lymphadenectomy, and that both treatments are necessary for the best overall outcome. DISCUSSION LN examined LN positive Ratio Inadequate LN dissection No radiation Neoadjuvant Adjuvant Adequate LN dissection No radiation Neoadjuvant Adjuvant While surgical extirpation remains the current mainstay of therapy for patients with EAC, local recurrence and distant metastasis remain an issue after surgery. Although recent studies have shown that neoadjuvant chemotherapy significantly improves survival in these patients, the additional survival benefit of neoadjuvant radiotherapy continues to be debated. 9,10 Some groups have found improved survival with so-called trimodal therapy, but the most efficacious treatment has yet to be clearly defined. 11,15,16,20 Another question that remains for surgeons is whether or not there are added survival benefits to performing complete lymphadenectomy. In this study, we analyzed the effect of neoadjuvant and adjuvant radiotherapy in patients with EAC, the potential benefit of lymphadenectomy, and the interactions between the two treatments in the overall survival for this patient population. In our 17-year study period, 4,224 patients with surgically treated EAC were analyzed. We found MST for the entire cohort to be 25 months, and that age \65 years, localized disease, well-differentiated tumor status, and neoadjuvant radiotherapy are independent predictors of improved survival. Since neoadjuvant radiotherapy for EAC is not used alone (radiation alone provides no added survival benefit without chemotherapy), it is assumed in our analysis that patients receiving neoadjuvant radiotherapy also receive neoadjuvant chemotherapy. 21 The additional survival benefit of neoadjuvant radiation over surgical resection for patients with EAC is not clearly established. In our analysis, we observed that most patients did not receive radiotherapy. In our node-positive EAC patients, those who received no radiotherapy had the worst survival (11 months). Patients who received neoadjuvant radiotherapy had significantly improved survival, regardless of adequacy of lymphadenectomy (19 months with inadequate lymphadenectomy and 32 months with adequate lymphadenectomy, Table 2). Those who received inadequate lymphadenectomy had significantly improved survival when adjuvant radiotherapy was added (11 vs. 17 months, P \ 0.001). This highlights the importance of neoadjuvant radiotherapy and the rescuing effect of adjuvant radiotherapy in the setting of inadequate

9 Neoadjuvant RT and Lymphadenectomy for EAC 799 (a) Survival Neoadjuvant radiation and inadequate LN dissectio n (n = 279) No radiation and adequat e LN dissection (n = 185) (b) Survival Neoadjuvant radiation and inadequate LN dissectio n (n = 279) No radiation and adequat e LN dissection (n = 185) 0.6 p = p = Months FIG. 2 Kaplan Meier curves comparing survival between nodepositive patients who received neoadjuvant radiotherapy and inadequate lymphadenectomy and node-positive patients who received no radiotherapy and adequate lymphadenectomy. a MST, for which there is a statistically significant difference (P = 0.01) between the two lymphadenectomy. In fact, node-positive EAC patients with the greatest survival benefit were those who received both adequate lymphadenectomy ([18 LN) and neoadjuvant radiotherapy (MST = 32 months, CSS = 34 months). On multivariate analysis, neoadjuvant radiation was an independent predictor of improved survival in patients with node-positive EAC (OHR 0.552, P \ 0.001; Table 4). Our analysis is supported by a previous SEER study from the University of Colorado, which showed that patients who received neoadjuvant radiotherapy had improved MST and CSS when compared with those who did not (27 vs. 18 months and 35 vs. 21 months, respectively; P \ ). 21 Also, their multivariate analysis showed neoadjuvant radiotherapy to be an independent predictor of survival. 21 Neoadjuvant chemoradiotherapy has several advantages over neoadjuvant chemotherapy alone, including increased rates of downstaging and increased resectability due to complete pathologic responses in some patients, as well as improved overall survival. 20,22 24 On the other hand, we found that patients with nodenegative EAC who received no radiotherapy had the longest overall survival, though this is likely a reflection of the light tumor burden in these patients. In fact, multivariate analysis for node-negative EAC patients found neoadjuvant radiotherapy to be an independent predictor of poorer prognosis (OHR 1.124, P = 0.017; Table 4), likely reflecting the larger tumor burden at initial diagnosis for these patients and the tumor downstaging effects of subsequent neoadjuvant radiotherapy, which caused these patients to be misclassified as node-negative patients when they were in fact node positive. This bias is unavoidable, as we cannot acquire nodal status preoperatively or prior to neoadjuvant radiotherapy Months groups. b CSS, for which there is no difference (P = 0.059) between the two groups. Neoadjuvant radiotherapy is not a replacement treatment option for adequate lymphadenectomy, and both should be employed to optimize survival Our multivariate analysis also found negative lymph node status and adequate lymphadenectomy to be independent predictors of improved survival. In addition to the staging purposes of lymphadenectomy, there is emerging data showing added benefit to extended lymphadectomy. 18,19,25 28 Current AJCC staging systems for nodal disease classify patients as N0 or N1 (any nodal metastasis), but the standard for the number of LN that need to be removed for accurate nodal staging remains to be established. 29 A recent study divided patients into groups with B10, 11 17, and C18 LN removed, and found that patients in the C18 LN group had significantly better survival than the other groups on univariate and multivariate analysis (HR 0.27, P \ 0.001). 27 Another study used recursive partitioning analysis to identify the number of nodes needed for an adequate staging, showing that patients with [4 positive LN had the same survival as patients with metastatic (M1) disease and that 18 LN needed to be removed to stage these patients adequately. 18 Using a minimum of 18 LN as the criterion for adequate dissection in our study, we showed that patients who had adequate lymphadenectomy enjoyed significantly longer survival and that adequate lymphadenectomy was an independent predictor of better survival (HR 0.722, P \ 0.001; Table 3). Furthermore, when node-positive patients were examined as a subgroup, those who received adequate lymphadenectomy and neoadjuvant radiation treatment had significantly improved MST compared with those with inadequate lymphadenectomy and neoadjuvant radiation (32 vs. 19 months, P = 0.036; Table 2). Adequate lymphadenectomy also improved survival in node-positive patients who received no radiotherapy (15 vs. 11 months, P = 0.002; Table 2), highlighting its importance as a standalone mode of therapy. As mentioned earlier, node-positive EAC patients

10 800 N. Solomon et al. with the best overall survival were those who had both adequate lymphadenectomy and neoadjuvant radiotherapy. Adequate lymphadenectomy was an independent predictor of improved survival in node-positive patients (OHR = 0.800, P = 0.003; Table 4). Similarly, patients with node-negative disease also had longer survival when they underwent adequate lymphadenectomy (MST = ND vs. 63 months, P \ 0.001; Table 2), emphasizing its importance even in this subset of patients with the least tumor burden. Interestingly, we also found that, in nodenegative patients, adequacy of lymphadenectomy did not significantly improve survival as long as either neoadjuvant (P = 0.148) or adjuvant (P = 0.759) radiotherapy was also given (Table 2). However, as demonstrated by Fig. 2, the survival benefit of neoadjuvant radiation does not completely replace the need for adequate lymphadenectomy. On the other hand, it appears to be additive with that of lymphadenectomy, and both neoadjuvant radiotherapy and adequate lymph node dissection are necessary for the best overall outcome. A scatter plot of LNR is shown in Fig. 3, which allows for examination of the LN dataset as a whole to evaluate and confirm previous studies regarding the number of lymph nodes that need to be examined to stage a patient adequately. Previous studies have shown that adequate staging can be achieved when at least 18 lymph nodes are examined, which ensures that all positive nodes are removed as well. 27,30 Our analysis shows that the majority of positive nodes removed occur at 20 LN examined. The curve begins to level off just before 20 LN examined, meaning that for most patients around 18 lymph nodes was enough to remove all positive nodes, allowing for adequate staging. The majority of patients in our study received inadequate lymphadenectomy (average of 8.72 LN removed). The mean number of positive LN was 3.57, although this was lower in patients who received neoadjuvant radiotherapy (2.81, LNR of 0.33). Patients who received adequate lymphadenectomy showed an average of LN removed (mean of 7.87 positive nodes), which on the scatter plot would ensure that all positive nodes are removed. The mean number of positive nodes removed in patients who received neoadjuvant radiotherapy was 4.79 (LNR 0.17). This attests to the benefit of neoadjuvant radiotherapy on LN status. Patients who had adequate lymphadenectomy and neoadjuvant treatment had the lowest LNR (0.17), which has been shown to be important in outcome prognosis. Greenstein et al. and Mariette et al. showed that LNR \0.2 was an independent predictor of improved survival. 12,13 The tumor downstaging effect of neoadjuvant therapy did not change the LNR. As mentioned earlier, C4 positive LN confers a worse prognosis, and using 18 LN as the cutoff for an adequate lymphadenectomy yields an LNR of 0.22 (4 positive LN/18 LN Number of Positive Nodes Number of Nodes Examined FIG. 3 Dot plot for all patients to examine the minimum number of LN that need to be examined to stage patients adequately. The majority of positive nodes are removed when 20 lymph nodes are examined examined), which supports the recommendation to remove at least 18 LN to stage a patient properly for prognostic purposes. 18 In our analysis, the LNR was [0.2 for all treatment groups except those who had adequate lymphadenectomy combined with neoadjuvant radiation (LNR = 0.17). Since this group also had the highest MST (32 months), this provides strong supportive evidence for the use of neoadjuvant radiotherapy and lymphadenectomy for the treatment of EAC. The two major types of operations performed for esophageal carcinoma are transhiatal esophagectomy (THE) and transthoracic esophagectomy (TTE, or Ivor Lewis esophagectomy), each with its own advantages and shortcomings. 31 The anastomosis for THE occurs in the neck, which makes leaks easier to manage and respiratory complications minimal. However, bulky lesions are more difficult to remove and lymphadenectomy is not as extensive Ivor Lewis esophagectomy, on the other hand, allows for removal of bulkier tumors and more extensive lymph node dissection, but it is a lengthier operation and anastomotic leaks are more difficult to manage, requiring chest tubes or percutaneous drain placement. 35,36 Since extended lymphadenectomy shows a survival benefit, the question remains whether patients should undergo operations with increased morbidity to ensure that an adequate number of LN are removed. Many studies have shown that the more invasive TTE does not portend better survival than THE. 31,36 39 Two recent large-cohort publications from the SEER and Nationwide Inpatient Sample (NIS) databases, comparing the operative procedures, also show similar long-term survival. 30,40 The SEER study (n = 868)

11 Neoadjuvant RT and Lymphadenectomy for EAC 801 Diagnosis of esophageal adenocarcinoma Node ( ) disease (pre-op) Node (+) disease (pre-op) Sur gical resection Neoadjuvant therapy Inadequate dissection Adequate dissection Surgical resection w/ inadequate dissection Sur gical resection w/ adequate dissection Node ( ) diseas e (63 month Node (+ ) diseas e (11 month Node ( ) diseas e (media n surviva l not reached) Node (+ ) disease (15 mont h Node ( ) diseas e (41 mont h Node (+ ) disease (13 mont h Node ( ) diseas e (42 mont h Node (+ ) diseas e (32 mont h No further treatment Consider chemoradiation No further treatment Consider chemo - radiation No further treatmen t Consider additional chemotherapy No further treatmen t Consider additional chemotherapy FIG. 4 Proposed clinical treatment pathways for surgical patients diagnosed with esophageal cancer. Median survivals shown are taken from Table 2. Treatment recommendations for patients in each group are listed at the bottom found THE to have lower operative mortality (P = 0.009) and higher 5-year survival (P = 0.02), but these differences disappeared after adjusting for tumor stage, patient, and provider factors. 30 The NIS study (n = 17,395) represents the largest cohort in the literature to compare outcomes after THE and TTE, showing no difference in perioperative incidence of mediastinitis, wound, infectious, pulmonary, gastrointestinal, cardiovascular, systemic, or procedure-related or overall morbidity or mortality for both operations, although high-volume centers have significantly lower mortality rates than low-volume centers (P = 0.024). 40 In conclusion, regardless of the type of operation performed, a proper oncologic operation with adequate lymphadenectomy is the optimal manner in which to optimize patient outcome. A suggested treatment algorithm based upon these data that is utilized at the University of Miami is shown in Fig. 4. Patients at the University of Miami universally undergo a combination of staging studies that includes endoscopic ultrasound, computerized tomography scan, and positron emission tomography scan. Based upon these results, patients with node-negative disease (T1, T2, N0) are felt to not require neoadjuvant treatment and go directly to surgical extirpation. Patients with node-positive disease are referred for neoadjuvant chemoradiation prior to surgical extirpation. The pathology report following resection postoperatively is then used to determine further treatment. Patients who were initially node negative and upstaged generally receive adjuvant treatment regardless of type of dissection, to improve their survival. Patients who were initially node positive and subsequently downstaged generally receive no further treatment, regardless of final lymph node count. The SEER program of the National Cancer Institute (NCI) is the largest source of information on cancer incidence and survival in the USA. SEER collects from 17 population-based cancer registries, encompassing approximately 26% of the US population. SEER is the only comprehensive registry that includes stage at time of diagnosis, treatment modality, and patient survival data. 41 The scope and magnitude of SEER make it excellent for studying rare malignancies However, it is not without limitations. Since SEER collects data from different cancer registries across the country, incorrect reporting is an inherent possibility; for example, cause of death in the dataset is taken from death certificates, and inaccuracies in the reported cause of death have been observed.,51 Information regarding chemotherapy is also not available through the SEER program, and it is assumed that patients receiving neoadjuvant radiation also received neoadjuvant chemotherapy. 21,52 As mentioned earlier, neoadjuvant chemoradiotherapy may downstage patients prior to surgery and misclassify these patients as having node-negative disease, as well as change their stage as recorded in SEER. This could affect survival analysis, as these patients would have worse outcome than a patient who was truly node negative and received no radiotherapy. Despite their various limitations, population-based registries do have important benefits. Limitations of previous studies for esophageal adenocarcinoma include accrual numbers and

12 802 N. Solomon et al. limited follow-up time due to the rarity of disease. Large population-based registries have allowed for evaluation of diseases such as esophageal adenocarcinoma, as well as benefits outside clinical trials, as outcomes in a large number of patients can be evaluated and survival data analyzed over longer follow-up periods. In conclusion, we attempted to define the role for neoadjuvant radiotherapy as well as the survival benefit of extended lymphadenectomy (C18 nodes) in the treatment of EAC. We have demonstrated a survival benefit for neoadjuvant radiotherapy and adequate lymphadenectomy in patients with node-positive EAC. Both extended lymphadenectomy and neoadjuvant radiation are independent predictors of improved survival. Therefore, patients who are properly staged with regional disease or have clinically node-positive disease should undergo both neoadjuvant radiotherapy and extended lymphadenectomy to ensure optimal outcome. ACKNOWLEDGMENT Supported in part by the James and Ester King Tobacco Research Grant from the State of Florida and the Sylvester Comprehensive Cancer Center. REFERENCES 1. American Cancer Society. Cancer facts and figures; Baquet CR, Commiskey P, Mack K, et al. Esophageal cancer epidemiology in blacks and whites: racial and gender disparities in incidence, mortality, survival rates and histology. J Natl Med Assoc. 2005;97(11): Blot WJ, Devesa SS, Kneller RW, Fraumeni JF, Jr. Rising incidence of adenocarcinoma of the esophagus and gastric cardia. JAMA. 1991;265(10): Blot WJ, McLaughlin JK. The changing epidemiology of esophageal cancer. Semin Oncol. 1999;26(5): Chalasani N, Wo JM, Waring JP. Racial differences in the histology, location, and risk factors of esophageal cancer. J Clin Gastroenterol. 1998;26(1): Devesa SS, Blot WJ, Fraumeni JF, Jr. Changing patterns in the incidence of esophageal and gastric carcinoma in the United States. Cancer. 1998;83(10): Greenstein AJ, Litle VR, Swanson SJ, et al. Racial disparities in esophageal cancer treatment and outcomes. Ann Surg Oncol. 2008;15(3): Younes M, Henson DE, Ertan A, Miller CC. Incidence and survival trends of esophageal carcinoma in the United States: racial and gender differences by histological type. Scand J Gastroenterol. 2002;37(12): Walsh TN, Noonan N, Hollywood D, et al. A comparison of multimodal therapy and surgery for esophageal adenocarcinoma. N Engl J Med. 1996;335(7): Gebski V, Burmeister B, Smithers BM, et al. Survival benefits from neoadjuvant chemoradiotherapy or chemotherapy in oesophageal carcinoma: a meta-analysis. Lancet Oncol. 2007;8(3): Tepper J, Krasna MJ, Niedzwiecki D, et al. Phase III trial of trimodality therapy with cisplatin, fluorouracil, radiotherapy, and surgery compared with surgery alone for esophageal cancer: CALGB J Clin Oncol. 2008;26(7): Greenstein AJ, Litle VR, Swanson SJ, et al. Prognostic significance of the number of lymph node metastases in esophageal cancer. J Am Coll Surg. 2008;206(2): Mariette C, Piessen G, Briez N, Triboulet JP. The number of metastatic lymph nodes and the ratio between metastatic and examined lymph nodes are independent prognostic factors in esophageal cancer regardless of neoadjuvant chemoradiation or lymphadenectomy extent. Ann Surg. 2008;247(2): Fritz A. International classification of diseases for oncology: ICD-O. 3rd ed. Geneva: World Health Organization; Ajani JA, Komaki R, Putnam JB, et al. A three-step strategy of induction chemotherapy then chemoradiation followed by surgery in patients with potentially resectable carcinoma of the esophagus or gastroesophageal junction. Cancer. 2001;92(2): Apisarnthanarax S, Tepper JE. Crossroads in the combinedmodality management of gastroesophageal junction carcinomas. Gastrointest Cancer Res. 2008;2(5): Altorki NK, Zhou XK, Stiles B, et al. Total number of resected lymph nodes predicts survival in esophageal cancer. Ann Surg. 2008;248(2): Rizk N, Venkatraman E, Park B, et al. The prognostic importance of the number of involved lymph nodes in esophageal cancer: implications for revisions of the American Joint Committee on Cancer staging system. J Thorac Cardiovasc Surg. 2006;132(6): Peyre CG, Hagen JA, DeMeester SR, et al. The number of lymph nodes removed predicts survival in esophageal cancer: an international study on the impact of extent of surgical resection. Ann Surg. 2008;248(4): Donahue JM, Nichols FC, Li Z, et al. Complete pathologic response after neoadjuvant chemoradiotherapy for esophageal cancer is associated with enhanced survival. Ann Thorac Surg. 2009;87(2):392 8; discussion Schwer AL, Ballonoff A, McCammon R, et al. Survival effect of neoadjuvant radiotherapy before esophagectomy for patients with esophageal cancer: a Surveillance, Epidemiology, and End- Results study. Int J Radiat Oncol Biol Phys. 2009;73(2): Malaisrie SC, Untch B, Aranha GV, et al. Neoadjuvant chemoradiotherapy for locally advanced esophageal cancer: experience at a single institution. Arch Surg. 2004;139(5):532 8; discussion Ku GY, Ilson DH. Multimodality therapy for the curative treatment of cancer of the esophagus and gastroesophageal junction. Expert Rev Anticancer Ther. 2008;8(12): Berger AC, Farma J, Scott WJ, et al. Complete response to neoadjuvant chemoradiotherapy in esophageal carcinoma is associated with significantly improved survival. J Clin Oncol. 2005;23(19): Lerut T, Nafteux P, Moons J, et al. Three-field lymphadenectomy for carcinoma of the esophagus and gastroesophageal junction in 174 R0 resections: impact on staging, disease-free survival, and outcome: a plea for adaptation of TNM classification in upperhalf esophageal carcinoma. Ann Surg. 2004;240(6):962 72; discussion van de Ven C, De Leyn P, Coosemans W, et al. Three-field lymphadenectomy and pattern of lymph node spread in T3 adenocarcinoma of the distal esophagus and the gastro-esophageal junction. Eur J Cardiothorac Surg. 1999;15(6): Greenstein AJ, Litle VR, Swanson SJ, et al. Effect of the number of lymph nodes sampled on postoperative survival of lymph node-negative esophageal cancer. Cancer. 2008;112(6): Kang CH, Kim YT, Jeon SH, et al. Lymphadenectomy extent is closely related to long-term survival in esophageal cancer. Eur J Cardiothorac Surg. 2007;31(2):

13 Neoadjuvant RT and Lymphadenectomy for EAC American Joint Committee on Cancer. AJCC cancer staging manual. Philadelphia: Lippincott-Raven; p Chang AC, Ji H, Birkmeyer NJ, et al. Outcomes after transhiatal and transthoracic esophagectomy for cancer. Ann Thorac Surg. 2008;85(2): Boyle MJ, Franceschi D, Livingstone AS. Transhiatal versus transthoracic esophagectomy: complication and survival rates. Am Surg. 1999;65(12): ; discussion Hulscher JB, van Sandick JW, de Boer AG, et al. Extended transthoracic resection compared with limited transhiatal resection for adenocarcinoma of the esophagus. N Engl J Med. 2002;347(21): Johansson J, DeMeester TR, Hagen JA, et al. En bloc vs transhiatal esophagectomy for stage T3 N1 adenocarcinoma of the distal esophagus. Arch Surg. 2004;139(6):627 31; discussion Vigneswaran WT, Trastek VF, Pairolero PC, et al. Transhiatal esophagectomy for carcinoma of the esophagus. Ann Thorac Surg. 1993;56(4):838 44; discussion Omloo JM, Law SY, Launois B, et al. Short and long-term advantages of transhiatal and transthoracic oesophageal cancer resection. Eur J Surg Oncol. 2009;35(8): Gluch L, Smith RC, Bambach CP, Brown AR. Comparison of outcomes following transhiatal or Ivor Lewis esophagectomy for esophageal carcinoma. World J Surg. 1999;23(3):271 5; discussion Horstmann O, Verreet PR, Becker H, et al. Transhiatal oesophagectomy compared with transthoracic resection and systematic lymphadenectomy for the treatment of oesophageal cancer. Eur J Surg. 1995;161(8): Rentz J, Bull D, Harpole D, et al. Transthoracic versus transhiatal esophagectomy: a prospective study of 945 patients. J Thorac Cardiovasc Surg. 2003;125(5): Rindani R, Martin CJ, Cox MR. Transhiatal versus Ivor Lewis oesophagectomy: is there a difference? Aust N Z J Surg. 1999; 69(3): Connors RC, Reuben BC, Neumayer LA, Bull DA. Comparing outcomes after transthoracic and transhiatal esophagectomy: a 5- year prospective cohort of 17,395 patients. J Am Coll Surg. 2007;205(6): Surveillance, Epidemiology and End Results (SEER) Program. National Cancer Institute; Cheung MC, Perez EA, Molina MA, et al. Defining the role of surgery for primary gastrointestinal tract melanoma. J Gastrointest Surg. 2008;12(4): Gutierrez JC, De Oliveira LO, Perez EA, et al. Optimizing diagnosis, staging, and management of gastrointestinal stromal tumors. J Am Coll Surg. 2007;205(3): (Quiz 524). 44. Gutierrez JC, Fischer AC, Sola JE, et al. Markedly improving survival of neuroblastoma: a 30-year analysis of 1,646 patients. Pediatr Surg Int. 2007;23(7): Gutierrez JC, Franceschi D, Koniaris LG. How many lymph nodes properly stage a periampullary malignancy? J Gastrointest Surg. 2008;12(1): Gutierrez JC, Housri N, Koniaris LG, et al. Malignant breast cancer in children: a review of 75 patients. J Surg Res. 2008; 147(2): Hodgson N, Koniaris LG, Livingstone AS, Franceschi D. Gastric carcinoids: a temporal increase with proton pump introduction. Surg Endosc. 2005;19(12): Perez EA, Gutierrez JC, Jin X, et al. Surgical outcomes of gastrointestinal sarcoma including gastrointestinal stromal tumors: a population-based examination. J Gastrointest Surg. 2007;11(1): Perez EA, Livingstone AS, Franceschi D, et al. Current incidence and outcomes of gastrointestinal mesenchymal tumors including gastrointestinal stromal tumors. J Am Coll Surg. 2006;202(4): Kircher T, Nelson J, Burdo H. The autopsy as a measure of accuracy of the death certificate. N Engl J Med. 1985;313(20): Smith Sehdev AE, Hutchins GM. Problems with proper completion and accuracy of the cause-of-death statement. Arch Intern Med. 2001;161(2): Coburn NG, Govindarajan A, Law CH, et al. Stage-specific effect of adjuvant therapy following gastric cancer resection: a population-based analysis of 4,041 patients. Ann Surg Oncol. 2008; 15(2):0 7.