J. Jan B. van Lanschot

Transthoracic Versus Transhiatal Resection for Carcinoma of the Esophagus: A Meta-Analysis

There is much controversy about the surgical approach to esophageal carcinoma: should an extensive resection be done to optimize long-term survival or should the extent of the operation be limited to obtain lower perioperative morbidity and mortality rates? We systematically reviewed the English-language literature published during the past decade, with emphasis on the differences between transthoracic and transhiatal resections regarding early morbidity, in-hospital mortality rates, and 3- and 5-year survival. Although transthoracic resections had significantly higher early (pulmonary) morbidity and mortality rates, 5-year survival was approximately 20% after both transthoracic and transhiatal resections.

Extended Transthoracic Resection Compared With Limited Transhiatal Resection for Adenocarcinoma of the Mid/distal Esophagus: Five-year Survival of a Randomized Clinical Trial

Objective:To determine whether extended transthoracic esophagectomy for adenocarcinoma of the mid/distal esophagus improves long-term survival. Background:A randomized trial was performed to compare surgical techniques. Complete 5-year survival data are now available. Methods:A total of 220 patients with adenocarcinoma of the distal esophagus (type I) or gastric cardia involving the distal esophagus (type II) were randomly assigned to limited transhiatal esophagectomy or to extended transthoracic esophagectomy with en bloc lymphadenectomy. Patients with peroperatively irresectable/incurable cancer were excluded from this analysis (n = 15). A total of 95 patients underwent transhiatal esophagectomy and 110 patients underwent transthoracic esophagectomy. Results:After transhiatal and transthoracic resection, 5-year survival was 34% and 36%, respectively (P = 0.71, per protocol analysis). In a subgroup analysis, based on the location of the primary tumor according to the resection specimen, no overall survival benefit for either surgical approach was seen in 115 patients with a type II tumor (P = 0.81). In 90 patients with a type I tumor, a survival benefit of 14% was seen with the transthoracic approach (51% vs. 37%, P = 0.33). There was evidence that the treatment effect differed depending on the number of positive lymph nodes in the resection specimen (test for interaction P = 0.06). In patients (n = 55) without positive nodes locoregional disease-free survival after transhiatal esophagectomy was comparable to that after transthoracic esophagectomy (86% and 89%, respectively). The same was true for patients (n = 46) with more than 8 positive nodes (0% in both groups). Patients (n = 104) with 1 to 8 positive lymph nodes in the resection specimen showed a 5-year locoregional disease-free survival advantage if operated via the transthoracic route (23% vs. 64%, P = 0.02). Conclusion:There is no significant overall survival benefit for either approach. However, compared with limited transhiatal resection extended transthoracic esophagectomy for type I esophageal adenocarcinoma shows an ongoing trend towards better 5-year survival. Moreover, patients with a limited number of positive lymph nodes in the resection specimen seem to benefit from an extended transthoracic esophagectomy.

The Number of Lymph Nodes Removed Predicts Survival in Esophageal Cancer: An International Study on the Impact of Extent of Surgical Resection

Objective:Surveillance, Epidemiology and End Results (SEER) data indicate that number of lymph nodes removed impacts survival in gastric cancer. Our aim was to study this relationship in esophageal cancer. Methods:The study population included 2303 esophageal cancer patients (1381 adenocarcinoma, 922 squamous) from 9 international centers that had R0 esophagectomy prior to 2002 and were followed at regular intervals for 5 years or until death. Patients treated with neoadjuvant or adjuvant therapy were excluded. Results:Operations consisted of esophagectomy with (1700) and without (603) thoracotomy. Median number of nodes removed was 17 (IQR10-29). There were 508 patients with stage I, 853 stage II, and 942 stage III. Five-year survival was 40%. Cox regression analysis showed that the number of lymph nodes removed was an independent predictor of survival (P < 0.0001). The optimal threshold predicted by Cox regression for this survival benefit was removal of a minimum of 23 nodes. Other independent predictors of survival were the number of involved nodes, depth of invasion, presence of nodal metastasis, and cell type. Conclusions:The number of lymph nodes removed is an independent predictor of survival after esophagectomy for cancer. To maximize this survival benefit a minimum of 23 regional lymph nodes must be removed.

Single-dose brachytherapy versus metal stent placement for the palliation of dysphagia from oesophageal cancer: multicentre randomised trial

BACKGROUND Both single-dose brachytherapy and self-expanding metal stent placement are commonly used for palliation of oesophageal obstruction due to inoperable cancer, but their relative merits are unknown. We undertook a randomised trial to compare the outcomes of brachytherapy and stent placement in patients with oesophageal cancer. METHODS Nine hospitals in the Netherlands participated in our study. Between December, 1999, and June, 2002, 209 patients with dysphagia from inoperable carcinoma of the oesophagus or oesophagogastric junction were randomly assigned to stent placement (n=108) or single-dose (12 Gy) brachytherapy (n=101), and were followed up after treatment. Primary outcome was relief of dysphagia during follow-up, and secondary outcomes were complications, treatment for persistent or recurrent dysphagia, health-related quality of life, and costs. Analysis was by intention to treat. FINDINGS Nine patients (six [brachytherapy] vs three [stent placement]) did not receive their allocated treatments. None was lost to follow-up. Dysphagia improved more rapidly after stent placement than after brachytherapy, but long-term relief of dysphagia was better after brachytherapy. Stent placement had more complications than brachytherapy (36 [33%] of 108 vs 21 [21%] of 101; p=0.02), which was mainly due to an increased incidence of late haemorrhage (14 [13%] of 108 vs five [5%] of 101; p=0.05). Groups did not differ for persistent or recurrent dysphagia (p=0.81), or for median survival (p=0.23). Quality-of-life scores were in favour of brachytherapy compared with stent placement. Total medical costs were also much the same for stent placement (8215) and brachytherapy (8135). INTERPRETATION Despite slow improvement, single-dose brachytherapy gave better long-term relief of dysphagia than metal stent placement. Since brachytherapy was also associated with fewer complications than stent placement, we recommend it as the primary treatment for palliation of dysphagia from oesophageal cancer.

Outcome of surgical treatment for early adenocarcinoma of the esophagus or gastro-esophageal junction.

Adenocarcinoma of the esophagus, or GEJ, has a poor prognosis. Early lesions [i.e. high grade dysplasia (HGD) or T1-carcinoma] are potentially curable. Local endoscopic therapies are promising treatment options for superficial lesions; however, for deeper lesions, surgical resection is considered to be the treatment of choice. To contribute to therapeutic decision-making, we retrospectively analysed the outcome of transhiatal esophagectomy in 120 patients with pathologically proven HGD (n=13) or T1-adenocarcinoma (n=107) of the distal esophagus or gastro-esophageal junction (GEJ). Tumors were subdivided into six different depths of invasion (‘T1-mucosal’ m1-m3, ‘T1-submucosal’ sm1-sm3), and the frequency of lymphatic dissemination and time to locoregional and/or distant recurrence were analysed. Only one of the 79 T1m1-3/sm1 tumors (1%) showed lymph node metastases as compared with 18 out of 41 T1sm2-3 tumors (44%). There was a significant difference in recurrence-free period between T1m1-m3/sm1 versus T1sm2-sm3 tumor patients (P log rank <0.0001), with 5-year recurrence-free percentages of 97% and 57%, respectively. In multivariate analysis including age, gender, tumor differentiation grade, N-stage and depth of invasion, only N-stage was an independent prognostic factor for recurrence-free period (hazard rate=5.9, 95% CI 1.7–20.7). However, if N-stage was excluded from analysis, only depth of invasion (T1sm2-3 versus T1m1-m3/sm1) was an independent prognostic factor for recurrence-free period (hazard rate=7.5, 95% CI 2.0–27.7). These data indicate that T1m1-m3/sm1 adenocarcinomas of esophagus or GEJ show a very low risk of lymphatic dissemination and are therefore eligible for local endoscopic therapy. After transhiatal surgical resection, almost half of the patients with T1sm2-sm3 lesions develop recurrent disease within 5 years, and therefore need additional therapy to improve survival.

Predicting Systemic Disease in Patients With Esophageal Cancer After Esophagectomy: A Multinational Study on the Significance of the Number of Involved Lymph Nodes

Objective:The aim of this study was to determine whether the risk of systemic disease after esophagectomy can be predicted by the number of involved lymph nodes. Summary Background Data:Primary esophagectomy is curative in some but not all patients with esophageal cancer. Identification of patients at high risk for systemic disease would allow selective use of additional systemic therapy. This study is a multinational, retrospective review of patients treated with resection alone to assess the impact of the number of involved lymph nodes on the probability of systemic disease. Methods:The study population included 1053 patients with esophageal cancer (700 adenocarcinoma, 353 squamous carcinoma) who underwent R0 esophagectomy with ≥15 lymph nodes resected at 9 international centers: Asia (1), Europe (5), and United States (3). To ensure a minimum potential follow-up of 5 years, only patients who had esophagectomy before October 2002 were included. Patients treated with neoadjuvant or adjuvant therapy were excluded. The impact of the number of involved lymph nodes on the risk of systemic disease recurrence was assessed using univariate and multivariate analyses. Results:Systemic disease occurred in 40%. The number of involved lymph nodes ranged from 0 to 26 with 55% of patients having at least 1 involved lymph node. The frequency of systemic disease after esophagectomy was 16% for those without nodal involvement and progressively increased to 93% in patients with 8 or more involved lymph nodes. Conclusions:This study shows that the number of involved lymph nodes can be used to predict the likelihood of systemic disease in patients with esophageal cancer. The probability of systemic disease exceeds 50% when 3 or more nodes are involved and approaches 100% when the number of involved nodes is 8 or more. Additional therapy is warranted in these patients with a high probability of systemic disease.

Hospital volume and hospital mortality for esophagectomy

Hospital mortality after esophagectomy has decreased from 29% to 7.5% over the last decades because of improved surgical techniques and better perioperative care. Suggestions have been made that a further decrease in hospital mortality may be achieved by centralization of esophagectomies in high volume centers.

Prediction of appropriateness of local endoscopic treatment for high-grade dysplasia and early adenocarcinoma by EUS and histopathologic features

BACKGROUND Endoscopic techniques are being developed for the local treatment of early stage esophageal cancer. However, such therapy is not appropriate for patients with lymph node metastasis. The aim of this study was to analyze the histopathologic features of high-grade dysplasia and early stage adenocarcinoma and to relate these to lymph node involvement. METHODS Pathology reports were reviewed for all 367 patients who underwent subtotal esophagectomy for high-grade dysplasia or adenocarcinoma of the esophagus or the gastroesophageal junction between January 1993 and December 2001. Patients with histopathologically confirmed high-grade dysplasia or T1 carcinoma were included (n = 77). Pre-operative EUS results were assessed. All lesions were histopathologically subdivided in 6 different stages (mucosal 1-3 and submucosal 1-3). RESULTS EUS staged 61 patients as N0. EUS correctly predicted the absence of positive lymph nodes in 57 (93%) of these patients. Histopathologically, m1, m2, m3, and sm1 cancers never had lymph node metastases, whereas 3 of 13 sm2 tumors (23%) and 9 of 13 sm3 tumors (69%) had lymph node involvement. Lymphangio invasion was present exclusively in sm2 and sm3 cancers. Factors that predicted the presence of lymph node metastasis were the following: tumor diameter greater than 3 cm, infiltration of malignancy beyond sm1, poor differentiation grade, and lymphangio invasion, although only infiltration beyond sm1 remained significant in the definitive multivariate analysis. CONCLUSIONS EUS and the histopathologic features of high-grade dysplasia and early stage adenocarcinoma of the esophagus or the gastroesophageal junction can predict the presence of lymph node involvement. These data can be used to identify patients for whom local endoscopic treatment may be appropriate.

Stepwise Radical Endoscopic Resection Is Effective for Complete Removal of Barrett's Esophagus with Early Neoplasia: A Prospective Study

OBJECTIVES:Endoscopic therapy for early neoplasia in Barretts esophagus (BE) is evolving rapidly. Aim of this study was to prospectively evaluate safety and efficacy of stepwise radical endoscopic resection (ER) of BE containing early neoplasia.METHODS:Patients with early neoplasia (i.e., high-grade intraepithelial neoplasia or early cancer) in BE ≤5 cm, without signs of submucosal infiltration or lymph node/distant metastases, were included. Patients underwent resection sessions (cap technique after submucosal lifting) with intervals of 6 wk.RESULTS:Between January 2003 and December 2004, 39 consecutive patients were included. Therapy was discontinued in two patients due to unrelated comorbidity. Complete eradication of early neoplasia was achieved in all 37 treated patients in a median number of three sessions. Complete removal of all Barretts mucosa was achieved in 33 (89%) patients: 4 patients (all had undergone APC [argon plasma coagulation]) were found to have small isles of Barretts mucosa underneath neosquamous mucosa. Complications occurred in two out of 88 (2%) ER procedures: one asymptomatic perforation, one delayed bleeding. Symptomatic stenosis occurred in 10 of 39 (26%) patients and was effectively treated by endoscopic bougienage. During a median follow-up of 11 months, no patients died and none had recurrence of neoplasia or Barretts mucosa.CONCLUSIONS:Stepwise radical ER is effective for selected patients with early neoplasia in BE; provides optimal histopathological diagnosis; and may reduce recurrence rate, since all mucosa at risk is effectively removed. Use of APC should be limited to prevent buried Barretts mucosa. Methods for prevention of stenosis should be developed.

Patterns of Recurrence After Surgery Alone Versus Preoperative Chemoradiotherapy and Surgery in the CROSS Trials

PURPOSE To analyze recurrence patterns in patients with cancer of the esophagus or gastroesophageal junction treated with either preoperative chemoradiotherapy (CRT) plus surgery or surgery alone. PATIENTS AND METHODS Recurrence pattern was analyzed in patients from the previously published CROSS I and II trials in relation to radiation target volumes. CRT consisted of five weekly courses of paclitaxel and carboplatin combined with a concurrent radiation dose of 41.4 Gy in 1.8-Gy fractions to the tumor and pathologic lymph nodes with margin. RESULTS Of the 422 patients included from 2001 to 2008, 418 were available for analysis. Histology was mostly adenocarcinoma (75%). Of the 374 patients who underwent resection, 86% were allocated to surgery and 92% to CRT plus surgery. On January 1, 2011, after a minimum follow-up of 24 months (median, 45 months), the overall recurrence rate in the surgery arm was 58% versus 35% in the CRT plus surgery arm. Preoperative CRT reduced locoregional recurrence (LRR) from 34% to 14% (P < .001) and peritoneal carcinomatosis from 14% to 4% (P < .001). There was a small but significant effect on hematogenous dissemination in favor of the CRT group (35% v 29%; P = .025). LRR occurred in 5% within the target volume, in 2% in the margins, and in 6% outside the radiation target volume. In 1%, the exact site in relation to the target volume was unclear. Only 1% had an isolated infield recurrence after CRT plus surgery. CONCLUSION Preoperative CRT in patients with esophageal cancer reduced LRR and peritoneal carcinomatosis. Recurrence within the radiation target volume occurred in only 5%, mostly combined with outfield failures.