- Email: [email protected]
Management of Gastroesophageal Junction Tumors
Management of G a s t ro e s o p h a g e a l J u n c t i o n Tu mo r s Matthew P. Fox,
MD
a
, Victor van Berkel,
MD, PhD
b,
*
KEYWORDS Gastroesophageal junction tumors Esophagectomy Lymphadenectomy Chemoradiotherapy KEY POINTS The incidence of adenocarcinomas of the esophagogastric junction is rising dramatically. While the overall prognosis for these tumors remains poor, surgery and multimodality therapy can be curative. Endoscopic therapy or limited resection is indicated for tumors confined to the mucosa. Tumors penetrating into the submucosa have a high likelihood of lymph node involvement and require radical resection. For Siewert 1 tumors, transthoracic en bloc esophagectomy with 2-field lymph node dissection is the procedure of choice. Transhiatal (THE) esophagectomy should be considered in patients with compromised pulmonary function. For type 2 and 3 tumors, either esophagectomy with proximal gastrectomy or THE extended total gastrectomy with D2 lymphadenectomy may be performed provided adequate margins are obtained. All patients with T3 or greater tumors or nodal involvement should be considered for chemoradiotherapy, preferably in the neoadjuvant setting. Platinum-based chemotherapy is indicated for palliation of stage 4 disease.
INTRODUCTION
Over the past few decades, the incidence of adenocarcinoma of the esophagogastric junction (AEG) has risen dramatically in western countries.1,2 The mechanism of this change is unclear. Despite endoscopic screening and advances in multimodality therapy, the prognosis of these tumors remains poor, with an overall 5-year survival
a
Department of Surgery, School of Medicine, University of Louisville, 201 Abraham Flexner Way, Suite 1200, Louisville, KY 40202, USA; b Division of Cardiothoracic Surgery, Department of Surgery, School of Medicine, University of Louisville, 201 Abraham Flexner Way, Suite 1200, Louisville, KY 40202, USA * Corresponding author. E-mail address: [email protected] Surg Clin N Am 92 (2012) 1199–1212 http://dx.doi.org/10.1016/j.suc.2012.07.011 surgical.theclinics.com 0039-6109/12/$ – see front matter Ó 2012 Elsevier Inc. All rights reserved.
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rate of approximately 20%.3 This article will discuss the current pathologic classification, epidemiology, staging, and standard treatment of these tumors. SIEWERT CLASSIFICATION
Because of their location, a great deal of controversy has been present regarding whether AEGs represent gastric or esophageal cancer. Siewert attempted to rectify this problem in 1996 with a standardized system classifying these tumors based on topographic anatomic criteria.4,5 By definition, all of these tumors must invade the esophagogastric junction (EGJ). Type 1 tumors were defined as those with an epicenter 1 to 5 cm above the EGJ. Type 2 tumors were defined as having a center 1 cm above to 2 cm below the EGJ. Finally, type 3 tumors were defined as being centered 2 to 5 cm below the EGJ (Fig. 1). Therefore, type 1 tumors represent distal esophageal adenocarcinoma. Type 2 tumors are true adenocarcinomas of the cardia, and type 3tumors are subcardial gastric cancers. It is worth noting that precise endoscopic localization of the EGJ can be difficult,6 leading to possible misclassification of tumors preoperatively. This classification system was adopted at the Second International Gastric Cancer Congress in 1997 and has since been used extensively without modification. EPIDEMIOLOGY AND ETIOLOGY OF ADENOCARCINOMA OF THE EGJ
The relation between Barrett’s esophagus and adenocarcinoma of esophagus is well established.7,8 Given their esophageal epicenter, it is no surprise that type 1 AEGs have the strongest association with Barrett’s esophagus, with approximately 80% of resected specimens showing intestinal metaplasia.9 Conversely, Barrett’s metaplasia was present in only 5.6% and 0.8% of patients with type 2 and 3 tumors, respectively. Asian case series have shown a weaker association between Barrett and type 1 AEGs.10 Furthermore, in different populations, the ratio of type 1 to type 2 and 3 tumors is different; eastern counties have a relative preponderance for type 2 and 3 carcinomas compared with the United States and Europe.11,12 This differential distribution in tumor location is likely due to the rise in esophageal adenocarcinoma (EAC) in the West. In the United States, the relative incidence of + 5 cm Type I Type II
+ 1 cm – 2 cm
Type III
– 5 cm
Fig. 1. Classification of adenocarcinoma of the esophagogastric junction according to the localization of the center of the tumor by Siewert and colleagues (1987). (From Ho¨lscher AH. Adenocarcinoma of the cardia. In: Patterson GA, Cooper JD, Deslauriers J, et al, editors. Pearson’s thoracic and esophageal surgery. 3rd edition. Philadelphia: Churchill Livingstone; 2008. p. 493; with permission.)
Management of Gastroesophageal Junction Tumors
EAC increased by 400% in white men and 300% in white women over 26 years.13 In the same study, African American men had a 100% relative increase in EAC, while incidence of squamous carcinoma (SCC) of the esophagus remained unchanged. In a review of the surveillance, epidemiology, and end result (SEER) database from 1992 to 1998, Kubo and Corely showed the incident rate of esophageal adenocarcinomas increased, while the rate of cardial carcinomas remained steady across time.14 Other studies have shown a slight increase in type 2 and type 3 cancers.15 When combined with data showing the steep decline of distal gastric cancers in the West, there is clear epidemiologic evidence that AEGs represent a heterogeneous set of tumors with etiologies that are partially related to, but are distinct from, EAC, distal gastric cancer, and esophageal SCC. DIAGNOSIS AND STAGING
Before the advent of the American Joint Committee on Cancer (AJCC) 7th edition staging manual, AEGs could be staged using either the esophageal or gastric adenocarcinoma systems, potentially leading to discordant staging that could adversely affect therapy. The 7th edition attempts to harmonize esophageal and gastric cancer staging, and all AEGs are staged according to the esophageal system.16 A typical staging workup for esophageal cancer includes combined computed tomography (CT)/positron emission tomography (PET) scans of the chest, abdomen, and pelvis along with endoscopic ultrasound. For esophageal cancers, the sensitivity and specificity of both these methods are well documented, and they provide complimentary information. In a study of esophageal cancers undergoing esophagectomy with neoadjuvant therapy, esophageal ultrasound (EUS) was able to distinguish between early (T1-2, N0) and advanced disease (T3-4, N1) in 83% of patients.17 EUS may also potentially be useful in identifying mucosal carcinomas that may be candidates for endoscopic therapy.18 Its assessment of T and N stage is likely more accurate than PET, which has been shown to accurately determine T stage in only 40% of cases,19 and has a sensitivity of only 50% for detecting regional nodal disease.20,21 Additionally, EUS may assist traditional upper endoscopic techniques in defining the Siewert classification.22 EUS has been shown to be accurate for gastric cancers23 and AEGs.24 Limitations with EUS include invasiveness, reproducibility,25–27 and most importantly, an inability to identify distant metastases. PET is therefore a useful adjunct. In a recent retrospective review of 83 patients with esophageal cancer undergoing pretherapy PET/CT and EUS, PET was found to provide additional staging information that altered treatment in 10% of patients.28 Another retrospective review of 130 patients undergoing CT, EUS, and PET/CT showed PET excluded surgery from 25% of patients deemed resectable by CT and EUS alone.29 These results are similar to a prospective study of 74 patients in whom PET upstaged 20% of patients deemed resectable by CT/EUS.30 While PET’s usefulness in EAC and type 1 AEGs is well documented, its place in the staging of gastric cancer and type 2/3 AEGs is less clear. In a review of 52 patients with type 1 and type 2 tumors, Ott and colleagues31 showed all of the type 1 tumors were PET-avid, whereas only 75% of type 2 tumors were. This coincides with a study in distal gastric cancer, which produced a PET detection rate of 60%. When the authors stratified patients by histology, tumors with intestinal histology showed a higher PET detection rate (83%) compared with nonintestinal type tumors (41%).32 This literature illustrates the differing biology of esophageal and gastric adenocarcinoma and further supports the hypothesis that type 2 AEGs are a heterogeneous mix of esophageal and gastric cancers.
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As the sensitivity of PET for detecting metastases in type 2 and type 3 AEGs is reduced, staging laparoscopy may play a role in the pretreatment assessment. This technique has been validated in gastric cancer33 as well as distal esophageal and gastro-esophageal junction (GEJ) adenocarcinoma.34 However, in the largest series of the patients advocating the use of routine staging laparoscopy, EUS was performed in only 10% of patients.35 To the authors’ knowledge, no study has ever directly compared PET with staging laparoscopy for AEGs. SURGICAL TREATMENT
Multiple studies have shown that R0 resection remains among the most significant predictors of long-term survival in patients with an AEG.36–38 Consequently, the therapeutic goals should be complete surgical resection of the tumor and any associated intestinal metaplasia with adequate lymphadenectomy. If doubt exists over the ability to achieve an R0 resection, neoadjuvant therapy should be considered.39,40 As with any operation, the functional and physiologic status of the patient should be considered and optimized before proceeding. Some controversy remains over the required extent of resection and lymphadenectomy, along with the correct operative approach. These issues will be discussed in depth for each Siewert classification. Siewert 1 Tumors
Given the increase in screening of patients with Barrett’s esophagus, many of these patients are presenting with early stage tumors.41 Consequently, there has been renewed interest in limited resections, which may offer shorter recovery times, less morbidity, and better quality of life compared with radical esophagectomy.42 Options include endoscopic mucosal resection,43 local resection such as the Merendino procedure,42,44 and vagal-sparing esophagectomy.45 The technical aspects of these procedures are beyond the scope of this article; however, consideration must be given to length of the tumor and any associated high-grade dysplasia. Both must be completely resected or ablated, with negative margins. Oncologic outcomes for tumors confined to the mucosa after any of these procedures and radical esophagectomy are similar,45,46 although large-scale trials are still needed. Once the tumor has infiltrated the submucosa, the rate of lymph node metastases increases drastically with the 10% to 67% of patients having nodal involvement, depending on the depth of invasion.47,48 Consequently, the operation of choice remains radical esophagectomy with proximal gastrectomy and reconstruction with a gastric tube. The necessary extent of lymphadenectomy and decision to perform a transthoracic (TTE) or transhiatal (THE) resection remain controversial. For type 1 AEGs, the rate of metastases to the lower mediastinum and abdomen is approximately 60% and 74%, respectively.49 One study advocating a 3-field lymphadenectomy showed cervical nodal metastases in 17.6% of type 1 AEGs.50 However, given the rarity of upper mediastinal recurrences, it is questionable whether an extensive superior lymphadenectomy is needed.51 Due to the propensity for paracardial, lesser curvature, and celiac axis metastases, a complete lymph node dissection should be performed in these locations. The question of whether to perform a TTE or THE resection is also controversial. Five randomized controlled trials have been performed comparing THE with TTE.52–56 The largest trial randomized 220 patients with adenocarcinoma of the distal esophagus or gastric cardia to either TTE with an extended en bloc lymphadenectomy via a right thoracic approach or THE.56 The TTE group also underwent mandatory dissection
Management of Gastroesophageal Junction Tumors
of the celiac, common hepatic artery, and splenic hilar nodes. The THE group only had a celiac node dissection performed if there was clinical suspicion of involvement. Reconstruction with a gastric tube and cervical anastomosis was performed in both groups. Postoperative morbidity was higher in the TTE group, including pulmonary complications (57% vs 27%, P<.001), chylous leakage (10% vs 2%, P5.02), longer median ventilator time (2 days vs 1 day, P<.001), intensive care unit (ICU) stay (6 days vs 2 days, P<.001), and hospital stay (19 days vs 15 days, P<.001). However, there was no difference in in-hospital mortality (4% vs 2%, P 5 .45). With regard to oncologic outcomes, the rate of R0 resection in this study was not different (71% vs 72%, P 5 .28), but the mean number of lymph nodes harvested was higher with TTE(31 vs 16, P<.001). More importantly, there was a statistically nonsignificant trend toward better long-term survival in the TTE group (median survival 2 years vs 1.8 years P 5 .38, estimated 5-year survival of 39% vs 29%).56 A follow-up study with more complete data published in 2007 showed a similar 5-year survival between the 2 groups (36% vs 34%, P 5 .71). However, in the Siewert type 1 tumors, there was again a strong trend toward better overall 5-year survival in the TTE group (51% vs 37%, P 5 .33), and particularly in the subgroup of patients with 1 to 8 positive nodes (64% vs 23%, P 5 .02).57 Although cofounded by the differences in abdominal node dissection, these results strongly suggest that an oncologic survival benefit is present for en bloc TTE esophageal resection for type 1 tumors. While there may be some increased risk of pulmonary complications, anastomotic complications are reduced by the use of an intrathoracic anastomosis, and intrathoracic leaks are no longer associated with high mortality.58 Minimally invasive esophagectomy, while beyond the scope of this article, is likely a valid alternative to traditional open THE or TTE. Preliminary data suggest oncologic outcomes and lymph node harvests are similar to that of TTE when a thoracoscopic dissection of the esophagus is performed.59,60 Randomized trials are ongoing to ascertain its optimal role.61 Siewert 2 and 3 Tumors
There are few randomized trials comparing surgical approaches to type 2 and type 3 tumors. Generally, type 3 tumors have been treated as a true gastric cancer, while type 2 tumors have been treated as both gastric and esophageal cancer. Lymphatics from both sites generally drain to the paracardial and lesser curvature nodes first. Isolated mediastinal metastases are found in less than 12% of cases. Nodal recurrences are most frequent in the para-aortic nodes.62,63 Patients with positive mediastinal nodes have an extremely poor prognosis.64 As both esophagectomy and gastrectomy harvest the most frequently involved lymph node stations, both are oncologically sound provided adequate margins are obtained. A retrospective review of 505 patients undergoing either of these procedures suggested 3.8 cm as the proximal margin length most predictive of cure.65 In this study, there was no difference between gastrectomy and esophagectomy in operative mortality, R1 resection lymph node harvest, or overall survival when controlling for stage. Similar results have been obtained in other retrospective studies.37,66 A single phase 3 randomized trial (Japan Clinical Oncology Group 9502) randomized 167 patients with Siewert 2 and 3 tumors to extended total gastrectomy with D2 lymphadenectomy via the THE route or the same procedure along with lower mediastinal lymphadenectomy via a left thoracoabdominal (LTA) approach. Complications (49% vs 34%, P 5 .006) and in-hospital mortality (4% vs 0%, P 5 .06) were higher in the LTA group. Five-year survival was lower in the LTA group (37.9% vs 52.3%). Results were similar in the type 2 and type 3 tumor subgroups.67
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While a mediastinal lymph node dissection in these patients has not been proven to be beneficial, extended abdominal lymph node dissection (D2 lymphadenectomy, Fig. 2) appears to confer an oncologic benefit. The original Dutch Gastric Cancer Trial randomized patients with gastric adenocarcinoma to D1 or D2 lymphadenectomy along with total or distal gastrectomy. As part of their dissection, the D2 patients received a distal pancreatectomy and splenectomy. Their overall complication rate (43% vs 25%, P<.001) and in-hospital mortality rate (10 vs 4%, P 5 .004) were higher.68 However, after 15-year follow-up, gastric cancer-related death was lower in the D2 group (37% vs 48%, P 5 .01). Other studies have shown that pancreatectomy and splenectomy are not necessary for D2 lymphadenectomy,69 and D2 lymphadenectomy may be accomplished with low morbidity, 17.9%, and mortality, 2.2%.70 Given the overall similarity in outcomes between esophagectomy and gastrectomy in these patients, the authors feel either procedure is valid provided adequate negative margins are obtained. If gastrectomy is performed, a D2 lymph node dissection should be considered. If esophagectomy is performed, a THE approach may be beneficial given the low likelihood of mediastinal lymph node involvement.
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Ao 7
LG
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4sa
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Ce H
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RG 8 CH
GD
Sp
4sb 3
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Fig. 2. Abdominal lymphatic stations to achieve a D2 lymphadenectomy. (From Peracchia A, Rosati R. Total gastrectomy and Roux-en-Y reconstruction. In: Patterson GA, Cooper JD, Deslauriers J, et al, editors. Pearson’s thoracic and esophageal surgery. 3rd edition. Philadelphia: Churchill Livingstone; 2008. p. 615; with permission.)
Management of Gastroesophageal Junction Tumors
As with esophagectomy, the role of minimally invasive surgery for total gastrectomy is unclear. Presently, a few case series from Asian centers and a meta-analysis exist showing similar oncologic results between laparoscopic and open operations with reduced postoperative pain and length of stay.71 Further prospective trials are required to elicit laparoscopic surgery’s true role for type 2 and type 3 AEGs. MULTIMODALITY THERAPY
While complete surgical resection remains the largest influence outcome in patients with AEGs, only 11% to 21% of patients will present with potentially resectable disease and have the physiologic capacity to tolerate surgery.72 Additionally, 70% of patients have systemic recurrences,73 and increasingly radical surgery has not produced better results. Consequently, there has been much interest in perioperative chemotherapy and/or radiotherapy for esophageal, gastric and EGJ tumors. Adjuvant Therapy
The SWOG 9008/INT 0116 trial randomized 556 patients with resected stage 1B–4 gastric or EGJ cancer to surgery with postoperative adjuvant chemoradiotherapy or to surgery alone. Adjuvant therapy consisted of 425 mg of fluorouracil per square meter of body surface area per day, plus 20 mg of leucovorin per square meter per day, for 5 days, followed by 4500 cGy of radiation at 180 cGy per day, given 5 days per week for 5 weeks, with modified doses of fluorouracil and leucovorin on the first 4 and the last 3 days of radiotherapy. One month after the completion of radiotherapy, 2 5-day cycles of fluorouracil (425 mg/m2/d) plus leucovorin (20 mg/m2/d) were given 1 month apart.74 The median overall survival was 36 months in the multimodality group compared with 27 months in the surgery only cohort (P<.005). While this trial illustrated the usefulness of adjuvant therapy in gastric cancer, only 21% of tumors were located in the cardia. Furthermore, 90% of patients underwent a D0 or D1 lymph node dissection, which is limited compared with the currently accepted D2 dissection. The ongoing CALGB-80101 trial is comparing this regimen to chemoradiation with epirubicin, cisplatin, and 5-FU. Adjuvant chemotherapy alone in gastric cancer was studied in the Japanese SCTSGC trial. One thousand fifty-nine patients with stage 1 or 3 gastric cancer who had undergone curative gastrectomy with D2 lymphadenectomy were randomized to oral S-1, a fluoropyramidine, for 1 year, or surgery alone.75 The 3-year overall survival rate in the adjuvant therapy group was 80.5% compared with 70.1%. Unfortunately, the proportion of AEGs composing the study cohort was not reported. Although the results of this trial can be extended to AEGs in Asian countries, which are predominantly type 2/3 and similar to gastric cancer, it is questionable whether they apply to western patients who are more likely to have type 1 tumors and undergo less extensive lymphadenectomy. Furthermore, the metabolism of S-1 in Asian and western patients is different, although a recent global phase 3 study comparing cisplatin/S-1 to cisplatin/5-FU in patients with metastatic gastroesophageal junction or gastric cancer showed this can be accounted for, suggesting this regimen may be effective in western patients with Siewert 2 or 3 tumors.76 Neoadjuvant Therapy
In the INT-0116 study, only 64% of patients were able to complete the treatment. These results were similar to adjuvant therapy trials showing difficulty with treatment tolerance. Therefore, most recent trials have focused upon neoadjuvant therapy.
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The Medical Research Council Adjuvant Gastric Infusional Chemotherapy (MAGIC Trial) compared 3 cycles of epirubicin, cisplatin, and 5-FU before and after surgery to surgery alone in patients with resectable gastric, GEJ, and lower esophageal adenocarcinoma.77 Importantly, this study protocol did not include the use of neoadjuvant radiation therapy. Five-year survival was significantly improved in the multimodality group (36% vs 23%, P 5 .009). Although only 14.5% of patients had lower esophageal tumors, and 11.5% had GEJ tumors, there was no significant interaction between tumor location and survival. These results were confirmed by a multicenter French phase 3 that randomized patients with distal esophageal, EGJ, or stomach adenocarcinoma to perioperative cisplatin/5-FU or surgery alone.78 The perioperative chemotherapy group had improved overall and disease-free survival as well as an increased rate of R-0 resection. Importantly, 64% of the patients had AEGs. Definitive Chemoradiotherapy
Given the efficacy of neoadjuvant chemoradiotherapy, there has been interest in the use of definitive chemoradiotherapy (dCRT) for esophageal cancer.79 Most trials comparing dCRT to esophagectomy were comprised primarily of patients with SCC. Furthermore, the literature suggests that in adenocarcinoma the rate of complete pathologic response is less than squamous carcinoma,80 and survival is significantly worse after dCRT compared with surgery.81 Consequently, the authors believe that surgery is indicated for all resectable AEG patients who are a reasonable operative risk. PALLIATIVE THERAPY FOR ADVANCED DISEASE
Approximately one-third of AEG patients present with stage 4 disease.15 While surgical, endoscopic, or radiotherapeutic treatment may be needed on a case-bycase basis for local palliation and symptom control, systematic chemotherapy remains the mainstay of treatment for these patients. Multiple trials and meta-analyses have shown improved survival and quality of life with palliative chemotherapy in gastric cancer.82–85 Only 2 randomized trials have shown such benefits in esophageal adenocarcinoma.86,87 After initially being developed for SCC, cisplatin/5-FU has been considered the standard treatment regimen for metastatic esophageal and gastric adenocarcinoma with a response rate of 34%.88 Various phase 2 trials have shown improved response rates with the addition of anthracycline agents (doxorubicin or epirubicin)86,87,89–91 or taxanes (docetaxel or paclitaxel).92,93 Other trials have focused on limiting the toxic effects of chemotherapeutic agents. The randomized epirubacin, cisplatin, and fluorouracil [ECF] for advanced and locally advanced esophagogastric cancer 2 (REAL-2) trial demonstrated survival noninferiority when cisplatin and 5-FU in the ECF regimen were replaced with oxaliplatin and oral capecitabine.94 The recent fluorouracil in advanced gastric or gastroesophageal adenocarcinoma (FLAG) trial showed survival noninferiority of cisplatin/S-1 compared with cisplatin/5-FU along with an improved safety profile.76 There has been substantial investigation into targeted biologic agents in the treatment of metastatic gastroesophageal cancer. Approximately 10% of AEGs in the United States overexpress HER2. Trastuzumab, a monoclonal HER-2 antibody, has been widely used in the treatment of breast cancer. The trastuzumab for gastric adenocarcinoma (ToGA) trial randomized patients with stomach or EGJ HER2-positive adenocarcinoma to chemotherapy with and without trastuzumab. Response rate (47% vs 35%) and median overall survival (13.8 months and 11.1 months) were significantly better in the treatment group.95,96 The utility of other agents, such as cetuximab, gefitinib, and erlotinib, are currently under investigation.
Management of Gastroesophageal Junction Tumors
SUMMARY
The incidence of adenocarcinomas of the EGJ is rising dramatically. Although the overall prognosis for these tumors remains poor, surgery and multimodality therapy can be curative. For tumors confined to the mucosa, endoscopic therapy or limited resection is indicated. Tumors penetrating into the submucosa have a high likelihood of lymph node involvement and require radical resection. TTE en bloc esophagectomy with 2-field lymph node dissection is the procedure of choice for patients with Siewert 1 tumors. In patients with compromised pulmonary function, THE esophagectomy should be considered. All patients with T3 or greater tumors or nodal involvement should be considered for chemoradiotherapy, preferably in the neoadjuvant setting. For palliation of stage 4 disease, platinum-based chemotherapy is indicated. If adequate margins can be obtained, either esophagectomy with proximal gastrectomy or THE extended total gastrectomy with D2 lymphadenectomy may be performed for type 2 and type 3 tumors. REFERENCES
1. Devesa S, Blot W, Fraumeni J. Changing patterns in the incidence of esophageal and gastric carcinoma in the United States. Cancer 1998;83:2049–53. 2. Pera M, Manterola C, Vidal O, et al. Epidemiology of esophageal adenocarcinoma. J Surg Oncol 2005;92:151–9. 3. Whitson BA, Groth SS, Li Z, et al. Survival of patients with distal esophageal and gastric cardia tumors: a population-based analysis of gastroesophageal junction carcinomas. J Thorac Cardiovasc Surg 2010;139:43–8. 4. Siewert JR, Stein H. Adenocarcinoma of the gastroesophageal junction: classification, pathology and extent of resection. Dis Esophagus 1996;9:173–82. 5. Siewert JR, Stein H. Classification of carcinoma of the oesphagogastric junction. Br J Surg 1998;85:1457–9. 6. Ishimura N, Amano Y, Kinoshita Y. Endoscopic definition of esophagogastric junction for diagnosis of Barrett’s esophagus: importance of systematic education and training. Dig Endosc 2009;21:213–8. 7. Hameeteman W, Tytgat GN, Houthoff HJ, et al. Barrett’s esophagus: development of dysplasia and adenocarcinoma. Gastroenterology 1989;96:1249–56. 8. Bresalier RS. Barrett’s esophagus and esophageal adenocarcinoma. Ann Rev Med 2009;60:221–31. 9. Siewert JR, Feith M, Stein HJ. Biologic and clinical variations of adenocarcinoma at the esophago–gastric junction: relevance of a topographic–anatomic subclassification. J Surg Oncol 2005;90:139–46. 10. Bai JG, Lv Y, Dang CX. Adenocarcinoma of the esophagogastric junction in China according to Siewert’s classification. Jpn J Clin Oncol 2006;36:364–7. 11. Hasegawa S, Yoshikawa T, Cho H, et al. Is adenocarcinoma of the esophagogastric junction different between Japan and western countries? The incidence and clinicopathological features at a Japanese high-volume cancer center. World J Surg 2009;33:95–103. 12. Fang WL, Wu CW, Chen JH, et al. Esophagogastric junction adenocarcinoma according to Siewert classification in Taiwan. Ann Surg Oncol 2009;16:3237–44. 13. Brown LM, Devesa SS. Epidemiologic trends in esophageal and gastric cancer in the United States. Surg Oncol Clin N Am 2002;11:235–56. 14. Kubo A, Corley DA. Marked multi-ethnic variation of esophageal and gastric cardia carcinomas within the United States. Am J Gastroenterol 2004;99: 582–8.
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15. Pohl H, Welch HG. The role of overdiagnosis and reclassification in the marked increase of esophageal adenocarcinoma incidence. J Natl Cancer Inst 2005;97: 142–6. 16. Rice TW, Blackstone EH, Rusch VW. 7th edition of the AJCC Cancer Staging Manual: esophagus and esophagogastric junction. Ann Surg Oncol 2010;17: 1721–4. 17. Barbour AP, Rizk NP, Gerdes H, et al. Endoscopic ultrasound predicts outcomes for patients with adenocarcinoma of the gastroesophageal junction. J Am Coll Surg 2007;205:593–601. 18. Rampado S, Bocus P, Battaglia G, et al. Endoscopic ultrasound: accuracy in staging superficial carcinomas of the esophagus. Ann Thorac Surg 2008;85: 251–6. 19. Lowe VJ, Booya F, Fletcher JG, et al. Comparison of positron emission tomography, computed tomography, and endoscopic ultrasound in the initial staging of patients with esophageal cancer. Mol Imaging Biol 2005;7:422–30. 20. van Westreenen HL, Westerterp M, Bossuyt PM, et al. Systematic review of the staging performance of 18F-fluorodeoxyglucose positron emission tomography in esophageal cancer. J Clin Oncol 2004;22:3805–12. 21. Sandha GS, Severin D, Postema E, et al. Is positron emission tomography useful in locoregional staging of esophageal cancer? Results of a multidisciplinary initiative comparing CT, positron emission tomography, and EUS. Gastrointest Endosc 2008;67:402–9. 22. Pedrazzani C, Bernini M, Giacopuzzi S, et al. Evaluation of Siewert classification in gastro–esophageal junction adenocarcinoma: what is the role of endoscopic ultrasonography? J Surg Oncol 2005;91:226–31. 23. Ang TL, Ng TM, Fock KM, et al. Accuracy of endoscopic ultrasound staging of gastric cancer in routine clinical practice in Singapore. Chin J Dig Dis 2006;7: 191–6. 24. Blackshaw G, Lewis WG, Hopper AN, et al. Prospective comparison of endosonography, computed tomography, and histopathological stage of junctional oesophagogastric cancer. Clin Radiol 2008;63:1092–8. 25. Meining A, Rosch T, Wolf A, et al. High interobserver variability in endosonographic staging of upper gastrointestinal cancers. Z Gastroenterol 2003;41:391–4. 26. Burtin P, Napoleon B, Palazzo L, et al. Interobserver agreement in endoscopic ultrasonography staging of esophageal and cardia cancer. Gastrointest Endosc 1996;43:20–4. 27. Catalano MF, Sivak MV Jr, Bedford RA, et al. Observer variation and reproducibility of endoscopic ultrasonography. Gastrointest Endosc 1995;41:115–20. 28. Thurau K, Palmes D, Franzius C, et al. Impact of PET-CT on primary staging and response control on multimodal treatment of esophageal cancer. World J Surg 2011;35:608–16. 29. Gananadha S, Hazebroek EJ, Leibman S, et al. The utility of FDG-PET in the preoperative staging of esophageal cancer. Dis Esophagus 2008;21:389–94. 30. Heeren PA, Jager PL, Bongaerts F, et al. Detection of distant metastases in esophageal cancer with (18)F-FDG PET. J Nucl Med 2004;45:980–7. 31. Ott K, Weber WA, Fink U, et al. Fluorodeoxyglucose-positron emission tomography in adenocarcinomas of the distal esophagus and cardia. World J Surg 2003;27:1035–9. 32. Stahl A, Ott K, Weber WA, et al. FDG PET imaging of locally advanced gastric carcinomas: correlation with endoscopic and histopathological findings. Eur J Nucl Med Mol Imaging 2003;30:288–95.
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33. Mahadevan D, Sudirman A, Kandasami P, et al. Laparoscopic staging in gastric cancer: an essential step in its management. J Minim Access Surg 2010;6: 111–3. 34. de Graaf GW, Ayantunde AA, Parsons SL, et al. The role of staging laparoscopy in oesophagogastric cancers. Eur J Surg Oncol 2007;33:988–92. 35. Krasna MJ, Reed CE, Nedzwiecki D, et al. CALGB 9380: a prospective trial of the feasibility of thoracoscopy/laparoscopy in staging esophageal cancer. Ann Thorac Surg 2001;71:1073–9. 36. Ott K, Bader FG, Lordick F, et al. Surgical factors influence the outcome after IvorLewis esophagectomy with intrathoracic anastomosis for adenocarcinoma of the esophagogastric junction: a consecutive series of 240 patients at an experienced center. Ann Surg Oncol 2009;16:1017–25. 37. Johansson J, Djerf P, Oberg S, et al. Two different surgical approaches in the treatment of adenocarcinoma at the gastroesophageal junction. World J Surg 2008;32:1013–20. 38. Lerut T, Coosemans W, Decker G, et al. Surgical techniques. J Surg Oncol 2005; 92:218–29. 39. Stiles BM, Mirza F, Coppolino A, et al. Clinical T2-T3N0M0 esophageal cancer: the risk of node positive disease. Ann Thorac Surg 2011;92:491–6. 40. Matuschek C, Bolke E, Peiper M, et al. The role of neoadjuvant and adjuvant treatment for adenocarcinoma of the upper gastrointestinal tract. Eur J Med Res 2011; 16:265–74. 41. Wong T, Tian J, Nagar AB. Barrett’s surveillance identifies patients with early esophageal adenocarcinoma. Am J Med 2010;123:462–7. 42. Stein HJ, Feith M, Mueller J, et al. Limited resection for early adenocarcinoma in Barrett’s esophagus. Ann Surg 2000;232:733–42. 43. Ell C, May A, Pech O, et al. Curative endoscopic resection of early esophageal adenocarcinomas (Barrett’s cancer). Gastrointest Endosc 2007;65:3–10. 44. Merendino KA, Dillard DH. The concept of sphincter substitution by an interposed jejunal segment for anatomic and physiologic abnormalities at the esophagogastric junction; with special reference to reflux esophagitis, cardiospasm and esophageal varices. Ann Surg 1955;142:486–506. 45. Peyre CG, DeMeester SR, Rizzetto C, et al. Vagal-sparing esophagectomy: the ideal operation for intramucosal adenocarcinoma and Barrett with high-grade dysplasia. Ann Surg 2007;246:665–71. 46. Ho¨lscher AH, Vallbo¨hmer D, Schro¨der W, et al. Limited surgery for “early” cancer of the esophagus. Eur Surg 2007;39:273–80. 47. Westerterp M, Koppert LB, Buskens CJ, et al. Outcome of surgical treatment for early adenocarcinoma of the esophagus or gastro-esophageal junction. Virchows Arch 2005;446:497–504. 48. Liu L, Hofstetter WL, Rashid A, et al. Significance of the depth of tumor invasion and lymph node metastasis in superficially invasive (T1) esophageal adenocarcinoma. Am J Surg Pathol 2005;29:1079–85. 49. Dresner SM, Lamb PJ, Bennett MK, et al. The pattern of metastatic lymph node dissemination from adenocarcinoma of the esophagogastric junction. Surgery 2001;129:103–9. 50. 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. Ann Surg 2004;240:962–74. 51. Hulscher JB, van Sandick JW, Tijssen JG, et al. The recurrence pattern of esophageal carcinoma after transhiatal resection. J Am Coll Surg 2000;191:143–8.
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52. Jacobi CA, Zieren HU, Muller JM, et al. Surgical therapy of esophageal carcinoma: the influence of surgical approach and esophageal resection on cardiopulmonary function. Eur J Cardiothorac Surg 1997;11:32–7. 53. Areja D, Subhan A, Mirza MR, et al. Transhiatal versus Ivor-Lewis procedure for the treatment of carcinoma esophagus. Pak J Surg 2006;22:126–9. 54. Chu KM, Law SY, Fok M, et al. A prospective randomized comparison of transhiatal and transthoracic resection for lower-third esophageal carcinoma. Am J Surg 1997;174:320–4. 55. Goldminc M, Maddern G, Le Prise E, et al. Oesophagectomy by a transhiatal approach or thoracotomy: a prospective randomized trial. Br J Surg 1993;80: 367–70. 56. Hulscher JB, Van Sandick JW, de Boer A, et al. Extended transthoracic resection compared with limited transhiatal resection for adenocarcinoma of the esophagus. N Engl J Med 2002;347:1662–9. 57. Omloo JM, Lagarde SM, Hulscher JB, et al. Extended transthoracic resection compared with limited transhiatal resection for adenocarcinoma of the mid/distal esophagus: five-year survival of a randomized clinical trial. Ann Surg 2007;246: 992–1000. 58. Escofet X, Manjunath A, Twine C, et al. Prevalence and outcome of esophagogastric anastomotic leak after esophagectomy in a UK regional cancer network. Dis Esophagus 2010;23:112–6. 59. Dantoc MM, Cox MR, Eslick GD. Does minimally invasive esophagectomy (MIE) provide for comparable oncologic outcomes to open techniques? A systematic review. J Gastrointest Surg 2012;16:486–94. 60. Gao Y, Wang Y, Chen L, et al. Comparison of open three-field and minimallyinvasive esophagectomy for esophageal cancer. Interact Cardiovasc Thorac Surg 2011;12:366–9. 61. Biere SS, Maas KW, Bonavina L, et al. Traditional invasive vs. minimally invasive esophagectomy: a multi-center, randomized trial (TIME-trial). BMC Surg 2011; 11:2. 62. Yamashita H, Katai H, Morita S, et al. Optimal extent of lymph node dissection for Siewert type II esophagogastric junction carcinoma. Ann Surg 2011;254: 274–80. 63. Wayman J, Bennett MK, Raimes SA, et al. The pattern of recurrence of adenocarcinoma of the oesophago–gastric junction. Br J Cancer 2002;86:1223–9. 64. Wakatsuki K, Takayama T, Ueno M, et al. Characteristics of gastric cancer with esophageal invasion and aspects of surgical treatment. World J Surg 2009;33: 1446–53. 65. Barbour AP, Rizk NP, Gonen M, et al. Adenocarcinoma of the gastroesophageal junction: influence of esophageal resection margin and operative approach on outcome. Ann Surg 2007;246:1–8. 66. Schumacher G, Schmidt SC, Schlechtweg N, et al. Surgical results of patients after esophageal resection or extended gastrectomy for cancer of the esophagogastric junction. Dis Esophagus 2009;22:422–6. 67. Sasako M, Sano T, Yamamoto S, et al. Left thoracoabdominal approach versus abdominal–transhiatal approach for gastric cancer of the cardia or subcardia: a randomised controlled trial. Lancet Oncol 2006;7:644–51. 68. Bonenkamp JJ, Hermans J, Sasako M, et al. Extended lymph-node dissection for gastric cancer. N Engl J Med 1999;340:908–14. 69. Kunisaki C, Makino H, Suwa H, et al. Impact of splenectomy in patients with gastric adenocarcinoma of the cardia. J Gastrointest Surg 2007;11:1039–44.
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70. Degiuli M, Sasako M, Ponti A. Morbidity and mortality in the Italian Gastric Cancer Study Group randomized clinical trial of D1 versus D2 resection for gastric cancer. Br J Surg 2010;97:643–9. 71. Wei HB, Wei B, Qi CL, et al. Laparoscopic versus open gastrectomy with D2 lymph node dissection for gastric cancer: a meta-analysis. Surg Laparosc Endosc Percutan Tech 2011;21:383–90. 72. Verhoef C, van de Weyer R, Schaapveld M, et al. Better survival in patients with esophageal cancer after surgical treatment in university hospitals: a plea for performance by surgical oncologists. Ann Surg Oncol 2007;14:1678–87. 73. Abate E, DeMeester SR, Zehetner J, et al. Recurrence after esophagectomy for adenocarcinoma: defining optimal follow-up intervals and testing. J Am Coll Surg 2010;210:428–35. 74. Macdonald JS, Smalley SR, Benedetti J, et al. Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophagael junction. N Engl J Med 2001;345:725–30. 75. Sakuramoto S, Sasako M, Yamaguchi T, et al. Adjuvant chemotherapy for gastric cancer with S-1, an oral fluoropyrimidine. N Engl J Med 2007;357:1810–20. 76. Ajani JA, Rodriguez W, Bodoky G, et al. Multicenter phase III comparison of cisplatin/S-1 with cisplatin/infusional fluorouracil in advanced gastric or gastroesophageal adenocarcinoma study: the FLAGS trial. J Clin Oncol 2010;28:1547–53. 77. Cunnignham D, Allum WH, Stenning SP, et al. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med 2006;355: 11–20. 78. Ychou M, Boige V, Pignon JP, et al. Perioperative chemotherapy compared with surgery alone for resectable gastroesophageal adenocarcinoma: an FNCLCC and FFCD multicenter phase III trial. J Clin Oncol 2011;29:1715–21. 79. Morgan MA, Lewis WG, Casbard A, et al. Stage-for-stage comparison of definitive chemoradiotherapy, surgery alone and neoadjuvant chemotherapy for oesophageal carcinoma. Br J Surg 2009;96:1300–7. 80. Tougeron D, Di Fiore F, Hamidou H, et al. Response to definitive chemoradiotherapy and survival in patients with an oesophageal adenocarcinoma versus squamous cell carcinoma: a matched-pair analysis. Oncology 2007;73:328–34. 81. Tougeron D, Scotte M, Hamidou H, et al. Definitive chemoradiotherapy in patients with esophageal adenocarcinoma: an alternative to surgery? J Surg Oncol 2012; 105:761–6. 82. Glimelius B, Ekstrom K, Hoffman K, et al. Randomized comparison between chemotherapy plus best supportive care with best supportive care in advanced gastric cancer. Ann Oncol 1997;8:163–8. 83. Wagner AD, Unverzagt S, Grothe W, et al. Chemotherapy for advanced gastric cancer. Cochrane Database Syst Rev 2010;(3):CD004064. 84. Thuss-Patience PC, Kretzschmar A, Bichev D, et al. Survival advantage for irinotecan versus best supportive care as second-line chemotherapy in gastric cancer— a randomised phase III study of the Arbeitsgemeinschaft Internistische Onkologie (AIO). Eur J Cancer 2011;47:2306–14. 85. Wagner AD, Grothe W, Haerting J, et al. Chemotherapy in advanced gastric cancer: a systematic review and meta-analysis based on aggregate data. J Clin Oncol 2006;24:2903–9. 86. Ross P, Nicolson M, Cunningham D, et al. Prospective randomized trial comparing mitomycin, cisplatin, and protracted venous-infusion fluorouracil (PVI 5-FU) with epirubicin, cisplatin, and PVI 5-FU in advanced esophagogastric cancer. J Clin Oncol 2002;20:1996–2004.
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87. Webb A, Cunningham D, Scarffe JH, et al. Randomized trial comparing epirubicin, cisplatin, and fluorouracil versus fluorouracil, doxorubicin, and methotrexate in advanced esophagogastric cancer. J Clin Oncol 1997;15:261–7. 88. Ohtsu A. Randomized phase III trial of fluorouracil alone versus fluorouracil plus cisplatin versus uracil and tegafur plus mitomycin in patients with unresectable, advanced gastric cancer: The Japan Clinical Oncology Group Study (JCOG9205). J Clin Oncol 2003;21:54–9. 89. Lee JJ, Kim SY, Shin IS, et al. Randomized phase III trial of cisplatin, epirubicin, leucovorin, 5-fluorouracil (PELF) combination versus 5-fluorouracil alone as adjuvant chemotherapy in curative resected stage III gastric cancer. Cancer Res Treat 2004;36:140–5. 90. Zaniboni A, Barni S, Labianca R, et al. Epirubicin, cisplatin, and continuous infusion 5-fluorouracil is an active and safe regimen for patients with advanced gastric cancer. An Italian Group for the Study of Digestive Tract Cancer (GISCAD) report. Cancer 1995;76:1694–9. 91. Highley MS, Parnis FX, Trotter GA, et al. Combination chemotherapy with epirubicin, cisplatin and 5-fluorouracil for the palliation of advanced gastric and oesophageal adenocarcinoma. Br J Surg 1994;81:1763–5. 92. Roth AD, Fazio N, Stupp R, et al. Docetaxel, cisplatin, and fluorouracil; docetaxel and cisplatin; and epirubicin, cisplatin, and fluorouracil as systemic treatment for advanced gastric carcinoma: a randomized phase II trial of the Swiss Group for Clinical Cancer Research. J Clin Oncol 2007;25:3217–23. 93. Thuss-Patience PC, Kretzschmar A, Repp M, et al. Docetaxel and continuousinfusion fluorouracil versus epirubicin, cisplatin, and fluorouracil for advanced gastric adenocarcinoma: a randomized phase II study. J Clin Oncol 2005;23: 494–501. 94. Cunningham D, Starling N, Rao S, et al. Capecitabine and oxaliplatin for advanced esophagogastric cancer. N Engl J Med 2008;358:36–46. 95. Bang YJ, Van Cutsem E, Feyereislova A, et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet 2010;376:687–97. 96. Pearson FG, Patterson GA. Pearson’s thoracic & esophageal surgery. 3rd edition. Philadelphia: Churchill Livingstone/Elsevier; 2008.
MD
a
, Victor van Berkel,
MD, PhD
b,
*
KEYWORDS Gastroesophageal junction tumors Esophagectomy Lymphadenectomy Chemoradiotherapy KEY POINTS The incidence of adenocarcinomas of the esophagogastric junction is rising dramatically. While the overall prognosis for these tumors remains poor, surgery and multimodality therapy can be curative. Endoscopic therapy or limited resection is indicated for tumors confined to the mucosa. Tumors penetrating into the submucosa have a high likelihood of lymph node involvement and require radical resection. For Siewert 1 tumors, transthoracic en bloc esophagectomy with 2-field lymph node dissection is the procedure of choice. Transhiatal (THE) esophagectomy should be considered in patients with compromised pulmonary function. For type 2 and 3 tumors, either esophagectomy with proximal gastrectomy or THE extended total gastrectomy with D2 lymphadenectomy may be performed provided adequate margins are obtained. All patients with T3 or greater tumors or nodal involvement should be considered for chemoradiotherapy, preferably in the neoadjuvant setting. Platinum-based chemotherapy is indicated for palliation of stage 4 disease.
INTRODUCTION
Over the past few decades, the incidence of adenocarcinoma of the esophagogastric junction (AEG) has risen dramatically in western countries.1,2 The mechanism of this change is unclear. Despite endoscopic screening and advances in multimodality therapy, the prognosis of these tumors remains poor, with an overall 5-year survival
a
Department of Surgery, School of Medicine, University of Louisville, 201 Abraham Flexner Way, Suite 1200, Louisville, KY 40202, USA; b Division of Cardiothoracic Surgery, Department of Surgery, School of Medicine, University of Louisville, 201 Abraham Flexner Way, Suite 1200, Louisville, KY 40202, USA * Corresponding author. E-mail address: [email protected] Surg Clin N Am 92 (2012) 1199–1212 http://dx.doi.org/10.1016/j.suc.2012.07.011 surgical.theclinics.com 0039-6109/12/$ – see front matter Ó 2012 Elsevier Inc. All rights reserved.
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rate of approximately 20%.3 This article will discuss the current pathologic classification, epidemiology, staging, and standard treatment of these tumors. SIEWERT CLASSIFICATION
Because of their location, a great deal of controversy has been present regarding whether AEGs represent gastric or esophageal cancer. Siewert attempted to rectify this problem in 1996 with a standardized system classifying these tumors based on topographic anatomic criteria.4,5 By definition, all of these tumors must invade the esophagogastric junction (EGJ). Type 1 tumors were defined as those with an epicenter 1 to 5 cm above the EGJ. Type 2 tumors were defined as having a center 1 cm above to 2 cm below the EGJ. Finally, type 3 tumors were defined as being centered 2 to 5 cm below the EGJ (Fig. 1). Therefore, type 1 tumors represent distal esophageal adenocarcinoma. Type 2 tumors are true adenocarcinomas of the cardia, and type 3tumors are subcardial gastric cancers. It is worth noting that precise endoscopic localization of the EGJ can be difficult,6 leading to possible misclassification of tumors preoperatively. This classification system was adopted at the Second International Gastric Cancer Congress in 1997 and has since been used extensively without modification. EPIDEMIOLOGY AND ETIOLOGY OF ADENOCARCINOMA OF THE EGJ
The relation between Barrett’s esophagus and adenocarcinoma of esophagus is well established.7,8 Given their esophageal epicenter, it is no surprise that type 1 AEGs have the strongest association with Barrett’s esophagus, with approximately 80% of resected specimens showing intestinal metaplasia.9 Conversely, Barrett’s metaplasia was present in only 5.6% and 0.8% of patients with type 2 and 3 tumors, respectively. Asian case series have shown a weaker association between Barrett and type 1 AEGs.10 Furthermore, in different populations, the ratio of type 1 to type 2 and 3 tumors is different; eastern counties have a relative preponderance for type 2 and 3 carcinomas compared with the United States and Europe.11,12 This differential distribution in tumor location is likely due to the rise in esophageal adenocarcinoma (EAC) in the West. In the United States, the relative incidence of + 5 cm Type I Type II
+ 1 cm – 2 cm
Type III
– 5 cm
Fig. 1. Classification of adenocarcinoma of the esophagogastric junction according to the localization of the center of the tumor by Siewert and colleagues (1987). (From Ho¨lscher AH. Adenocarcinoma of the cardia. In: Patterson GA, Cooper JD, Deslauriers J, et al, editors. Pearson’s thoracic and esophageal surgery. 3rd edition. Philadelphia: Churchill Livingstone; 2008. p. 493; with permission.)
Management of Gastroesophageal Junction Tumors
EAC increased by 400% in white men and 300% in white women over 26 years.13 In the same study, African American men had a 100% relative increase in EAC, while incidence of squamous carcinoma (SCC) of the esophagus remained unchanged. In a review of the surveillance, epidemiology, and end result (SEER) database from 1992 to 1998, Kubo and Corely showed the incident rate of esophageal adenocarcinomas increased, while the rate of cardial carcinomas remained steady across time.14 Other studies have shown a slight increase in type 2 and type 3 cancers.15 When combined with data showing the steep decline of distal gastric cancers in the West, there is clear epidemiologic evidence that AEGs represent a heterogeneous set of tumors with etiologies that are partially related to, but are distinct from, EAC, distal gastric cancer, and esophageal SCC. DIAGNOSIS AND STAGING
Before the advent of the American Joint Committee on Cancer (AJCC) 7th edition staging manual, AEGs could be staged using either the esophageal or gastric adenocarcinoma systems, potentially leading to discordant staging that could adversely affect therapy. The 7th edition attempts to harmonize esophageal and gastric cancer staging, and all AEGs are staged according to the esophageal system.16 A typical staging workup for esophageal cancer includes combined computed tomography (CT)/positron emission tomography (PET) scans of the chest, abdomen, and pelvis along with endoscopic ultrasound. For esophageal cancers, the sensitivity and specificity of both these methods are well documented, and they provide complimentary information. In a study of esophageal cancers undergoing esophagectomy with neoadjuvant therapy, esophageal ultrasound (EUS) was able to distinguish between early (T1-2, N0) and advanced disease (T3-4, N1) in 83% of patients.17 EUS may also potentially be useful in identifying mucosal carcinomas that may be candidates for endoscopic therapy.18 Its assessment of T and N stage is likely more accurate than PET, which has been shown to accurately determine T stage in only 40% of cases,19 and has a sensitivity of only 50% for detecting regional nodal disease.20,21 Additionally, EUS may assist traditional upper endoscopic techniques in defining the Siewert classification.22 EUS has been shown to be accurate for gastric cancers23 and AEGs.24 Limitations with EUS include invasiveness, reproducibility,25–27 and most importantly, an inability to identify distant metastases. PET is therefore a useful adjunct. In a recent retrospective review of 83 patients with esophageal cancer undergoing pretherapy PET/CT and EUS, PET was found to provide additional staging information that altered treatment in 10% of patients.28 Another retrospective review of 130 patients undergoing CT, EUS, and PET/CT showed PET excluded surgery from 25% of patients deemed resectable by CT and EUS alone.29 These results are similar to a prospective study of 74 patients in whom PET upstaged 20% of patients deemed resectable by CT/EUS.30 While PET’s usefulness in EAC and type 1 AEGs is well documented, its place in the staging of gastric cancer and type 2/3 AEGs is less clear. In a review of 52 patients with type 1 and type 2 tumors, Ott and colleagues31 showed all of the type 1 tumors were PET-avid, whereas only 75% of type 2 tumors were. This coincides with a study in distal gastric cancer, which produced a PET detection rate of 60%. When the authors stratified patients by histology, tumors with intestinal histology showed a higher PET detection rate (83%) compared with nonintestinal type tumors (41%).32 This literature illustrates the differing biology of esophageal and gastric adenocarcinoma and further supports the hypothesis that type 2 AEGs are a heterogeneous mix of esophageal and gastric cancers.
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As the sensitivity of PET for detecting metastases in type 2 and type 3 AEGs is reduced, staging laparoscopy may play a role in the pretreatment assessment. This technique has been validated in gastric cancer33 as well as distal esophageal and gastro-esophageal junction (GEJ) adenocarcinoma.34 However, in the largest series of the patients advocating the use of routine staging laparoscopy, EUS was performed in only 10% of patients.35 To the authors’ knowledge, no study has ever directly compared PET with staging laparoscopy for AEGs. SURGICAL TREATMENT
Multiple studies have shown that R0 resection remains among the most significant predictors of long-term survival in patients with an AEG.36–38 Consequently, the therapeutic goals should be complete surgical resection of the tumor and any associated intestinal metaplasia with adequate lymphadenectomy. If doubt exists over the ability to achieve an R0 resection, neoadjuvant therapy should be considered.39,40 As with any operation, the functional and physiologic status of the patient should be considered and optimized before proceeding. Some controversy remains over the required extent of resection and lymphadenectomy, along with the correct operative approach. These issues will be discussed in depth for each Siewert classification. Siewert 1 Tumors
Given the increase in screening of patients with Barrett’s esophagus, many of these patients are presenting with early stage tumors.41 Consequently, there has been renewed interest in limited resections, which may offer shorter recovery times, less morbidity, and better quality of life compared with radical esophagectomy.42 Options include endoscopic mucosal resection,43 local resection such as the Merendino procedure,42,44 and vagal-sparing esophagectomy.45 The technical aspects of these procedures are beyond the scope of this article; however, consideration must be given to length of the tumor and any associated high-grade dysplasia. Both must be completely resected or ablated, with negative margins. Oncologic outcomes for tumors confined to the mucosa after any of these procedures and radical esophagectomy are similar,45,46 although large-scale trials are still needed. Once the tumor has infiltrated the submucosa, the rate of lymph node metastases increases drastically with the 10% to 67% of patients having nodal involvement, depending on the depth of invasion.47,48 Consequently, the operation of choice remains radical esophagectomy with proximal gastrectomy and reconstruction with a gastric tube. The necessary extent of lymphadenectomy and decision to perform a transthoracic (TTE) or transhiatal (THE) resection remain controversial. For type 1 AEGs, the rate of metastases to the lower mediastinum and abdomen is approximately 60% and 74%, respectively.49 One study advocating a 3-field lymphadenectomy showed cervical nodal metastases in 17.6% of type 1 AEGs.50 However, given the rarity of upper mediastinal recurrences, it is questionable whether an extensive superior lymphadenectomy is needed.51 Due to the propensity for paracardial, lesser curvature, and celiac axis metastases, a complete lymph node dissection should be performed in these locations. The question of whether to perform a TTE or THE resection is also controversial. Five randomized controlled trials have been performed comparing THE with TTE.52–56 The largest trial randomized 220 patients with adenocarcinoma of the distal esophagus or gastric cardia to either TTE with an extended en bloc lymphadenectomy via a right thoracic approach or THE.56 The TTE group also underwent mandatory dissection
Management of Gastroesophageal Junction Tumors
of the celiac, common hepatic artery, and splenic hilar nodes. The THE group only had a celiac node dissection performed if there was clinical suspicion of involvement. Reconstruction with a gastric tube and cervical anastomosis was performed in both groups. Postoperative morbidity was higher in the TTE group, including pulmonary complications (57% vs 27%, P<.001), chylous leakage (10% vs 2%, P5.02), longer median ventilator time (2 days vs 1 day, P<.001), intensive care unit (ICU) stay (6 days vs 2 days, P<.001), and hospital stay (19 days vs 15 days, P<.001). However, there was no difference in in-hospital mortality (4% vs 2%, P 5 .45). With regard to oncologic outcomes, the rate of R0 resection in this study was not different (71% vs 72%, P 5 .28), but the mean number of lymph nodes harvested was higher with TTE(31 vs 16, P<.001). More importantly, there was a statistically nonsignificant trend toward better long-term survival in the TTE group (median survival 2 years vs 1.8 years P 5 .38, estimated 5-year survival of 39% vs 29%).56 A follow-up study with more complete data published in 2007 showed a similar 5-year survival between the 2 groups (36% vs 34%, P 5 .71). However, in the Siewert type 1 tumors, there was again a strong trend toward better overall 5-year survival in the TTE group (51% vs 37%, P 5 .33), and particularly in the subgroup of patients with 1 to 8 positive nodes (64% vs 23%, P 5 .02).57 Although cofounded by the differences in abdominal node dissection, these results strongly suggest that an oncologic survival benefit is present for en bloc TTE esophageal resection for type 1 tumors. While there may be some increased risk of pulmonary complications, anastomotic complications are reduced by the use of an intrathoracic anastomosis, and intrathoracic leaks are no longer associated with high mortality.58 Minimally invasive esophagectomy, while beyond the scope of this article, is likely a valid alternative to traditional open THE or TTE. Preliminary data suggest oncologic outcomes and lymph node harvests are similar to that of TTE when a thoracoscopic dissection of the esophagus is performed.59,60 Randomized trials are ongoing to ascertain its optimal role.61 Siewert 2 and 3 Tumors
There are few randomized trials comparing surgical approaches to type 2 and type 3 tumors. Generally, type 3 tumors have been treated as a true gastric cancer, while type 2 tumors have been treated as both gastric and esophageal cancer. Lymphatics from both sites generally drain to the paracardial and lesser curvature nodes first. Isolated mediastinal metastases are found in less than 12% of cases. Nodal recurrences are most frequent in the para-aortic nodes.62,63 Patients with positive mediastinal nodes have an extremely poor prognosis.64 As both esophagectomy and gastrectomy harvest the most frequently involved lymph node stations, both are oncologically sound provided adequate margins are obtained. A retrospective review of 505 patients undergoing either of these procedures suggested 3.8 cm as the proximal margin length most predictive of cure.65 In this study, there was no difference between gastrectomy and esophagectomy in operative mortality, R1 resection lymph node harvest, or overall survival when controlling for stage. Similar results have been obtained in other retrospective studies.37,66 A single phase 3 randomized trial (Japan Clinical Oncology Group 9502) randomized 167 patients with Siewert 2 and 3 tumors to extended total gastrectomy with D2 lymphadenectomy via the THE route or the same procedure along with lower mediastinal lymphadenectomy via a left thoracoabdominal (LTA) approach. Complications (49% vs 34%, P 5 .006) and in-hospital mortality (4% vs 0%, P 5 .06) were higher in the LTA group. Five-year survival was lower in the LTA group (37.9% vs 52.3%). Results were similar in the type 2 and type 3 tumor subgroups.67
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While a mediastinal lymph node dissection in these patients has not been proven to be beneficial, extended abdominal lymph node dissection (D2 lymphadenectomy, Fig. 2) appears to confer an oncologic benefit. The original Dutch Gastric Cancer Trial randomized patients with gastric adenocarcinoma to D1 or D2 lymphadenectomy along with total or distal gastrectomy. As part of their dissection, the D2 patients received a distal pancreatectomy and splenectomy. Their overall complication rate (43% vs 25%, P<.001) and in-hospital mortality rate (10 vs 4%, P 5 .004) were higher.68 However, after 15-year follow-up, gastric cancer-related death was lower in the D2 group (37% vs 48%, P 5 .01). Other studies have shown that pancreatectomy and splenectomy are not necessary for D2 lymphadenectomy,69 and D2 lymphadenectomy may be accomplished with low morbidity, 17.9%, and mortality, 2.2%.70 Given the overall similarity in outcomes between esophagectomy and gastrectomy in these patients, the authors feel either procedure is valid provided adequate negative margins are obtained. If gastrectomy is performed, a D2 lymph node dissection should be considered. If esophagectomy is performed, a THE approach may be beneficial given the low likelihood of mediastinal lymph node involvement.
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Fig. 2. Abdominal lymphatic stations to achieve a D2 lymphadenectomy. (From Peracchia A, Rosati R. Total gastrectomy and Roux-en-Y reconstruction. In: Patterson GA, Cooper JD, Deslauriers J, et al, editors. Pearson’s thoracic and esophageal surgery. 3rd edition. Philadelphia: Churchill Livingstone; 2008. p. 615; with permission.)
Management of Gastroesophageal Junction Tumors
As with esophagectomy, the role of minimally invasive surgery for total gastrectomy is unclear. Presently, a few case series from Asian centers and a meta-analysis exist showing similar oncologic results between laparoscopic and open operations with reduced postoperative pain and length of stay.71 Further prospective trials are required to elicit laparoscopic surgery’s true role for type 2 and type 3 AEGs. MULTIMODALITY THERAPY
While complete surgical resection remains the largest influence outcome in patients with AEGs, only 11% to 21% of patients will present with potentially resectable disease and have the physiologic capacity to tolerate surgery.72 Additionally, 70% of patients have systemic recurrences,73 and increasingly radical surgery has not produced better results. Consequently, there has been much interest in perioperative chemotherapy and/or radiotherapy for esophageal, gastric and EGJ tumors. Adjuvant Therapy
The SWOG 9008/INT 0116 trial randomized 556 patients with resected stage 1B–4 gastric or EGJ cancer to surgery with postoperative adjuvant chemoradiotherapy or to surgery alone. Adjuvant therapy consisted of 425 mg of fluorouracil per square meter of body surface area per day, plus 20 mg of leucovorin per square meter per day, for 5 days, followed by 4500 cGy of radiation at 180 cGy per day, given 5 days per week for 5 weeks, with modified doses of fluorouracil and leucovorin on the first 4 and the last 3 days of radiotherapy. One month after the completion of radiotherapy, 2 5-day cycles of fluorouracil (425 mg/m2/d) plus leucovorin (20 mg/m2/d) were given 1 month apart.74 The median overall survival was 36 months in the multimodality group compared with 27 months in the surgery only cohort (P<.005). While this trial illustrated the usefulness of adjuvant therapy in gastric cancer, only 21% of tumors were located in the cardia. Furthermore, 90% of patients underwent a D0 or D1 lymph node dissection, which is limited compared with the currently accepted D2 dissection. The ongoing CALGB-80101 trial is comparing this regimen to chemoradiation with epirubicin, cisplatin, and 5-FU. Adjuvant chemotherapy alone in gastric cancer was studied in the Japanese SCTSGC trial. One thousand fifty-nine patients with stage 1 or 3 gastric cancer who had undergone curative gastrectomy with D2 lymphadenectomy were randomized to oral S-1, a fluoropyramidine, for 1 year, or surgery alone.75 The 3-year overall survival rate in the adjuvant therapy group was 80.5% compared with 70.1%. Unfortunately, the proportion of AEGs composing the study cohort was not reported. Although the results of this trial can be extended to AEGs in Asian countries, which are predominantly type 2/3 and similar to gastric cancer, it is questionable whether they apply to western patients who are more likely to have type 1 tumors and undergo less extensive lymphadenectomy. Furthermore, the metabolism of S-1 in Asian and western patients is different, although a recent global phase 3 study comparing cisplatin/S-1 to cisplatin/5-FU in patients with metastatic gastroesophageal junction or gastric cancer showed this can be accounted for, suggesting this regimen may be effective in western patients with Siewert 2 or 3 tumors.76 Neoadjuvant Therapy
In the INT-0116 study, only 64% of patients were able to complete the treatment. These results were similar to adjuvant therapy trials showing difficulty with treatment tolerance. Therefore, most recent trials have focused upon neoadjuvant therapy.
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The Medical Research Council Adjuvant Gastric Infusional Chemotherapy (MAGIC Trial) compared 3 cycles of epirubicin, cisplatin, and 5-FU before and after surgery to surgery alone in patients with resectable gastric, GEJ, and lower esophageal adenocarcinoma.77 Importantly, this study protocol did not include the use of neoadjuvant radiation therapy. Five-year survival was significantly improved in the multimodality group (36% vs 23%, P 5 .009). Although only 14.5% of patients had lower esophageal tumors, and 11.5% had GEJ tumors, there was no significant interaction between tumor location and survival. These results were confirmed by a multicenter French phase 3 that randomized patients with distal esophageal, EGJ, or stomach adenocarcinoma to perioperative cisplatin/5-FU or surgery alone.78 The perioperative chemotherapy group had improved overall and disease-free survival as well as an increased rate of R-0 resection. Importantly, 64% of the patients had AEGs. Definitive Chemoradiotherapy
Given the efficacy of neoadjuvant chemoradiotherapy, there has been interest in the use of definitive chemoradiotherapy (dCRT) for esophageal cancer.79 Most trials comparing dCRT to esophagectomy were comprised primarily of patients with SCC. Furthermore, the literature suggests that in adenocarcinoma the rate of complete pathologic response is less than squamous carcinoma,80 and survival is significantly worse after dCRT compared with surgery.81 Consequently, the authors believe that surgery is indicated for all resectable AEG patients who are a reasonable operative risk. PALLIATIVE THERAPY FOR ADVANCED DISEASE
Approximately one-third of AEG patients present with stage 4 disease.15 While surgical, endoscopic, or radiotherapeutic treatment may be needed on a case-bycase basis for local palliation and symptom control, systematic chemotherapy remains the mainstay of treatment for these patients. Multiple trials and meta-analyses have shown improved survival and quality of life with palliative chemotherapy in gastric cancer.82–85 Only 2 randomized trials have shown such benefits in esophageal adenocarcinoma.86,87 After initially being developed for SCC, cisplatin/5-FU has been considered the standard treatment regimen for metastatic esophageal and gastric adenocarcinoma with a response rate of 34%.88 Various phase 2 trials have shown improved response rates with the addition of anthracycline agents (doxorubicin or epirubicin)86,87,89–91 or taxanes (docetaxel or paclitaxel).92,93 Other trials have focused on limiting the toxic effects of chemotherapeutic agents. The randomized epirubacin, cisplatin, and fluorouracil [ECF] for advanced and locally advanced esophagogastric cancer 2 (REAL-2) trial demonstrated survival noninferiority when cisplatin and 5-FU in the ECF regimen were replaced with oxaliplatin and oral capecitabine.94 The recent fluorouracil in advanced gastric or gastroesophageal adenocarcinoma (FLAG) trial showed survival noninferiority of cisplatin/S-1 compared with cisplatin/5-FU along with an improved safety profile.76 There has been substantial investigation into targeted biologic agents in the treatment of metastatic gastroesophageal cancer. Approximately 10% of AEGs in the United States overexpress HER2. Trastuzumab, a monoclonal HER-2 antibody, has been widely used in the treatment of breast cancer. The trastuzumab for gastric adenocarcinoma (ToGA) trial randomized patients with stomach or EGJ HER2-positive adenocarcinoma to chemotherapy with and without trastuzumab. Response rate (47% vs 35%) and median overall survival (13.8 months and 11.1 months) were significantly better in the treatment group.95,96 The utility of other agents, such as cetuximab, gefitinib, and erlotinib, are currently under investigation.
Management of Gastroesophageal Junction Tumors
SUMMARY
The incidence of adenocarcinomas of the EGJ is rising dramatically. Although the overall prognosis for these tumors remains poor, surgery and multimodality therapy can be curative. For tumors confined to the mucosa, endoscopic therapy or limited resection is indicated. Tumors penetrating into the submucosa have a high likelihood of lymph node involvement and require radical resection. TTE en bloc esophagectomy with 2-field lymph node dissection is the procedure of choice for patients with Siewert 1 tumors. In patients with compromised pulmonary function, THE esophagectomy should be considered. All patients with T3 or greater tumors or nodal involvement should be considered for chemoradiotherapy, preferably in the neoadjuvant setting. For palliation of stage 4 disease, platinum-based chemotherapy is indicated. If adequate margins can be obtained, either esophagectomy with proximal gastrectomy or THE extended total gastrectomy with D2 lymphadenectomy may be performed for type 2 and type 3 tumors. REFERENCES
1. Devesa S, Blot W, Fraumeni J. Changing patterns in the incidence of esophageal and gastric carcinoma in the United States. Cancer 1998;83:2049–53. 2. Pera M, Manterola C, Vidal O, et al. Epidemiology of esophageal adenocarcinoma. J Surg Oncol 2005;92:151–9. 3. Whitson BA, Groth SS, Li Z, et al. Survival of patients with distal esophageal and gastric cardia tumors: a population-based analysis of gastroesophageal junction carcinomas. J Thorac Cardiovasc Surg 2010;139:43–8. 4. Siewert JR, Stein H. Adenocarcinoma of the gastroesophageal junction: classification, pathology and extent of resection. Dis Esophagus 1996;9:173–82. 5. Siewert JR, Stein H. Classification of carcinoma of the oesphagogastric junction. Br J Surg 1998;85:1457–9. 6. Ishimura N, Amano Y, Kinoshita Y. Endoscopic definition of esophagogastric junction for diagnosis of Barrett’s esophagus: importance of systematic education and training. Dig Endosc 2009;21:213–8. 7. Hameeteman W, Tytgat GN, Houthoff HJ, et al. Barrett’s esophagus: development of dysplasia and adenocarcinoma. Gastroenterology 1989;96:1249–56. 8. Bresalier RS. Barrett’s esophagus and esophageal adenocarcinoma. Ann Rev Med 2009;60:221–31. 9. Siewert JR, Feith M, Stein HJ. Biologic and clinical variations of adenocarcinoma at the esophago–gastric junction: relevance of a topographic–anatomic subclassification. J Surg Oncol 2005;90:139–46. 10. Bai JG, Lv Y, Dang CX. Adenocarcinoma of the esophagogastric junction in China according to Siewert’s classification. Jpn J Clin Oncol 2006;36:364–7. 11. Hasegawa S, Yoshikawa T, Cho H, et al. Is adenocarcinoma of the esophagogastric junction different between Japan and western countries? The incidence and clinicopathological features at a Japanese high-volume cancer center. World J Surg 2009;33:95–103. 12. Fang WL, Wu CW, Chen JH, et al. Esophagogastric junction adenocarcinoma according to Siewert classification in Taiwan. Ann Surg Oncol 2009;16:3237–44. 13. Brown LM, Devesa SS. Epidemiologic trends in esophageal and gastric cancer in the United States. Surg Oncol Clin N Am 2002;11:235–56. 14. Kubo A, Corley DA. Marked multi-ethnic variation of esophageal and gastric cardia carcinomas within the United States. Am J Gastroenterol 2004;99: 582–8.
1207
1208
Fox & van Berkel
15. Pohl H, Welch HG. The role of overdiagnosis and reclassification in the marked increase of esophageal adenocarcinoma incidence. J Natl Cancer Inst 2005;97: 142–6. 16. Rice TW, Blackstone EH, Rusch VW. 7th edition of the AJCC Cancer Staging Manual: esophagus and esophagogastric junction. Ann Surg Oncol 2010;17: 1721–4. 17. Barbour AP, Rizk NP, Gerdes H, et al. Endoscopic ultrasound predicts outcomes for patients with adenocarcinoma of the gastroesophageal junction. J Am Coll Surg 2007;205:593–601. 18. Rampado S, Bocus P, Battaglia G, et al. Endoscopic ultrasound: accuracy in staging superficial carcinomas of the esophagus. Ann Thorac Surg 2008;85: 251–6. 19. Lowe VJ, Booya F, Fletcher JG, et al. Comparison of positron emission tomography, computed tomography, and endoscopic ultrasound in the initial staging of patients with esophageal cancer. Mol Imaging Biol 2005;7:422–30. 20. van Westreenen HL, Westerterp M, Bossuyt PM, et al. Systematic review of the staging performance of 18F-fluorodeoxyglucose positron emission tomography in esophageal cancer. J Clin Oncol 2004;22:3805–12. 21. Sandha GS, Severin D, Postema E, et al. Is positron emission tomography useful in locoregional staging of esophageal cancer? Results of a multidisciplinary initiative comparing CT, positron emission tomography, and EUS. Gastrointest Endosc 2008;67:402–9. 22. Pedrazzani C, Bernini M, Giacopuzzi S, et al. Evaluation of Siewert classification in gastro–esophageal junction adenocarcinoma: what is the role of endoscopic ultrasonography? J Surg Oncol 2005;91:226–31. 23. Ang TL, Ng TM, Fock KM, et al. Accuracy of endoscopic ultrasound staging of gastric cancer in routine clinical practice in Singapore. Chin J Dig Dis 2006;7: 191–6. 24. Blackshaw G, Lewis WG, Hopper AN, et al. Prospective comparison of endosonography, computed tomography, and histopathological stage of junctional oesophagogastric cancer. Clin Radiol 2008;63:1092–8. 25. Meining A, Rosch T, Wolf A, et al. High interobserver variability in endosonographic staging of upper gastrointestinal cancers. Z Gastroenterol 2003;41:391–4. 26. Burtin P, Napoleon B, Palazzo L, et al. Interobserver agreement in endoscopic ultrasonography staging of esophageal and cardia cancer. Gastrointest Endosc 1996;43:20–4. 27. Catalano MF, Sivak MV Jr, Bedford RA, et al. Observer variation and reproducibility of endoscopic ultrasonography. Gastrointest Endosc 1995;41:115–20. 28. Thurau K, Palmes D, Franzius C, et al. Impact of PET-CT on primary staging and response control on multimodal treatment of esophageal cancer. World J Surg 2011;35:608–16. 29. Gananadha S, Hazebroek EJ, Leibman S, et al. The utility of FDG-PET in the preoperative staging of esophageal cancer. Dis Esophagus 2008;21:389–94. 30. Heeren PA, Jager PL, Bongaerts F, et al. Detection of distant metastases in esophageal cancer with (18)F-FDG PET. J Nucl Med 2004;45:980–7. 31. Ott K, Weber WA, Fink U, et al. Fluorodeoxyglucose-positron emission tomography in adenocarcinomas of the distal esophagus and cardia. World J Surg 2003;27:1035–9. 32. Stahl A, Ott K, Weber WA, et al. FDG PET imaging of locally advanced gastric carcinomas: correlation with endoscopic and histopathological findings. Eur J Nucl Med Mol Imaging 2003;30:288–95.
Management of Gastroesophageal Junction Tumors
33. Mahadevan D, Sudirman A, Kandasami P, et al. Laparoscopic staging in gastric cancer: an essential step in its management. J Minim Access Surg 2010;6: 111–3. 34. de Graaf GW, Ayantunde AA, Parsons SL, et al. The role of staging laparoscopy in oesophagogastric cancers. Eur J Surg Oncol 2007;33:988–92. 35. Krasna MJ, Reed CE, Nedzwiecki D, et al. CALGB 9380: a prospective trial of the feasibility of thoracoscopy/laparoscopy in staging esophageal cancer. Ann Thorac Surg 2001;71:1073–9. 36. Ott K, Bader FG, Lordick F, et al. Surgical factors influence the outcome after IvorLewis esophagectomy with intrathoracic anastomosis for adenocarcinoma of the esophagogastric junction: a consecutive series of 240 patients at an experienced center. Ann Surg Oncol 2009;16:1017–25. 37. Johansson J, Djerf P, Oberg S, et al. Two different surgical approaches in the treatment of adenocarcinoma at the gastroesophageal junction. World J Surg 2008;32:1013–20. 38. Lerut T, Coosemans W, Decker G, et al. Surgical techniques. J Surg Oncol 2005; 92:218–29. 39. Stiles BM, Mirza F, Coppolino A, et al. Clinical T2-T3N0M0 esophageal cancer: the risk of node positive disease. Ann Thorac Surg 2011;92:491–6. 40. Matuschek C, Bolke E, Peiper M, et al. The role of neoadjuvant and adjuvant treatment for adenocarcinoma of the upper gastrointestinal tract. Eur J Med Res 2011; 16:265–74. 41. Wong T, Tian J, Nagar AB. Barrett’s surveillance identifies patients with early esophageal adenocarcinoma. Am J Med 2010;123:462–7. 42. Stein HJ, Feith M, Mueller J, et al. Limited resection for early adenocarcinoma in Barrett’s esophagus. Ann Surg 2000;232:733–42. 43. Ell C, May A, Pech O, et al. Curative endoscopic resection of early esophageal adenocarcinomas (Barrett’s cancer). Gastrointest Endosc 2007;65:3–10. 44. Merendino KA, Dillard DH. The concept of sphincter substitution by an interposed jejunal segment for anatomic and physiologic abnormalities at the esophagogastric junction; with special reference to reflux esophagitis, cardiospasm and esophageal varices. Ann Surg 1955;142:486–506. 45. Peyre CG, DeMeester SR, Rizzetto C, et al. Vagal-sparing esophagectomy: the ideal operation for intramucosal adenocarcinoma and Barrett with high-grade dysplasia. Ann Surg 2007;246:665–71. 46. Ho¨lscher AH, Vallbo¨hmer D, Schro¨der W, et al. Limited surgery for “early” cancer of the esophagus. Eur Surg 2007;39:273–80. 47. Westerterp M, Koppert LB, Buskens CJ, et al. Outcome of surgical treatment for early adenocarcinoma of the esophagus or gastro-esophageal junction. Virchows Arch 2005;446:497–504. 48. Liu L, Hofstetter WL, Rashid A, et al. Significance of the depth of tumor invasion and lymph node metastasis in superficially invasive (T1) esophageal adenocarcinoma. Am J Surg Pathol 2005;29:1079–85. 49. Dresner SM, Lamb PJ, Bennett MK, et al. The pattern of metastatic lymph node dissemination from adenocarcinoma of the esophagogastric junction. Surgery 2001;129:103–9. 50. 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. Ann Surg 2004;240:962–74. 51. Hulscher JB, van Sandick JW, Tijssen JG, et al. The recurrence pattern of esophageal carcinoma after transhiatal resection. J Am Coll Surg 2000;191:143–8.
1209
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Fox & van Berkel
52. Jacobi CA, Zieren HU, Muller JM, et al. Surgical therapy of esophageal carcinoma: the influence of surgical approach and esophageal resection on cardiopulmonary function. Eur J Cardiothorac Surg 1997;11:32–7. 53. Areja D, Subhan A, Mirza MR, et al. Transhiatal versus Ivor-Lewis procedure for the treatment of carcinoma esophagus. Pak J Surg 2006;22:126–9. 54. Chu KM, Law SY, Fok M, et al. A prospective randomized comparison of transhiatal and transthoracic resection for lower-third esophageal carcinoma. Am J Surg 1997;174:320–4. 55. Goldminc M, Maddern G, Le Prise E, et al. Oesophagectomy by a transhiatal approach or thoracotomy: a prospective randomized trial. Br J Surg 1993;80: 367–70. 56. Hulscher JB, Van Sandick JW, de Boer A, et al. Extended transthoracic resection compared with limited transhiatal resection for adenocarcinoma of the esophagus. N Engl J Med 2002;347:1662–9. 57. Omloo JM, Lagarde SM, Hulscher JB, et al. Extended transthoracic resection compared with limited transhiatal resection for adenocarcinoma of the mid/distal esophagus: five-year survival of a randomized clinical trial. Ann Surg 2007;246: 992–1000. 58. Escofet X, Manjunath A, Twine C, et al. Prevalence and outcome of esophagogastric anastomotic leak after esophagectomy in a UK regional cancer network. Dis Esophagus 2010;23:112–6. 59. Dantoc MM, Cox MR, Eslick GD. Does minimally invasive esophagectomy (MIE) provide for comparable oncologic outcomes to open techniques? A systematic review. J Gastrointest Surg 2012;16:486–94. 60. Gao Y, Wang Y, Chen L, et al. Comparison of open three-field and minimallyinvasive esophagectomy for esophageal cancer. Interact Cardiovasc Thorac Surg 2011;12:366–9. 61. Biere SS, Maas KW, Bonavina L, et al. Traditional invasive vs. minimally invasive esophagectomy: a multi-center, randomized trial (TIME-trial). BMC Surg 2011; 11:2. 62. Yamashita H, Katai H, Morita S, et al. Optimal extent of lymph node dissection for Siewert type II esophagogastric junction carcinoma. Ann Surg 2011;254: 274–80. 63. Wayman J, Bennett MK, Raimes SA, et al. The pattern of recurrence of adenocarcinoma of the oesophago–gastric junction. Br J Cancer 2002;86:1223–9. 64. Wakatsuki K, Takayama T, Ueno M, et al. Characteristics of gastric cancer with esophageal invasion and aspects of surgical treatment. World J Surg 2009;33: 1446–53. 65. Barbour AP, Rizk NP, Gonen M, et al. Adenocarcinoma of the gastroesophageal junction: influence of esophageal resection margin and operative approach on outcome. Ann Surg 2007;246:1–8. 66. Schumacher G, Schmidt SC, Schlechtweg N, et al. Surgical results of patients after esophageal resection or extended gastrectomy for cancer of the esophagogastric junction. Dis Esophagus 2009;22:422–6. 67. Sasako M, Sano T, Yamamoto S, et al. Left thoracoabdominal approach versus abdominal–transhiatal approach for gastric cancer of the cardia or subcardia: a randomised controlled trial. Lancet Oncol 2006;7:644–51. 68. Bonenkamp JJ, Hermans J, Sasako M, et al. Extended lymph-node dissection for gastric cancer. N Engl J Med 1999;340:908–14. 69. Kunisaki C, Makino H, Suwa H, et al. Impact of splenectomy in patients with gastric adenocarcinoma of the cardia. J Gastrointest Surg 2007;11:1039–44.
Management of Gastroesophageal Junction Tumors
70. Degiuli M, Sasako M, Ponti A. Morbidity and mortality in the Italian Gastric Cancer Study Group randomized clinical trial of D1 versus D2 resection for gastric cancer. Br J Surg 2010;97:643–9. 71. Wei HB, Wei B, Qi CL, et al. Laparoscopic versus open gastrectomy with D2 lymph node dissection for gastric cancer: a meta-analysis. Surg Laparosc Endosc Percutan Tech 2011;21:383–90. 72. Verhoef C, van de Weyer R, Schaapveld M, et al. Better survival in patients with esophageal cancer after surgical treatment in university hospitals: a plea for performance by surgical oncologists. Ann Surg Oncol 2007;14:1678–87. 73. Abate E, DeMeester SR, Zehetner J, et al. Recurrence after esophagectomy for adenocarcinoma: defining optimal follow-up intervals and testing. J Am Coll Surg 2010;210:428–35. 74. Macdonald JS, Smalley SR, Benedetti J, et al. Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophagael junction. N Engl J Med 2001;345:725–30. 75. Sakuramoto S, Sasako M, Yamaguchi T, et al. Adjuvant chemotherapy for gastric cancer with S-1, an oral fluoropyrimidine. N Engl J Med 2007;357:1810–20. 76. Ajani JA, Rodriguez W, Bodoky G, et al. Multicenter phase III comparison of cisplatin/S-1 with cisplatin/infusional fluorouracil in advanced gastric or gastroesophageal adenocarcinoma study: the FLAGS trial. J Clin Oncol 2010;28:1547–53. 77. Cunnignham D, Allum WH, Stenning SP, et al. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med 2006;355: 11–20. 78. Ychou M, Boige V, Pignon JP, et al. Perioperative chemotherapy compared with surgery alone for resectable gastroesophageal adenocarcinoma: an FNCLCC and FFCD multicenter phase III trial. J Clin Oncol 2011;29:1715–21. 79. Morgan MA, Lewis WG, Casbard A, et al. Stage-for-stage comparison of definitive chemoradiotherapy, surgery alone and neoadjuvant chemotherapy for oesophageal carcinoma. Br J Surg 2009;96:1300–7. 80. Tougeron D, Di Fiore F, Hamidou H, et al. Response to definitive chemoradiotherapy and survival in patients with an oesophageal adenocarcinoma versus squamous cell carcinoma: a matched-pair analysis. Oncology 2007;73:328–34. 81. Tougeron D, Scotte M, Hamidou H, et al. Definitive chemoradiotherapy in patients with esophageal adenocarcinoma: an alternative to surgery? J Surg Oncol 2012; 105:761–6. 82. Glimelius B, Ekstrom K, Hoffman K, et al. Randomized comparison between chemotherapy plus best supportive care with best supportive care in advanced gastric cancer. Ann Oncol 1997;8:163–8. 83. Wagner AD, Unverzagt S, Grothe W, et al. Chemotherapy for advanced gastric cancer. Cochrane Database Syst Rev 2010;(3):CD004064. 84. Thuss-Patience PC, Kretzschmar A, Bichev D, et al. Survival advantage for irinotecan versus best supportive care as second-line chemotherapy in gastric cancer— a randomised phase III study of the Arbeitsgemeinschaft Internistische Onkologie (AIO). Eur J Cancer 2011;47:2306–14. 85. Wagner AD, Grothe W, Haerting J, et al. Chemotherapy in advanced gastric cancer: a systematic review and meta-analysis based on aggregate data. J Clin Oncol 2006;24:2903–9. 86. Ross P, Nicolson M, Cunningham D, et al. Prospective randomized trial comparing mitomycin, cisplatin, and protracted venous-infusion fluorouracil (PVI 5-FU) with epirubicin, cisplatin, and PVI 5-FU in advanced esophagogastric cancer. J Clin Oncol 2002;20:1996–2004.
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87. Webb A, Cunningham D, Scarffe JH, et al. Randomized trial comparing epirubicin, cisplatin, and fluorouracil versus fluorouracil, doxorubicin, and methotrexate in advanced esophagogastric cancer. J Clin Oncol 1997;15:261–7. 88. Ohtsu A. Randomized phase III trial of fluorouracil alone versus fluorouracil plus cisplatin versus uracil and tegafur plus mitomycin in patients with unresectable, advanced gastric cancer: The Japan Clinical Oncology Group Study (JCOG9205). J Clin Oncol 2003;21:54–9. 89. Lee JJ, Kim SY, Shin IS, et al. Randomized phase III trial of cisplatin, epirubicin, leucovorin, 5-fluorouracil (PELF) combination versus 5-fluorouracil alone as adjuvant chemotherapy in curative resected stage III gastric cancer. Cancer Res Treat 2004;36:140–5. 90. Zaniboni A, Barni S, Labianca R, et al. Epirubicin, cisplatin, and continuous infusion 5-fluorouracil is an active and safe regimen for patients with advanced gastric cancer. An Italian Group for the Study of Digestive Tract Cancer (GISCAD) report. Cancer 1995;76:1694–9. 91. Highley MS, Parnis FX, Trotter GA, et al. Combination chemotherapy with epirubicin, cisplatin and 5-fluorouracil for the palliation of advanced gastric and oesophageal adenocarcinoma. Br J Surg 1994;81:1763–5. 92. Roth AD, Fazio N, Stupp R, et al. Docetaxel, cisplatin, and fluorouracil; docetaxel and cisplatin; and epirubicin, cisplatin, and fluorouracil as systemic treatment for advanced gastric carcinoma: a randomized phase II trial of the Swiss Group for Clinical Cancer Research. J Clin Oncol 2007;25:3217–23. 93. Thuss-Patience PC, Kretzschmar A, Repp M, et al. Docetaxel and continuousinfusion fluorouracil versus epirubicin, cisplatin, and fluorouracil for advanced gastric adenocarcinoma: a randomized phase II study. J Clin Oncol 2005;23: 494–501. 94. Cunningham D, Starling N, Rao S, et al. Capecitabine and oxaliplatin for advanced esophagogastric cancer. N Engl J Med 2008;358:36–46. 95. Bang YJ, Van Cutsem E, Feyereislova A, et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet 2010;376:687–97. 96. Pearson FG, Patterson GA. Pearson’s thoracic & esophageal surgery. 3rd edition. Philadelphia: Churchill Livingstone/Elsevier; 2008.