Diseases of the Esophagus (2008) 21, 612–618 DOI: 10.1111/j.1442-2050.2008.00826.x
Original article
Does systematic 2-field lymphadenectomy for esophageal malignancy offer a survival advantage? Results from 178 consecutive patients D. J. Martin,1,2 N. G. Church,1 C. W. Kennedy,2 G. L. Falk1,2,3 Concord Repatriation General Hospital, 2Strathfield Private Hospital, and 3Sydney Adventist Hospital, University of Sydney, Sydney, Australia 1
SUMMARY. More extensive resection for esophageal cancer has been reported to improve survival in several series. We compared results from an unselected consecutive cohort of patients undergoing radical esophagectomy, including removal of all periesophageal tissue with a 2-field abdominal and mediastinal lymphadenectomy for esophageal and gastroesophageal malignancy. A prospective electronic database was reviewed for patients with esophageal malignancy undergoing an open esophagectomy between 1991 and 2004. Data were analyzed on an SPSS file (version 12.0, Chicago, IL, USA) using c2 or Fisher’s exact test; odds ratio and 95% confidence interval; and the Kaplan–Meier method, log–rank test and Cox’s proportional hazards regression for survival analysis. There were 178 patients with a median age of 65 years and a 70/30 male to female ratio. Median follow-up was 20.4 months. Pathology comprised adenocarcinoma in 64% of patients, squamous cell carcinoma 30%, and other malignancies 6%. Seventeen patients had neoadjuvant therapy. Hospital mortality was 3.3%. Complete resection was achieved in 87%. Local recurrence occurred at a median of 13 months in 6.7% of patients. Overall 5-year survival was 42%. For patients with invasive squamous cell carcinoma and adenocarcinoma the 5-year survival was 47% and 40.3%, respectively, and for patients without nodal involvement it was 71.5%, with one to four nodes involved, 23.5% and with >4 nodes, 5% (P < 0.001). Survival decreased with increasing direct tumor spread (P < 0.001) and pathological stage (P < 0.001). Esophageal resection with systematic 2-field lymphadenectomy can be performed with acceptable operative mortality and favorable survival. KEY WORDS: esophageal cancer, esophagectomy, lymphadenectomy, survival.
INTRODUCTION Survival after surgery for esophageal cancer has traditionally been poor. Jamieson described an in-hospital mortality of 8.8% and a 27.9% 5-year survival in a recent review of all published literature between 1990 and 2000.1 Evidence for extended lymphadenectomy and extended lateral dissection is scant,2–5 with only one randomized trial reporting a trend towards improved survival with a more extensive procedure.6 Three Western series, utilizing two or three field dissections,2,5,7 report perioperative mortality rates of 3–6.8%; comparatively low recurrence rates,4 and 5-year survival rates of 40–52% supporting the possibility of a survival advantage from a more extensive surgical approach. This paper reports Address correspondence to: Assoc. Prof. Gregory L. Falk, 3 Everton Road, Strathfield, Sydney 2135, Australia. Email:
[email protected] 612
the postoperative mortality, locoregional recurrence and overall survival after esophagectomy with preservation of the pleura and pericardium, and removal of the subcarinal nodes and all mediastinal adventitia below the carina, and 2-field lymphadenectomy (2FL) in an unselected consecutive cohort of patients referred for surgery.
METHODS A prospective database of consecutive esophagectomy patients was reviewed for demographic, hospital mortality, pathology, recurrence and survival data. All patients underwent a standardized surgical resection involving a mediastinal adventitial resection and a 2FL under the care of a single surgeon. Pathology was reported from three separate departments and all cases were staged using the American Joint
© 2008 Copyright the Authors Journal compilation © 2008, Wiley Periodicals, Inc. and the International Society for Diseases of the Esophagus
Radical esophagectomy improves survival
Committee on Cancer (AJCC) criteria8 from definitive operative histology. Preoperative staging was performed by computerized tomography scan and selective endoscopic ultrasound. Bulky mid and lower esophageal lesions also underwent bronchoscopy and staging laparoscopy, respectively. All patients were offered surgery if the disease could be encompassed by resection, including when enlarged mediastinal, hepatic artery, celiac or splenic artery lymph nodes were apparent on preoperative assessment. Lesions primarily based in the gastric cardia, or Siewert III-type adenocarcinomas (AC), were treated by radical abdominal gastrectomy and hence not included in this series. Operative fitness was determined by clinical assessment, pulmonary function testing (forced expiratory volume in 1 second > 1l), arterial blood gas (pO2 > 60 mmHg) and cardiac imaging as clinically indicated. Surgery was performed by a modified Ivor-Lewis abdomino– thoracic (two-stage) technique or McKeown cervico– thoraco–abdominal (three-stage) technique as determined by the tumor site. Neoadjuvant therapy was used for tumors considered to be borderline resectable on preoperative imaging. Selected patients received postoperative chemotherapy if there was high predicted risk of recurrence. Data were analyzed by SPSS (version 12.0, Chicago, IL, USA) using c2 or Fisher’s exact test; odds ratio and 95% confidence interval (CI); and the Kaplan–Meier method, log–rank test and Cox’s proportional hazards regression for survival analysis. Survival time was calculated from the date of surgery until death from any cause. Local tumor recurrence was defined as that occurring at the anastomosis or primary site of the tumor and regional recurrence as otherwise within the field of enbloc and lymph node clearance. Data were compared in table form with those from contemporary large esophagectomy series (>100 patients) where either radical dissection with two or three field lymphadenectomy or more conventional techniques were described as the surgical method. Conventional techniques included either transhiatal esophagectomy or two- or three-stage resections without dedicated lymphadenectomy.
Surgical technique The Ivor-Lewis-type procedure consisted of an open abdominal gastric mobilization and modified D2 gastric lymphadenectomy with splenic preservation followed by a right thoracotomy, lower and middle mediastinal adventitial resection with lymphadenectomy, and an intrathoracic anastomosis. The threestage Mckeown procedure started with a similar thoracic dissection followed by open abdominal dissection and cervical anastomosis. Reconstruction was
613
Fig. 1 Labeled clinical photograph: abdominal cavity post lymph node resection. Shaded areas represent nodal clearance around celiac trunk and its branches.
performed with a greater curve-based gastric conduit or when not available, an isoperistaltic colon. The abdominal procedure was performed through an upper midline laparotomy with construction of a gastric conduit based on right gastric and right gastroepiploic arterial pedicles. A Kocher’s maneuver and pyloroplasty were routinely performed. The stomach was divided prior to ligation of the left gastric pedicle to facilitate exposure for lymph node dissection (Fig. 1). The nodal beds removed were equivalent to a gastric D2 lymphadenectomy, as defined and classified into numbered groups (LN) by the Japanese Gastric Cancer Association for a proximal gastric cancer with esophageal involvement with the exception of the splenic hilar nodes.9 These included the nodal groups of the infradiaphragmatic hiatus and crura (LN 19 and 20); left gastric artery (LN 7); celiac trunk (LN 9); proximal and distal splenic artery (LN 11p and 11d); and the anterosuperior group of the common hepatic artery (LN 8a). D3 and M (metastatic) level lymph nodes along the hepatoduodenal ligament (LN 12) and proximal aorta (LN 16a1) were removed when clinically suspicious. Lower intrathoracic nodal groups (LN 110–112) were removed routinely as part of the thoracic component. Thoracic dissection was performed with the patient in the lateral position through a right fourth or fifth intercostal posterolateral thoracotomy. The esophagus was resected on the mediastinum removing all periesophageal tissue, the thoracic duct, a segment of azygous vein, and diaphragmatic, periesophageal, subcarinal and bronchial nodes. The nodes immediately above the carina were removed with more proximal selective node removal in the upper third preserved for obvious nodes.
© 2008 Copyright the Authors Journal compilation © 2008, Wiley Periodicals, Inc. and the International Society for Diseases of the Esophagus
614 Diseases of the Esophagus Table 1 Other malignancy
1
Stage 1
0.9
1 2 3 4 5 6 7 8 9 10 11
Pathology Basaloid squamous carcinoma Neuroendocrine carcinoma Small cell neuroendocrine carcinoma Leiomyosarcoma Mixed SCC and small cell Adenosquamous Carcinoma Mixed SCC, adenocarcinoma and neuroendocrine Adenosquamous carcinoma Adenosquamous carcinoma Large cell with squamous differentiation Melanoma
3 2B 2A 2A† 2A 1 2B 3 4B 2B 2B
Overall 5-year survival for this group of patients was 20.8%. †Not classifiable by TNM with AJCC – tumor invaded muscularis propria. AJCC, American Joint Committee on Cancer; SCC, squamous cell carcinoma; TNM, tumor–node–metastasis.
0.8 Percentage surviving
Patient
AJCC TNM stage
Stage 2A
0.7 0.6
Stage 2B
0.5 0.4
Stage 3
0.3
Stage 4
0.2 0.1 0 0
12
24
36
48
60
Months since operation
Fig. 2 Patient survival according to tumor American Joint Committee on Cancer tumor–node–metastasis status.
more than four positive nodes (HR2.2, CI 1.3–3.8); and residual tumor (HR1.8, CI 1.3–1.8). Bivariate analysis showed no difference in survival between tumors at the gastro-esophageal junction (GEJ) (n = 66) tumors and more proximal lesions (n = 112, P = 0.96).
RESULTS DISCUSSION Conventional surgery for esophageal cancer over the last decade has produced 5-year survivals of 20–27% where as ‘en bloc’ and systematic lymphadenectomy series report 40–52% 5-year survival (Table 2).2,5,7,10–16 Theoretical advantage of more radical resection includes more complete clearance of the primary tumor and both standard and microscopic lymph node metastases. Hagen and colleagues5 produced a 5-year survival rate of 52% in a series of 100 R0 resections for AC using a dissection similar to this series but involving the removal of the azygous vein and, in 62%, the spleen. The majority of patients also had a colonic conduit, facilitating the removal of much of the greater curve and omental nodes. Altorki and Skinner in a series of 111 patients undertook an aggressive approach that included removal of a cuff of diaphragm for tumors at the hiatus, routine removal of the anterior pericardium and, in 61 patients, a superior mediastinal and lower cervical
Node Negative 1-4 Nodes >4 Nodes
1 0.9 Percentage surviving
One hundred seventy-eight patients were operated on between May 1991 and September 2004 with a median age of 65 years and male/female ratio of 70/30. Follow-up was achieved in 96.5% of cases, with a median of 20.4 months (0–4851 days). Resection was complete (R0) in 87%, microscopically incomplete (R1) in 10% and macroscopically (R2) in 3%. Tumor distribution was AC 64%, squamous cell carcinoma (SCC) 30% and other malignancies 6% (Table 1). The AJCC stage distribution was: stage 0, n = 8; stage 1, n = 35; stage 2A, n = 36; stage 2B, n = 28; stage 3, n = 57; and stage 4, n = 14. Nodal disease existed in 55.3% of patients. Neoadjuvant therapy was given in 17 patients with lesions of marginal resectability, (10 chemoradiation, six chemotherapy, one radiation) with clinical downstaging in six (35%). Postoperative adjuvant therapy was given in 13 patients with poor tumor or stage characteristics. Surgical in-hospital mortality was 3.3%. Locoregional recurrence occurred in 22 patients (12.5%), of which 12 (6.7%) had local recurrence occurring at median of 13 months. (3–31 months). All but one have died of their disease during follow-up. Kaplan– Meier 5-year survival for the whole series was 42%, with in situ disease excluded 39% and for R0 resection 46%. Survival at 5 years for SCC was 47.4% (CI 32.3–61.0); AC 40.3% (CI 30.1–50.2); and other malignancy 20.8%. Survival decreased with increasing T (primary tumor) stage (P < 0.001) and AJCC pathological stage (P < 0.001) as seen in Figure 2. Survival in node negative patients (n = 83) was 71.5% at 5 years; with one to four positive nodes 23.4%; and more than four positive nodes 5% (P < 0.001) as shown in Figure 3. Multivariate analysis (after adjustment for patient age [ 75 years] and tumor stage) revealed an independent association for diminished survival with male sex (HR2.0, CI 1.2–3.2);
0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0
12
24
36
48
60
Months since operation
Fig. 3 Patient survival according to the number of lymph node metastases.
© 2008 Copyright the Authors Journal compilation © 2008, Wiley Periodicals, Inc. and the International Society for Diseases of the Esophagus
Radical esophagectomy improves survival
615
Table 2 Recent esophagectomy studies Staging distribution (%) Author
Year
n
Conventional esophagectomy 2005 121 Zhang16 Orringer10
1999
800
Operation
Perioperative mortality rate (%)
Pathology adeno/SCC/ Other (%)
TT
5
100/0/0
TH
4.5
69/28/0
Vigneswarren15
1993
132
TH
2.3
77/23/0
Lieberman12
1995
258
TT
5
52/48/0
Putman11
1994
221
TT/TH
6.8
66/33/0
Gertsch13
1993
100
TH
3
57/43/0
Karl14
2000
143
TT
2.1
85/11/4
(T) (TNM)
Tis 0
1 1
3 2
3 3
4 3
Survival % (5 years)
(T) (TNM) (T) (TNM) (T) (TNM) (T) (TNM) (T) (TNM) (T) (TNM) (T) (TNM)
0 0
37 35
47 35
6 6
20
9 4.5 4 0
12 14 12 9
37 57 50 72
8 4.5 1 0
0
6
10
13
10 24 np 34 20 33 19 np np np 18 np np 38
23
40
36
31
8
63/30/7
(T) (TNM)
4 4
24 20
21 36
45 32
6 8
En bloc and extended lymphadenectomy 2001 100 TT Hagen5
6
100/0/0
(T) (TNM) (T) (TNM) (T) (TNM)
0 0 0 1 1
26 22 21 14 9
np 24 19 27 14 28
32 56 31 70 29
18 3 21 1 34
111
TT
6.8
63/27/0
Lerut2
2004
174
TT
3
54/46/0
23 29 (3 years)
3.3
2001
27†‡ 19†
Systematic 2-field lymphadenectomy Martin 2005 178 TT
Altorki7
21
42 52†§ 40 42§
†Actuarial survival; ‡complete and microscopically incomplete resections included only; §complete resections included only – R0 rate 91%. np, not published; SCC, squamous cell carcinoma; TNM, tumor–node–metastasis; T, tumor stage; TT, transthoracic; TH, transhiatal.
lymph node dissection along both recurrent laryngeal nerves, giving a 5-year survival of 40%.7 The 5-year survival of 42% and 3.3% in-hospital mortality in our series using a systematic 2FL is not different from ‘en bloc’ series, with overall survival of 46% for complete resection. Three field lymphadenectomy, advocated by many in Japan,17,18 is also now being performed with some success in the West. Lerut2 et al. have produced favorable survivals of 42% with a low 2.5% recurrent laryngeal nerve injury rate. The addition of the third field, although not appearing to benefit patients with gastroesophageal junction (GEJ) tumors, may offer improved survival for more proximal lesions.2,19,20 Other experiences with this procedure however have reported significant morbidity and a decreased quality of life with respect to less radical esophagectomies.21 The survival for the three-field dissection reported by Lerut is not different from the 2FL reported herein although there were more advanced lesions in the three-field cohort with a 25% difference in T3 lesions (Table 2). The only randomized controlled trial (RCT) comparing a transthoracic (TT) radical dissection and transhiatal (TH) surgery in esophageal cancer, involving 220 patients all with AC, showed a trend towards improved 5-year survival favoring the TT procedure (39% vs 29%).6 In this study from the University of Amsterdam the resection in the TT proce-
dure was more extensive than our series, including the removal of the azygous vein and nodes of the aortopulmonary window. The TH procedure involved ligation of the left gastric artery at its base with further removal of D2 lymph nodes if clinically suspicious. Earlier randomized studies22,23 involving a total of 106 patients, all with SCC, found no significant difference in morbidity or survival between conventional TT and TH approaches. A further study of 26 patients,24 which only ever published 1-year survival data, did not show a difference in outcome in comparing “en bloc” TT and “systematic lymphadenectomy” TH approaches. It did however demonstrate that lymph node retrieval was greater for the TT approach: 37.6 versus 19.9 nodes. This is consistent with cadaveric studies show the extensive TH approach does not achieve an equivalent lymphadenectomy to that done via thoracotomy.25 A potential oncological advantage of a radical TT approach is that it allows routine removal of thoracic nodes, such as the supracarinal group that are not readily accessible from a TH approach.24,25 Supracarinal nodes are involved in Barrett’s related esophageal AC, in 4% and 16% of T2 and T3 lesions, respectively (Fig. 4).26 More minimal disease may also be a factor with immunohistochemistry in esophageal and GEJ AC increasing nodal positivity, which has shown to be prognostic, by 33–60%.27,28 The more radical TT arm of the large RCT from the University of Amster-
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616 Diseases of the Esophagus
Fig. 4 Distribution of lymph nodes metastases with Barrett’s cancer of the esophagus. The pattern of lymph node spread in adenocarcinomas of the distal esophagus is closely related to T-staging of the primary and occurs primarily in the paratumoral region of the lower posterior mediastinum, the paracardial region and along the lesser gastric curvature. A study of lymph node metastases in 286 cases of Barrett-type tumors with more than 15 nodes was sampled at esophagectomy (Reproduced from Feith M, Stein H J, Siewert J R,26 with permission.)
dam study6 had the same 5-year survival rate for AC as with our series, in comparison with the TH series listed in Table 2 with their subsequent less radical thoracic lymph node clearance.10–16 As the nodal drainage area of the lower esophagus (Fig. 4) includes cardiac gastric nodes, left gastric nodes and the celiac trunk, gastric D2 lymphadenectomy is theoretically appropriate to achieve R0 resection. Although there is little RCT evidence supporting the D2 procedure in gastric cancer, data from observational studies (including a Cochrane review) demonstrate that D2 resection for gastric cancer in specialist units is safe and achieves superior results.29,30 The only two European RCT gastric lymphadenectomy trials have been confounded by the effect of high perioperative mortality of 10–13% of low volume surgeons.31,32 In our series a 2FL, consisting of a modified gastric D2 lymphadenectomy with a mediastinal lymphadenectomy to above the level of the azygous, was achieved with mortality much less than that of the gastrectomy + D2 lymphadenectomy in these two trials. It appears therefore that experienced units can
offer an abdominal lymphadenectomy safely and that this can be incorporated in techniques of esophageal resection with potential survival advantage.2,3,6,7 Various possibilities exist to explain the seeming improved figures of the ‘en bloc’ series. Patient sampling is one possibility, but as evident in Table 2, the T stage and tumor–node–metastasis (TNM) stage distribution is similar across the range of conventional and the other more radical series. Where published, we have included T-staging for comparison, which is less likely to be affected by upstaging with increased lymph node retrieval than the TNM system. The potential for upstaging however with the current AJCC N0 (node negative) or N1 (node positive) lymph node criteria is thus limited except when distal nodal involvement occurs as occurs in three field series. One hundred forty-one cases in our series were distal esophageal or GEJ carcinomas. AC tumors in this location are rapidly increasing in incidence and have a pattern of lymph node spread that is closely related to T-staging of the primary and occurs primarily in the paratumoral region (Fig. 4) of the lower posterior mediastinum, the paracardial region and along the lesser gastric curvature with skipped nodal stations reported in only 5% of cases.26 Cervical lymphadenectomy however, as reported by Lerut, demonstrated further skipped nodal stations in 8% of patients, accounting for a large number of Stage 4 tumors in their results.2 Increased tumor clearance, with subsequent improved local control and longer survival, may be a factor. Dexter et al. found a clearance margin of 1 mm or less significantly decreased 3-year survival from 78% to 44% in patients with minimal nodal disease.3 The R0 resection rate of 88% in our series may be in part due to the dissection on the mediastinum and subsequent increased pathological tumor clearance with respect to more minimalist techniques. The high proportion of distal tumors may also allow R0 resection due to the relative ease of clearance in the lower third. These factors may contribute to our series’ relatively low local recurrence rate of 6.7% (locoregional 12%) at moderate follow-up of 20.4 months, compared with reported rates of local recurrence of 20–60% after standard surgical resection.4 In contemporary surgical practice it is also relevant as to whether this type of radical clearance can be applied to minimal invasive esophagectomy. It is our experience,33 as well as that in large minimally invasive esophageal centers,34 that although thoracoscopic and laparoscopic esophagectomy can be achieved with acceptable safety, completeness of tumor clearance and lymphadenectomy – especially in the thorax – does not yet match a radical open approach such as that described herein. Although it would be expected that a growing experience with laparoscopic radical abdominal lymphadenctomy for gastric cancer35,36 would evolve to more aggressive
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Radical esophagectomy improves survival
thoracoscopic clearance for esophageal cancer, the combined learning curves of both radical and minimally invasive techniques is unlikely to see this adopted nor achieved as a universal standard in the near future. This series demonstrates that an ‘en bloc’ type of primary tumor excision for esophageal cancer and lymphadenectomy based on the known pattern of metastasis yields survival rates that are 10–20% better than contemporary and historical series, with acceptable mortality. Acknowledging the flaws in cohort comparison, the mechanism for this potential difference in survival remains uncertain, but may encompass more complete radial excision or lymphadenectomy. The operation performed in this series is less radical than the ‘en bloc’ operation reported by Skinner, Lerut and DeMeester, and has been applied unselectively. It has however yielded comparable results. Though randomized controlled trial evidence is lacking, the fact that this type of procedure can be performed without undue mortality in experienced hands would add support to the adoption of this technique as the contemporary surgical standard. Acknowledgment Dr Owen F. Dent for valuable statistical analysis and advice. References 1 Jamieson G G, Mathew G, Ludemann R, Wayman J, Myers J C, Devitt P G. Postoperative mortality following oesophagectomy and problems in reporting its rate. Br J Surg 2004; 91: 943–7. 2 Lerut T, Nafteux P, Moons J et al. Three-field lymphadenectomy for carcinoma of the esophagus and gastroesophageal junction in 174 R0 resections: impact on staging, disease-free survival, and outcome: a plea for adaptation of TNM classification in upper-half esophageal carcinoma. Ann Surg 2004; 240: 962–72. 3 Dexter S P, Sue-Ling H, McMahon M J, Quirke P, Mapstone N, Martin I G. Circumferential resection margin involvement: an independent predictor of survival following surgery for oesophageal cancer. Gut 2001; 48: 667–70. 4 Altorki N K. The rationale for radical resection. Surg Oncol Clin N Am 1999; 8: 295–305. 5 Hagen J A, DeMeester S R, Peters J H, Chandrasoma P, DeMeester T R Curative resection for esophageal adenocarcinoma: analysis of 100 en bloc esophagectomies. Ann Surg 2001; 234: 520–30. 6 Hulscher J B, van Sandick J W, de Boer A G et al. Extended transthoracic resection compared with limited transhiatal resection for adenocarcinoma of the esophagus. N Engl J Med 2002; 347: 1662–9. 7 Altorki N, Skinner D. Should en bloc esophagectomy be the standard of care for esophageal carcinoma Ann Surg 2001; 234: 581–7. 8 Greene F L, Page D L, Fleming I D. et al., (eds). AJCC Cancer Staging Manual, 6th edn. New York, NY: Springer, 2002; 127– 37. 9 Japanese Gastric Cancer Association. Japanese classification of gastric carcinoma – 2nd English edn. Gastric Cancer 1998; 1: 10–24.
The authors have no conflicting interests to declare.
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