World J Surg (2013) 37:1757–1767 DOI 10.1007/s00268-013-2018-5
Extended Lymphadenectomy in Esophageal Cancer is Debatable Fernando A. M. Herbella • Rafael M. Laurino Neto Marco E. Allaix • Marco G. Patti
•
Published online: 4 April 2013 Ó Socie´te´ Internationale de Chirurgie 2013
Abstract Surgery is an essential part of the treatment of patients with esophageal carcinoma. However, there is no consensus on whether the surgical technique can be improved to promote better survival outcome. Specifically, the real value of the addition of a radical lymphadenectomy to the esophageal resection is still elusive and controversial. This paper focuses on the debate of esophagectomy and lymphadenectomy for the treatment of esophageal cancer.
Introduction Esophageal carcinoma (EC) is a devastating disease. The global incidence of EC has regional discrepancies (Fig. 1) [1]; however, the World Health Organization listed EC as the eighth most common cancer worldwide in 2008 with 481,000 new cases (3.8 % of the total), and the sixth most common cause of death from cancer with 406,000 deaths (5.4 % of the total), leading to a mortality rate of 84 %. The United States National Cancer Institute estimates an incidence of 17,460 new cases of EC in US in 2012 with 15,070 deaths expected, a mortality rate of 86 %. Surgery is considered an essential part of the treatment of patients with EC [2] as it has been shown that the nonsurgical approach to EC is associated with poor
F. A. M. Herbella (&) R. M. Laurino Neto Department of Surgery, Escola Paulista de Medicina, Federal University of Sao Paulo, Sao Paulo, Brazil e-mail:
[email protected] M. E. Allaix M. G. Patti Department of Surgery, University of Chicago Pritzker School of Medicine, Chicago, IL, USA
survival outcome [3]. The improvement in survival was initially achieved at the cost of very high morbidity and mortality. For instance, in 1980, Earlam and Cunha-Melo [4] reviewed the literature and reported a 29 % mortality rate for esophagectomy. Some oncologists still quote these numbers as a justification for a nonsurgical approach to EC. However, recent studies have shown that particularly in high-volume centers the mortality rate is about tenfold lower, probably as a result of improvement in anesthesia, analgesia, intensive care, and surgical technique. Nowadays, esophageal resection, with or without chemotherapy or radiotherapy, still was shown to have a better survival rate than the nonsurgical approach [5]. Although some reports have a mortality rate of less than 2 % [6, 7], still a rate of up to 15 % of deaths linked to the surgical procedure is commonly reported in multicenter studies [8, 9]. Unfortunately, the 5-year survival rate has not passed the 40 % level [10]. It is unclear if surgery has reached its limit. Some authors believe that efforts should be focused on perioperative care based on standard protocols [11, 12], while others believe that the surgical procedure still can be improved. This generates controversies in regard to operative technique, such as what is the ideal approach, i.e., open versus minimally invasive [13] and the addition of radical lymphadenectomy to esophageal resection [14]. Based on his research on breast cancer, Halsted [15] once stated that an adequate operation for cancer should remove the entire cancer along with its lymphatic drainage. While the validity of this statement for some type of cancers has been shown over time, it is still unclear if the addition of lymphadenectomy improves the outcome of esophageal resection for cancer. This paper focuses on the debate of esophagectomy and lymphadenectomy for the treatment of EC.
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Fig. 1 Global incidence for esophageal cancer. Figure in public domain as a courtesy of Ferlay et al.
The esophagus has a peculiar anatomy In order to start the debate on the benefit of lymphadenectomy in the treatment of EC, some peculiar characteristics of the surgical anatomy of the esophagus must be summarized: (1) important organs surround the esophagus, (2) the esophagus crosses the neck, the chest, and the abdomen, (3) the lymphatic distribution is abundant, and (4) the lymph nodes’ distribution is erratic. The esophagus lies in the mediastinum and is near or in close contact with vital organs [16]. This situation limits the application of classic oncologic premises such as extended margins and questions how oncologically correct an esophagectomy can be. In 1963, Logan [17] defined the principles of en bloc esophagectomy. This included
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resection of the right and left parietal pleura, pericardium, and all tissues between the esophagus and aorta or vertebral bodies, including the thoracic duct, azygos vein, segments of the right intercostal arteries, and right and left intercostal vein segments on the anterior vertebral bodies. Even this radical technique allowed resection margins not greater than 2 or 3 cm from the esophagus. This approach had a mortality rate of 11 %, with a survival rate of 20 %, not different from less morbid approaches [18]. The esophagus crosses the neck, the chest, and the abdomen. This long path across the body has two consequences: (1) lymph nodes in these three areas may be involved and (2) esophageal resection becomes a challenging operation. Three-field lymphadenectomy is discussed latter in this paper, but lymph node metastasis in the
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neck, thorax, and abdomen has been found in EC from all parts of the esophagus, even skip metastasis [19]. An abundant intramural lymphatic distribution in the esophagus has been described [20], facilitating the spread of cancer cells through the lymph nodes. In theory, a complete lymphadenectomy should include the three fields mentioned. Esophagectomy is probably one of the most complex operations of the digestive system, and the addition of an extended lymphadenectomy increases the complexity of the dissection, the duration of the operation, and the morbidity rate [21]. Anatomy textbooks show a regular disposition of nodes not seen by surgeons [22], but very few studies describe a surgically oriented mediastinal lymph node distribution. Halsted can be quoted again regarding the view provided by the dissection of a patient during an operation: ‘‘There is a gap between the surgeon and pathologist which can be filled only by the surgeon. The pathologist seldom has the opportunity to see diseased conditions as the surgeon sees them’’ [15]. Moreover, there is no standardization of the classification and nomenclature of mediastinal lymph nodes. Although various classifications have been developed by societies and individual authors [23], none has gained unanimous acceptance. Different anatomical studies [23–26] showed an inconsistent and variable distribution in the number and location of lymph nodes. Clinical studies also have shown an outstanding variance in the number of nodes resected in the mediastinum during an esophagectomy and lymphadenectomy for cancer, with an average per patient ranging from 13 to 38 [27–30], with individual variations ranging from 24 to 127 in a single study [18].
Indications for lymphadenectomy Every cancer, irrespective of the organ of origin or histologic type, evolves naturally from local to regional to systemic disease [31]. In theory, surgery alone cures local cancers, may bring a cure in regional disease if all compromised tissues are resected, and is palliative for systemic tumors [32]. For some neoplasms the stage in which the tumor is localized is easily determined. This is not the case for the esophagus (Table 1). The peculiar anatomy of the lymphatics of the esophagus makes the systemic spread of the disease very easy. Between 20 and 40 % of EC cases are unresectable at the time of diagnosis [33]. Another significant number of cases have subclinical metastases detected during specialized tests, e.g., 20–30 % of bone marrow metastases in resectable EC [34–36] and a 50 % presence of micrometastasis in patients with histologynegative nodes [37]. It may be argued that surgery alone cannot control regional disease but a combined therapy may. However, is there a threshold of cytoreduction? In
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other words, if all compromised lymph nodes do not need to be resected, do they need to be resected at all? Based on these considerations, some believe that the addition of lymphadenectomy to esophagectomy should be limited to early EC in order to ensure that there is no clinical detectable lymph node metastasis but all micrometastases will be resected [38], since they may impact survival negatively [39, 40]. Others believe that only clinical metastases should be resected, extending the indication for lymphadenectomy to stage III of the disease [41]. Very interestingly, Tabira et al. [42] showed that an extended three-field lymphadenectomy brings better survival in patients with one to four positive nodes while N0 patients or those with more than five compromised lymph nodes did not benefit from the procedure.
How complete lymphadenectomy can (is intended to) be achieved Transhiatal esophagectomy is inadequate for lymph node retrieval. Some authors tried to extend dissection under direct vision or add splitting the mediastinum above the hiatus, thus creating a ‘‘radical transhiatal esophagectomy’’ [43, 44], but this technique never became very popular. Experiments with cadavers [45] showed that this type of operation is not able to resect upper mediastinal lymph nodes and retrieves only 25 % of the lower mediastinum nodes. There is no consensus among the advocates of esophagectomy plus lymphadenectomy on the minimal number of lymph nodes that should be resected, ranging between 6 and 30 [10, 46, 47]. Transthoracic esophagectomy without formal lymphadenectomy (Ivor-Lewis operation) may also be an inadequate operation for complete lymphadenectomy if advocates of a greater number of lymph nodes are consulted. On average, an Ivor-Lewis operation retrieves anywhere between 15 and 18 lymph nodes [48, 49]. A radical en bloc esophagectomy, as proposed by Logan [17] and followed by others [18, 50], often includes only infracarinal lymph nodes (Fig. 2), especially in cases of distal adenocarcinoma [51]. Three-field esophagectomy is currently performed by Asian surgeons mostly in patients with mid-thoracic squamous cell carcinoma [52–54], although cervical lymph node metastases can be detected in 25–37 % of the distal adenocarcinoma cases [55, 56]. Minimally invasive esophagectomy seems to allow a similar lymphadenectomy compared to the open techniques [7, 13]. Similarly, robotic esophagectomy seems to offer a lymphadenectomy comparable to open or minimally invasive techniques [57, 58].
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Can anyone do an esophagectomy plus lymphadenectomy? There is a striking correlation between the frequency of esophagectomy performed at a hospital and its outcome, suggesting that such a complex and high-risk surgical procedure should be restricted to facilities with a yearly minimum volume [59–61]. There is no consensus on the number of esophagectomies that constitutes a learning curve for the procedure; conversely, Sutton et al. [59] showed that there is continuing improvement in the outcome of esophagectomy over a 7-year period. Boone et al. [62] surveyed 269 surgeons around the world about surgical techniques for esophageal resection for EC. Although most of the responders (72 %) performed a two-field lymphadenectomy routinely, a three-field lymphadenectomy was routinely performed by only 12 % of surgeons. Table 1 Characteristics and estimated prevalence of the extent of disease at presentation (from [31]) Local disease: (15 %) Asymptomatic Minimal or no visible lesion Regional disease: (25 %) Minimal symptoms (anemia) Small (\2–3 cm) noncircumferential Systemic disease: (60 %) Dysphagia [3 cm circumferential tumor, plus nodes on EUS
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Interestingly, this group comprised mostly surgeons from high-volume centers with over 21 years of experience. Not only surgeon’s experience makes difference in the outcome but the perioperative care facilities and staff do as well [63]. Patti et al. [59] showed that although the incidence of postoperative complications is similar in hospitals with different volumes of esophageal resections, the associated mortality rates were lowest in high-volume centers.
Is it only a matter of better staging? Lymphadenectomy is sometimes considered just a way to improve staging of esophageal cancer rather than a way to promote better survival; the more lymph nodes resected the more precise the staging will be. This may be attributed to stage migration due to the Will Rogers phenomenon [64]. For instance, a node-positive patient who undergoes a transhiatal esophagectomy without sampling of the metastatic lymph nodes will be classified as N0 and his/her survival will be compared to that of N0 patients who instead had a transthoracic esophagectomy with lymphadenectomy. Furthermore, the confusion increases with the detection of micrometastases [65]. If survival of transthoracic esophagectomy patients is compared with that of transhiatal esophagectomy patients one stage above as compensation for stage migration, the numbers favor transhiatal esophagectomy, probably due to a lower procedure-linked mortality rate (Table 2). Even within series the same phenomenon may be found [65]. A careful
Fig. 2 Specimen from an esophagectomy plus distal radical lymphadenectomy
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analysis of survival in a large study by the University of Southern California [66] showed that the survival rate of stage I patients after transhiatal esophagectomy was around 60 %, similar to the survival rate of patients with stage II who underwent an en bloc esophagectomy. Also, survival for stage III of the disease, when stage migration is not possible since further lymph node metastases will not advance to stage IV, is not different whether a lymphadenectomy is performed or not [66]. In a large multicenter series with 4,627 patients, Rizk et al. [67] showed that when seven or more lymph nodes are positive, the advantages of a more extended lymphadenectomy vanish. Very interestingly; however, the number of negative lymph nodes resected seems to improve survival even in N0 patients [68, 69]. This may be due to the resection of lymph nodes with micrometastases that may influence survival, even in early EC [39], or to better staging due to a more adequate sampling of the nodes. The 2010 7th edition of the American Joint Committee on Cancer/International Union Against Cancer Staging Manual changed the N classification for EC from the simple absence (N0) or presence (N1) of metastatic lymph nodes to a more complex classification based on the number of compromised lymph nodes (N0 = absence of metastasis, N1 = metastases in 1–2 regional lymph nodes, N2 = metastases in 3–6 regional lymph nodes, N3 = metastases in C7 regional lymph nodes). This new staging system is based on datadriven recommendations from a database of more than 7,800 esophageal cancer patients created by a large multi-institutional collaboration involving 13 institutions [70]. Some studies showed that these criteria resulted in better prognostic stratification than the 6th edition [71–73]. Again, the number of nodes needed for an adequate staging is still elusive.
Table 2 Comparison of survival from transthoracic esophagectomy patients compared to transhiatal esophagectomy patients one stage above as a compensation for stage migration due to the extended lymphadenectomy
Lymphadenectomy-associated morbidity/mortality The addition of lymphadenectomy to esophagectomy demands more operative time, harvesting of more mediastinal lymphatic ducts that drain the lungs, and the need to mobilize the patient during the procedure compared to transhiatal esophagectomy. These factors intuitively appear to increase morbidity and mortality. Different studies compared the morbidity associated with transhiatal or transthoracic esophagectomy. A recent meta-analysis of these studies [74] confirmed a higher risk for pulmonary complications (35.7 vs. 28.0 %) and early mortality (10.6 vs. 7.2 %) after thoracotomy than after the transhiatal approach. In a large multicenter study in which only 20 % of the surgeons performed a three-field esophagectomy, a threefield lymphadenectomy was also shown to be more associated with an increased rate of pulmonary complications than a two-field lymphadenectomy [75]. A high incidence of recurrent nerve injury, up to 70 %, has also been associated with a three-field esophagectomy [76].
Recurrence after esophagectomy – lymphadenectomy The pattern of cancer recurrence after an esophagectomy with or without lymphadenectomy may shed light on the necessity of lymph node harvesting. Thus, a significant rate of local recurrence after an esophagectomy with lymphadenectomy may imply that complete lymph node resection is not possible or that periesophageal perinodal tissue may also be compromised [76]. On the other hand, systemic recurrence may lead to the assumption that the disease is systemic at the time of treatment. The recurrence
Transhiatal esophagectomy stage I
Transthoracic esophagectomy stage II Transhiatal esophagectomy stage II
Transthoracic esophagectomy Stage III
Author
5-year survival (%)
Average (%)
Orringer et al. [87]
65
62
Portale et al. [66]
60
Montenovo et al. [90]
80
Yannopoulos et al. [91]
61
Vigneswaran et al. [92]
47
Portale et al. [66]
60
Tachibana et al. [93]
51 (average T2A & B)
Orringer et al. [87]
28 (average T2A & B)
Portale et al. [66]
50
Montenovo et al. [90]
59 (average T2A & B)
Yannopoulos et al. [91]
48
Vigneswaran et al. [92]
38
Portale et al. [66] Tachibana et al. [93]
20 28
55 45
24
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Table 3 Pattern of disease recurrence for esophageal cancer treated by esophagectomy plus lymphadenectomy (reproduced with permission from [78]) Author (institution)
Year reported
Lymph node dissection
Recurrence/ total
Incidence of each recurrence pattern
Recurrence time after surgery
Locoregional (%)
Distant (%)
Lymphatic
Local
Hematogenous
Mixed
4
24
23
46 Liver [ lung [ bone
12
33
4
Morita et al. (Kyushu Univ. and National Kyushu Cancer Center)
1994
Two-field
95/187 (51 %)
48
Matsubara et al. (Cancer Institute Hosp.)
1996
Threefield
83/230 (36 %)
42
Kato et al. (National Cancer Center)
1996
Threefield
33/115 (29 %)
27
Bhansali et al. (Kurume Univ.)
1997
Threefield
39/90 (43 %)
49
21
51
56 % within 1 year 84 % within 2 years
11.1 months (mean) for pT3 tumor
10.5 months (mean) for locoregional recurrence 11.4 months (mean) for distant recurrence
Kiazanos et al. (Shimane Medical Univ.)
2003
Threefield
41/151 (27 %)
42
Osugi et al. (Osaka City Univ.)
2003
Threefield
98/246 (40 %)
21
11
68
Nakagawa et al. (Niigata Univ.)
2004
Threefield
74/171 (43 %)
48
6
38
Doki et al. (Osaka Medical Center)
2005
Two-field or threefield
180/501 (36 %)
67
7
55 Liver [ lung [ bone
Motoyama et al. (Akita Univ.)
2006
Two-field or threefield
90/270 (33 %)
48
8
31
1
Natsugoe et al. (Kagoshima Univ.)
2006
Two-field or threefield
131/367 (36 %)
33
3
34 Lung [ liver = bone
31
Kato et al. (Gunnma Univ.)
2006
Two-field or threefield
59/160 (37 %)
22
51 Liver [ lung [ bone [ brain
27
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22
37
19 months (median) for locoregional recurrence 8.4 months (median) for distant recurrence 83 % within 2 years
8
17.5 months (median) for locoregional recurrence 8.0 months (median) for distant recurrence Patients with multiple recurrences counted as overlapped
18.8 months (mean) for loco-regional recurrence 13.9 months (mean for hematogenous recurrence 8.4 months (mean) for mixed recurrence
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Table 3 continued Author (institution)
Current study
Year reported
2011
Lymph node dissection
Two-field or threefield
Recurrence/ total
61/208 (29 %)
Incidence of each recurrence pattern
Recurrence time after surgery
Locoregional (%)
Distant (%)
Lymphatic
Local
Hematogenous
Mixed
48
5
36 Lung [ liver [ bone
11
71 % within 1 year 84 % within 2 years 14.4 months (mean) for locoregional recurrence 11.8 months (mean) for hematogenous recurrence 8.3 months (mean) for mixed recurrence
pattern following a transhiatal esophagectomy without lymphadenectomy shows that local and systemic spread parallels in EC, with an index of 23 % for locoregional recurrence, 25 % for systemic recurrence (hematogenous metastases), and 15 % in both [77]. Literature data (Table 3) shows that locoregional recurrence after esophagectomy and lymphadenectomy occurs in a significant proportion of patients, ranging from 22 to 67 %, and that it parallels the systemic spread. Technical limitations are blamed for incomplete lymphadenectomy, especially in the upper mediastinum [78].
Survival Does lymphadenectomy added to esophagectomy improve survival? Or is it the more extensive lymph node harvesting that allows better staging and migration? This is the main question that needs to be answered. As previously mentioned, the analysis of case series comparing survival stage by stage may lead to unreliable results due to stage migration. Probably the analysis of the global oncologic outcomes of randomized studies may shed light on the question if lymphadenectomy improves survival for EC since a single population with an equal chance to be allocated to either group irrespective of stage is studied, thus minimizing the Will Rogers phenomenon. Unfortunately, there are no prospective trials comparing survival with or without the formal addition of extended lymphadenectomy. However, when limited transhiatal esophagectomy and transthoracic esophagectomy are compared, neither prospective trials [79–82] or nor a metaanalysis of the literature data [74, 83, 84] showed differences in survival between these two operations, even though the number of lymph nodes dissected was frequently higher for the transthoracic approach. Onloo et al.
[85] published the most significant trial with 220 randomized patients. Five-year survival was not different between transhiatal (34 %) and transthoracic esophagectomy (36 %) even though a radical en bloc technique was used for the transthoracic group. Three meta-analyses have compared the survival of transhiatal versus transthoracic esophagectomy. Rindani et al. [83] reviewed the studies published between 1986 and 1996. The authors found no difference in 5-year survival between transhiatal esophagectomy (24 %) and transthoracic esophagectomy (26 %). Interestingly, a subanalysis of early EC (stages I ? II) also did not show differences between the two approaches when the data from adjuvant therapy were excluded. Hulscher et al. [84] in 2001 reported similar results. Boshier et al. [86] reviewed the literature in a recent meta-analysis that included 52 studies and also found no differences in survival, with numbers very similar to the other reviews (26 vs. 27 %). Morbidity was also significantly lower for the transhiatal group. This review may be criticized because of the preference to use the transhiatal approach in patients with lower stages of the disease. However, the average figures obtained are very similar for large series from experienced centers that employ transhiatal or transthoracic esophagectomy routinely in all patients. Thus, Orringer et al. [87] showed a 29 % 5-year survival rate for a cohort of 1,500 cases of EC who underwent a transhiatal esophagectomy. Similarly, a 30 % 5-year survival rate was found by Morita et al. [86] in a cohort of 1,000 patients who had transthoracic esophagectomy. The survival benefits according to the extent of the lymphadenectomy have been addressed in comparative trials when two-field and three-field lymphadenectomy are compared. Nishihira et al. [88] compared two-field and three-field lymphadenectomy in a subgroup of selected patients comprising 27 % of all patients treated for EC. The authors, contrary to other authors from the East
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[42, 89], did not show a survival benefit for three-field esophagectomy, with a higher morbidity rate associated with the need for a tracheostomy, a longer period with mechanical ventilation, and a higher incidence of recurrent nerve injury and phrenic nerve palsy.
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10.
11.
Conclusions: the case against lymphadenectomy The esophagus has a peculiar anatomy that makes (1) esophagectomy a challenging operation and thus morbidity should be minimized, (2) oncologic margins theoretical, and (3) lymphatic drainage to be abundant, erratic, and unpredictable, leading to early dissemination of the disease and precluding a complete lymphadenectomy. In view of these facts, esophagectomy plus lymphadenectomy to treat EC is debatable. It is probably not the type of operation we perform that makes a difference but rather the stage of the disease at the time the operation is performed. This operation should be better scrutinized and performed only in high-volume centers with experienced multidisciplinary teams.
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15.
16. 17.
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