Surgical Management of Esophageal Malignancy Dennis Blom, MD
Address Divisions of Minimally Invasive and Gastrointestinal Surgery, Gastroenterology, and Hepatology, Department of Surgery, Medical College of Wisconsin, 9200 West Wisconsin Avenue, Milwaukee, WI 53226, USA. E-mail:
[email protected] Current Gastroenterology Reports 2003, 5:192–197 Current Science Inc. ISSN 1522-8037 Copyright © 2003 by Current Science Inc.
Esophageal carcinoma is a highly lethal disease with increasing prevalence and an equally dramatic epidemiologic shift. Its causal association with gastroesophageal reflux disease and adenocarcinoma of the esophagus is well established, and the molecular events underlying this progression from mucosal injury to metaplasia to dysplasia to carcinoma are now becoming clear. Current diagnostic modalities and preoperative staging systems have significant limitations. The extent of surgical resection for esophageal carcinoma remains controversial. Disease confined to the mucosa and submucosa is more common, and endoscopic ablative techniques have been proposed. However, preoperative evaluation of tumor depth and regional nodal metastases remains inadequate in these very early lesions and urges caution before adoption of therapies that may compromise cure. Patients with disease confined to the mucosa or submucosa should undergo resectional therapy aimed at removing the entire esophageal wall, including the periesophageal and perihiatal lymph nodes. For disease penetrating the submucosa, the extent of surgical therapy must be tailored to the objectives of treatment (cure vs palliation) and preoperative stage. Although data from seven prospective, randomized trials are encouraging, no clear survival benefit has been documented for neoadjuvant combined-modality therapy. Surgical resection remains the standard of care and best chance for cure in the treatment of esophageal malignancy, with combined-modality therapy reserved for prohibitive surgery candidates.
Introduction Esophageal carcinoma is a relatively uncommon and highly lethal malignancy. Most of the estimated 13,100 patients in the United States who developed the disease in 2002 will die from it in a relatively short time [1•]. Unfortunately, its prevalence is also increasing faster than that of any other gastrointestinal malignancy, by approximately
10% annually [2,3]. In most Western countries, esophageal carcinoma has undergone a profound epidemiologic shift, from predominantly squamous cell carcinoma associated with tobacco and alcohol abuse to adenocarcinoma associated with Barrett’s metaplasia, seen most commonly in Caucasian middle-aged men with gastroesophageal reflux disease (GERD) [4]. The association between GERD, Barrett’s esophagus, and esophageal adenocarcinoma is now well established [5••]. However, the reasons for this epidemiologic change remain unknown. Earlier detection, combined with complete extirpation of disease and lower postoperative mortality, has contributed to recent improvements in survival [6–8]. The extent of surgical resection and the addition of adjuvant therapies remain controversial. However, recent advances in our understanding of the natural history and behavioral characteristics of these esophageal malignancies have brought clinically relevant changes in patient management.
The Importance and Limitations of Preoperative Staging in Determining Surgical Therapy Many believe that the outcome for patients with esophageal cancer is biologically determined at diagnosis and that surgery should be limited to removal of the primary tumor with the hope that adjuvant therapy will destroy regional and systemic disease. Others believe that surgical cure is possible and that treatment options should be selected with curative intention. With the latter approach, the goal of surgery, whether cure or palliation, should be identified prior to the operation, and preoperative staging becomes especially important. Accurate staging before treatment is no longer important for survival analysis alone. Staging is also increasingly relevant to clinical decision making [9]. The purpose of preoperative staging is to define the extent of disease at presentation and, when possible, to gain an understanding of the behavioral characteristics of a given tumor. With this information, logical treatment decisions can be made to optimize the probability of cure while decreasing treatment-related morbidity and mortality. At diagnosis, all cancers must be local, regional, or systemic. It is reasonable to conclude that the extent of surgery will have little effect on the survival of patients with systemic disease. However, radical surgical resection provides little or
Surgical Management of Esophageal Malignancy • Blom
no benefit to patients with locally confined disease and exposes them to increased surgical morbidity and mortality. The extent of surgical resection has a critical impact on the survival of patients with isolated regional disease. The existence of a population of patients with isolated regional disease has been proven by extensive documentation that longterm cure is possible with surgical resection alone in the presence of positive regional lymph nodes [10,11,12••,13••]. The relatively small size of this group and the difficulty in clinically identifying these patients preoperatively accounts for the difficulty in establishing the benefit of a more extensive operation, underscoring the vital importance of accurate preoperative staging. Historically, staging of solid tumors has relied solely on assessment of their depth of penetration into the gastrointestinal wall, the presence of nodal metastases, and the existence of distant organ involvement. Most clinicians caring for patients with esophageal cancer realize quickly that reliance on these anatomic characteristics is inadequate. It is now established that T1 tumors limited to the mucosa by the lamina propria are rarely (<10%) associated with lymph node metastases and are highly curable. However, approximately 30% of patients with T1 tumors invading the submucosa have associated lymph node metastases and experience a corresponding decrease in survival [12••]. The American Joint Committee on Cancer Criteria does not discriminate between stage IIA and IIB or stage IIB and III esophageal carcinoma with respect to 5-year survival differences [9,14,15]. The current TNM staging criteria are too broad to be useful in determining the appropriate therapy and prognosis. Despite these deficiencies in preoperative staging, a systematic approach to the diagnosis and evaluation of patients with esophageal cancer is mandatory. Once a histologic diagnosis of esophageal carcinoma has been confirmed, a detailed evaluation of the local, regional, and metastatic extent of the disease must be performed. All the present diagnostic modalities, including computed tomography (CT), positron emission tomography (PET), magnetic resonance imaging (MRI), endoscopic ultrasonography (EUS), and thoracoscopic and laparoscopic examination, have significant limitations [16–21]. CT scanning of the chest and abdomen is usually obtained first as part of the clinical evaluation. CT underestimates tumor stage in approximately 40% of patients and has an accuracy rate of 55% to 63% in detecting regional disease, relegating its utility to the detection of metastatic disease [16]. PET scanning is under investigation as an adjunct to conventional staging modalities. Its main advantage over CT appears to be in the detection of distant metastases, but its final role is yet to be established [22]. EUS is the modality of choice for evaluating the depth of tumor penetration, but it, too, incorrectly predicts tumor depth in 15% to 20% of patients and nodal status in 25% to 30% [21]. EUS is vastly underutilized in clinical practice and is even less accurate as a tool for restaging after neoadjuvant therapy. Recent data from The Cleveland
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Clinic Foundation indicate that EUS predicts complete pathologic response (T0N0) correctly after combinedmodality therapy in only 17% of patients; T stage accuracy was 37%, and the sensitivity for N1 disease was 38% [23•]. Thus, Zuccaro et al. [23•] concluded that EUS is unable to distinguish fibrosis and inflammation from residual tumor after radiotherapy and is inadequate for use in clinical decision making. Thoracoscopic and laparoscopic staging are highly accurate in identifying metastatic lymph nodes [19,20]. Unfortunately, port site metastasis has been reported [24]. It also remains unclear whether isolated metastatic lymph nodes (ie, celiac) are equated with incurability or if, in the absence of carcinomatosis, this information actually changes surgical therapy [12••]. Finally, because these modalities are highly invasive, requiring hospitalization, general anesthesia, and lengthy surgical procedures, they remain investigational.
Extent and Outcome of Surgical Resection of Disease Confined to the Mucosa and Submucosa Detection of esophageal cancer at a stage when the disease may be confined to the mucosa, once a decidedly rare clinical occurrence, has recently become more commonplace. The clear link between Barrett’s esophagus and esophageal adenocarcinoma, the liberal use of flexible endoscopy, and the widespread adoption of surveillance programs have all contributed to this change. Thirty percent of patients with esophageal adenocarcinoma undergoing esophageal resection at the University of Southern California have tumors confined to the mucosa or submucosa [12••]. Other institutions have documented this important trend as well [25]. These changing demographics markedly increase the population of patients with curable esophageal cancer and underscore the importance of curative resection. Techniques for curative resection range from endoscopic mucosal ablation and mucosal resection to radical en bloc three-field esophagectomy. Recently, ablative techniques involving electrosurgery, laser and argon directed light waves, photodynamic therapy, and endoscopic mucosal resection have been advocated [26,27]. However, the risks and benefits of these procedures have not yet been evaluated adequately. Endoscopic mucosal ablation remains investigational and should not be performed outside of clinical trials. Surgical options for curative esophageal resection have included transhiatal or transthoracic esophagectomy, en bloc esophagectomy, or, more recently, vagal-sparing esophagectomy. Reconstruction is most commonly accomplished with either the stomach or colon and with the anastomosis in the neck. Selection among these options without compromising the chance of a curative resection is critically dependent on accurate identification of the location and depth of the
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tumor (intramucosal vs submucosal) and the presence of regional nodal metastases. The accuracy of EUS in determining the depth of a tumor confined to the esophageal wall is questionable. In most hands, the resolution of current EUS systems is insufficient to predictably distinguish small tumors that may or may not have invaded beyond the muscularis mucosa [28]. The presence or absence of an endoscopically visible lesion (ie, ulceration or nodule) in patients with biopsyproven, high-grade dysplasia (HGD) or intramucosal carcinoma has been used recently as a predictor of tumor depth and nodal metastases. The data indicate that a positive biopsy in the absence of an endoscopically visible lesion almost always corresponds to an intramucosal tumor without nodal metastases [29•]. In the patients with HGD, 43% were proven to harbor occult adenocarcinoma at resection. Importantly, when no lesion was visible on endoscopy, 88% of the tumors were intramucosal and 12% were submucosal. Only one of 10 patients with no visible lesion had lymph node involvement either histologically or immunohistochemically, and this patient had only one lymph node involved. In contrast, patients with endoscopically visible tumors had a high prevalence of tumors that penetrated beyond the mucosa (75%), and 56% were positive for lymph node metastases. All of the patients in this study had en bloc esophagectomy, with actuarial 5-year survival rates of 90% and 82% for those without and with endoscopically visible lesions, respectively [29•]. These data call into question the increasing use of endoscopic ablative techniques in the treatment of HGD and early adenocarcinoma. They suggest that cure may be compromised in the presence of a visible lesion when the probability of submucosal disease and lymph node metastasis is high. In the absence of a visible lesion, adequate direction of these endoscopic therapies becomes quite difficult. In an analysis of 100 en bloc esophagectomies performed with curative intent for esophageal adenocarcinoma, only 19% of tumors determined to be limited to the submucosa by preoperative EUS were associated with lymph node metastases, and only 3% of patients had more than four positive lymph nodes. All but one of these lymph node metastases were limited to the periesophageal and perihiatal nodes [12••]. Consequently, for patients with documented HGD or adenocarcinoma in the absence of a visible endoscopic lesion who appear to have a very low probability of regional lymph node metastases, a vagal-sparing or simple transhiatal esophagectomy is advocated. These procedures remove the entire affected esophageal wall and should not compromise the chance for a curative resection. Patients with tumors confined to the submucosa should receive an extended transhiatal esophagectomy including a complete lower mediastinal and upper abdominal lymphadenectomy. This resection includes the periesophageal and perihiatal lymph nodes and should remove all disease in 97% of patients while limiting morbidity and mortality. Splenectomy and
extended gastric resection need not be part of the resection because recent data indicate that, given an early adenocarcinoma in Barrett's esophagus, nodal metastases are limited to the periesophageal location and do not involve the splenic artery, hilum, or greater curvature of the stomach [30]. Whether these findings alone will suffice to select the extent of surgical resection awaits further study.
Extent and Outcome of Surgical Resection of Disease Invading Beyond the Submucosa Most clinicians recognize that cure of esophageal tumors infiltrating beyond the submucosa into or through the esophageal wall remains challenging. Thus, therapy is focused toward palliation of dysphagia, usually with a transthoracic or transhiatal esophagectomy [31,32••]. Orringer et al. [32••] reported their experience with transhiatal esophagectomy, emphasizing its associated excellent palliation, decreased surgical mortality, and acceptable survival outcomes. Of the 800 patients undergoing transhiatal esophagectomy at the University of Michigan over a 22year period, dysphagia was permanently relieved in 80%, surgical mortality decreased from 25% to 4.5%, and the overall rate of 5-year survival was 23%. Others have reported 5year survival rates of between 5% and 20% after transthoracic or transhiatal esophagectomy. Prospective studies, including the Dutch and Radiation Oncology Therapy Group (ROTG) trials, report median survival of 11 to 16 months and a 5-year survival rate of 20% [33,34•]. These disappointing survival rates obtained with standard surgical techniques have prompted some surgeons to practice en bloc resection, including extended mediastinal and upper abdominal lymphadenectomy, even in patients with more extensive disease [10,11,12••,13••,35]. The benefits of en bloc resection and extended lymphadenectomy are threefold: improved pathologic staging, improved control of local and regional recurrences, and improved survival. During the performance of a simple transthoracic or transhiatal esophagectomy, lymph node sampling is incidental at best, compared with systematic removal of all lymphatic bearing tissue in the mediastinum and upper abdomen during an en bloc resection. The median number of removed lymph nodes per patient undergoing en bloc resection was recently reported as 48 (interquartile range [IQR], 38.5–62.0) [12••]. This improved sampling unquestionably allows better staging, prognostication, and tailoring of subsequent adjuvant therapies to those patients who will benefit most. Esophageal carcinoma invading the muscularis propria or beyond is associated with lymph node involvement in 75% to 85% of patients. As many as 45% of these patients have four or more nodes involved, with 30% to 40% in distant nodal sites, including celiac nodes in approximately 25% of patients [12••]. Several recent studies have reported local recurrence as the first site of failure in 31% to 42% of patients treated with surgery alone [32,33,36•]. Control of local recurrence is critical to management of esophageal carcinoma. Recent evidence
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suggests that systemic disease may originate from unresected involved lymph nodes, supporting the importance of systematic lymph node dissection as part of a curative operation [12••]. Also, the 5-year survival of patients with involved celiac or distant lymph nodes did not differ from that of patients with only local nodal involvement. This finding supports the benefit of a complete R0 en bloc resection regardless of the location of positive lymph nodes [12••,13••]. Local recurrence is uncommon following en bloc resection. Rates of 5% or less have been reported, with the most recent study of 100 consecutive en bloc resections finding only one patient who experienced recurrence in the resected field [6,12••,13••,37]. These rates contrast with a 42% prevalence of local failure after transhiatal esophagectomy alone and a 19% local failure rate after the addition of neoadjuvant radiation and chemotherapy [36•]. En bloc resection also seems to lead to prolonged survival. Overall actuarial 5-year survival rates as high as 52% have been reported. Three recent studies suggest that, even in stage III disease, long-term survival rates of 23%, 25%, 34.5%, and 39%, respectively, are possible after en bloc esophagectomy [6,12••,13••,37]. Although these studies were not randomized or prospective (both difficult given the prevalence of esophageal cancer and the expertise required for en bloc resection), their findings compare favorably with the 23% overall 5-year survival and 10% 5-year survival rates for patients with stage III disease after transhiatal resection [32••]. Although a survival benefit is not yet proven definitively, technical modifications and improvements in perioperative care have minimized morbidity and reduced mortality rates to less than 10%. In expert hands, the complication and mortality rates of en bloc esophagectomy are equivalent to those in many series of simple esophagectomy. These findings support the use of a more extensive en bloc resection with a complete mediastinal and upper abdominal lymphadenectomy in appropriate patients with disease that extends to the muscularis propria and beyond. Extension of the lymphadenectomy to include the cervical lymph nodes (three-field dissection) has also been advocated [38–41]. European and North American surgeons have been reluctant to adopt this procedure because of the increased morbidity and mortality associated with a peritracheal and cervical lymphadenectomy, the fact that most cancers in the Western world occur in the distal third of the esophagus, and the minimally proven benefit between a twofield and three-field lymphadenectomy. The rationale is stronger for middle thoracic and upper-third tumors, where cervical nodal metastases and cervical recurrence are common (40%–50%) [42]. In a study designed to determine the utility of extended radical esophagectomy, Nishimaki et al. [43] reported that, among 51 patients with squamous cell carcinoma (four intramucosal, 47 submucosal), 57% had lymph node metastases and required an extensive resection to achieve complete tumor clearance. The overall rate of 5-year survival was 68% (93% for node-negative and 47% for nodepositive patients, P=0.01). However, no survival difference
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was found between those with cervical metastases and those with noncervical metastases (46% vs 57%). Although there were no operative deaths, major morbidities developed in 80% of patients receiving an extended three-field lymphadenectomy. Tabira et al. [44] compared 46 patients undergoing two-field resection with 40 patients having three-field resection. All of the patients were thought to have invasion into the muscularis propria or adventitia preoperatively, and all received preoperative chemotherapy. Multivariate analysis revealed that patient age, pT4 stage, and number of positive nodes were significant negative predictors of survival. No difference in overall survival was found. However, in patients with positive lymph nodes, particularly those with one to four positive lymph nodes, 5-year survival was significantly improved in those who underwent three-field resections (54% vs 22%, P=0.01). Finally, many clinicians believe that the principal role for surgical management of esophageal malignancies is removal of the primary tumor, whereas adjuvant therapy, such as radiation or chemotherapy, offers the best chance for cure. However, this belief has not been validated. The use of either radiotherapy or chemotherapy alone has not demonstrated a survival benefit [34•]. The results of combined-modality therapy in the neoadjuvant setting before surgical resection have been more encouraging but are far from showing definitive benefit. To date, seven prospective, randomized studies comparing surgery alone with neoadjuvant combined-modality therapy have been reported (Table 1) [36•,45–49,50•]. Most of these studies evaluated patients with both adenocarcinoma and squamous cell carcinoma and did not control for type of resection. Only two studies revealed a survival advantage in the combined-modality group [46,50•]. The first, reported by Walsh et al. [46], has been criticized extensively because of short follow-up, an unusually high operative mortality rate (9%), and low survival (6%) in the surgical control arm. By comparison, the surgery-only arm of the ROTG 89-11 trial reported a surgical mortality rate of 6% and 5-year survival of 20% [34•]. The second study, by Bancewicz et al. [50•], demonstrated a significant improvement in overall 2-year survival (43% vs 34%, P=0.002), with a median survival difference of only 4 months (17 vs 13 mo). However, these are only 2-year survival results, and previous studies reporting significant differences in short-term survival (<3 years) found that significance was lost with longer follow-up [36•]. Interestingly, neoadjuvant chemoradiotherapy has been adopted in many institutions despite its lack of clear benefit and potential for increased morbidity and mortality.
Conclusions Surgical resection is the current standard of care for treatment of patients with resectable esophageal carcinoma, with primary combined-modality therapy reserved for prohibitive surgical candidates. The extent of resection should be based on the objectives of treatment (cure vs palliation) and preoperative staging. A systematic approach to preoperative staging
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Table 1. Prospective, randomized trials comparing surgery alone with neoadjuvant chemoradiotherapy plus surgery for carcinoma of the esophagus Overall survival Study
Year
Nygaard et al. [45] Le Prise et al. [48] Apinop et al. [49] Walsh et al. [46] Bossett et al. [47] Urba et al. [36•] Bancewicz et al. [50•]
1992 1994 1994 1996 1997 2001 2002
Patients, n
Surgery alone, % (y)
186 104 69 113 282 100 802
9 (3) 13.8 (3) 10 (5) 6 (3) 32 (5) 16 (3) 34 (2)
CRT + surgery, % (y) 17 (3) 19.2 (3) 24 (5) 32 (3) 33 (5) 30 (3) 43 (2)
P-value 0.30 0.56 0.40 0.01 0.78 0.15 0.004
CRT—chemoradiotherapy; y—years.
should include CT of the chest and abdomen, esophagogastroduodenoscopy, and EUS. In our institution, patients with documented Barrett’s esophagus and HGD or intramucosal adenocarcinoma and no visible lesions on endoscopy receive a vagal-sparing esophagectomy and colon interposition. Poor-risk patients receive a transhiatal esophagectomy and gastric pull-up. Patients with a visible endoscopic lesion or tumor confined to the submucosa by EUS undergo an extended transhiatal esophagectomy including a complete lower mediastinal and upper abdominal lymphadenectomy. Patients with tumor confined to or through the muscularis propria and with no contraindications undergo a radical en bloc esophagectomy and colon interposition. Although most North American surgeons perform transhiatal or transthoracic esophagectomy, these more radical resections can be performed with acceptable morbidity and mortality by surgeons experienced in these procedures. Patients who demonstrate extensive preoperative regional or distant metastasis and are suitable candidates should be placed into clinical trials of neoadjuvant therapies or receive palliative resection with a simple esophagectomy and esophagogastrostomy; poor-risk patients should receive nonsurgical therapies. No clear survival benefit has been documented for preoperative radiotherapy or chemotherapy alone. The results with preoperative combinedmodality therapy are encouraging but have not shown a definite benefit. Such novel treatment options as the combination of en bloc esophagectomy and systemic chemotherapy and chemotherapy tailored to the molecular aspects of the patient’s tumor are exciting prospects for the future.
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