Esophageal cancer: A systematic review

Current Problems in

C a n c e r ° Ig

Peter A. S. Johnstone, MD, MA Radiation Oncology Division

Naval Medical Center San Diego, California

n

Associate Editors

Chris H. M. Takimoto, MD, PhD Department of Medicine

Division of Medical Oncology University of Texas Health Sciences Center

San Antonio, Texas

Robert Goulet, MD Department of Surgery

Indiana University School of Medicine Indianapolis, Indiana

Current Problems in

C a n c e r ° Volume 24 Number 6 November/December 2000

Esophageal Cancer: A Systematic

Abstract

Epidemiology

Staging System

Review

Esophagogastric Junction Tumors Staging Investigations

Method of the Review Esophagogastroscopy and EUS Minimally Invasive Surgical Staging PET MR[

Management of Localized Carcinoma of the Esophagus Background Curability Versus Resectability Surgery as a Curative Therapy Neoadjuvant and Adjuvant Therapies: A Systematic Review Radiotherapy as a Curative Therapy

Palliative Management of Malignant Dysphagia Background Method of Review Metal Stent Versus Other Modalities External Beam Radiotherapy Brachytherapy Chemotherapy Chemoradiotherapy

Existing Guidelines

298

299

302

304

3O6 306 306 311 312 313

315 315 316 316 324 335

344 334 344 345 345 348 349 353

355

Curr Probt Cancer, November/December 2000 295

Population Patterns of Practice

Summary

References

357

360

361

The opinions and assertions contained herein are those of the authors and are not to be construed as official or representing the views of the United States Navy or Department of Defense.

The assistance of Waine MacAIlister, EdM, in manuscript preparation and submission is acknowledged and gratefully appreciated.

296 Curr Probl Cancer, November/December 2000

Rebecca Wang, MB, ChB, FRCPC, is a radiation oncologist at the Toronto-Sunnybrook Regional Cancer Centre. Dr Wang graduated from medical school in England and completed postgraduate training in radiation oncology at Queens University. She then joined the Toronto-Sunnybrook Regional Cancer Centre in 1990. She is currently an assistant professor in the Department of Radiation Oncalogy at the University of Toronto. The clinical and research areas of interest for Dr Wang include gastrointestinal malignancies, rectal and esophageal cancers in particular, and the use of radiotherapy for the palliation of patients living with advanced cancers. Dr Wang is a reviewer with the Cochrane Collaboration and the Cancer Care Ontario GI Treatment Guidelines Group. She is also an active investigator at the National Cancer Institute of Canada and Research Director for the Rapid Response Radiotherapy Program of palliative radiotherapy at Toronto- Sunnybrook Regional Cancer Centre.

Richard Malthaner, MD, MSc, FRCS(C), FACS, FCCP, graduated from the University of Toronto with a BSc in 1981 and an MD in 1985 and received an MSc from the University of Western Ontario in 1999. After completing a surgical internship at the Toronto General Hospital, he completed his general surgical training at George Washington Univer- sity in Washington, DC, in 1992. Dr Malthaner then received additional subspeciality training in thoracic surgery at the University of Toronto in 1994. He was admitted as a Fellow of the Royal College of Physicians and Surgeons of Canada in 1992 and of the American College of Sur- geons in 1997. He is also a Fellow of the College of Chest Physicians. Dr Malthaner is currently an assistant professor in the Divisions of Tho- racic Surgery, Surgical Oncology, and Epidemiology and Biostatistics at the university of Western Ontario. He is on active staff at the London Health Sciences Centre and the London Regional Cancer Centre. His research interests include surgical epidemiology and quality of life, lung volume reduction surgery, surgical robotics, minimally invasive thoracic surgery, and general thoracic surgery. A recipient of research grants from the Ontario Thoracic Society, London Health Sciences Cen- tre, and the Medical Research Council of Canada, Dr Malthaner has authored 20 peer-reviewed articles, 2 book chapters, 12 scientific abstracts, and 31 presentations. Dr Malthaner holds a black-stripe belt in Tae Kwon Do, enjoys windsurfing, and plays competitive soccer.

Curr Probl Cancer, November/December 2000 297

. l l

Esophageal Cancer: A Systematic Review

Abstract.--Carcinoma of the esophagus has one of the lowest possibilities of cure, with 5-year survival rates estimated to be approximately 10% overall; these rates are second only to hepatobiliary and pancreatic cancers. This fact and the rapid increase in the incidence of adenocarcinomas of the esophagus in recent years challenges us to identify areas of improvement for all aspects of this disease. We discuss potential reasons for the increase in the incidence of adenocarcinomas, evidence that defines the simi- larity between tumors of the gastroesophageal junction and the tubular esophagus, and other prognostic factors that may influence future modifications of our staging classification of this disease. Surgical advances have translated into improvements in surgical morbidity and mortality rates. Current therapeutic options and the relative merits of the options are discussed. Improvements in patient outcome most likely hinge on earlier diagnosis, more accurate staging, and the optimal use of combined modalities, cou- pled with technical advances in the modalities. A systematic review approach was undertaken to evaluate the performance characteristics of newer staging tools and the value of different combined modality approaches with particular focus on the use of those approaches for patients with potentially curable disease. A similar methodologic approach was used to address the utility of the many strategies currently used in practice for the palliation of esophageal tumors, with particular focus on the relief of malignant dysphagia. Finally, a summary of published guidelines and population-based patterns of care are presented. This serves as an overview of how all of this evidence actually translates into the care we are providing. A coordinated international effort in population-based research and randomized controlled trials would be the cornerstone to future advances in this relatively uncom- mon but devastating disease.


Esophageal Cancer: A Systematic Review

Epidemiology B sophageal cancer occurs in 3.5 per 100,000 white people and in

9.8 per 100,000 black people. There were more than 12,000 estimated new cases in the United States in 1998. Five-year relative

survival rates were estimated to be 12.6% in white people and 9% in black people. Therefore esophageal cancer has one of the lowest long- term survival rates; it is second only to liver, biliary tract, and pancreatic primaries. There is worldwide variation in incidence, but in general, there is a male preponderance: the risk for men is twice that for women. 1

The major epidemiologic issue that has attracted the most attention in recent years is the increasing incidence of esophageal adenocarcinoma reported in many geographic areas. In the United States, population- based incidence data available through the Surveillance, Epidemiology, and End Results (SEER) program of the National Cancer Institute 2 showed an increase in the annual rates of adenocarcinoma of the esophagus in white men from 0.7 per 100,000 in the period of 1974 to 1976 to 3.2 per 100,000 in the period of 1992 to 1994; this is an increase of more than 350%. During the same period, the incidence of adenocarcinoma of the gastric cardia underwent a similar increase, from 2.1 to 3.3. The rate of squamous cell carcinoma of the esophagus decreased from 3.4 to 2.2, whereas the incidence of noncardia gastric tumors remains stable (Table 1; Figure 1). 2 This general trend has been observed in many other coun- tries? 4°

Multiple reasons are thought to account for the increase in the incidence of adenoeare inoma of the esophagus. Commonly cited mecha- nisms for the development of adenocarcinoma are the roles of reflux esophagitis 11 and Barrett's esophagus. One potential mechanism is the widespread use of proton pump inhibitors, with the resultant long-term achlohydria state. 12 This factor may account for the promotion of Bar- rett's esophagus, and subsequent transformation from metaplasia to malignancy has been well described. However, the extent to which Bar- rett's esophagus could be responsible for the increasing incidence of esophageal adenocarcinoma is questioned by Bytzer et al 3,~3 because of the low incidence of background Barrett's esophagus that is observable in index cases.


TABLE 1. Incidence of malignancy by location and time period*

Squamous carcinoma Adenocarcinoma

ofthe of the Gastric Gastric esophagus esophagus cardia (not cardia)

United States, 3.4 ~ 0.7/100,000 2.1/100,000 5.7 1974-1976 (white men) 2

United States, 2.2 3.2/100,000 3.3/100,000 3.7 1992-1994 (white men) 2

*Surveillance Epidemiology and End Results Program data.

A second potential mechanism relates to the changing patterns in smoking. It has been postulated that smoking is responsible for the early stages of carcinogenesis in adenocarcinomas, with a much delayed period between exposure and the development of cancer. This is in contrast to the late promotional stages for squamous cell carcinomas of the esophagus in which a shorter delay is expected. The increase in prevalence of smoking until the 1960s and the subsequent decrease is reflected in the gradual decrease in the incidence of squamous cell carcinomas that we are now observing. However, the lengthier interval between exposure and the development of adenocarcinomas means that we are only now seeing the effects of high rates of cigarette consumption on the incidence of adenocarcinomas of the esophagus. 2

Other potential factors in the increase in incidence of adenocarcinoma of the esophagus include the effects of added oils and polyunsaturated fats in our diets, which have also been positively correlated with adenocarcinoma. 14 Anthropometric risk factors such as obesity and body mass index have also been correlated with increased risks. ~5

New predisposing factors for esophageal carcinoma (in addition to those that are well established) such as smoking and alcohol intake, 16 lye ingestion, Plummer-Vinson syndrome, achalasia, and previous exposure to radiation have also been described. Certain cultural practices, such as the consumption of hot alcohol in FrancO 7 and tobacco chewing in India 18 are accompanied by increased risks. Dietary factors, including a diet low in fruits and vegetables, are associated with a 2-fold increase in risk. Certain food types, such as nitrosamines found in pickled vegetables and moldy or fermented foods, have been correlated with increased risk for esophageal adenocarcinoma. Chinese investigators found a 2.4-fold increased risk of esophageal carcinoma in patients with a history of autoimmune diseases, whereas a history of allergies reduced the risk (odds ratio, 0.6); this suggests that there is an immunologic mechanism in the carcinogenesis pathway for some patients. 19 A history of breast irradia-


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Squamous Cell Carcinoma Black Males

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) / / / Adenocarcinoma p O// . . . .O. .~l /O Black Males

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Year FIG 1. Trends in age-adjusted incidence rates for esophageal carcinoma among men in the United States by race and cell type, 1974 to 1976 and 1992 to 1994. Courtesy of Devesa SS, Blot WJ, Fraumeni JF Jr. Changing patterns in the incidence of esophageal and gastric carcinoma in the United States. Cancer 1998;83:2049-53. Copyright © 1998 American Cancer Society. Reprinted by permission of Wiley-Liss, Inc, a subsidiary of John Wiley & Sons, Inc.

tion was found to be associated with a 5-fold increase in esophageal cancer at more than 10 years after the radiation? °

There appears to be a role for lifestyle modifications to minimize the risk for individuals and for populations at large. This identification of new potential factors contributes to our understanding of the carcinogenesis pathway for esophageal cancer.


TABLE 2. TNM system for the staging of esophageal carcinoma (fifth edition)

T: primary tumor

Tx: primary tumor cannot be assessed TO: no evidence of primary tumor Tis: no evidence of primary tumor TI: tumor invades lamina propria or submucosa T2: tumor invades muscularis propria T3: tumor invades adventitia T4: tumor invades adjacent structures

N: regional lymph nodes

Nx: regional lymph nodes cannot be assessed NO: no regional lymph node metastasis NI: regional lymph node metastasis

M: distant metastasis

Mx: distant metastasis cannot be assessed MO: no distant metastasis MI : distant metastasis

For tumors of lower thoracic esophagus Mla: metastasis in celiac lymph nodes Mlb: other distant metastasis

For tumor of upper thoracic esophagus Mla: metastasis in cervical lymph nodes Mlb: other distant metastasis

For tumors of mid-thoracic esophagus Mla: not applicable Mlb: nonregional lymph node or other metastasis

PTNM pathologic classification

PNO: histologic examination of a mediastinal lymphadenectomy specimen will ordinarily include 6 or more lymph nodes

Stage O: Tis NO MO Stage I: T1 NO MO Stage IIA: T2 NO MO; T3 NO MO Stage liB: T1 N1 MO; T2 N1 MO Stage II1:T3 N1 MO; T4 Any N MO Stage IV: Any T Any N M1 Stage IVA: Any T Any N Mla Stage IVB: Any T Any N Mlb

Staging System The TNM staging system is recommended for routine clinical use

(Table 2). An improving understanding of the prognostic factors in esophageal cancer is reflected by the evolution of our staging system. In 1983, the American Joint Commission for Cancer classification used tumor length as the factor to determine the T stage. 21 In 1987, the Inter- national Union Against Cancer adopted the proposal by the Japanese Research Society for Esophageal Diseases 22 and began to use the depth of tumor involvement to define the T stage. 23 This change was based on


prognostic factor analysis with the use of outcomes of resected esophageal cancer cases in Japan during a 10-year period. 24 In 1997, the fifth edition of the TNM classification had further modifications. 25 These changes were in the designation of the M stage. The designation of M l a (stage IVA) was given to metastases in the celiac lymph nodes only (for lower esophageal tumors only) and cervical nodes (in patients with upper esophageal tumor involvement only), whereas M l b (stage IVB) was given to other nonregional and distant metastases. The T and N stage def- initions remained unchanged.

Since the latest edition (the fifth edition, 1997) of the TNM classification has been in place, 25 several authors have cited shortcomings of the current classification system. Some of these include the following:

1. Lack of specific consideration for the growing group of gastroesophageal tumors and for which lymph nodes should be considered regional and nonregional. 28

2. Absence of consideration for the prognostic significance of the number of involved lymph nodes. 27,28

3. The relative difficulty in the application of the current staging system for patients being treated with nonsurgical curative therapies (ie, situations in which pathologic specimens are not available).

Suggested modifications to the current staging system have been proposed. The wall node metastases system proposed by Skinner et a126 that was first described in 1986 and subsequently modified by Ellis et a127 in 1993 is noteworthy. This system was modeled after the Dukes' classification for colon cancer and was verified on the basis of 265 surgically treated patients. In this system, T3 and T4 was collapsed into one cate- gory. The number of nodes involved was found to be of significance, and the authors proposed a classification of N stage into N1 (1 to 4 nodes) and N2 (5 or more nodes). 27

Within the current TNM staging system, the regional lymph nodes for the cervical esophagus include the supraclavicular nodes, whereas for the thoracic esophagus, mediastinal and perigastric nodes are considered to be regional. There are no further details provided about which groups of mediastinal nodes are considered to be regional, and no specific considerations for esophagogastric junction tumors. Korst et a128 conducted a retrospective review of 216 patients who underwent surgical resection at a single institution and had a follow-up of at least 3 years. The review par- ticulary focused on the nodal stations involved and the impact of those stations on survival outcomes. Nodal involvement was classified as N1 and N2, as defined by Casson et al? 9 TWo observations were pertinent. First, there was a significant survival difference between patients with


regional nodal involvement and patients with nonregional nodal involvement. z8 The median survival time of the patients with stage N2 cancer was 13.8 months; this was felt to be superior to the survival time of patients with visceral metastases, who historically have a median survival time of 4 to 6 months. Second, the number of lymph nodes involved (0-3 vs >4) also significantly influenced survival. 28 Modification of the current staging system to include N1 and N2 designations was proposed.

For patients who are treated curatively without surgery (ie, with radical radiotherapy with or without chemotherapy) or in a situation in which neoadjuvant therapies are recommended before surgery, the ability of the current clinical TNM staging system to discriminate between different prognostic groups is not as well established as for patients who are treated with surgery. 3°,31 Although contemporary imaging techniques have resulted in substantial improvements in the accuracy of T staging, our ability to accurately detect or exclude nodal involvement remains relatively poor. Accurate T staging, in addition to other factors such as tumor length and patient performance status, may prove to be the most useful criterion for the assessment of the prognosis of patients who are being considered for nonsurgical curative approaches.

Several authors have corre!ated the likelihood of local regional nodal involvement with T stage. 32'33 Rice et aP 2 retrospectively studied pathologic findings in 359 consecutive patients with local regional disease who underwent esophageal resection. Compared with T1 disease, the risk of N1 nodal involvement was 6, 23, and 35 times higher for T2, T3, and T4 disease. Similarly, Liu et aP 3 found a strong correlation between tumor depth of invasion and lymph node metastases.

As more diagnostic tools and therapeutic options become available, additional modifications may become relevant. Until there is collective agree- ment on the appropriate modifications to include, it is important that the TNM system is consistently applied for facilitation of the reporting and assessment of outcomes. Collective efforts in the compiling of large clinical databases would provide us with the best tools to identify and validate new prognostic factors that would improve our understanding of the disease and refine our treatment strategies for patients with different prognostic risks.

Esophagogastric Junction Tumors Esophagogastric tumors deserve special attention in a review of

esophageal cancer for two major reasons: (1) the increasing disease bur- den of adenocarcinoma of the esophagus, which is predominantly esophagogastric junction tumors, and (2) the controversy around how the esophagogastric junction tumors should be managed. In particular, are


these tumors more similar to tumors of the tubular esophagus or should they be treated in a similar fashion as gastric tumors? The curative and palliative treatment options differ significantly between these two types of tumors. Therefore the classification of the anatomic origin of junctional tumors has major implications on how patients are treated.

On the basis of the criteria established by the International Union Against Cancer for the TNM staging of tumors, a tumor of the tubular esophagus extending from the tracheal bifurcation to the gastroesophageal junction, including the intra-abdominal esophagus, is classified as esophageal cancer. 33 There is no special designation for esophagogastric junction tumors.

Several authors have explored whether tumors that involve the esophagogastric junction behave more like esophageal tumors than gastric tumors. Dolan et al6 conducted a population-based analysis with the use of data from the Merseyside and Cheshire (UK) cancer registry. Patient demo- graphic factors for adenocarcinoma of the lower esophagus, the cardia, and the subcardia region were compared. Adenocarcinomas of the lower esophagus and of the cardia were similar in terms of median age at diagnosis, sex distribution, and history of smoking. In contrast, these characteristics were significantly different from carcinomas of the subcardia region. 6

Wijnhoven et a135 compared the characteristics of 252 patients with adenocarcinoma of the esophagus or gastric cardia who were treated with transhiatal resection. Five-year overall survival rates and survival rates according to tumor stage were similar between the two groups. Multivari- ate analysis showed that the location of the primary tumor (tubular esophagus versus cardia tumors) was not an independent prognostic factor. 35 This evidence suggests that tumors of the esophagogastric junction and the lower esophagus are similar and probably represent the same disease.

What criteria can be used to define tumors of the esophagogastric junction? Siewert et aP 6 reported the recommendations from a consensus con- ference of the International Gastric Cancer Association and the Interna- tional Society for Disease of the Esophagus. A tumor with an epicenter within 5 cm proximal and distal of the anatomical cardia is considered to be an esophagogastric junction tumor. Three subtypes for further classification were described: type I tumors, which arise from specialized intesti- nal metaplasia; type II tumors, which are true junctional tumors; and type III tumors, which are subcardial tumors that infiltrate superiorly. 35

Consistent classification criteria and the ability to identify tumors that arise from the esophagogastric junction and to allow the outcomes to be analyzed in large population databases will help consolidate our understanding of tumors that arise from this area.


Staging Investigations Diagnostic tools for optimal staging of esophageal tumors have

improved significantly. In particular, endoscopic ultrasonography (EUS) has become the most accurate method for the determination of the extent of T stage. EUS also compliments more traditional imaging tools, such as computed tomographic (CT) scan, in the assessment of the extent of local regional nodal involvement. More recent developments include the use of positron emission tomography (PET) and minimally invasive staging procedures, including lymph node biopsies performed with the use of endo- scopically guided ultrasonography. Magnetic resonance imaging (MRI), which is useful in many other disease sites, has relatively limited utility in esophageal tumors. In the sections that follow, we discuss the characteristics of each of these staging tools as determined in a systematic review.

Method of the Review

The following sections on PET, MRI, and EUS are based on a systematic search for relevant articles with the use of a search strategy including the following medical subject headings (MESH): esophageal neoplasms/, neoplasms staging/, *esophageal neoplasms/di and textword staging. Modality-specific search terms were used for the appropriate sections, including exp tomography, emission- computed/(for PET), exp Magnetic resonance imaging/ (for MRI), and endosonography/ (for EUS). Data were extracted by one reviewer who used standardized forms. The literature search was confined to the period of 1996 to 1999; this limited the information to more contemporary imaging tools.

Studies were included in the appropriate sections if the primary study used pathologic findings (resection specimen or biopsy results) as the reference standard. Studies in which the performance of the method was compared with other imaging methods only were excluded. The endpoints of interest were (1) sensitivity in detecting the primary tumor; (2) sensitivity and specificity for detecting periesophageal, or regional, nodes, nonregional nodes, and distant metastases; and (3) comparative data from CT scans (where applicable).

Esophagogastroscopy and EUS Esophagogastroscopy. Esophagogastroscopy allows the diagnosis of

esophageal cancer by direct visual inspection and histologic sampling. It provides clues to the stage of disease and permits surveillance in high-risk patients with a columnar-lined (Barrett's) esophagus.

The endoscopic assessment of esophageal cancer should include an evaluation of the location of the proximal and distal margins, the longitu-


FIG 2. A, Endoscopic ultrasonographic appearance of the normal esophagus. A 5-layer wall pattern is shown (1-5). Alternating hyperechoic and hypoechoic lines correlate with mural histology. B, Schematic illustration of A. M, Mucosa; DM, deep mucosa; SM, submucosa; MP, muscularis propria; Adv, adventitia. Courtesy of Van Dam J. Endosonographic evaluation of the patient with esophageal carcinoma. Chest Surg Clin N Am 1994;4:269-84.

dinal and circumferential extent, the relation to the gastric cardia, and the appearance of the larynx (including vocal cord palsy). A diagnostic accuracy of greater than 90% should be expected if more than 6 biopsy specimens are obtained. 37,38 Brush cytology is complementary to biopsy and should be used to increase the diagnostic yield to 100%. 38,39 Fine-needle aspiration biopsies can be performed safely to further enhance diagnosis of difficult tumors.

Vital staining at endoscopy with Lugol's solution has been advocated for the identification of subtle mucosal changes in the esophagus. After initial ingestion of a mucolytic, 20 mL of 1.5% Lugol's solution is sprayed onto the mucosa under direct vision. When the esophagus is flushed with 50 mL of water, normal epithelium, with its high glycogen content, stains brown, whereas ulcers, cancer, dysplasia, or ectopic columnar epithelium remain unstained. 4°'41 Toluidine blue staining has also been used to define early changes in the esophageal mucosa. 42 The identification of esophageal cancer at an early stage remains a difficult task, but the 5-year survival is encouraging and can be as high as 73%. 43

EUS. EUS combines the diagnostic access of endoscopy with the diagnostic versatility of ultrasonography. It is useful in the evaluation of the depth of penetration of tumors and the periesophageal lymph node involvement. The instrument uses a rotating transducer with 7.5 to 12 MHz frequencies and has an outer diameter of 13 ram. This slightly larger size can, however, limit examination of patients with severe stenoses.

EUS shows the gastrointestinal tracts as 5 concentric rings of alternating echogenicities. 44,45 The thickness of the layers of the esophagus on


TABLE 3. Commonly used criteria for defining malignant lymph nodes on endoscopic ultrasonograms

Size >1 cm Hypoechoic internal echo pattern Sharp borders Round shape Direct contiguity with the primary tumor

ultrasonographic images is not an exact measure of the histologic thickness. Ultrasonographic images need to be interpreted with an understanding of the physics of ultrasonography as well as knowledge of three- dimensional anatomy (Figure 2).

Tumor involvement is diagnosed as a hypoechoic disruption of the layers. T1 tumors penetrate to the third EUS (submucosa) layer of the esophageal wall (layers 1 and 2 represent water mucosa interface and the mucosa itself), T2 tumors penetrate to the fourth E US (muscularis propria) layer of the esophageal wall, T3 tumors extend through the fourth EUS layer (invading adventitia), and T4 tumors extend into adjacent structures (eg, the trachea, pericardium, and aor ta ) . 46

Unlike CT scans, which can only determine lymph node size, EUS provides additional information on lymph node shape, border characteristics, and central echogenicity (Figure 3). 47 Some variations exist in the criteria used by different authors to distinguish between malignant and benign lymph nodes. Size criteria of more than 1 cm in diameter, hypoechoic internal echo pattern, sharp borders, round shape, and direct contiguity with the primary tumor are frequently used as features for malignancy (Table 3). 46,48-50 Variations on these criteria include those described by Natsugoe et a151 who use boundary (poorly defined vs others) and internal echoes alone (diffuse homogeneous vs others). 52 Chandawarkar et a153 used variation in size criteria with more than 5 mm as the smallest diameter, as well as round or elliptical shape with a clear margin and hypoechoic structure as metastatic; whereas they used triangular-shaped nodes, nodes that were less than 5 mm with ill-defined margins, and homogeneous echo structure as criteria for benign lymph nodes, s3

Evidence that supports EUS as superior to computed tomography for the preoperative staging of T and N status of esophageal carcinoma has been available for more than 10 years. 54-6° A summary of the current diagnostic characteristics of EUS is provided in Table 4.

Primary Tumor. On the basis of recent series, 46,51,52,61-66 the accuracy of EUS in the determination of the T stage is approximately 60% to 90%. The accuracy of EUS in the evaluation of presence or absence of nodal involvement is approximately 65% to 90%, with an average sensitivity of 75% (range, 50%-88%) and specificity of 70% (range, 33%-88%). 46'51'52'61-66


FIG 3. Endoscopic ultrasonogram of a T3N1 adenocarcinoma of the esophagus. Courtesy of Van Dam J, Rice TW, Catalano MF, Kirby T, Sivak MVJ. High-grade malignant stricture is predictive of esophageal tumor stage: risks of endosonographic evaluation. Cancer 1993;71:2910-7. Copyright © 1993 Ameri- can Cancer Society. Reprinted by permission of Wiley-Liss, Inc, a subsidiary of John Wiley & Sons, Inc.

Nodal Involvement. Chandawarkar et a153 performed a detailed assessment based on the location of these regional nodes. Although the overall accuracy of EUS was 88%, there were significant differences between lower and cervical paraesophageal nodes. The overall specificity was 70% to 97%, but sensitivity was low for lower paraesophageal nodes, ranging from 20% improving to 66% for cervical paraesophageal nodes.

The presence or absence of nonregional node involvement (eg, celiac lymph nodes) has a significant impact on curability and resectability. The accuracy rate of EUS was reported as 80% to 95%, with sensitivity of 70% to 80% and specificity of 95%. 5°'67

Utility After Neoadjuvant Therapies. Another area of interest is the utility of EUS in the staging of disease before and after neoadjuvant therapies. It is generally observed that after neoadjuvant therapy, the accuracy of EUS is significantly lower, with an accuracy rate for the correct stage of 40%. A problem in distinguishment among fibrosis, inflammation, and residual disease was the main reason for the lower accuracy rate. 4s,68,69 The ability to identify nodal involvement appears to be relatively pre- served, with an accuracy of 60% to 70%, sensitivity of 40% to 70%, and specificity of 70% to 80%. 48,68

Limitations of EUS. Despite the generally favorable diagnostic proper-


TABLE 4. Summary of diagnostic characteristics of endoscopic u[trasonography with the use of pathol-

ogy as a reference standard

T stage N stage

Accuracy Sensitivity Specificity Accuracy Source N (%) (%) (%) (%)

Holden et a146 15 87 - - - - - -

Pham et al m 28 60 88 58 75 Vickers and Alderson 62,63 50 92 - - - - - -

Natsugoe et al ~1 37 - - 80 88 87 Hasegawa et a164 18 76 50 80 67

Hiele et a165 68 68 79 33 69

Luketich et a166 21 - - 67 66 66 Massari et al s2 40 90 87 94 90

ties of EUS, two significant barriers limit the generalized application of EUS for patients with esophageal carcinoma: the steep learning curve associated with EUS and the presence of high grade malignant strictures. The learning curve for the adoption of EUS was described by Rice et al. 7° Fockens et a171 described the accuracy of EUS examinations for 1 gas- troenterologist who had just completed 8 weeks of hands-on training. The accuracy (with the use of a surgical specimen as the reference standard) was assessed for 2 cohorts of patients. The first 100 patients (group I) were compared with those examined later with endoscopy (group II). The accuracy for group I was 58%, and the accuracy for group II was 83% (P < .05). 71 The improvement over time was because of understaging, which was more common in group I (28%) than in group II (3%). Schlick et a172 described similar observations, with an improvement of accuracy of T staging of 65% after fewer than 50 examinations that increased to 90% after more than 70 cases. The accuracy of the detection of nodal involvement did not display the same dependence on experience. 72

Malignant strictures that preclude a complete examination were a second limitation. Stricture alone is an important prognostic factor. 73 The feasibility rate for EUS ranges from approximately 70% to 95%. 62'63'6s'68 This rate is obviously a function of the distribution of T stages encountered in the population being assessed. Most endosonographers now suggest that esophageal dilation to achieve the passage of the echoendoscope for staging is not warranted and poses a risk of esophageal perforation that outweighs the benefits of more accurate staging. 73'74

The high-frequency (20 MHz) ultrasonographic probe is an alternative method for the assessment of patients with high-grade malignant strictures. In several studies, researchers have successfully used a "miniprobe" to evaluate patients with high-grade malignant strictures. 55,56,75 Continued refinements of ultrasonographic probes may eventually yield tools capa-

310 Curr Probl Cancer, November /December 2 0 0 0

ble of reliably staging tumors that cannot be evaluated with current echoendoscopes.

The limitations from these and other factors result in a significant variation in the pattern of use of EUS. This was evaluated by Kim et al. 76 In a survey of gastroenterologists practicing in Northern California, only 50% (33 of 66) stated that EUS was available within their community. 76 Forty-one percent judged EUS to be very useful or essential for the evaluation of esophageal cancer. Among the respondents for whom EUS was available and who considered it useful, 78% had actually used this method in their practice. 76

EUS is not equivalent to histologic examination of sampled tissue. More direct approaches to regional node evaluation include EUS-guided fine- needle aspiration of suspected nodes, 77 but the most accurate and effective approach appears to be minimally invasive video-assisted biopsies.

EUS is not a substitute for CT scanning, but it is complimentary. EUS is not appropriate for the staging of distant metastases. CT scanning is more useful in the assessment of liver, lung, and celiac nodes. The combination of CT scanning for distant metastases and EUS for wall penetration and node involvement is more accurate. The two diagnostic techniques should be used together.

Minimally Invasive Surgical Staging The staging of esophageal cancer allows the most accurate estimation of

prognosis. Minimally invasive surgical techniques continue to be refined. Pretreatment staging may determine the extent of surgical resection, as well as the advisability of neoadjuvant chemoradiotherapy. Current methods of computed tomography, MRI, and EUS have various limitations that continue to result in high false-negative and false-positive rates.

Minimally invasive surgical staging is not new. Cervical mediastinoscopy is routinely used for the assessment of the paratracheal, anterior subcarinal, and tracheobronchial mediastinal lymph nodes in the staging of lung cancer. Anterior mediastinotomy can sample para-aortic and aortopulmonary window lymph nodes. Unfortunately, neither of these methods can be used for the assessment of the paraesophageal or pulmonary ligament nodes.

Regional nodes on both sides of the diaphragm can be assessed by laparoscopy combined with thoracoscopy. Video-assisted techniques also allow for assessment and histologic biopsies of the liver, peritoneum, lung, and pleural spaces. 78,v9 In addition, thoracoscopy allows mobilization of the primary tumor in the assessment of resectability. A multi-institutional pilot study has shown an accuracy rate of 94%. TM This improvement over CT scanning is largely due to the absence of false-positive


results. The sensitivity of laparoscopic lymph node sampling is 83%, whereas the sensitivity of thoracoscopic sampling is only 50%. However, a negative predictive value of 92% and specificity of 100% were shown? ° Complications have been minimal.

Preoperative staging with the placement of feeding jejunostomies is currently being used before induction chemotherapy and radiation in many centers. Debate continues in the surgical community about the wis- dom of subjecting these often frail patients to two lengthy surgical procedures in the setting of combined modality treatment. Future studies should refine the role of surgical staging in esophageal cancer.

PET

The utility of PET has been explored in many tumor systems, including esophageal tumors. 18F-Flurodeoxyglucose (FDG), as a glucose, is pref- erentially taken up by tumors. The FDG is not further metabolized after phosphorylation but accumulates in malignant tissues. The distribution of FDG therefore serves to distinguish benign tissues from malignant tissues.

Patients fast for at least 4 hours before scanning. Six to 8 mCi of FDG is injected intravenously. PET scanning is performed 45 minutes after the injection. The scan time is approximately 30 to 45 minutes, and patients are required to remain quite still during this time. Three-dimensional images are reconstructed from the scan information.

We identified 11 studies of PET. 81-86'89-93 Four studies were excluded because of small numbers (n = 3 sl and n = 182), lack of pathologic reference standard, s3 and lack of categorical data for defining test characteristics. 84 Luketich et alss,86 published a report in 1997 and updated their results in 1999. All of the studies included patients with pathologically confirmed esophageal tumors who were referred for consideration of surgery. PET scans were generally performed only on those patients who were potential surgical candidates after conventional imaging, including barium studies and chest radiographs. All of the included studies also presented properties of CT scans findings for the same cohorts of patients. Whether surgical resection was performed was not entirely independent of the PET findings. When the results from these reports are interpreted, that aspect should be taken into consideration. 87'8s Luketich et a185 combined minimally invasive surgical staging and resected specimens as the reference standard and specifically addressed the test characteristics for the detection of distant metastases. Test characteristics for the detection of distant metastases were not confirmed with pathology or were not available for the whole cohort for 4 studies. 89-92 PET scan properties in 7 studies are shown in Tables 5 to 7. 81'83'85;86'89-93


TABLE 5. Summary of PET scan properties in the detection of biopsy-proven primary esophageal tumors

Author Eligibility* N Sensitivity

Luketich et al, 199985 McAteer et al, 199989 Rankin et al, 1998 m Kole et al, 199892

Luketich et al, 199786

Block et al, 199790 Flanagan et al, 199793

Exclude overt metastases 91 NA Esophagus and gastric tumor 10 100% GE junction tumor 19 100% GE junction tumor; excluded patients 26 96%

with overt metastases or locally advanced disease

Excluded patients with distant 25 96% metastases by imaging (CT, bone scan)

No exclusion 59 97% Excluded patients with local ext and 36 94% met and who were not medically fit for surgery

NA, Not available; GE, gastroesophageal; ext, extension; met, metastasis. *All studies included biopsy-proven esophageal tumors that were referred for consideration of surgery.

Primary esophageal tumors are detectable with PET technology, with a sensitivity of more than 95%. In patients who have undergone standard imaging to exclude obvious metastatic disease, the ability for PET to detect paraesophageal nodes has been greater than that of conventional CT scans used during the study period. However, there is a wide range of sensitivity and specificities; this reflected the selection criteria and the relatively small sample sizes in these reports. PET scanning has a sensitivity that ranges from 40% to 90%, a specificity of more than 70%, and accuracy that ranges from 48% to 86% in the detection of regional nodal involvement. This is, in general, superior to CT scans, which have a sensitivity of 28% to 50%, a specificity of 80% to 100%, and accuracy of 45% to 67%. For distant metastases, the sensitivity of PET ranged from 46% to 71%, specificity ranged from 73% to 100%, and accuracy ranged from 63% to 94%. How this compares to and can be best integrated with other novel staging investigations would in part depend on the cost, local clinical expertise, and availability of treatment strategies that could max- imally benefit from this improved diagnostic accuracy.

MRI

MRI has provided significant advantages in the staging of malignancies such as soft tissue sarcomas and pelvic tumors because MRI has a higher intrinsic contrast resolution than computed tomography. However, the role of MRI in the staging of esophageal tumors has been limited.

Early experiences with MRI for esophageal tumors were described by Lehr et al.94 The utility of MRI in the evaluation of T, N, and M stages requires separate considerations. For the evaluation of the primary tumor,


TABLE 6. Summary of properties of PET and CT scans in the detection of regional nodal involvement

Reference Author standard N Sensitivity

McAteer et al, 199989 Surgical resection specimen 10 0% (0/6) Rankin et al, 199891 Surgical resection specimen 18 38% (3/8) Kole et al, 199892 Surgical resection specimen, including 22 92% (12/13)

minimally invasive surgery Luketich et al, 199786* Surgical resection specimen, surgical 21

sampling Block et al, 199790 Surgical resection specimen 38 52% (11/21) Flanagan et al, 199793 Surgical resection specimen 29 72% (13/18)

47% (9/19)

NA, Not available. *Results were confined to the assessment of distant metastases.

the use of body coil provides inferior spatial resolution when compared with EUS. Attempts to overcome this limitation include the use of endoluminal receiver coil. The use of endoluminal receiver coil was assessed in vitro by Stoker et a195 and Yamada et al. 96 The accuracy of MRI in this setting was similar to that of EUS. This approach was tested clinically by Kulling et al. 97 An endoluminal receiver coil was incorporated into a non- ferrous endoscope and placed in the region of the primary tumor. Although the accuracy was similar to that of EUS, the generalized applic- ability was limited by the impact of motion artifact, the need for optimal placement of the coil for favorable images, and the limitation posed by malignant strictures. These factors are similarly relevant when one attempts to study local regional lymph nodes with the endoscopic receiver coil.

Local regional and nonregional lymph nodes can be assessed with standard body coil imaging techniques. 98 This approach was compared with other staging investigations, including EUS, CT, and abdominal ultrasonography, with the use of pathologic findings as the reference standard. EUS was significantly more accurate and sensitive for lymph nodes in the upper and mid-periesophageal and infracranial nodal regions. CT and MRI were better for mid-paraesophageal and infra-aortic nodes. How- ever, ultrasonography was most accurate and sensitive for abdominal and cervical lymph nodes.

There is no anatomical area where MRI is superior to more commonly used imaging techniques. The authors recommended that MRI should be reserved for patients in whom standard investigations cannot be performed for optimal staging or in situations in which further confirmation of the results is needed. 98


PET

Specificity Accuracy

CT

Sensitivity Specificity Accuracy

100% (4/4) 40% - - - - - - 90% (9/10) 67% 50% (4/8) 80% (8/10) 67% 88% (7/8) 86% 38% (5/13) 100% (8/8) 59%

100% (1/1) 48% NA NA NA

82% (14/17) 68% 28% (6/21) 88% (15/17) 55% 82% (9/11) 76% 28% (5/18) 73% (8/11) 45%

Management of Localized Carcinoma of the Esophagus

Background In patients who are found to have localized carcinoma of the esophagus

after optimal clinical staging workup, the goal of management is to attempt to cure. Within this context, both primary surgery and primary radiotherapy have been used with modest survival outcomes.

The relative effectiveness of a primary surgical approach versus a primary radiotherapy approach (ie, no surgery) continues to be debated. 99-1°1 The lack of high-quality evidence (from well-designed randomized controlled trials) to determine which treatment approach is superior, and under what circumstances, means that clinical opinion dominates treatment selection. Those who advocate surgery continue to cite a higher overall survival rate and a superior palliation for dysphagia in surgically treated patients, whereas those who advocate radiotherapy maintain that overall survival rates of radiotherapy are probably comparable to those obtained with primary surgery, especially if equivalent patients are being compared. Established opinions of physicians and the significant difference between surgery and radiotherapy have resulted in no published completed randomized trials comparing these 2 methods. The results of 1 incomplete trial have been published. 1°2

Thus, to address the management of localized carcinoma of the esophagus, we divided our discussion into two parts. The first part includes information around a primary surgical approach and is followed by a systematic review of the randomized controlled trial evidence for strategies designed to improve the outcomes of surgery alone. The second part includes information about a primary radiotherapy approach and is fol-


TABLE 7. Summary of properties of PET scans in the detection of distant metastases

PET CT

Author N Sensitivity Specificity Accuracy Sensitivity Specificity Accuracy

Luketich et a185 91 46% 73% 63% 46% 73% 63% Flanagan et a193 36 71% 100% 94% 0% 97% 78%

Data not available for McAteer et al, 89 Rankin et al, 91 and Kole et al. 92 Data for distant metastases described by Luketich et a181 in 1997 was updated by Luketich et a185 in 1999.

lowed by a systematic review of the randomized controlled trial evidence for strategies designed to improve the outcomes of radiotherapy alone.

Curability Versus Resectability

One important aspect in the discussion of localized carcinoma of the esophagus is the use of resectability rather than curability as inclusion criteria for studies. This approach is different from that used with almost all other diseases. This difference in approach is a function of the relatively low curative potential of esophageal carcinoma and the belief that interventions (surgery or radiotherapy) that are similar to those used in the curative management of this disease are needed to provide the best palliation. These working criteria may well be applicable for particular sub- sets of patients. However, a clarification of the distinction between an intent of cure and palliation and the separate consideration of tumor resectability will improve our ability to better define the therapeutic ratios associated with different interventions in different circumstances.

Surgery as a Curative Therapy

This review will highlight some of the options and controversies sur- rounding the surgical management of esophageal carcinoma, including the extent of resection, extent of dissection, choice of conduit, position of the conduit, anastomotic techniques, and surgical approaches. A single universally accepted approach for esophageal excision and reconstruction has not been devised. A variety of procedures have satisfactory function with equal morbidity rates. Although there is no consensus about what constitutes adequate resection margins for the primary or the lymph node resection, prolonged survival is dependent on the completeness of resection and the pathologic stage of the disease. Resectability reflects the aggressive philosophy of the individual surgeon. Some believe that esophagectomy is futile unless all gross disease can be removed en bloc with an envelope of normal tissue. Other surgeons are willing to remove tissues that have been invaded (such as pleura, pericardium, diaphragm, and even liver) along with the tumor and lymph nodes to achieve resec-


tions. Still others accept an incomplete resection and leave residual tumor to offer palliation. It has been said that the role of surgery is to provide palliation of dysphagia and that a cure is a bonus. Unfortunately, the median survival time after the surgical removal of all gross disease is between 12 to 18 months in most centers and the 5-year survival rate sel- dom exceeds 25%.

Extent of Esophageal Resection. Whenever possible, a minimum of 5 cm of esophagus proximal and distal to the tumor should be removed. The goal of resection is the complete removal of disease, and this most often requires a near total esophagectomy. An adequate proximal and distal resection margin reduces the likelihood of local recurrence from the tumor involvement of submucosal lymphatics frequently seen with both squamous cell carcinoma and adenocarcinoma. Cancers of the gastroesophageal junction require the resection of more stomach than do esophageal cancers, especially along the lesser curve where lymph node involvement is more common. Akiyama et al 1°3 have advocated a total gastrectomy with a Roux-en-Y jejunal loop reconstruction. Most surgeons in North America prefer to preserve as much stomach as possible and perform a high thoracic or cervical anastomosis.

Extent of Esophageal Dissection. The definition of a complete or adequate resection remains elusive. There is no strong evidence that the extent of dissection provides a survival advantage. Opinions vary from radical en bloc 3-field lymphadenectomy that includes uninvolved adjacent tissue to simple esophagectomy with adjacent nodes. 1°4-1°7 The radical approach involves complete resection of the esophagus 10 cm proximal and distal to the tumor, with resection of the blood supply of the tumor, adjacent pericardium, pleura, thoracic duct, azygos yein, and periesophageal tissue. ~°~ In the abdomen, large portions of the stomach, spleen, left crus of diaphragm, and retroperitoneal nodes superior to the pancreas are removed. A 3-field lymph node dissection as described by Akiyama et al l°8 includes the intra-abdominal, intrathoracic, and cervical nodes. Few surgeons have experience with this technique. Most surgeons, however, perform an en bloc dissection that includes the pleura and fibroareolar tissue that surrounds the tumor. Adjacent structures, such as pericardium, diaphragm, thoracic duct, and azygos vein, are only excised if they are directly involved.

Choice of Conduit. Stomach The mobilized stomach is the conduit of choice for most surgeons (Fig-

ure 4). The blood supply is reliable, mobilization is straightforward, there is only one anastomosis, and the functional results are consistent. Careful


preservation of the right gastric and gastroepiploic blood supply is essential. Whether the entire stomach is used or a portion of the lesser curve is removed to create a narrow gastric tube depends on the location of the tumor. Construction of a gastric tube is performed with the aid of staplers and has been reported to provide additional length and to prevent intrathoracic rotation. We prefer to use the entire stomach and have found it to be suitable. Time is saved if a gastric tube is not performed, the blood supply to the proximal stomach is improved, and there is adequate length for all reconstructions.l°9

Functional results with the stomach are excellent overall. Gastric emptying occurs mainly by gravity and most patients will report early satiety and dumping syndrome if food is eaten too quickly. ~1° If the anastomosis is placed within the chest, rather than in the neck, gastric reflux can be a problem and may lead to late anastomotic strictures.

There now appears to be a consensus that a gastric drainage procedure is necessary to help with stomach emptying. 11~,112 In one randomized trial, researchers compared a pyloroplasty and a pyloromyotomy in 92 patients. 1~3 Gastric emptying was better with the pyloroplasty at 6 months, but there was no difference at long-term follow-up examinations up to 5 years after the pyloroplasty. The incidence Of regurgitation, diarrhea, bile reflux, and dumping syndrome was no different with the 2 procedures, u3 The choice of procedure depends on the preference and experience of the surgeon. In a second trial, 30 patients were randomly assigned to three groups: group 1 underwent pyloroplasty, group 2 underwent pyloromyotomy, and group 3 underwent pylorus stretching.H4 Gastric emptying was evaluated 6 to 8 weeks after the operations and there were no differences in the 3 groups. All pylorus drainage procedures appear to function equally well. Colon. The colon is favored when the stomach in not available. A colon transposition requires 3 anastomoses, has a more tenuous blood supply, and requires a prolonged procedure. Although any segment of the colon may be used, either in an isoperistaltic or antiperistaltic position, most surgeons prefer an isoperistaltic left colon based on the left colic artery or the transverse colon based on the middle colic artery. Anticolic transpositions have a ten- dency to produce vomiting because of sporadic mass contractions and seg- mentation. Colon segments are also more likely to become redundant over time, which causes chronic chest pain and dysphagia. Jeiunom. Pedicled jejunal conduits are the most difficult to construct. H5 They are limited by length, by the necessity for 3 anastomoses, and by venous or arterial insufficiency. However, a cervical esophageal resection with microvascular free jejunal flap reconstruction is an excellent alternative to a gastric "pull-up."


Organ Teshntque Inherent

No. of Morbidity Anastomoses Difficulty

Stomach . , -~ -~ 1 +

° - ' Curvature 1 + . Tube ~ ; , I

Reversed = Gastric 1 +++

Tube

reversed 1 ++ Gastric

Tube ,;,

Rioht I [ 3 +++ Colon

Lelt Colon ~ 3 + + + +

Jejunum

Free Graft

i 2 = (Roux Loop}

; ~ 3 ++ _ . _ (mteq~os~t~on/

' I I . ~ ~ . 5

{2 micro- + + + + + vascular)

Upper Level of Disadvantages Usefu!neas

Cervicat Esophagus Bulky and Pharynx Ret~x Risk

Cerv#cal Esophagus Rellux Risk and Pharynx

Cervioal Long Suture Line Esophagus Limited Blood and Pharynx Supply

Lower Cervical Long Suture Line Esophagus

Thin-walled Lower Cervical Bulky Esophagus Short Pedicle

Most versatile Extensive o~gan lot use operation at any levet Redundancy Lm'~or third to over time Pharynx

Limited graft Lower Third length without

revision O! pedir..Je or bowel -

Pharynx and i Micrevascular Cervical anastomoses Esophagus required

FIG 4. Comparison of various esophageal substitutes. Courtesy of Pearson FG, Hiebers CA, Deslauriers J, McKneal ly MF, Ginsberg R J, Urschel HC Jr. Esophageal surgery. 1st ed. New York: Churchill Living-

stone; 1995.

Position of the Conduit. The conduit can be placed subcutaneously, ret- rosternally, orthotopically in the posterior mediastinum, or in either pleural space. Most surgeons in North America favor the posterior mediastinum, whereas many Japanese surgeons prefer the substernal route. The placement of the esophagus behind the sternum has been touted to avoid later problems with local mediastinal or celiac axis recurrence and to allow higher doses of postoperative irradiation to be delivered to the esophageal

Curr Probl Cancer , N o v e m b e r / D e c e m b e r 2 0 0 0 3 1 9

Scapula

Anterior axillary line

X

. ~ . )g . . . . . .

/ / i( ~:--::

" q : > - 2

~ii: " \

:.%

. . . . . . >'%' d ; ' : ' : ' ~ ,,-~222:,~-~:25:'--'-.z. "~ ' ).x . . . . . 222--

I . . f t , . . . . . . . . . . . . . 4 ~'-. -_ . . - " ,4 ! I

.J

,,!~...--~.. ,, . . . . . ;;.,,

",?:'2 Fifth rib removed ' '

FIG 5. The standard incisions for a Lewis-Tanner esophagectomy. An upper midline abdominal incision is used for mobilization of the stomach, and a right thoracotomy is used far resection of the esophagus and for performance of the esophagogastric anastomosis. Courtesy of Pearson FG, Hiebers CA, Deslauriers J, McKneally MF, Ginsberg RJ, Urschel HC Jr. Esophageal surgery. 1st ed. New York: Churchill Living- stone; 1995.

bed. However, in 2 randomized trials, researchers compared the retrosternal gastric tube reconstruction with the posterior mediastinal gastric tube reconstmction.l16,1t7 The retrosternal reconstruction had an increased morbidity rate (25%-60% vs i3%-52%) and mortality rate (10%-14% vs 4%- 8%). There was significantly longer radionuclide retention in the gastric tube in the retrosternal position, and patients spent more time in the intensive c a r e un i t . 116,117 The posterior mediastinal route appears to be superior, and the retrosternal route should be used whenever palliative or incomplete resection has been performed or when postoperative radiation is planned.

Anastomosis'. A properly performed anastomosis should eliminate dysphagia and should not leak. The debate about the optimum technique for the esophagogastric anastomosis continues. Methods vary from 1, 2, and 3 layers of inversion with the use of interrupted or continuous absorbable or nonabsorbable sutures to mechanical staples. Circular staples are most often used for an intrathoracic anastomosis, whereas the endogastrointestinal anastomosis staples have become more common for cervical anastomoses, us The endogastrointestinal anastomosis staple technique cre-


ates a posterior 30-mm V-shaped spatulated anastomosis that provides an adequate opening with a low leak rate. In 3 randomized trials, researchers have compared handsewn staples to circular staples. 112,118,119 Although each trial had small numbers, 2 trials favored a handsewn technique and one favored the staple technique because it was faster. The stapled anastomosis had a 5% to 20% leak rate compared with a leak rate of 2% to 5% for the handsewn anastomosis, 12°,121 The stricture rates ranged from 9 % in the handsewn anastomosis to 40% in the stapled anastomosis.12°

Surgical Approaches. The surgical approach is most often dictated by the location of the tumor, the extent of resection, the condition of the patient, and the preference of the surgeon. We describe several techniques; none of these techniques are considered to be ideal for all tumors. Good judgement and experience should prevail to ensure an adequate and safe operation.

Right Thoracic Procedures Lewis-Tanner Procedure. The Lewis-Tanner procedure (also called the

Ivor-Lewis or Tanner procedure) is the classic approach for distal or midesophageal tumors (Figure 5). The patient is initially positioned supine, and an upper midline abdominal incision is made. The stomach is mobilized, and the perigastric lymph nodes are dissected. A pyloroplasty or pyloromyotomy is performed. The patient is then turned to the fight thoracotomy position for completion of the mobilization of the esophagus and resection of the tumor. The stomach is brought up through the hiatus, and the anastomosis is performed well above the level of the azygos vein. The fight thoracotomy allows direct visualization of the midesophagus near the trachea. If there are dense adhesions, mediastinal adenopathy, or locally invasive tumor, this approach is safest. If the stomach transposition becomes redundant, it may prolapse into the posterior costophrenic sulcus and produce gastric dysfunction.

Three-Hole Approach. For the three-hole approach, the patient is positioned supine with the right side of the chest elevated and the left side of the neck exposed. An abdominal incision is performed. The incision is followed by a fight thoracotomy without repositioning of the patient. When the esophagus is free, the cervical esophagus is mobilized and divided and the stomach is transposed to the neck for the anastomosis. This approach allows completion of the surgery without repositioning of the patient; however, thoracic exposure is less than ideal.

McKeown Right Thoracotomy-Abdominal-Cervical Procedure. The McKeown right thoracotomy approach is similar to the Ivor-Lewis approach but involves a cervical anastomosis. The esophagus is first


mobilized with a right thoracotomy. The patient is then repositioned supine for the gastric and cervical mobilization. The stomach is then transposed up to the neck transhiatally for the anastomosis.

Left Thoracic Procedures Left Thoracotomy. The entire esophagus can be removed through a left

thoracotomy, but the gastric mobilization, abdominal lymphadenectomy, and pyloromyotomy are difficult. Abdominal exposure is enhanced by enlarging of the hiatus with either a radial or a circumferential incision. The anastomosis is placed above the aortic arch.

Left Thoracoabdominal Incision. The left thoracoabdominal incision provides ideal exposure for proximal gastric cancers. The sixth intercostal space is usually chosen, and the cartilaginous portion of the rib cage is divided or a portion is resected. The anastomosis can be placed either orthotopically or outside the aortic arch. Postoperative pain is the major limitation of this approach.

Left Thoracoabdominal-Cervical Procedure. The thoracoabdominal incision can be combined with a left neck incision for a cervical anastomosis. This can be accomplished without turning the patient or after the chest is closed and the patient is repositioned.

Transhiatal Esophagectomy An esophagectomy without a thoracotomy can now be performed safely

and effectively (Figure 6). 109'122'123 A transhiatal approach is particularly useful for distal esophageal and gastroesophageal junction tumors and for early malignant changes seen in dysplastie Barrett's epithelium. The procedure can be performed with visualization up to the carina, but the subcarinal nodes cannot be dissected under direct vision. Despite this disadvantage, there appears to be no survival difference between a transhiatal esophagectomy and a transthoracic esophagectomy. 124-126 In a randomized trial, the transhiatal resection was compared with the transthoracic resection in 39 patients. 124 There was no 30-day mortality rate in either group, but 3 patients in the transhiatal group died in the hospital. The median survival times were 16 and 14 months, respectively, for the transhiatal group and the transthoracic group. The authors found no statistical difference between the 2 techniques but preferred the transthoracic approach because it allowed more control. 124 The potential value of avoiding a thoracotomy with the use of a transhiatal approach was evaluated in 2 randomized t r ia ls . 125,~26 Goldminic et a1125 found no difference in postoperative morbidity rates, mortality rates, or survival times, but the transthoracic approach took longer to complete. Jacobi 126 found only a


FIG 6. The initial phase of transhiatal esophagectomy. Thoracotomy is avoided, and dissection is performed with a laparotomy and left cervical incision. Courtesy of Orringer MB. Transhiatal esophagectomy without thoracotomy for carcinoma of the esophagus. Adv Surg 1986;19:t-49.

transient intraoperative pulmonary strain with single lung ventilation during the transthoracic approach and no other significant differences between the 2 techniques in cardiopulmonary effects.

Transoral Esophagectomy Akiyama et al m7 have described a technique of esophagectomy through

the mouth. Using an abdominal and left neck incision, the surgeon removes the esophagus by turning it inside out and pulling it through the mouth. This approach is a modification of the transhiatal technique and is best suited for severe dysplasia and carcinoma in situ.

Minimally Invasive Operations Video-Assisted Techniques

The combination of thoracoscopic and laparoscopic techniques is now being used to resect the esophagus (Figure 7). 128-132 Access to the right or


left hemithoraces or peritoneal cavity can be obtained without the large, painful muscle-dividing incisions of a thoracotomy or laparotomy. Most combined thoracoscopic and laparoscopic techniques have involved an open cervical esophageal anastomosis, but some researchers have reported thoracoscopically stapled intrathoracic anastomosis. 132a Few surgeons have this expertise, there is a long learning curve, and the procedure is lengthy and initially more costly. The potential benefits of decreased length of stay in the hospital and quicker postoperative recovery remain to be proven. Future refinements in instrumentation and even robotic-assisted approaches will undoubtedly make minimally invasive procedures more common. Currently, however, thoracoscopy is not the preferred approach for esophagectomy and should be regarded as experimental.

In summary, there are several options available to the thoracic surgeon when he or she is considering surgical resection of the esophagus because of cancer. Regardless of the extent of resection, extent of dissection, choice of conduit, anastomotic technique, and approach, attention to detail in the perioperative care and meticulous technique will minimize morbidity and mortality rates.

Neoadjuvant and Adjuvant Therapies: A Systematic Review Although surgery is the mainstay of therapy for localized resectable

carcinoma of the esophagus, the outcome continues to be guarded. Vari- ous combined modality strategies have been used in an attempt to improve the outcomes of surgery alone. Major strategies that have been studied are discussed in the following sections.

Methods of the Review. A systematic review approach was undertaken by the reviewers. This, in part, represents work performed under the Ontario Treatment Guidelines Initiative for esophageal cancer. 133 A search of the literature was performed with the following search strategy. Medline and Cancerlit databases for 1966 to November 1998 were searched. The MeSH headings Used included esophageal neoplasms; the keywords used included adjuvant chemotherapy, adjuvant radiation, preoperative chemotherapy, and preoperative radiation. Inclusion criteria included randomized controlled trials in which neoadjuvant or adjuvant treatment with surgery was compared with surgery alone in patients with resectable and operable esophageal cancer.

Data were extracted from the articles in duplicate by the reviewers with the use of standard data collection sheets. Information extracted included patient demographics, criteria for entry into the study, and reasons for exclusion from the study. Data pertinent to the quality of the trial report, including method of randomization (which is pertinent for the assessment


FIG 7. Port placement for a right thoracoscopic esophagectomy. Courtesy of Gamliel Z, Krasna Mj. The role of video-assisted thoracic surgery in esophageal disease. Chest Surg Clin N Am 1998;8:853-70.

of whether there was any risk of bias in the randomization procedure) and method of follow-up (how frequently recurrences were identified), were recorded. Details of the interventions, radiotherapy and chemotherapy dose regimens, and type of surgery used were recorded. Endpoints of interest include overall survival, local recurrence, acute and chronic toxicities, and 90-day perioperative mortality rate when relevant and available. Quality-of-life data were not uniformly reported. The data were recorded when they were available. The reporting of local recurrences was usually a secondary endpoint that was not well captured. The studies involved were uniformly not blinded studies because of the nature of the intervention. With nonblinded studies, the intensity with which patients and investigators would seek out and document local recurrences is potentially biased depending on the type of intervention delivered. The presence of distant metastases as a first recurrence would also frequently deter vigorous documentation for recurrent disease, especially if the general condition of the patient is declining. These factors have to be taken


TABLE 8. Summary of characteristics of randomized clinical trials in which surgery was compared with surgery and preoperative radiotherapy

No. of deaths/No.

Series BED Dose fractionation S + CT

Launois et a1138 52.7 40 Gy in 12 fr 87% (40/46) Gignoux et a1139 43.9 33 Gy in 10 fr 96% (108/113) Wang et a1142 N~ 40 GyJ 74% (165/223) Arnott et a1141 24 20 Gy in 10 fr 87% (75/86) Nygaard et a114° (group A) 41 35 Gy in 20 fr 100% (50/50) Nygaard et a114° (group B) 41 35 Gy in 20 fr 95% (53/56) Total 86% (491/574)

CT, Chemotherapy; S, surgery; RT, radiotherapy; fr, fractions; NA, not available. *Death within 30 days per the number of patients who underwent surgery. tNumber of fractions not stated.

into account when local recurrence rates are interpreted. Toxicity reporting, especially in the older studies, was generally not based on a specified grading system; this may also have caused bias in the reporting of toxicities, depending on the focus of the study.

Because the biological effect of radiotherapy dose fractionation varies as a combined effect of dose per fraction, number of fractions, and the types of tissues under consideration (acute reacting tissues and tumor vs late reacting tissues), a method of integrating these components is desir- able to facilitate comparison between different radiotherapy regimens. The concept of biological effective dose (BED) has been widely used for this purpose and will be used for this review. 134 Although this is at least partly a theoretical concept, it incorporates the effect of the major vari- ables that are important in the determination of the biological effect of a course of radiotherapy on the relevant tissues. When BED is used for comparison of the relative intensity of different regimens, it is an effective and valid tool.

BED can be calculated with the following equation:

BED = n d (1 + d/a/b)

in which n is the number of fractions, d is the dose per fraction, and a/b is 10 for tumor and acute-reacting tissues or 3 for late-reacting tissues.

Preoperative Radiotherapy. For the purpose of examining preoperative radiotherapy, we included only trials in which preoperative radiotherapy and surgery were used as the study arm. There have been no new primary studies since this area was reviewed by Coia et a1135 in 1994. Five randomized trials were identified in this area. 138-14° In addition, a meta-analysis was published in which this strategy was addressed with the use o f


entered in the study Perioperative mortality rate*

RT _+ CT + S S + CT RT -+ CT + S

92% (56/61) 21% (7/33) 15.4% (13/47) 93% (108/116) 22% (19/87) 32% (24/75) 67% (131/195) 5% (5/87) 5% (5/97) 97% (87/90) 13% (8/62) 15% (10/67) 90% (52/58) 13% (5/38) 11% (4/36) 97% (46/53) 15% (6/41) 24% (8/34) 84% (480/573) 15% 17%

individual patient data and additional follow-up data obtained from the original investigation136; this meta-analysis has been converted into a Cochrane review) 37

Characteristics of the primary studies are shown in Table 8. Three studies included squamous cell carcinoma only] 38-14° and 2 also included adenocarcinomas. 141,142 The sample sizes of the individual studies ranged from 109 to 229; the studies included a total of 843 patients. These studies were performed between 1973 and 1988. One of the 5 studies specified whether the surgery was undertaken with a curative intent) 39 The randomization procedure, which reflects the potential for bias to occur in the randomization process, was recorded. This was described as sealed envelope method in 1 study 14~ and as random numbers in one study138; it was not specified in the other studies. ~39,14°,142 None of the studies used blinding of the evaluator; this is relevant in the interpretation of toxicity and local recurrence reporting. A wide range of doses was used in the radiotherapy regimens (BED range, 24-53 Gy-1). The radiotherapy planning volume encompassed the tumor with a wide margin in all cases. The duration of follow-up was not specified by Launois et al, a37 it was more than 1.5 years in 3 studies, 14°-~42 and it was a median of 3.6 years in the study by Gignoux et al. 139

In the individual patient data analysis published in 1998, an additional 200 patients were included in the study reported by Wang et al. 142 The reason these patients were not reported in the original publication was not clear. However, the patient characteristics for these patients appear to be well balanced. ~37 The results were updated to provide a median follow-up of 9 years. On the basis of the published systematic review, the hazard ratio was 0.89 (~2 (1) = 0.89, P = .06), which is not conventionally sig-


TABLE 9. Randomized clinical trials in which outcomes of preoperative chemotherapy and surgery were compared with outcomes of surgery alone

No.

Series CT No CT Excluded CT

Schlag 143 22 24 1 Maipang et a1144 24 22 0

Law et a1145 74 73 0

Kok et al ±46 NA NA NA

Kelsen et al z47 233 234 23 Nygaard et al ±4° 50 56 15 Roth et al ¢48 19 20 3

Cisplatin, 5-FU Cisplatin, vinblastine,

bleomycin Cisplatin, 5-FU

Cisplatin, etoposide

Cisplatin, 5-FU Cisplatin, bleomycin Cisplatin, vindesine,

bleomycin

CT, Chemotherapy; N, nausea; V, vomiting; NA, not available. *Postoperative complications. l-Toxicity grade not given. tSurvival rate at 3 years. {}Postoperative morbidity rate described for a cohort of randomized and nonrandomized patients.

nificant. On the basis of this analysis, there was no significant survival benefit from the addition of preoperative radiotherapy. Even if a benefit does exist, as suggested by the point estimate, the absolute benefit is approximately 4% at 2 years (95% CI, 0-9) and 3% at 5 years, which improves survival from 30% to 34% and from 15% to 18%, respectively. Reports of local recurrence rates were sparse and noncontributory.

Toxicity is summarized on the basis of the original published data. The perioperative mortality rates were similar between the 2 arms: 15.2% (range, 5%-22%) for surgery and 15.4% (range, 5%-32%) for surgery plus radiotherapy. This rate of perioperative mortality is much higher than would be expected with contemporary surgical practices. Different methods were used to report the incidence of acute and late toxicities in the studies. In general, there do not appear to be any major differences in terms of toxicity being reported with the dose fractionations used. No quality-of-life data were available. Because of the lack of survival benefit, preoperative radiotherapy is not recommended.

Preoperative Chemotherapy. For the purpose of examining preoperative chemotherapy, we included only trials in which preoperative chemotherapy and surgery was compared with surgery alone. Seven randomized trials, 140'143-148 1 of which was only available in abstract form, 146 were identified. In 2 ser ies , 147'148 the researchers incorporated chemotherapy postoperatively after surgery for the study arm and compared that with surgery alone. A Cochrane review is being prepared on this topic. 149 One meta-analysis was identified in which the role of cisplatin-based

328 Curr Probl Cancer, November /December 2000

Operative mortality

CT No CT

Toxicity grade 3,4 Median survival

CT No CT CT No CT

23% 14% N + V: 11; myelotoxicity: 2* None described 10 mo 10 mo 0 0 N + V: 4 /15 None described 17 mo 17 mo

(4 toxicity-related deaths) 0 0, Anemia: 4; Splatelets: 3; None described 16.8 mo 13 mo

J'creatinine: 1; Ssodium: 1 NA NA Alopecia: 9%; renal: 14% (1 - - 18.5 mo 11 mo

toxicityCelated death) for entire group 6% 6% 29% 25% 14.9 mo 16.1 mo

15% 13% 25%¢ 26%1- 3%t 9%# 12% 0% 29%§ 47%§ 9 mo 9 mo

chemotherapy was addressed. 15° The focus of this latter review differed from ours; the objective of that review was the assessment of the role of cisplatin combined with radiotherapy or surgery, or both.

The characteristics of the primary studies are shown in Table 9. The studies were performed between 1982 and 1995. Study sample sizes ranged from 39 to 467, with a total of 1011 patients involved in these trials. All studies included squamous cell carcinoma exclusively, with the exception of the study by Kelsen et al, 147 in which more than half (257) of the patients had adenocarcinoma. None of the studies provided details about the method of randomization used. All studies incorporated cisplatin as one of the regimens, 3 included 5-fluorouracil (5-FU), 143'145'147 and 3 included bleomycin. 14°,144J48

There were no differences in the median survival times between the two arms in any of the studies except in the study by Kok et al. 146 They reported a significant difference of 18.5 versus 11 months in favor of neoadjuvant CT. No full articles published after the abstract could be identified for additional details. In general, the median survival range for all the studies identified was 10 to 18 months.

Perioperative mortality rates were similar between the two arms; the rates were generally around 10%, which is high for the time when these studies were conducted. Toxicities are significantly greater with the chemotherapy arm. Local recurrence rates and quality-of-life were not uniformly available among these trials. On the basis of these results, preoperative chemotherapy is not recommended.


TABLE 10. Randomized clinical trials in which outcomes of surgery and postoperative chemotherapy were compared with outcomes of surgery alone

No. Survival rate at 5 y

Author N excluded CT No CT

Pouliquen et a1152 124 4 7% 8% Ando et a1151 205 0 48.3% 45%

Postoperative Chemotherapy. For the review of postoperative chemotherapy, we included only trials in which surgery alone was compared with surgery and postoperative chemotherapy. Two randomized trials were identified that met this criterion. 151,152 Sample size estimation was provided and reached the desired accrual for both studies. Randomization methods were use of "the right upper comer of a booklet ''152 and use of a central randomization office. ~51 The study arms in the study by Ponliquen et a1152 appeared to exhibit some imbalance, with younger patients in the chemotherapy group, whereas the arms appear to be well balanced in the study by Ando et al.151 Both studies included squamous cell carcinoma only. Ponliquen et a1152 targeted patients with more advanced disease. In their study, patients were subdivided into 2 strata: stratum 1 included patients with positive nodal involvement (but with complete removal) and stratum 2 included patients with incomplete resections (macroscopic and microscopic). Ando et a1151 randomized only patients who had complete removal of the primary and involved lymph nodes. The cisplatin-based chemotherapy was used in the study arms of both studies. Ponliquen et 0.1152 used cisplatin and 5-FU for 6 to 8 cycles, and Ando et 0.1151 used cisplatin and vindesine for 2 cycles.

Reported outcomes of interest were overall survival and toxicity (Table 10). There was no difference in survival outcome between the two arms in either study. There were significantly more toxicities in the treated group, as would be expected. On the basis of these outcomes, postoperative chemotherapy as used in these studies did not improve patient outcome and is not recommended.

Postoperative Radiotherapy. For the review of postoperative radiotherapy, we included randomized studies in which surgery alone was compared with surgery and postoperative radiotherapy. Three randomized studies were identified. 153-155 The randomization method was described in all of the studies. Tienere et a1155 used the folded corner of a questionnaire method, Fok et a1154 used the sealed envelope method, and Zieren et aP 53 used the random table method. The study by Zieren et al153 was discontinued earlier than planned because of observed toxicities in that study and other studies, with no evidence of survival benefits. All researchers


TABLE 11. Randomized clinical trials in which outcomes of surgery were compared with outcomes of surgery and postoperative radiotherapy

Survival Local N rate at 3 y recurrence

NO, Author $ S + RT excluded S S + l iT S S + l iT

Zieren et a1153 35 33 0 21% 22% 54% 45% Fok et a1154 65 65 0 21% 16% 31% 15% Teniere et a1155 119 102 0 29% 27% 85% 70%

S, Surgery; S + RT, surgery and postoperative radiotherapy.

used an intention-to-treat approach in reported outcomes. Although all of the researchers specified the absence of distant metastases as an inclusion criterion, Zieren et a1153 and Teniere et al155 included patients with celiac node involvement (M1 disease) and Fok et a1154 included patients with positive margins and "a high chance of residual tumor."

The timing of the radiotherapy was described in all studies. The trials by Fok et al154 and Zieren et a1153 began within 6 weeks of surgery, whereas the trial by Teniere et a115~ began within 3 months of surgery. The radiotherapy doses were higher than those used in the preoperative series. Of note, Fok et a1154 used hypofractionation schedules with 3 fractions per week and 3.5 Gy per fraction to a total dose of 49 Gy for patients with negative margins and 52.5 Gy for patients with positive margins. Teniere et a1155 used 45 to 55 Gy in 25 fractions with a boost of 0 to 10 Gy. Zieren et a1153 used a total of 55.8 Gy in 31 fractions.

The endpoints of interest were overall survival and local recurrence rates and toxicity. No standardized toxicity grading system was used. Summaries of the findings of these studies are presented in Tables 11 and 12. Despite the negative conclusions of these studies in terms of survival, one important aspect is the reduction in the incidence of local recurrence, which is most noticeable with the highest biological dose used by Fok et al.xs4 However, this approach is also accompanied by a high risk of toxicities. The level of toxicities encountered by Fok et a1154 is not typically anticipated when standard 2-Gy fractions are used.

On the basis of the data available, there is a disadvantage in overall survival (attributable to treatment-related deaths) with this approach, and this approach is generally not recommended. In selected patients who have residual disease after surgery and for whom the risk of local recurrence and its associated morbidity is high, the use of postoperative radiotherapy may convey local control benefit. Therefore 2-Gy fractions to moderately high doses should be considered.

Preoperative Chemoradiotherapy. For the review of preoperative


TABLE 12. Randomized clinical trials in which toxicity of surgery was compared with toxicity of surgery and postoperative radiotherapy

Toxicity

Author Definition S S + RT

Zieren et al ±53 Tolerance to radiotherapy self-reported N~ 16 patients with at the end of radiotherapy '!slight reaction,"

29 with "general weakness," 24 with "dysphagia," and 7 with "nausea"

Fibrotic stricture at I y 27% 50% Fok et a1154 Fibrotic stricture 6/65 6/65

Gastric ulcer, gastritis, bleeding 4/65 24/65 (5 patients died of bleeding, and for 2 there was no evidence of metastasis)

Teniere et a1155 Toxicity severe enough to require I~ 4/102 discontinuation of RT

S, Surgery; S + RT, surgery and postoperative radiotherapy; NA, not applicable.

chemoradiotherapy, we included randomized trials in which combined chemoradiotherapy and surgery was compared with surgery alone. Dif- ferentiation into concomitant or sequential approach could be made on the basis of the timing of the chemoradiotherapy. This is relevant because these approaches are founded on different biological principles. However, there was only one trial in which sequential chemotherapy and radiotherapy was used. 156 Because of the small number of trials, the results of this study are presented with those of the studies in which concomitant designs were used.

Seven randomized studies were identified14°,156-161; two of the studies were reported in abstract form only. 16°,161 These studies included between 69 and 297 patients; a total of 863 patients were included in the studies. Walsh et a115s planned to study 190 patients, but they discontinued the study early, with only 113 patients because after performing an interim analysis they believed that there was clinically noticeable difference between the outcomes for the patients in the treatment arms. Bosset et a1159 discontinued their study early with 297 patients (they had planned to study 320 patients) because of the observation that there was a higher postoperative mortality rate in the group receiving combined treatment. Sample size estimation was not provided for the other studies. The randomization method was only described in the study by Bosset et a1159; they used a central randomization office.

Only one study focused exclusively on adenocarcinoma. 15s The only other study in which patients with adenocarcinoma were included was the


TABLE 13. Randomized clinical trials in which preoperative chemoradiotherapy and surgery was compared with surgery alone

No. Chemo- Radio- BED Time to Author N excluded therapy therapy (GYlo) surgery

LePrise et al ¢56 104 18 Cisplatin on d I and 20 Gy in 10 24 >2 wk

d 21; 5-FU on d 2-5 fr on d 8-19 and d 22-25

Apinop et a1157 69 N& 2 cycles of cisplatin 40 Gy* N& NA on d 1; 2 cycles of 5-FU on d 1-8

Walsh et a1158 113 17 Cisplatin on d 7; 40 Gy in 15 fr 33.8 8wk 5-FU on d 1-5 and d 35-39

Bosset et a1159 297 15 I dose of cisplatin 18.5 Gy in 5 fr, 50.7t 2-4 wk 2-wk gap, and then 18.5 Gy in 5 fr

Nygaard et a114° 103 15 2 cycles of cisplatin 35 Gy in 20 fr on d 1-5; 2 cycles of bteomycin on d 1 45 Gy in 30 fr bid

Urba et a116° 100 IN& Cisplatin on d 1-5 (ie treatment for and d 17-21; 3 wk) 5-FU on d 1-21; vinblastine on d 1-4, d 17, and d 20

Launois ~6~ 77 NA Cisplatin, 5-FU 20 Gy

41 NA

51.8t NA

NA NA

fr, Fractions; NA, not available; bid, twice a day, *Fractions not provided. tDoes not account for the effect of split course. ~'Does not account for the effect of twice-a-day treatments.

study by Urba et a116° in which 75% of the patients enrolled had adenocarcinoma. All the other studies included patients with squamous cell carcinoma only. 14°'156'157'159A61 Except for the 2 studies reported in abstract format only (in which further details about the patients studied were not available), all studies excluded patients with cervical esophageal tumors and patients with distant metastases, and some of the studies had some criteria to exclude patients with poor performance status, The criteria used included age younger than 70,156'159 age younger than 65,14° age younger than 76,158 and performance status of less than 2140'156'159 and 3 or less. 15s Nygaard et a114° also excluded patients with T3 disease.

In all of the studies, cisplatin was used as one of the chemotherapy agents. The regimens used are outlined in Table 13. The radiotherapy dose fractionation ranged from 20 Gy in 10 fractions to 45 Gy in 30 fractions twice a day. The BED used ranged from 24 to 52 GYl0. The time from neoadjuvant therapy to surgery ranged from 2 weeks to 8 weeks (where available).

Only the study by Walsh et al ~58 showed a statistically significant bene-


TABLE 14. Randomized clincial trials in which outcomes of preoperative chemoradiotherapy and surgery were compared with outcomes of surgery alone

Pathologically complete 3-y overall survival rate

Author response CRT No CRT

LePrise et al ±56 27% (11/41) 19.2 13.8 Apinop et a1157 20% (7/35) 26 21 Walsh et a1158 25% (13/52) 32 6 (P = .01) Bossett et a1159 26% (29/112) 39 37 Nygaard et aF 4° - - 17 10 Urba et a116° - - 32 16 Launois 161 - - NA* NA*

CRT, Preoperative chemoradiotherapy; NA, not available. *Survival at i year was not significantly different between the two study arms.

fit of chemoradiotherapy, but all of the other studies showed a trend for survival benefit (Table 14). When the survival outcomes were evaluated statistically for consideration of pooling of results, 162 there was significant heterogeneity, 133 which suggests that there may be systematic differences among the studies being examined.

The obvious difference between the studies is the pathologic subtype being studied; the study by Walsh et a1158 was devoted to adenocarcinomas, whereas the other studies were focused on squamous cell carcinomas. In addition, the outcome of the no chemoradiotherapy arm in the study by Walsh et a1158 was worse than that observed in all of the other studies, in examining the pathologic tumor stage of the control arm with the assumption that the randomization process was effective, we found that there were significantly more patients with nodal disease in the study by Walsh et a1158 compared with the other studies (Table 15). These characteristics may account for the differences in the observed outcome. It can be hypothesized that a combination of chemotherapy and radiotherapy is most effective in advanced local regional disease; however the effect is less noticeable in patients with earlier disease. Larger sample sizes and better supportive care measures are required to reduce toxicities for this therapy to be potentially useful in patients with less advanced disease.

In the overall effect of the combined neoadjuvant chemotherapy and radiotherapy with surgery, there is a general trend in favor of survival benefit, which was statistically significant in the 1 study in which adenocarcinoma in particular was examined. 158 Local recurrence rates were not consistently reported. None of the studies presented quality-of-life information. The pathologic response rate was similar in all of the studies and was approximately 25%. In particular, there were no obvious differences between the response rate observed in the study by Walsh et al, 158 in which the patients only had adenocarcinoma, compared with the other studies.


TABLE 15. Proportion of patients with positive nodal involvement in the control arm*

Author Postive nodes

LePrise et a1156 1 6 / 4 5 (35%) Walsh et a1158 4 5 / 5 5 (82%) Bossett et a1159 2 3 / 1 3 9 (32%)

*Pathologic nodal status not available for Nygaard et al, 14° Apinop et al, ~57 Urba et al, 16° and Launois. 161

Toxicity attributable to chemoradiotherapy and to perioperative death and disease and long-term toxicity were reported separately (Table 16). There were definite incremental toxicities with chemoradiotherapy; Walsh et a1158 estimated approximately 12% grade 3 to 4 toxicities. The degree of postoperative death and disease was similar in the 2 groups.

Neoadjuvant chemoradiotherapy with surgery is the most promising approach, with evidence supporting incremental survival benefit with definite but acceptable toxicities. It is interesting to speculate that this benefit may be most noticeable with more advanced disease. Additional studies are warranted to further confirm the effectiveness of this strategy and the population of patients for whom this approach has the greatest therapeutic ratio.

Postoperative Chemoradiotherapy. There were no studies in which a randomized study design to address the role of postoperative chemoradiotherapy was used.

Radiotherapy as a Curative Therapy

External beam radiotherapy alone has generally been replaced in North America by the use of chemoradiotherapy when a nonsurgical curative approach is the desired strategy. Patients with diseases confined to the primary and local regional nodal involvement are potential candidates for this approach. In general, T4 fistula formation and celiac nodal involvement (defined as M1 disease by the current TNM staging system) are not considered curable. However, clinicians do have different opinions about whether these patients should be uniformly approached with a palliative intent, especially when combined modality therapy is used. The techniques used for the planning of a curative course of radiotherapy for esophageal tumor have been well described in most oncology textbooks. In general, the 5-year survival rate is approximately 5% to 10%.

The ability to accurately define the target volume and deliver the intended treatment is the cornerstone for a localized form of treatment such as radiotherapy. Recent work by Tai et a1163 suggests that interob- server variability in defining the target volume on the basis of equivalent imaging is significant. Further improvements in imaging, target volume

Curr Probl Cancer, November /December 2000 335

TABLE 16. Randomized clincal trials in which toxicity of preoperative chemoradiotherapy and surgery was compared with toxicity of surgery alone*

Grade 3-4 Postoperative toxicity Postoperative mortality rate after CRT morbidity rate

Author CRT No CRT CRT CRT No CRT

Walsh et a1158 8% 3% 12% Respiratory, 48% 55% Cardiac, 24% 22%

Bossett et a1159 12% 4%t - - Severe complications, 33% 26% Nygaard et al ¢4° 24% 13% N& 38% 42%

CRT, preoperative chemoradiotherapy; NA, not available. *Toxicity data not available for Apinop et al, ±57 Urba et al, 16° and Launois. 161 ~Statistically significant (P = .012).

delineation, and immobilization are necessary to compliment the potential gains in the adoption of a combined modality approach and would pave the way for definition of the role of conformal approaches 164 as part of the armamentarium to improve outcome and reduce toxicities.

It is worth reiterating that the current TNM staging system is based on prognostic factors derived from surgical series. In addition, the factors found to be most useful in pathologic staging are not all available through clinical staging (eg, paraesophageal node assessment in patients with obstructing lesions). Confirmation of the relative value of the existing prognostic factors and other accessible clinical parameters (eg, length of primary and performance status) may facilitate advances in our ability to better define the role of different treatment approaches that are not surgically based.

Method of Review. A computerized literature search was conducted on Cancerlit and Medline databases for literature published between 1966 and December 1999. The search strategy used combined MESH, including esophageal neoplasms, experimental clinical trials, controlled clinical trials, randomized trials, and random allocation; subject headings including radiotherapy and therapy chemotherapy were used. Textwords used in the search included random. In addition, articles from personal files, article references, and content experts were included where appropriate] 65

Studies were included if they were randomized controlled trials that targeted patients with localized esophageal neoplasms and the radiotherapy dose fractionation used was plausible for a potentially curative approach. Studies were excluded if surgery was part of the planned intervention. The endpoints of interest included overall survival, local recurrence, acute and chronic toxicities, and quality of life.

Chemoradiotherapy. Chemoradiotherapy has been studied in a number of disease systems with proven advantage over single modality radiother-


apy alone. 166-~68 Because both radiotherapy and chemotherapy have independent antitumor activities, the combination of the two is expected to provide at least additive, if not synergistic, effect in eradicating the tumor. In the evaluation of chemoradiotherapy, it is important to make the distinction between concomitant and sequential approaches. The biological bases for these approaches are different, and indeed, when these strategies are tested in other disease sites such as in cervical and head and neck tumors, the effectiveness of the two approaches does differ.

All randomized studies in which chemoradiotherapy (without surgery) was compared with radiotherapy alone were included. Studies in which esophagectomy was part of the planned intervention or medications other than chemotherapy were used (eg misonidazole used as a radiosensitizer) were excluded. Fifteen randomized studies that fulfilled these criteria were identified. 169-183 For 4 of these trials, the criteria were satisfied but were excluded for the following reasons.

Hukku et a1169 compared radiotherapy with radiotherapy plus 5-FU and bleomycin. Results were reported on evaluable patients; there were 44 evaluable patients in the radiotherapy arm and 26 in the chemoradiotherapy arm. The gross imbalance between the treatment arms and the Jack of information on the numbers actually randomized made the results of this difficult to interpret. Kolari et a117°,184q89 randomly assigned patients to receive 60 Gy of radiotherapy or 40 Gy of radiotherapy with concurrent cisplatin and 5-FU. Only interim results have been published in several similar abstracts. The final number of patients that were entered into the study was unknown, and therefore we excluded this study.

Smith et allva randomly assigned patients to receive 40 Gy of radiotherapy alone or a combination 5-FU mitomycin and 40 Gy of radiotherapy. When the radiotherapy was completed, patients were evaluated for surgery and underwent either surgery or further radiotherapy to a total of 60 Gy with 5-FU. The study did not allow for direct comparison of the outcomes of patients treated with chemoradiotherapy alone versus radiotherapy alone and was therefore excluded. Dinshaw et al 1v2 delivered external beam radiotherapy followed by randomization to brachytherapy or brachytherapy and 5-FU. Because the chemotherapy was not delivered with the onset of radiotherapy, this study was not included, av3

Of the remaining eligible studies, 8 were classified as studies of concomitant chemoradiotherapy and 3 were classified as studies of sequential chemoradiotherapy. These will be discussed separately.

Sequential Chemoradiotherapy. In 3 studies, 173-~75 radiotherapy was compared with sequential chemoradiotherapy. The studies ranged in size from 64 to 170 patients, involving a total of 331 patients. Roussel et a1173


TABLE 17. RandomJzed clinical trials in which sequential chemoradiotherapy was compared with radiotherapy alone

No. Author N excluded

Rousselet a1173 170 20

Zhou 174 64 0

Hatlevoll et a1175 97 3

CT, Chemotherapy; RT, radiotherapy; fr, fractions. *Does not account for treatment time gap.

TABLE 18. Randomized clincal trials in which survival after sequential chemoradiotherapy was compared with survival after radiotherapy alone

2-y survival rate

Author CRT RT

Roussel et a1173 13% 13% Z hou 174 28% 28% Hatlevoll et al 1T5 4% 10%

mad Zhou et a1174 excluded patients with distant metastases, whereas Hatlevoll et 1tl 175 included 2 patients (2%) with distant metastases. Other criteria to exclude patients with poor prognosis included tumors that were more than 7.5 cm, 174 weight loss of more than 2 5 % ] 73 and Karnofsky performance status of less than 50.

The study interventions are summarized in Table 17. Cisplatin chemotherapy was used by Zhou et a1174 and Hatlevoll et al. 175 The radiotherapy doses used were consistent with those generally used with the intention of providing a potential for cure for epithelial tumors.

No survival advantage was observed in any of the trials (Table 18). Tox- icity was reported in 2 t r ia ls . 173'174 As would be expected, there were incremental toxicities, predominantly hematologic toxicities and esophagitis in the group of patients who received sequential chemoradiotherapy (data not shown). On the basis of these results and similar results with other tumors sequential chemoradiotherapy is not recommended.

Concomitant Chemoradiotherapy. Eight studies in which concomitant chemoradiotherapy was used were identified. 176-183 Of the 8 studies included, sample sizes ranged from 24 to 221 patients; the studies involved a total of 819 patients. All of the studies excluded patients with distant metastases. In the earliest study, researchers started recruiting patients in


Time between

CT RT BED CT and RT

Methotrexate on d 14 40.5 Gy in 18 fr; 68 8-12 d boost, 15.75 Gy in 7 fr

Cisplatin on d 1-2; 54-75 Gy in 6-7 wk 81-94 2-27 d 5-FU on d 3, d 6, d 10, and d 13

Cisplatin on d 1-5 and d 15-19; 35 Gy in 20 fr, 74* Not bleomycin on d 1-5, d 15, and d 19 3-wk gap, and then stated

28 Gy in 16 fr

1974, and the latest study closed in 1996. The type of imaging available to exclude metastatic disease generally was based predominantly on clinical examinations. Some form of abdominal imaging was performed in only 3 studies. 176'177 Only the study by Cooper et al176 included mandatory CT to exclude distant metastases. It is therefore likely that a significant proportion of patients included in these trials actually had radiologic evidence of distant metastases that would have been detected with contemporary staging techniques.

In terms of the extension of local regional disease in these studies, 2 trials specifically permitted patients with supraclavicular node involvement.lv6,182 No study specified any exclusion because of mediastinal nodal involvement. Most trials did incorporate some criteria to exclude patients in poor general condition. These criteria included age younger than 72 years, 18e age younger than 79 years, 178 performance status of less than 2,178 performance status of less than 3,176'177 and survival of more than 3 months. 179

The interventions used are shown in Table 19. In 2 studies researchers used cisplatin chemotherapy a lone , 178A79 in 2 studies researchers used cisplatin and 5-FU 177,18° (Araujo et aP 8° also included bleomycin in this combination), and in 3 studies researchers used bleomycin only. 181-183 The radiotherapy dose fractionation was consistent with the dose typically used to provide the potential of cure for localized epithelial tumors with a BED ranging from 56 to 76.8 GYl0. The endpoints of interest included overall survival, local recurrence, toxicity, dysphagia response, and quality of life.

Survival outcomes are shown in Table 20. Overall survival for 1-year mortality was not available in the study by Andersen et al,180 and overall survival for 2-year mortality was not available in the study by Kaneta et al. 178 Long-term survival at 5 years was only available in 2 s tudies , a76,aS°


TABLE 19. Randomized clinical trials in which concomitant chemoradiotherapy was compared with radiotherapy alone

Author N No. excluded

Earle et a1183 91 14

Z hang ±82 99 0

Andersen et al TM 82 6

Araujo et al ~8° 59 0

Roussel et al lzg 221 NA

Kaneta et al ¢78 24 0

Slabber et a1177 70 0

Cooper et a1176 123 10

CT, Chemotherapy; RT, radiotherapy; fr, fractions; max, maximum; IM, intramuscular; NA, not available; CRT, chemoradiotherapy *BED calculation does not take into account time gap between treatments.

TABLE 20. Randomized clinical trials in which survival after concomitant chemoradiotherapy was

compared with survival after radiotherapy alone

1-y survival 2-y survival 5-y survival rate (%) rate (%) rate (%)

Author N CRT RT CRT RT CRT RT

Earle et a1183 91 23 32 9 11 - - - - Zhang 182 99 60 41 42 20 * - - - -

Andersen et a1181 82 - - - - 13 12 - - - - Araujo et a118° 59 64 55 39 23 14 6 Roussel et a1179 221 47 31 20 16 - - - -

Kaneta et al 1~8 24 42 25 . . . . Slabber et a117~ 70 15 14 3 3 - - - -

Cooper et a1176 123 48 34 38 1 1 " 26 O*

CRT, Chemoradiotherapy; RT, radiotherapy. *Statistically significant difference between CRT and RT arms.

There was a general trend for survival benefit at 1, 2, and 5 years, although this was significant at 2 years only in the study by Zhang) 82 When the heterogeneity of the studies was explored) 65 the results were found to be homogeneous. When the results were pooled statistically, the


CT RT BED

Bleomycin weekly

2-3 doses of bleomycin per wk to a max of 100 mg

Bleomycin IM

5-FU IV infusion on d 1-3, mitomycin on d 1, bleomycin IM on d 1, 7, 14, 21, and 28

Cisplatin on d 1 and 23

Cisplatin

Cisplatin and 5-FU on d 1-5, 29, and 33

5-FU infusion on d 14 for wk 1, 5, 8, and 11; cisplatin on wk 1, 5, 8, and 11

50 Gy in 5-6 wk (in 30% of patients); 60 Gy (in 70% of patients)

39-73 Gy in ~7 wks

CRT arm: 35 Gy in 20 fr, 3-wk gap, and then 25 Gy in 15 fr

RT arm: 35 Gy in 20 fr, 3-wk gap, and then 28 Gy in 15 fr

50 Gy in 25 fr

60-72

76.8

63.7*

74*

60

20 Gy in 5 fr, 15-d gap, 56* and then 20 Gy in 5 fr

60 Gy in 30 fr; boost, 72 (with 10-12 Gy in 2-6 fr boost, 0-19)

20 Gy in 5 fr, 3-wk gap, 56* and then 20 Gy in 5 fr

CRT arm" 30 Gy in 15 fr 60 boost, 20 Gy in 10 fr to large field

RT arm: additional 14 Gy in 7 fr. 76.8

overall results were statistically significant; this supports chemoradiotherapy as superior to radiotherapy alone in terms of survival.

Although the radiotherapy regimens used generally approached what are considered to be radical doses, the type of chemotherapy used and dose gcheduling were variable. Current practice in North America has been heavily influenced by the results of the Radiation Therapy Oncology Group (RTOG) study, 176 although most physicians do not prescribe the full chemotherapy (chemotherapy after completion of chemoradiotherapy) as described in the study because of the toxicities.

Subgroup analysis with the use of 1-year survival data, 165 including only studies in which cisplatin-based chemotherapy was used, showed a significant survival benefit for patients treated with chemoradiotherapy versus those treated with radiotherapy alone, whereas the studies of noncisplatin-based chemotherapy studies did not show a survival benefit for patients treated with chemoradiotherapy. However, when we performed this subgroup analysis with the use of 2-year survival data, the difference in outcome between cisplatin chemotherapy and noncisplatin chemotherapy was not maintained.

The local recurrence rate was available for only 3 of the studies. The


TABLE 21. Randomized clinical trials in which local recurrence after chemoradiotherapy was compared with local recurrence after radiotherapy alone

Author CRT (%) RT (%)

Araujo et a118° 61 83 Roussel et al ~79 59 66 Cooper et a1176 28 68*

CRT, Chemoradiotherapy; RT, radiotherapy. *Statistically significant.

RTOG s tudy 176 was the only study in which local recurrence rates were reported over time. In the other 2 studies, the rate was reported as an absolute value at the time of reporting. As is common in many studies in which the focus is survival, the reliability of local recurrence reporting is subject to potential bias caused by things such as the lack of routine surveillance designed to pick up local recurrence at regular intervals, the general reduced enthusiasm to diagnose local recurrence when patients have distant metastases, and the fact that neither the patient nor the investigator is blinded to the interventions undertaken. With these limitations, the local recurrence rates are shown in Table 21.

There was a general trend supporting reduced local recurrence rates with chemoradiotherapy compared with radiotherapy alone. This was statistically significant in the RTOG study. 176 It should be noted that the benefit was present despite the fact that the chemoradiotherapy arm in the RTOG study received a lower radiotherapy dose then did the radiotherapy arm. When the results were pooled, there was a statistically significant benefit for local recurrence favoring chemoradiotherapy. 165

In terms of toxicity, no information on adverse effects was available for the trial reported by Andersen et al. as° Four trials reported acute adverse effects with the use of a grading system, 176-179 whereas 3 did not. 18°,182,183 For the latter trials, a narrative description of the intensity of the severity was provided instead of grading of toxicity. To facilitate presentation of the data, toxicity for studies in which the description of the toxicity fulfilled the criteria for grades 3 to 4 toxicity, according to the RTOG toxicity criteria is shown in Table 22. There were consistently more acute toxicities in the chemoradiotherapy arms. Late toxicities and treatment-related deaths were similar between the treatment arms.

The data in Table 22 would support a survival benefit with a chemoradiotherapy approach compared with radiotherapy alone. The average absolute benefit was approximately 10% at 2 years. This was at the expense of a higher risk of acute grades 3 to 4 toxicities. This benefit was observed in patients who, in general, had more advanced local regional disease than those who received chemoradiotherapy as a neoadjuvant


TABLE 22. Randomized controled trials in which the toxicity of chemoradiotherapy was compared with the toxicity of radiotherapy alone

Incidence of Incidence No. of short-term of late-term Toxicity

patients grade 3-4 grade 3-4 related Author randomized toxicity* toxicity* deaths

CRT RT CRT RT CRT RT CRT RT

Earle et a1183 47 44 4 2 3 3 0 0 Zhang 182 48 51 NA N& NA N& 3 0 Araujo et a118° 28 31 3 0 26 25 0 0 Roussel et a1179 110 111 19 0 NA N& 0 0 Kaneta et a117s 13 12 1 0 N& NA 0 0 Slabber et a1177 34 36 6 1 N& N& 2 2 Cooper et al ±76 61 62 64 18 15 14 1 0

CRT, Chemoradiotherapy; RT, radiotherapy; NA, not available. *Incidence reporting was by organ system rather than by the maximum experienced for any individual The incidence data should be compared within each study only. The numbers of organ systems reported on by the different authors differed.

therapy or surgery alone. In patients with good performance status, chemoradiotherapy should be the treatment of choice when a curative nonsurgical approach is to be undertaken.

Intracavitary Radiotherapy. A single randomized study was identified in which radiotherapy was compared with radiotherapy and intraluminal brachytherapy. 19° One hundred three patients were registered and 9 patients were excluded. Patients with intrathoracic squamous cell carcinoma of less than 10 cm in length, with no distant metastases, and with performance status of 3 or less were included. The median follow-up was 24 months. Patients were treated with external beam radiotherapy of up to 60 Gy in 6 weeks. Patients with a complete response or partial response, as well as selected patients with less than partial response (at the discretion of the treating oncologist), were randomized to either a boost of 10 Gy in 5 fractions or brachytherapy of 10 Gy in 2 fractions 1 week apart. After the completion of radiotherapy, maintenance chemotherapy with etoposide for 3 cycles was planned.

The majority of patients (87 of 94) were enrolled after at least a partial response to 60 Gy of radiotherapy was attained. There was no difference in the overall survival or in cause-specific survival between the 2 groups. There was no difference between the 2 arms for both acute and late toxicities (Table 23).

On the basis of the findings shown in Table 23, intracavitary radiotherapy was not different from an external beam boost. The incidence of incomplete responses after 60 Gy in 30 fractions of approximately 30% supports the need for further dose intensification including the combined


TABLE 23 . External beam radiotherapy versus external beam radiotherapy and intracavitary radiotherapy in the study by Okawa et aP 9°

ERT ERT + ILBT

N (evaluable) 51 43 No. excluded 9 9 Cause specific survival at 5 y 27% 38% CR at 60 Gy 33 26 Short-term toxicity _>3 6% 12% (NS) Long-term toxicity _>3 9% 8% (NS)

ERT, External beam radiotherapy; ILBT, intracavity radiotherapy; CR, complete response; NS, not significant.

modality approach. Intracavitary radiotherapy used as a strategy for dose intensification, or in combination with combined chemoradiotherapy, has not been addressed in a randomized setting, and further trials are needed for the role of intracavitary radiotherapy to be defined.

Palliative Management of Malignant Dysphagia Background

There is a broad array of options available for the treatment of malignant dysphagia. These treatments can be broadly classified as mechanical and antineoplastic. Mechanical measures include dilatation procedures, tubes, and stents. Antineoplastic therapies directed at reduction of the tumor mass include radiotherapy, laser therapy, photodynamic therapy, and systemic therapy. Some of these treatments are less commonly used in contemporary practice (such as tubes and dilatation alone) because they are gradu- ally being replaced by other modalities such as metal stent insertion.

Method of Review We conducted a search for literature published between 1966 and 1999

using Medline, Embase, and Cancerlit databases. The search parameters included esophageal neoplasms, esophageal stenosis/th, deglutition disor- ders/th, palliative care/, and text word dysphagia, combined with a filter for the identification of randomized controlled trials.

Studies were included if the researchers used a randomized design and included patients with advanced carcinoma of the esophagus and either dysphagia relief or survival was presented as one of the study endpoints. Data extraction for study characteristics, including parameters for methodologic assessment, was conducted similarly to the data extraction for neoadjuvant and adjuvant therapies.

The primary study endpoints of interest included pretreatment and post- treatment dysphagia scores, durability of dysphagia relief, and complica- tion rates. Overall survival was particularly relevant when we considered


palliative chemotherapy because this modality is frequently undertaken with the goal of prolonging life expectancy as well as improving symptoms and quality of life. Survival data were extracted when available. For the metal stents versus other methods, technical success rate, perforation rate, and migration rate were components of toxicity that were consistently reported and extracted for comparison. Quality-of-life data were collected when available.

A total of 43 randomized studies were identified in which different comparative groups with locally advanced carcinoma of the esophagus were studied. Studies that addressed the role of metal stents, palliative radiotherapy, brachytherapy, chemotherapy, and chemoradiotherapy are presented in the following sections.

Metal Stent Versus Other Modalities In this review, we included randomized studies in which metal stents were

compared with other mechanical interventions. Five randomized studies satisfied the inclusion criteria. 191-195 Adam et aP 91 compared laser therapy with covered and uncovered metal stents, whereas in the other studies, researchers compared plastic stents with metal s t e n t s . 192195 These studies ranged in size from 20 to 75 patients and included a total of 219 patients. All of the studies included patients with dysphagia caused by esophageal tumors that were not amenable to curative therapy. In 2 studies, patients with fistulas were excluded. 191,192 The sample sizes for these studies were small; none of the authors described sample size estimations to explain what the studies were powered to detect. The reporting of toxicities was subject to the potential biases associated with the lack of a blinded assessor.

The study results are summarized in Table 24. The initial response rate to the use of metal stents was equivalent or slightly superior to the response rate with plastic stents. In general, the mean dysphagia score improved by approximately 2 points on a 5-point scale. The reintervention rate was lower with metal stents, and the incidence of major complications was also less (Table 25). From the cost analysis data (with the use of 1993 costing), the cost of each premature death avoided with the use of metal stents rather than plastic stents was approximately $457. On the basis of these data, metal stents are superior to plastic stents in terms of durability of response and toxicity profile and are the intervention of choice when a mechanical method of relieving dysphagia is believed to be most appropriate for the patient.

External Beam Radiotherapy External beam radiotherapy has been used widely for the palliation of

patients with dysphagia caused by incurable carcinoma of the esophagus.


TABLE 24. Randomized clinical trials in which plastic stents were compared with metal stents

Technical success

Change in (mean) dysphagia score post procedure

Author N Plastic Metal Plastic

Kryrim et a1195 42 20/21 21/21 2 point Adam et al tgl* 60 NA NA N& De Palma et a1192 39 18/20 18/19 2 point Siersema et al i93 75 38 /38 31/37 N& Sanyika et a1194 40 15/20 20/20 1 point

NA, Not available. *Adam et a~ 191 included three study arms to compare laser therapy, metal stents, and covered metal stents.

However, the data given in support for this approach are generally from retrospective case series that combine response rates from patients treated for a combination of curative and palliative approaches. For this review, we included all randomized studies in which radiotherapy was the method being evaluated in the study arm and compared with other treatment options for the palliation of dysphagia. Four studies satisfied these inclusion cr i te r ia . 196-2°° The study designs used are shown in Table 26.

All of the studies included patients with unresectable carcinoma of the esophagus. Reed et 3.] 196 randomly assigned patients to receive treatment with Atkinson tube, tube and radiotherapy, and tube and chemotherapy. Schmid et a1199 randomly assigned patients to receive, after intubation, radiotherapy or no additional treatment. Sargeant et a1197 performed the same comparison after laser therapy. Only patients with a dysphagia score of 2 or less (toleration of semisolids only) were included. Kolaric et a1198 randomly assigned patients to receive either bleomycin and adriamycin alone or combined with radiotherapy. Kharadi et al 2°1 compared radiotherapy combined with tube and dilatation with tube and dilatation alone. Although both patients with stage IlI and patients with stage IV were eligible for the study, only 3 patients had distant metastases. There were no studies in which different dose fractionations of radiotherapy were compared to address the dose-response relationship. These studies included sample sizes that ranged from 18 to 122 patients; a total of 325 patients were included.

Reed e t al, 196 Sargeant et al, 197 and Kharadi et al 2°1 used a dysphagia scale to assess symptomatic treatment response: Kolaric et a1198 did not assess dysphagia but focused on objective tumor response with the use of barium and endoscopy findings with response criteria described. Simi- larly, Schmid et a1199 did not assess dysphagia but used tumor response of greater or less than 50% as the endpoint. Survival was also an endpoint of


Change in (mean) dysphagia Durability of

score at 1 mo dysphagia relief

Metal Plastic Metal Plastic Metal

2 point N~, I'~ NA NA NA i point* 2 point Reintervention rate: 18/18 15/42 2.4 point N& N& Recurrent obstruction: 7 /13 6 /16 NA 2.2 point 2.5 point Recurrent dysphagia: 4 /38 8 /37 3 point 66% patent 90% patent Patency rate: 50% 88%

interest in all studies, although this was not compared between the randomized groups in the study by Kolaric et al. 198 In addition, only Reed et a1196 provided the data for the reader. Toxicity information was provided in all studies.

The radiotherapy dose fractionation used by Reed et aP 96 was 45 Gy in 25 fractions; Sargeant et aP 97 used 30 Gy in 10 fractions. Kolaric et a1199 used 36 to 40 Gy in 18 to 20 fractions (combined with 5 to 6 cycles of adriamycin and bleomycin). Schmid et a1199 used 20 Gy in 5 fractions. Kharadi et al 2°1 used 65 Gy in 5 to 6 weeks (Table 27). Toxicity reporting was not comprehensive: no toxicity grading system was used in any of the series and only severe toxicities were discussed. None of the authors incorporated quality-of-life assessment (Table 28).

Study outcomes are summarized in Table 27. In general, the addition of radiotherapy provided incremental benefit for initial response and prolonged the time to progression. Although survival was generally not significantly different, the survival outcomes for the patients in the study by Kharadi et al 2m differed significantly from those reported in the other studies. This may have been caused by the types of patients recruited (there were only 3 patients with stage IV disease in the study by Kharadi et al 2°1) or the higher dose fractionation used. The benefits of local control in patients who have potential risks of invasion into adjacent structures such as airway compromise and vocal cord paralysis with recurrent laryngeal nerve involvement could not be assessed with traditional endpoints such as dysphagia response and survival. However, these are indi- cations that must be considered in the decision of whether the addition of palliative radiotherapy is warranted.

The available data supports benefits in symptomatic and objective responses with the addition of radiotherapy. Radiotherapy reduces the time to recurrent symptoms and the need for repeated interventions. In patients with locally advanced disease, a survival benefit is associated


TABLE 25. Randomized clinical trials in which the toxicity of plastic stents was compared with the toxicity of metal stents

N Perforation Migration

Author Plastic Metal Plastic Metal Plastic Metal

Kryrim et a1195 21 21 3 0 5 0 Adam et al lgl 18 42* 0 0 6 0 De Palma et al ±92 20 19 3 0 2 0 Siersema et a1193 38 37 4 1 3 0 Sanyika et al ~94 20 20 2 0 0 0

Plastic, Plastic stents; metal, metal stents. *Adam et ai 191 combined two treatment arms: covered and uncovered metal stents.

with radiotherapy at higher doses. Lower doses of radiotherapy did not convey a similar survival advantage.

Brachytherapy To address the utility of brachytherapy in the palliation of dysphagia, all

studies in which a randomized design was used with brachytherapy as the intervention of interest were included. Five articles with reports of 4 studies that fulfilled this criteria were identified. 2°2-2°6 The different study designs are shown in Table 29.

Sur et al 2°2 and Tan et al 2°3 compared laser therapy with laser therapy and brachytherapy to address the utility of brachytherapy added to laser therapy. Sur et a1202 compared 3 different dose fractionation regimens and examined whether a dose-response relationship existed between the regimens selected. Direct comparison of brachytherapy with other modalities was addressed in 1 study in which laser therapy was compared with brachytherapy. 2°4 All studies included patients with inoperable carcinoma of the esophagus.

For intervention, Sander et al 2°5 used iridium 192 and delivered 3 x 7 Gy; each fraction was delivered 1 week apart. Suret al 2°2 used a high dose rate to deliver 1 of the following 3 regimens: A, 12 Gy in 2 fractions; B, 16 Gy in 2 fractions; and C, 18 Gy in 3 fractions. Low et a1204 used 15 Gy in 1 fraction.

Sander et al 2°5 described a sample size requirement of 100 patients. Only 39 patients were randomly assigned to a treatment group. In the study by Sur et al,202 interim analysis was performed after 68 patients were followed up for 6 months. The observation that protocol A was associated with a higher failure rate resulted in early discontinuation of this treatment arm, and the remainder of the study was devoted to the treatment arms B and C only. In the final comparison between the randomized groups, all patient characteristics appeared to be well balanced except for performance status. There was a higher proportion of patients with better


TABLE 26, Randomized clinical trials in which radiotherapy was compared with other treatments for dysphagia

Author Study design

Reed et a1196

Schmid et a1199 Kolaric et a119s Sargeant et a1197 Kharadi et al 2°1

Atkinson tube vs Atkinson tube and radiotherapy (third arm Atkinson tube and chemotherapy)

Intubation followed by no additional therapy or radiotherapy Bleomycin and adriamycin vs bleomycin, adriamycin, and radiotherapy Dilatation followed by no additional therapy or radiotherapy Dilatation and tube vs dilatation, tube, and radiotherapy

performance status in group A (67% with performance status > 70) compared with groups B and C (31% and 32% with PS > 70, respectively).

Study outcomes are summarized in Tables 30 through 32. When we compared laser therapy with laser therapy and brachytherapy, a more durable response was observed with the use of brachytherapy and laser therapy; the time to recurrent dysphagia that required additional intervention was doubled (from approximately 30 days; Table 30). 2o5 This reached statistical significance in one of the 2 studies, but the conclusions were limited by the small sample sizes included. 2°3 There was no survival benefit, and complications were minor (only esophagitis).

The study by Low et al 2°4 showed similar initial response rates and overall survival for both laser therapy and brachytherapy (Table 31). The authors also described a greater proportion of patients who required retreatment after laser therapy, although this may also reflect a greater willingness to treat in addition to the need to treat. The power of inference from this study is also limited by the small sample size.

The study by Sur et al 2°2 also supports the effectiveness of this modality by suggesting the presence of a dose-response relationship (Table 32). The highest dose fractionation was also associated with higher risk of stricture formation. A dose fractionation of 16 Gy in 2 fractions pre- scribed at 1 cm represents a reasonable dose fractionation to use in the palliative setting.

Chemotherapy The rationale for consideration of palliative chemotherapy as a single

antineoplastic modality is usually prolonging of life expectancy, improvement of quality-of-life through the delay of symptom progression, and palliation of symptoms. Not infrequently, palliative chemotherapy is considered in addition to other local modalities to provide the best palliation. In providing a review of this area, we address the value of chemotherapy with 2 types of study design (Table 33).

We included 3 randomized studies in which chemotherapy was com-


TABLE 27. Randomized clinical trials in which radiotherapy was compared with no radiotherapy for dysphagia

No, Author N excluded RT RT

Initial dysphagia

Studies with dysphagla response as endpoint Reed et ai 196 18 0 45 Gy in 25 fr Sargeant et a1197 67 0 30 Gy in 10 fr Kharadi et al 2°~ 122 18 55-65 Gy in 5-6 wk

Studies with no dysphagla assessment (use of objective response as endpoint) Koiaric et a119s 33 2 36-40 Gy in 18-20 fr

Schmid et al ~99 87 0 20 Gy in 5 fr

1 .8 t 13%-23%~ 4 3 / 4 7 (91%)t

60% (res)¶

22%*

RT, Radiotherapy; fr, fractions; NS, not significant; CL chemotherapy; NA, not available. *Percentage of patients with objective response. tMean change in dysphagia score. ~Percentage of patients with no dysphagia before and after treatment. §Median time to reintervention. IIData not presented. ¶Percentage of patients with complete or partial tumor response.

TABLE 28. Randomized clinical trials in which the toxicity of radiotherapy was compared with toxicity with no radiotherapy

Toxicity

Author Toxicity grading criteria used RT No RT

Reed et a1196 Perforation 2 1 Respiratory distress 0 1 Tube migration 0 1

Sargeant et a1197 Stricture 1 0 / 1 4 3 / 1 1 Other side effects include "mild" not other-

nausea lethargy, and odynophagia wise quantified Kolaric et a1198 Alopecia ~ 100% 93%

Nausea 75% 93% Leucopenia 25% 40% Fever 25% 20% Oral ulceration 25% 20% Retrosternal pain - - 53%

Schmid et a1199 Grade I esophagit is 85% - - Kharadi et al 2°1 Grade 3 esophagit is 12% - -

Stricture 7 / 4 1 - - Radiation pneumonitis 3 / 4 1 - -

RT, Radiotherapy.

pared with no chemotherapy 199,2°7,2°s and 4 studies in which comparisons of different types of chemotherapy w e r e m a d e . 2°9-212 Ancona et a1213 reported a randomized study in which intubation was compared with intubation and levamisole; because this is generally not considered a chemotherapeutic agent, the study by Ancona et a1213 was excluded from this review.


response* Time to progression Survival time

No RT RT No RT RT No RT

2.31" - - - - 72 d 119 d (NS) 18%-16%~ = 8.8 wk§ 5 wk No differencell No differencel[ 37/41 (90%)t 37 /46 (80%) 17/26 (65%) 7 mo 3 mo (P < .05)

at 3 mo at 3 mo

19% (also NA NA NA NA received CT)¶

0% 3 mo 3 mo Median, Median, 9 wk 15 wk (NS)

All of the studies included patients with inoperable, incurable carcinoma of the esophagus; Webb et a1212 included only patients with tumors at the gastroesophageal junction. Levard et al 2°7 included patients with positive nodal disease that had been completely resected; those patients made up 39% of the patients enrolled in that study. Patients were strati- fied as completely resected and as others. However, survival data for the resected and unresected groups were separately reported. All studies had some criteria for the exclusion of patients with very poor performance status; these criteria included Karnorvsky performance status of more than 4021° and more than 50, 2o7 moribundity, 2°s performance status of 3 or more 199 and 4 or more, 211 and life expectancy of less than 3 months. 212

The method of randomization was not described in 3 of the studies. 199,2°8,212 A system of sealed envelopes was used in 2 studies, 2°9'2l° a stapled corner of the questionnaire or consent form was used in 1 study, 2°7

and a central randomization office was used in 1 study. 211 The potential bias that may have been inherent with the randomization methods in the older studies has to be taken into account in the interpretation of these studies.

The study interventions and outcomes of the 3 studies in which chemotherapy was compared with no chemotherapy are shown in Table 34. Levard et al 2°7 studied the effect of 5-FU and cisplatin given for 6 to 8 cycles, Mannell et al 2°8 gave Neomycin for 5 days, and Schmid et a1199 used either 5-FU leucovorin or a combination of tremetrexate, ifosfamide, and mesna. The duration of therapy was not stated. A total of 418 patients


TABLE 29. Studies included for the assessment of the utility of brachytherapy far the relief of dysphagia

Author Study design

Sander et al 2°5 and Tan et al 2°3 Laser therapy vs laser therapy and brachytherapy Low and Pagliero 2°4 Laser therapy vs brachytherapy Sur et al 2°2 Brachytherapy with 3 different dose fractionations

TABLE 30. Randomized clinical trials in which outcomes of laser therapy were compared with outcomes of laser therapy and brachytherapy

Mean time to symptom Mean overall survival progression and reintervention (d) time (range)

Author N Laser Laser + brachy Laser Laser + brachy

Sander et al 2°5 39 32 68 (P = .1) 165 (25-616) 125 d (11-380; NS) Tan et al 2°3 26 36 83 (P = .026) 110 (8-369) 114 d (30-277; NS)

Laser, Laser therapy; brachy, brachytherapy; NS, not significant.

were involved in these trials. There were no data that supported any survival advantage with palliative chemotherapy compared with no chemotherapy with the described regimens.

The study interventions and outcomes of the studies in which different chemotherapy regimens were compared are summarized in Table 35. There was a survival advantage with the combination of bleomycin and doxorubicin hydrochloride compared with bleomycin alone in 1 study. 21° The value of doxorubicin hydrochloride was also supported by Kolaric et al, 21° who found it to be superior to bleomycin when used in combination with 5-FU and radiotherapy. These findings were different from the findings of Ezdinli et al, 211 who found that doxorubicin hydrochloride was inferior compared with methotrexate and 5-FU. Finally, Webb et al212 found superior results with epirubicin, cisplatin, and 5-FU compared with 5-FU, doxorubicin, and methotrexate for patients with adenocarcinoma of the gastroesophageal junction. The degree of palliation, if any, was not sufficiently well reported to allow us to evaluate the role of chemotherapy in symptom palliation effectiveness in palliation of symptoms.

Webb et a1212 w e r e the only researchers who addressed the quality of life in patients undergoing therapy with the use of the European Organization for Research and Treatment of Cancer QLQ C30 questionnaire. Quality- of-life data were available for 62% of the patients at week 12 and for 37% of the patients at week 24. There was a significant difference that favored epirubicin, cisplatin, and 5-FU at week 24. The toxicity of epirubicin, cisplatin, and 5-FU versus 5-FU, doxorubicin, and methotrexate is shown in Table 36. There was significantly less leucopenia, neutropenia, and infection with epirubicin, cisplatin, and 5-FU.

We concur with the conclusion of Webb et al.212 The data support epiru-


TABLE 31. Randomized clinical trial in which laser therapy was compared with brachytherapy

Percentage of patients with dysphagia improvement

Overall survival rate (at 6 mo)

Author N Laser (12) Brachy (11) Laser Laser + brachy

Low and Pagliero 2°4 23 91% 83% 55% (6 out 17% (2 out of 12 patients) of 11 patients

Laser, Laser therapy; brachy, brachytherapy.

TABLE 32. Randomized clinical trial by Sur et al 2°2 in which different dose fractionotions of brachytherapy were compared

Group A Group B Group C Overall

Number included 36 68 68 172 Dysphagia-free interval at 300 d 10 41 40 29% Overall survival at 6 mo No signi f icant d i f ference 50% Overall survival at 12 mo No s igni f icant d i f ference 19% Fibrotic strictures 5 /35 15 /60 23 /55 - -

(14%) (25%) (41%; P = .014)

TABLE 33. Randomized clinical trials assessing the palliative role of chemotherapy

Author Design

Levard et al, 2°7 Mannell et al, 2°8 Chemotherapy vs no chemotherapy and Schmid et a1199

Andersen et al, 2°9 Kolaric et al, 21° Comparison of two different chemotherapy regimens Ezdinli et at, 211 and Webb et a1212

bicin, cisplatin, and 5-FU as favorable in the treatment of patients with incurable carcinoma of the gastroesophageal junction, and treatment with epirubicin, cisplatin, and 5-FU improves life expectancy from 5.7 to 8.9 months.

Chemoradiotherapy In this review of chemoradiotherapy, we included all randomized stud-

ies in which chemoradiotherapy was the modality being evaluated in the study arm compared with other treatment options for the palliation of dysphagia. A summary of the study designs included is presented in Table 37.

Alberts et a1214 described a study in which after intubation, patients were randomized to receive a combination 5-FU and cisplatin or no further intervention. This study was performed in Africa and was discontinued prematurely because of the severe toxicities encountered. The rural setting of the study probably accounts for a significant component of the morbidity rate because intensive supportive care was not readily available. Kolaric et a1198 compared chemoradiotherapy with chemotherapy (Table 26); they compared bleomycin and doxorubicin hydrochloride (5-


TABLE 34. Studies in which chemotherapy was compared with no chemotherapy

No, Author N excluded CT regimen

Survival

CT

Levard et al 2°7 161 5 5-FU and cisplatin for 6-8 cycles 12 me* Mannell et al 2°s 170 12 Bleomycin for 5 d 103 d

Schmid et a1199 87 10 5-FU and leucovorin or 11 wk tremetrexate, ifoxfamide, mesna; duration unknown

CT, Chemotherapy; NS, not significant. *Median survival time for randomized patients (including patients who underwent resection).

TABLE 35. Studies in which different chemotherapy regimens were compared

Author N No, excluded

Andersen et al 2°9 57 5

Kolaric et a121° 61 5

Ezdinli et al ml 88 25

Webb et a1212 274 18

RT, Radiotherapy; ECF, epirubicin, cisplatin, and 5-FU; FAMTX, 5-FU, doxorubicin, and methotrexate. *Survival rate at 12 months.

6 cycles) and radiotherapy with bleomycin and doxorubicin hydrochloride alone. The radiotherapy dose fractionation used was 36 to 40 Gy in 18 to 20 fractions. Patients with unresectable disease and those who were younger than 80 years were included. Distant metastases were permitted, although only 15% of the patients (5 of 33) had distant metastases. No dysphagia response was presented, but objective response with the use of barium and endoscopic data was presented. There were no results presented to reflect the durability of the response, quality of life, or survival by treatment arm. Toxicity was greater in the chemoradiotherapy arm (Table 38).

All the studies identified in which chemoradiotherapy was compared with radiotherapy alone addressed patients with localized disease. The study characteristics have been detailed in Tables 18 and 19 when considering this approach as a curative modality. No additional studies were identified in which patients with metastatic disease were included. Of the 3 sequential studies, 2 included dysphagia outcomes. 174,175 Of the 8 concomitant studies, 3 included dysphagia outcomes and were included. 181:82,215


time Time to dysphagia progression

No CT CT No CT

12 me* 10.5 me 10.5 me (NS) 91 d (NS) Dysphagia data not available Dysphagia data not available

for 50% of patients for 50% of patients 15 w k No data No data

Intervention Median survival

Regimen I: bleomycin for 4 me Regimen I1: bleemycin and doxorubicin hydrochloride for 4 me Regimen I: doxorubicin hydrochloride and 5-FU RT Regimen I1: bleomycin and 5-FU RT (RT, 35-40 Gy in 18-20 fr) Regimen I: doxorubicin hydrochloride Regimen Ih methotrexate Regimen II1: 5-FU Regimen I: ECF Regimen I1: FAMTX

6.3 wk :/8.3 wk (P < .001) 43%* 11%*

8.1 me 13.7 me 15.4 me 8.9 me 5.7 me (P = .0009)

Survival and toxicity outcomes are shown in Tables 18 and 19. None of the studies described how dysphagia was measured, and none provided data on the durability of the response duration or any formal quality-of- life measure.

The palliative values in terms of dysphagia relief are summarized in Table 39. These values were inconsistent. Consideration should be given to the potential of underestimation when this parameter was not a major endpoint of interest. There are significant toxicities related to combined modality therapy. When palliation of dysphagia was the primary objective of treatment, there was insufficient evidence for recommendation of the use of combined modality therapy.

Existing Guidelines Practice guidelines are systematically developed statements to assist the

practitioner and the patient in making decisions about appropriate health care for specific clinical circumstances. Guideline recommendations should ideally be based primarily and explicitly on a comprehensive sys-


TABLE 36. Toxicities of epirubicin, cisplatin, and 5-FU and 5-FU, doxorubicin, and methotrexate in the study by Webb et a] 2~2

Grade 3 or 4 tox i c i t y (%)*

Toxicity ECF FAMTX

Nausea and vomiting 17 5 Alopecia 56 42 Leukopenia 12 39 Neutropenia 36 58 Infection 8 20

ECF, epirubicin, cisplatin, and 5-FU; FAMTX, 5-FU, doxorubicin, and methotrexate. *Only toxicities that were statistically significant between the two arms are shown.

TABLE 37. Randomized trial assessing the palliative role of combined chemoradiotherapy

Author Design

Aiberts et a1214 AEer intubation: CRT vs best supportive care Kolaric et a1198 CRT vs CT Zhou 174 and Hatlevoll et aF 75 Sequential CRT vs RT ZhangY 2 Andersen et al, 181 and Herskovic et a1215 Concomitant CRT vs RT

CRT, Chemoradiotherapy; CT, chemotherapy; RT, radiotherapy.

tematic review of the best available evidence from health care research. The process by which evidence is identified, evaluated, and selected is provided in detail. Guidelines are sometimes also based on formal consensus approaches in the absence of high-quality evidence to direct decision making.

We have considered the evidence for various treatment modalities; it is now informative to examine how national and international groups have interpreted this evidence and synthesized the evidence to provide guideline recommendations.

Coia et a1216 published guidelines for Patterns of Care with a modified Delphi process to achieve consensus for the management of esophageal cancer. The key recommendations include the following:

1. Patients with clinical stage I or II esophageal cancer can be treated with curative intent with either a primary surgical or a primary chemoradiotherapy approach.

2. For patients with clinical stage III tumors, for which the most common approaches are palliative, surgical resection is generally not recommended and chemoradiotherapy is the preferred treatment.

The National Comprehensive Cancer Network 217 published a guideline on upper gastrointestinal carcinomas. This guideline was developed through a combination of systematic review and a consensus process.

356 Curr Probl Cancer, November /December 2 0 0 0

TABLE 38. Randomized clinical triad in which the response rate after chemoradiotherapy was compared with the response rate after chemotherapy

>50% reduction in tumor No. Author N excluded CRT CT

Kolaric et a1198 33 2 3/15 (19%) 9/16 (60%)

CRT, Chemoradiotherapy; CT, chemotherapy.

TABLE 39. Randomized clinical trials in which the dysphagia response after chemoradiotherapy was compared with the dysphagia response after radiotherapy

Dysphagia relief

Author N CRT RT Concomitant Zhang 182 99 89% 69%* (P < .05) Andersen et al T M 82 63% 55% Herskovic et a1215 123 58% 66% (NS) Sequential Z hou ±74 64 81% 69% Hatlevoll et a1175 97 23%* 32%*

CRT, Chemoradiotherapy; RT, radiotherapy; NS, not significant. *Proportion of patients with complete relief of dysphagia at 3 months

1. Patients with resectable (stage I to III) carcinoma who can undergo surgery can be offered either esophagectomy or definitive chemoradiotherapy. Chemoradiotherapy with the use of 5-FU plus cisplatin or 5-FU plus mitomycin are both considered to be acceptable. For RO (complete resection) resections, no further therapy may be recommended. For patients with positive margins, radiotherapy with or without concurrent chemotherapy may be considered.

Other treatment guidelines published include an expert guideline on surgical practice produced by the Society of Surgical Oncology, 218 and guidelines for the application of brachytherapy in esophageal cancer provided by the American Brachytherapy Society and developed through a consensus process. 219 These guidelines serve as a basis for highlighting variations of treatment philosophies. They provide a framework for the evaluation of patterns of practice.

Population Patterns of Practice

The evaluation of the pattern of practice and population outcomes provides valuable information on whether we are practicing consistently and whether new strategies are making a significant impact on the outcomes for our patients. The practice pattern for the management of esophageal cancer has been reported for various regions.


Mannell et a1220 published their findings in 1989; they reported on the patterns of care in South Africa between 1985 and 1988. Mannell et a122° found 1926 new cases of squamous cell carcinoma of the esophagus, collected through a centralized database maintained for the National Study Group for Esophageal Cancer. The male to female ratio was 3:1, and the mean age of the patient was 56 years. Performance status was excellent to good in 49% of the cases. The stage distribution at presentation was as follows: stage I, 2.8%; stage I~I, 19.8%; and stage III, 77.4%. In terms of treatment modality, surgery was selected for 17%, radiotherapy alone was selected for 35%, chemotherapy alone was selected for 22%, and intubation with other therapy was selected for 37%. 22o The authors observed that the typical patient diagnosed with this condition was a 56-year-old man with a 6 cm, stage III disease, with good performance status and that intubation was the most common method of treatment offered. No outcome data were available. The authors concluded that more intensive therapy may provide a more optimistic outcome for their patient population. 22°

Oliver et a1221 published a population-based analysis for Nottingham, England, in 1992. Patients were identified retrospectively, between 1982 and 1985, through a combination of hospital activity, pathology databases, and endoscopic unit databases. Oliver et O.1TM identified 268 patients with primary esophageal cancer. The male to female ratio was 1.71:1. Stage, age, and performance status at presentation were not available. Thirty-five percent of the patients had adenocarcinoma. Surgery was attempted for 34% of the patients, with a median survival rate of 11% at 3 years. Radical radiotherapy was attempted in 13%, with a median survival rate of 6% at 3 years. Intubation alone was attempted in 40% of the cases, with a median survival time of 100 days and a 3-year survival rate of 0%. 221

Daly et a1222 reported the outcomes from the National Cancer Database (US), a project jointly funded by the American College of Surgeons commission on cancer and the American Cancer Society. This database included cancer registry data voluntarily submitted by acute care hospi- tals across the nation. The numbers suggest that the information from the database accounts for approximately 46% of the new cases seen in the United States during that time. In 1988, 4368 cases were included, and 5256 cases were included in 1993. The mean age at presentation was 65 years, and the male to female ratio was similar for both periods (2.7:1). The proportion of patients with adenocarcinoma increased from 33.2% to 43.1%. Stage at presentation was similar between the 2 periods. For 1993, the distribution was as follows: stage I, 15%; II, 26%; III, 25%; and IV, 32%. The most common treatment recommended in 1993 was chemoradiotherapy; it was recommended for 30.2% of the cases (which was an


increase from 22% in 1988). The second most common recommended treatment in 1993 was surgery alone; it was recommended in 18% of the cases (which was an increase from 17.9% in 1988). Radiotherapy alone was recommended in 12.8% of the cases in 1993 (an increase from 19.4% in 1988), and no treatment was recommended in 14% of the cases in 1993 (this showed no change from 1988). With surgery, there was an increase in the percentage of patients who received a partial or simple excision with lymph node dissection (20% in 1988 to 34% in 1993). With an allowance for sufficient time for follow-up information, survival data were available only for the 1988 cohort. Disease specific survival was 50% at 1 year and 20% at 5 years. 222

Coia et al223 published the findings of the Patterns of Care Study in 1999; they reported on the period from 1995 to 1997. Data were collected with a national survey of 61 institutions. Coia et a1223 collected specific information about patients with squamous cell carcinoma or adenocarcinoma of the thoracic esophagus who received radiation therapy as part of definitive or adjuvant management of the disease. Patients who had a tumor of the gastroesophageal junction with gastric extension were excluded. Four hundred patients were included. The median age at presentation was 66.7 years. The male to female ratio was 3.25:1. Adenocar- cinomas were found in 36.8% of the cases. Performance status was 80 or more. Stage distribution was as follows: stage I, 15%; stage II, 39.5%; and stage III, 29.5%. The following treatments were used: chemotherapy and radiation therapy (75%) and chemotherapy concurrent with radi- ographic therapy (63%). A more detailed breakdown of the treatment approaches undertaken is as follows: chemoradiotherapy (54%), radiotherapy alone (20.3%), preoperative chemoradiotherapy (13.3%), postoperative chemoradiotherapy (7.7%), postoperative radiotherapy (3.5%), and preoperative radiotherapy (1.2%). The chemotherapy agents most frequently used were 5-FU (84%), cisplatin (64%), and mitomycin (9%). Brachytherapy was used in 8.5% of the cases. The median radiotherapy dose was 50.4 Gy. For patients who received radiotherapy as part of their care, chemoradiotherapy and preoperative chemoradiotherapy were the treatment recommendation for 67% of the patients. Chemoradiotherapy was used more frequently than radiotherapy alone. 223

The patterns of care experience from the United States show a steady increase in the use of chemoradiotherapy, with a corresponding decrease in patients treated with radiotherapy alone. The proportion of patients treated with no antineoplastic therapy in the United States is estimated to be approximately 10%. This is generally higher in the United Kingdom and South Africa but the data from those areas are older. Chemoradio-


therapy with surgery and chemoradiotherapy alone appear to be gaining acceptance as standard approaches.

Summary Carcinoma of the esophagus remains a disease associated with high mor-

tality and morbidity rates. The incidence of adenocarcinoma of the esophagus is increasing, whereas that of squamous cell carcinoma remains stable. The mechanism that leads to this increase continues to be debated. A delayed effect from smoking, reflux esophagitis, and the development of dysplastic changes are some of the reasons being investigated. Tumors of the gastroesophageal junction probably behave and should be managed more similar to tumors of the esophagus rather than tumors of the stomach.

Endoscopic ultrasonography should become part of the standard staging work-up to compliment standard diagnostic tools. Minimallyinvasive procedures may contribute to our diagnostic accuracy in the assessment of patients before definitive therapies. Nodal involvement alone does not necessarily imply incurable disease, although the location and number of nodes involved have significant prognostic implications.

In patients for whom a curative goal is recommended, primary surgery or chemoradiotherapy is the strategy recommended, especially in North America. This conclusion is supported by randomized controlled trials. Neoadjuvant chemoradiotherapy is the most promising multimodality approach, when it is used with surgery. The data here are strongest for adenocarcinomas.

When palliation is the goal of therapy, the arrays of treatment options remain diverse; they range from palliative esophagectomy to best supportive care. Treatment selection depends to a great extent on the general condition of the patient and the extent of disease. When a mechanical method is recommended, metal stents are superior to older plastic stents, intubation, and dilatation in terms of durability of response, with incremental costs that are relatively modest. The addition of radiotherapy in patients with advanced local regional disease not suitable for curative intent provided survival benefit over mechanical measures used for palliation of dysphagia in 1 study 2°~ and may be considered in addition to other local therapies for the palliation of dysphagia, For patients with tumors that arise from the esophagocardia, superior survival outcomes were observed with the use of 5-FU, doxorubicin, and methotrexate (compared with epimbicin, cisplatin, and 5-FU), and this treatment should be considered. Randomized controlled trials and population patterns of practice and outcomes are research strategies that are cru- cial in the improvment of our ability to provide improvement in curability and quality of life for patients with esophageal cancer.

360 Curr probl Cancer, November/December 2000

REFERENCES 1. National Cancer Institute. National Cancer Institute fact book. Bethesda (MD): US

Departent of Health, Education, and Welfare, Public Health Service, National Insti- tutes of Health; 1998.

2. Devesa SS, Blot WJ, Fraumeni JFJ. Changing patterns in the incidence of esophageal and gastric carcinoma in the United States. Cancer 1998;83:2049-53.

3. Bytzer R Christensen PB, Damkier P, Vinding K, Seersholm N. Adenocarcinoma of the esophagus and Barrett's esophagus: a population-based study. Am J Gastroen- terol 1999;94:86-91.

4. Moyana TN, Janoski M. Recent trends in the epidemiology of esophageal cancer: Comparison of epidermoid- and adenocarcinomas. Ann Clin Lab Sci 1996;26:480-6.

5. Thomas RJ, Lade S, Giles GG, Thursfield V. Incidence trends in oesophageal and proximal gastric carcinoma in Victoria. Aust NZ J Surg 1996;66:271-5.

6. Dolan K, SuttonR, Walker SJ, Morris AI, Campbell F, Williams EM. New classification of oesophageal and gastric carcinomas derived from changing patterns in epidemiology. Br J Cancer 1999;80:834-42.

7. Liabeuf A, Faivre J. Time trends in oesophageal cancer incidence in Cote d'Or (France), 1976-93. Eur J Cancer Prev 1997;6:24-30.

8. Hansen S, Wiig JN, Giercksky KE, Tretli S. Esophageal and gastric carcinoma in Norway 1958-1992: incidence time trend variability according to morphological subtypes and organ subsites. Int J Cancer 1997;71:340-4.

9. Armstrong RW, Borman B. Trends in incidence rates of adenocarcinoma of the oesophagus and gastric cardia in New Zealand, 1978-1992. Int J Epidemiol 1996;25:941-7.

10. Lord RV, Law MG, Ward RL, Giles GG, Thomas RJ, Thursfield V. Rising incidence of oesophageal adenocarcinoma in men in Australia. J Gastroenterol Hepatol 1998;13:356-62.

11. Lagergren J, Bergstrom R, Lindgren A, Nyren O. Symptomatic gastroesophageal reflux as a risk factor for esophageal adenocarcinoma. N Engl J Med 1999;340:825-31.

12. DeMeester TR. Esophageal carcinoma: current controversies. Semin Surg Oncol 1997;13:217-33.

13. O'Connor JB, Falk GW, Richter JE. The incidence of adenocarcinoma and dysplasia in Barrett's esophagus: report on the Cleveland Clinic Barrett's Esophagus Reg- istry. Am J Gastroenterol 1999;94:2037-42.

14. Tzonou A, Lipworth L, Garidou A, Signorello LB, Lagiou R Hsieh C, et al. Diet and risk of esophageal cancer by histologic type in a low-risk population. Int J Can- cer 1996;68:300-4.

15. Chow WH, Blot WJ, Vaughan TL, Risch HA, Gammon MD, Stanford JL, et al. Body mass index and risk of adenocarcinomas of the esophagus and gastric cardia. J Natl Cancer Inst 1998;90:150-5.

16. Gajalakshmi CK, Ravichandran K, Shanta V. Tobacco-related cancers in Madras, India. Eur J Cancer Prey 1996;5:63-8.

17. Launoy G, Milan C, Day NE, Faivre J, Pienkowski R Gignoux M. Oesophageal cancer in France: potential importance of hot alcoholic drinks. Int J Cancer 1997;71:917-23.

18. Nandakumar A, Anantha N, Pattabhiraman V, Prabhakaran PS, Dhar M, Put- taswamy K, et al. Importance of anatomical subsite in correlating risk factors in


cancer of the oesophagus--report of a case-control study. Br J Cancer 1996;73:1306-11.

19. Dai Q, Zheng W, Ji BT, Shu XO, Jin F, Cheng HX, et al. Prior immunity-related medical conditions and oesophageal cancer risk: a population-based case-control study in Shanghai. Eur J Cancer Prev 1997;6:152-7.

20. Ahsan H, Neugut AI. Radiation therapy for breast cancer and increased risk for esophageal carcinoma. Ann Intern Med 1998; 128:114-7.

21. Beahrs OH, Myers MY, editors. Manual for staging of cancer. 2nd ed. Philadelphia: Lippincott; 1983.

22. A proposal for a new TNM classification of esophageal carcinoma. The Japanese Committee for Registration of Esophageal Carcinoma. Jpn J Clin Oncol 1985;14:625-36.

23. Hermanek R Sobin LH, editors. TNM classification of malignant tumours. 4th ed. New York: Springer-Verlag; 1987.

24. Parameters linked to ten-years survival in Japan in resected cases of esophageal carcinoma. The Japanese Committee for Registration of Esophageal Carcinoma. Chest 1989;96:1005-11.

25. TNM classification of malignant tumours. In: Sobin LH, Wittkind CH, editors. 5th ed. New York: John Wiley & Sons, Inc; 1997.

26. Skinner DB, Little AG, Ferguson MK, Soriano A, Staszak VM. Selection of operation for esophageal cancer based on staging. Ann Surg 1986;204:391-401.

27. Ellis FHJ, Watkins EJ, Krasna MJ, Heatley GJ, Balogh K. Staging of carcinoma of the esophagus and cardia: a comparison of different staging criteria. J Surg Oncol 1993;52:231-5.

28. Wobst A, Audisio RA, Colleoni M, Geraghty JG. Oesophageal cancer treatment: studies, strategies and facts. Ann Oncol 1998;9:951-62.

29. Casson AG, Rusch VW, Inculet RI, Ginsberg RJ, Zankowicz N, Rosenberg JC, et al. Lymph node mapping for resectable carcinoma of the esophagus: a guide for thoracic surgeons. Princeton (NJ): Bistol-Myers Oncology Division; 1992.

30. Hishinuma T. Radiotherapy of esophageal cancer: clinical usefulness of new group- ing [Japanese]. Nippon Igaku Hoshasen Gakkal Zasshi 1997;57:195-202.

31. Tanisada K, Teshima T, Ikeda H, Abe M, Yamashita T, Nishio M, et al. Prognostic factors for patients with esophageal cancer treated with radiation therapy in PCS: a preliminary study. Radiat Med 1998;16:461-8.

32. Rice TW, Zuccaro GJ, Adelstein DJ, Rybicki LA, Blackstone EH, Goldblum JR. Esophageal carcinoma: depth of tumor invasion is predictive of regional lymph node status. Ann Thorac Surg 1998;65:787-92.

33. Liu CC, Fahn HJ, Li WY, Wu YC, Huang MH, Wang LS. Lymph node metastasis in squamous cell carcinoma of the intrathoracic esophagus. Chung Hua I Hsueh Tsa Chih 1998;61:77-84.

34. Beahrs OH, Henson DE, Hutter RVP, Kennedy BJ, editors. Manual for staging of cancer. 4th ed. Philadelphia: Lippincott; 1992.

35. Wijnhoven BPL, Siersema PD, Hop WCJ, van Dekken H, Tilanus HW. Adenocar- cinomas of the distal oesophagus and gastric cardia are one clinical entity. Rotter- dam Oesopahgeal Tumour Study Group. Br J Surg 1999;86:529-35.

36. Sierwert JR, Stein HJ. Classification of adenocarcinoma of the oesophagogastric junction. Br J Surg 1998;85:1457-9.

37. Lal N, Bhasin DK, Malik AK, Gupta NM, Singh K, Mehta SK, Optimal number of


biopsy specimens in the diagnosis of carcinoma of the oesophagus. Gut 1992;33:724-6.

38. Witzel L, Halter F, Gretillat PA, Scheurer U, Keller M. Evaluation of specific value of endoscopic biopsies and brush cytology for malignancies of the oesophagus and stomach. Gut 1976;17:375-7.

39. Hanson JT, Thoreson C, Morrissey JF. Brush cytology in the diagnosis of upper gastrointestinal malignancy. Gastrointest Endosc 1980;26:33-5.

40. Misumi A, Harada K, Murakami A, Arima K, Kondo H, Akagi M, et al. Role of Lugol dye endoscopy in the diagnosis of early esophageal cancer. Endoscopy 1990;22:12-6.

41. Misumi A, Harada K, Murakami A, Arima K, Kondo H, Akagi M, et al. Early diagnosis of esophageal cancer: analysis of 11 cases of esophageal mucosal cancer. Ann Surg 1989;210:732-9.

42. Contini S, Consigli GF, Di Lecce F, Chiapasco M, Ferri T, Orsi E Vital staining of oesophagus in patients with head and neck cancer: still a worthwhile procedure. Ital J Gastroenterol 1991;23:5-8.

43. Yoshinaka H, Shimazu H, Fukumoto T, Baba M. Superficial esophageal carcinoma: a clinicopathological review of 59 cases. Am J Gastroenterol 1991;86:1413-8.

44. TanakaY, Yasuda K, Aibe T, Fuji T, Kawai K. Anatomical and pathological aspects in ultrasonic endoscopy for GI tract. Scand J Gastroenterol Suppl 1984;94:43-50.

45. Tio TL, Tytgat GN. Endoscopic ultrasonography of normal and pathologic upper gastrointestinal wall structure: comparison of studies in vivo and in vitro with histology. Scand J Gastroenterol Suppl 1986;123:27-33.

46. Holden A, Mendelson R, Edmunds S. Pre-operative staging of gastro-oesophageal junction carcinoma: comparison of endoscopic ultrasound and computed tomography. Australas Radiol 1996;40:206-12.

47. Hacklander T, Ziegenhahn E, Katoh E, Jungblut RM, Modder U. Dependence of axis deviation in the esophagram on computerized tomography determined wall thickness and its value in assessing depth of invasion of esophageal carcinoma [German]. Aktuelle Radiologie 1997;7:173-8.

48. Zuccaro GJ, Rice TW, Goldblum J, Medendorp SV, Becker M, Pimentel R, et al. Endoscopic ultrasound cannot determine suitability for esophagectomy after aggressive chemoradiotherapy for esophageal cancer. Am J Gastroentero! 1999;94:906-12.

49. Hunerbein M, Ghadimi BM, Haensch W, Schlag PM. Transendoscopic ultrasound of esophageal and gastric cancer using miniaturized ultrasound catheter probes. Gastrointest Endosc 1998;48:371-5.

50. Catalano MF, Alcocer E, Chak A, Nguyen CC, Raijman I, Geenen JE, et al. Eval- uation of metastatic celiac axis lymph nodes in patients with esophageal carcinoma: accuracy of EUS. Gastrointest Endosc 1999;50:352-6.

51. Natsugoe S, Yoshinaka H, Morinaga T, Shimada M, Baba M, Fukumoto T, et al. Ultrasonographic detection of lymph-node metastases in superficial carcinoma of the esophagus. Endoscopy 1996;28:674-9.

52. Massari M, Cioffi U, De Simone M, Lattuada E, Montorsi M, Segalin A, et al. Endoscopic ultrasonography for preoperative staging of esophageal carcinoma. Surg Laparosc Endosc 1997;7:162-5.

53. Chandawarkar RY, Kakegawa T, Fujita H, Yamana H, Toh Y, Fujitoh H. Endosonography for preoperative staging of specific nodal groups associated with esophageal cancer. World J Surg 1996;20:700-2.


54. Botet JF, Lightdale CJ, Zauber AG. Preoperative staging of esophageal cancer: comparison of endoscopic US and dynamic CT. Radiology 1991; 181:419-25.

55. Grimm H, Binmoeller KF, Soehendra N. Ultrasonic esophagoprobe (prototype 1). Gastrointest Endosc 1992;38:490-3.

56. Souquet JC, Napoleon B, Pujol B, Valette PJ, Chollet R, Lambert R. Endosonography- guided treatment of esophageal carcinoma. Endoscopy 1992;24(suppl 1):324-8.

57. Tio TL, Coene PP, Schouwink MH, Tytgat GN. Esophagogastric carcinoma: preoperative TNM classification with endosonography. Radiology 1989;173:411-7.

58. Tio TL, Cohen P, Coene PP, Udding J, den Hartog J, Tytgat GN. Endosonography and computed tomography of esophageal carcinoma: preoperative classification compared to the new (1987) TNM system. Gastroenterology 1989;96:1478-86.

59. Ziegler K. Evaluation of endosonography in TN staging of oesophageal cancer. Gut 1991;32:16-20.

60. Ziegler K, Sanft C, Zimmer T, Zeitz M, Felsenberg D, Stein H, et al. Comparison of computed tomography, endosonography, and intraoperative assessment in TN staging of gastric carcinoma. Gut 1993 ;34:604-10.

61. Pharn T, Roach E, Falk GL, Chu J, Ngu MC, Jones DB. Staging of oesophageal carcinoma by endoscopic ultrasound: preliminary experience. Aust NZ J Surg 1998;68:209-12.

62. Vickers J, Alderson D. Influence of luminal obstruction on oesophageal cancer staging using endoscopic ultrasonography. Br J Surg 1998;85:999-1001.

63. Vickers J, Alderson D. Oesophageal cancer staging using endoscopic ultrasonography. Br J Surg 1998;85:994-8.

64. Hasegawa N, Niwa Y, Arisawa T, Hase S, Goto H, Hayakawa T. Preoperative staging of superficial esophageal carcinoma: comparison of an ultrasound probe and standard endoscopic ultrasonography. Gastrointest Endosc 1996;44:388-93.

65. Hiele M, De Leyn P, Schurmans E Lerut A, Huys S, Geboes K, et al. Relation between endoscopic ultrasound findings and outcome of patients with tumors of the esophagus or esophagogastric junction. Gastrointest Endosc 1997;45:381-6.

66. Luketich JD, Schauer P, Landreneau R, Nguyen N, Urso K, Ferson E et al. Minimally invasive surgical staging is superior to endoscopic ultrasound in detecting lymph node metastases in esophageal cancer. J Thorac Cardiovasc Surg 1997;114:817-21.

67. Reed CE, Mishra G, Sahai AV, Hoffman B J, Hawes RH. Esophageal cancer staging: improved accuracy by endoscopic ultrasound of celiac lymph nodes. Ann Tho- rac Surg 1999;67:319-21.

68. Laterza E, de Manzoni G, Guglielmi A, Rodella L, Tedesco P, Cordiano C. Endo- scopic ultrasonography in the staging of esophageal carcinoma after preoperative radiotherapy and chemotherapy. Ann Thorac Surg 1999;67:1466-9.

69. Isenberg G, Chak A, Canto MI, Levitan N, Clayman J, Pollack B J, et al. Endo- scopic ultrasound in restaging of esophageal cancer after neoadjuvant chemoradiation. Gastrointest Endosc 1998;48:158-63.

70. Rice TW, Boyce GA, Sivak MV. Esophageal ultrasound and the preoperative staging of carcinoma of the esophagus. J Thorac Cardiovasc Surg 1991;101:536-44.

71. Fockens P, Van den Brande JH, van Dullemen HM, van Lanschot JJ, Tytgat GN. Endosonographic T-staging of esophageal carcinoma: a learning curve. Gastroin- test Endosc 1996;44:58-62.

72. Schlick T, Heintz A, Junginger T. The examiner's learning effect and its influence on the quality of endoscopic ultrasonography in carcinoma of the esophagus and gastric cardia. Surg Endosc 1999;13:894-8.


90.

Curr Probl Cancer, November/December 2000

73. Van Dam J, Rice TW, Catalano MF, Kirby T, Sivak MVJ. High-grade malignant stricture is predictive of esophageal tumor stage: risks of endosonographic evaluation. Cancer 1993;71:2910-7.

74. Dittler HJ, Siewert JR. Role of endoscopic ultrasonography in esophageal carcinoma. Endoscopy 1993;25:156-61.

75. Nesje LB, Odegaard S, Kilmney MB. Transendoscopic ultrasonography during conventional upper gastrointestinal endoscopy: clinical evaluation of a linear 20- MHz probe system. Scand J Gastroenterol 1997;32:500-8.

76. Kim LS, Koch J. Do we practice what we preach? Clinical decision making and uti- lization of endoscopic ultrasound for staging esophageal cancer. Am J Gastroen- terol 1999;94:1847-52.

77. Wiersema MJ, Kochman ML, Chak A, Cramer HM, Kesler KA. Real-time endoscopic ultrasound-guided fine-needle aspiration of a mediastinal lymph node. Gas- trointest Endosc 1993;39:429-31.

78. Krasna MJ, McLanghlin JS. Thoracoscopic lymph node staging for esophageal cancer. Ann Thorac Surg 1993;56:671-4.

79. Krasna MJ, Reed CE, Jaklitsch MT, Cushing D, Sugarbaker DJ. Thoracoscopic staging of esophageal cancer: a prospective, multiinstitutional trial. Cancer and Leukemia Group B Thoracic Surgeons. Ann Thorac Surg 1995;60:1337-40.

80. Krasna MJ. Role of thoracoscopic lymph node staging for lung and esophageal cancer. Oncology (Huntingt) 1996;10:793-802.

81. Luketich JD, Schaner P, Urso K, Townsend DW, Belani CP, Cidis MC, et al. Min- imally invasive surgical biopsy confirms PET findings in esophageal cancer. Surg Endosc 1997; 11:1213-5.

82. Watanabe N, Hirano T, Fukushima Y, Yukihiro M, Aoyagi K, Tomiyoshi K, et al. Esophageal cancer detection with Tc-99m tetrofosmin SPECT. Clin Nucl Med 1997;22:431-3.

83. Couper GW, McAteer D, Wallis F, Norton M, Welch A, Nicolson M, et al. Detec- tion of response to chemotherapy using positron emission tomography in patients with oesophageal and gastric cancer. Br J Surg 1998;85:1403-6.

84. Fukunaga T, Okazumi S, Koide Y, Isono K, Imazeki K. Evaluation of esophageal cancers using fluorine-18-fluorodeoxyglucose PET. J Nucl Med 1998;39:1002-7.

85. Luketich JD, Friedman DM, Weigel TL, Meehan MA, Keenan RJ, Townsend DW, et al. Evaluation of distant metastases in esophageal cancer: 100 consecutive positron emission tomography scans. Ann Thorac Surg 1999;68:1133-6.

86. Luketich JD, Schaner PR, Meltzer CC, Landreneau RJ, Urso GK, Townsend DW, et al. Role of positron emission tomography in staging esophageal cancer. Ann Thorac Surg 1997;64:765-9.

87. Jaeschke R, Guyatt G, Sackett D. Users' guides to the medical literature; HI: how to use an article about a diagnostic test; A. Are the results of the study valid? JAMA 1994;271:389-91.

88. Jaeschke R, Guyatt G, Sackett D. Users' guides to the medical literature; III: how to use an article about a diagnostic test; B. What are the results and will they help me in caring for my patients? 1994;271:703-7.

89. McAteer D, Wallis F, Couper G, Norton M, Welch A, Bruce D, et al. Evaluation of t8F-FDG positron emission tomography in gastric and oesophageal carcinoma. Br J Radiol 1999;72:525-9. Block MI, Patterson GA, Sundaresan RS, Bailey MS, Flanagan FL, Dehdashti F, et

365

al. Improvement in staging of esophageal cancer with the addition of positron emission tomography. Ann Thorac Surg 1997;64:770-6.

91. Raaffdn SC, Taylor H, Cook GJ, Mason R. Computed tomography and positron emission tomography in the pre-operative staging of oesophageal carcinoma. Clin Radiol 1998;53:659-65.

92. Kole AC, Plukker JT, Nieweg OE, Vaalburg W. Positron emission tomography for staging of oesophageal and gastroesophageal malignancy. Br J Cancer 1998;78:521-7.

93. Flanagan FL, Dehdashti F, Siegel BA, Trask DD, Sundaresan SR, Patterson GA, et al. Staging of esophageal cancer with 18F-fluorodeoxyglucose positron emission tomography. AJR Am J Roentgenol 1997; 168:417-24.

94. Lehr L, Rupp N, Siewart JR. Assessment of resectability of esophageal cancer by computerized tomography and magnetic resonance imaging. Surgery 1988; 103:344-50.

95. Stoker J, van Velthuysen ML, van Overhagen H, van Kempen D, Tilanus HW, Lameris JS. Esophageal carcinoma: ex vivo endoluminal magnetic resonance imaging. Invest Radiol 1999;34:58-64.

96. Yarnada I, Murata Y, Izumi Y, Kawano T, Endo M, Kuroiwa T, et al. Staging of esophageal carcinoma in vitro with 4.7-T MR imaging. Radiology 1997;204:521-6.

97. Kulling D, Feldman DR, Kay CL, Hoffman B J, Reed CE, Young JW, et al. Local staging of esophageal cancer using endoscopic magnetic resonance imaging: prospective comparison with endoscopic ultrasound. Endoscopy 1998;30:745-9.

98. Chandawarkar RY, Kakegawa T, Fujita H, Yamana H, Hayabuthi N. Comparative analysis of imaging modalities in the preoperative assessment of nodal metastasis in esophageal cancer. J Surg Oncol 1996;61:214-7.

99. Cuschieri A. Invited introduction: treatment of carcinoma of the oesophagus. Ann R Coll Surg Engl 1991;73:1-3.

100. Coia LR. Esophageal cancer: is esophagectomy necessary? Oncology (Huntingt) 1989;3:101-11.

101. O'Reilly S, Forastiere AA. Is surgery necessary with multimodality treatment of oesophageal cancer? Ann Oncol 1995;6:519-21.

102. Earlam R. An MRC Prospective randomised trial of radiotherapy versus surgery for operable squamous cell carcinoma of the esophagus. Ann R Coil Surg Engl 1991;73:8-12.

103. Akiyama H, Miyazono H, Tsurumaru M, Hashimoto C, Kawamura T. Thoracoab- dominal approach for carcinoma of the cardia of the stomach. Am J Snrg 1979; 137:345-9.

104. Peracchia A, Bardini R, Segalin A, Tremolada C, Ruol A. 11 trattamento chirurgico del carcinoma dell'esofago toracico. Minerva Chir 1989;44:95-9.

105. Skinner DB. En bloc resection for neoplasms of the esophagus and cardia. J Tho- rac Cardiovasc Surg 1983;85:59-71.

106. Skinner DB, Little AG, Ferguson MK, Soriano A, Staszak VM. Selection of operation for esophageal cancer based on staging. Ann Surg 1986;204:391-401.

107. Wong J. Esophageal resection for cancer: the rationale of current practice. Am J Surg 1987;153:18-24.

108. Akiyama H, Tsurumaru M, Udagawa H, Kajiyama Y. Radical lymph node dissection for cancer of the thoracic esophagus. Ann Surg 1994;220:364-72.

109. Finley R J, Inculet RI. The results of esophagogastrectomy without thoracotomy for adenocarcinoma of the esophagogastric junction. Ann Sttrg 1989;210:535-42.


127.

128.

129.


110. Holscher AH, Voit H, Buttermann G, Siewert JR. Function of the intrathoracic stomach as esophageal replacement. World J Surg 1988;12:835-44.

111. Cheung HC, Siu KF, Wong J. Is pyloroplasty necessary in esophageal replacement by stomach? A prospective, randomized controlled trial. Surgery 1987;102:19-24.

112. Fok M, Cheng SW, Wong J. Pyloroplasty versus no drainage in gastric replacement of the esophagus. Am J Surg 1991;162:447-52.

113. Law S, Fok M, Chu KM, Wong J. Comparison of hand-sewn and stapled esophagogastric anastomosis after esophageal resection for cancer: a prospective randomized controlled trial. Ann Surg 1997;226:169-73.

114. Manjari R, Padhy AK, Chattopadhyay TK. Emptying of the intrathoracic stomach using three different pylorus drainage procedures: results of a comparative study. Surg Today 1996;26:581-5.

115. Saeki M, TsuchidaY, Ogata T, Nakano M, Akiyama H. Long-term results of jejunal replacement of the esophagus. J Pediatr Surg 1988;23:483-9.

116. Gawad KA, Hosch SB, Bumann D, Lubeck M, Moneke LC, Bloechle C, et al. How important is the route of reconstruction after esophagectomy: a prospective randomized study. Am J Gastroenterol 1999;94:1490-6.

117. Bartels H, Thorban S, Siewert JR. Anterior versus posterior reconstruction after transhiatal oesophagectomy: a randomized controlled trial. Br J Surg 1993;80: 1141-4.

118. Orringer MB, Marshall B, Iannettoni MD. Transhiatal esophagectomy: clinical experience and refinements. Ann Surg 1999;230:392-400.

119. Craig SR, Walker WS, Cameron EW, Wightman AJ. A prospective randomized study comparing stapled with handsewn oesophagogastric anastomoses. J R Coll Surg Edinb 1996;41:17-9.

120. Laterza E, de' MG, Veraldi GF, G~aglielmi A, Tedesco P, Cordiano C. Manual compared wit h mechanical cervical oesophagogastric anastomosis: a randomised trial. Eur J Surg 1999;165:105t-4.

121. Law S, Cheung MC, Fok M, Chu KM, Wong J. Pyloroplasty and pyloromyotomy in gastric replacement of the esophagus after esophagectomy: a randomized controlled trial. J Am Coll Surg 1997;I84:630-6.

122. Orringer MB. Technical aids in performing transhiatal esophagectomy without thoracotomy. Ann Thorac Surg 1984;38:128-32.

123. Orringer MB. Transhiatal esophagectomy without thoracotomy for carcinoma of the esophagus. Adv Surg 1986;19:1-49.

124. Chu KM, Law SY, Fok M, Wong J. A prospective randomized comparison of transhiatal and transthoracic resection for lower-third esophageal carcinoma. Am J Surg 1997;174:320-4.

125. Goldminc M, Maddern G, Le Prise E, Meunier B, Campion JP, Launois B. Oesophagectomy by a transhiatal approach or thoracotomy: a prospective randomized trial: BrJ Surg 1993;80:367-70.

126. Jacobi CA, Zieren HU, Muller JM, Pichlmaier H. Surgical therapy of esophageal carcinoma: the influence of surgical approach and esophageal resection on cardiopulmonary function. Eur J Cardiothorac Surg 1997;11:32-7. Akiyama H, Tsurumaru M, Ono Y, Udagawa H, Matsuda M, Kajiyama Y. Transo- ral esophagectomy. Surg Gynecol Obstet 1991;173:399-400. Domene CE, Volpe P, Santo MA, Onari P, Campos JR, Pinotti HW. Esofagectomia por videocirurgia. Rev Hosp Clin Fac Med Sat Paulo 1998;53:134-8. Kawahara K, Maekawa T, Okabayashi K, Hideshima T, Shiraishi T, Yoshinaga Y, et

367

al. Video-assisted thoracoscopic esophagectomy for esophageal cancer. Surg Endosc 1999;13:218-23.

130. Luketich JD, Nguyen NT, Weigel T, Ferson P, Keenan R, Schauer P. Minimally invasive approach to esophagectomy. J Soc Laparoendosc Surg 1998;2:243-7.

131. Sammartino P, Chirletti P, Calcaterra D, Cardi M, Caronna R, Biacchi D, et al. Videoassisted transhiatal esophagectomy for cancer. Int Surg 1997;82:406-10.

132. Yahata H, Sugino K, Takiguchi T, Yoshioka S, Tanji H, Shinozaki K, et al. Laparo- scopic transhiatal esophagectomy for advanced thoracic esophageal cancer. Surg Laparosc Endosc 1997;7:13-6.

132a. Liu HP, Chang CH, Lin PJ, Chang JP. Video-assisted endoscopic esophagectomy with stapled intrathoracic esophagogastric anastomosis. World J S urg 1995;19:745-7.

133. Earle C, Maroun J, Zuraw L and the Gastrointestinal Cancer Disease Site Group. Neoadjuvant or adjuvant therapy for resectable esophageal cancer. Available from: URL: http://hiru.mcmaster.ca/ccopgi/guidelines/gas/cpg2_14.html

134. Fowler JE The linear-quadratic formula and progress in fractionated radiotherapy. Br J Radiol 1989;62:679-94.

135. Coia LR, Sauter ER. Esophageal cancer. Curt Probl Cancer 1994;18:189-247. 136. Arnott SJ, William D, Gignoux M, Gifting D, Hansen HS, Launois B, et al. Preop-

erative radiotherapy in esophageal carcinoma: a meta-analysis using individual patient data (oesophageal cancer collaborative group). Int J Radiat Oncol Biol Phys 1998;41:579-83.

137. Oesophageal Cancer Collaborative Group. Preoperative radiotherapy in esophageal carcinoma. Cochrane Library Issue 4. Oxford: Update Softward; 1999.

138. Launois B, Delarue D, Campion JP, Kerbaol M. Preoperative radiotherapy for carcinoma of the esophagus. Surg Gynecol Obstet 1981;153:690-2.

139. Gignoux M, Roussel A, Paillot B, Gillet M, Schlag P, Favre JP, et al. The value of preoperative radiotherapy in esophageal cancer: results of a study of the EORTC. World J Surg 1987;11:426-32.

140. Nygaard K, Hagen S, Hansen HS, Hatlevoll R, Hultborn R, Jakobsen A, et al. Pre- operative radiotherapy prolongs survival in operable esophageal carcinoma: a randomized, multicenter study of pre-operative radiotherapy and chemotherapy. The second Scandinavian trial in esophageal cancer. World J Surg 1992;16:1104-10.

141. Arnott SJ, Duncan W, Kerr GR, Walbaum PR, Cameron E, Jack WJ, et al. Low dose preoperative radiotherapy for carcinoma of the oesophagus: results of a randomized clinical trial. Radiother Oncol 1992;24:108-13.

142. Wang M, Gu XZ, Yin WB, Huang GJ, Wang LJ, Zhang DW. Randomized clinical trial on the combination of preoperative irradiation and surgery in the treatment of esophageal carcinoma: report on 206 patients. Int J Radiat Oncol Biol Phys 1989;16:325-7.

143. Schlag E Randomized study of preoperative chemotherapy in squamous eel1 cancer of the esophagus. CAO Esophageal Cancer Study Group. Chintrg 1992;63:709-14.

144. Maipang T, Vasinanukorn P, Petpichetchian C, Chamroonkul S, Geater A, Chan- sawwaang S, et al. Induction chemotherapy in the treatment of patients with carcinoma of the esophagus. J Surg Oncol 1994;56:191-7.

145. Law S, Fok M, Chow S, Chu KM, Wong J. Preoperative chemotherapy versus surgical therapy alone for squamous cell carcinoma of the esophagus: a prospective randomized trial. J Thorac Cardiovasc Surg 1997; 114:210-7.

146. Kok TC, Lanscho JV, Siersema PD, Overhagen HV, Tilanus HW, Rotterdam Esophageal Tumor Study Group. Neoadjuvant chemotherapy in operable


161.


esophageal squamous cell cancer: final report of a phase III multicenter randomized controlled trial [abstract]. Proc Annu Meet Am Soc Clin Oncol 1997;16:984.

147. Kelsen DP, Ginsberg R, Pajak TF, Sheahan DG, Gunderson L, Mortimer J, et al. Chemotherapy followed by surgery compared with surgery alone for localized esophageal cancer. N Engl J Med 1998;339:1979-84.

148. Roth JA, Pass HI, Flanagan MM, Graeber GM, Rosenberg JC, Steinberg S. Ran- domized clinical trial of preoperative and postoperative adjuvant chemotherapy with cisplatin, vindesine, and bleomycin for carcinoma of the esophagus. J Thorac Cardiovasc Surg 1988;96:242-8.

149. Malthaner R, Fenlon D. Preoperative chemotherapy for resectable esophageal cancer. Cochrane Library Issue 4. Oxford: Update Softward; 1999.

150. Bhansali MS, Vaidya JS, Bhatt RG, Patil PK, Badwe RA, Desai PB. Chemotherapy for carcinoma of the esophagus: a comparison of evidence from meta-analysis of randomized trials and of historical control studies. Ann Oncol 1996;7:355-9.

151. Ando N, Iizuka T, Kakegawa T, Isono K, Watanabe H, Ide H, et al. A randomized trial of surgery with and without chemotherapy for localized squamous carcinoma of the thoracic esophagus: the Japan Clinical Oncology Group Study. J Thorac Car- diovasc Surg 1997; 114:205-9.

152. Pouliquen X, Levard H, Hay JM, McGee K, Fingerhut A, Langlois-Zantin O. 5- Fluorouracil and cisplatin therapy after palliative surgical resection of squamous cell carcinoma of the esophagus: a multicenter randomized trial. French Associa- tions for Surgical Research. Ann Surg 1996;223:127-33.

153. Zieren HU, Muller JM, Jacobi CA, Pichlmaier H, Muller RP, Staar S. Adjuvant postoperative radiation therapy after curative resection of squamous cell carcinoma of the thoracic esophagus: a prospective randomized study. World J Surg 1995;19:444-9.

154. Fok M, Sham JS, Choy D, Cheng SW, Wong J. Postoperative radiotherapy for carcinoma of the esophagus: a prospective, randomized controlled study. Surgery 1993;113:138-47.

155. Teniere P, Hay JM, Fingerhut A, Fagniez PL. Postoperative radiation therapy does not increase survival after curative resection for squamous cell carcinoma of the middle and lower esophagus as shown by a multicenter controlled trial. French Uni- versity Association for Surgical Research. Surg Gynecol Obstet 1991;173:123-30.

156. Le Prise E, Etienne PL, Meunier B, Maddern G, Ben Hassel M, Gedouin D, et al. A randomized study of chemotherapy, radiation therapy, and surgery versus surgery for localized squamous cell carcinoma of the esophagus. Cancer 1994;73:1779-84.

157. Apinop C, Puttisak P, Preecha N. A prospective study of combined therapy in esophageal cancer. Hepatogastroenterology 1994;41:391-3.

158. Walsh TN, Noonan N, Hollywood D, Kelly A, Keeling N, Hennessy TP. A comparison of multimodal therapy and surgery for esophageal adenocarcinoma. N Engl J Med 1996;335:462-7.

159. Bosset JF, Gignoux M, Triboulet JP, Tiret E, Mantion G, Elias D, et al. Chemora- diotherapy followed by surgery compared with surgery alone in squamous-cell cancer of the esophagus. N Engl J Med 1997;337:161-7.

160. Urba S, Orringer M, Turrisi A, Whyte R, Natale R, Iannettoni M, et al. A randomized trial comparing transhiatial esophagectomy (THE) to preoperative concurrent chemoradiation (CT/XRT) followed by esophagectomy in locoregional esophageal carcinoma (CA) [abstract]. Proc Annu Meet Am Soc Clin Oncol 1995;14:A475. Launois B. A randomized study of chemoradiotherapy and surgery for esophageal

369

cancer [abstract]. Proceedings of the International Congress on Cancer of the Esophagus: Recent Advances in Biology, Prevention, Diagnosis, and Treatment. 1994 June Genoa, Italy, 1992. p. 7-10.

162. DerSimonian R, Laird N. Metaanalysis in clinical trials. Control Clin Trials 1986;7:177-88.

163. Tai R Van Dyk J, Yu E, Battista Ji Stitt L, Coad T. Variability of target volume delineation in cervical esophageal cancer. Int J Radiat Oncol Biol Phys 1998;42:277-88.

164. Weil MD, Roach M, Pickett B, Young B, Kuerth S, Phillips TL. 3D conformal radiotherapy in the sagittal plane for centrally located thoracic tumors. Med Dosimetry 1995;20:11-4.

165. Provincial Gastrointestinal Disease Site Group. Combined modatity radiotherapy and chemotherapy in the non-sm'gical management of localized carcinoma of the esophagus. Cancer Care Ontario Practice Guidelines Initiative. 2000. Available from: URL: http://hiru.mcmaster.ca/ccopgi/gascpg.

166. Bourhis J, Eschwege E Radiotherapy-chemotherapy combinations in head and neck squamous cell carcinoma: overview of randomized trials. Anticancer Res 1996; 16:2397-402.

167. Thomas G. Improved treatment for cervical cancer: concurrent chemotherapy and radiotherapy. N Engl J Med 1999;340:1198-200.

168. Stafford SL, Martenson JA. Combined radiation and chemotherapy for carcinoma of the anal canal. Oncology (Huntingt) 1998; 12:373-7.

169. Hukku S, Fernandes R Vasishta S, Sharma VK. Radiation therapy alone and in combination with Neomycin and 5-fluorouracil in advanced carcinoma esophagus. Indian J Cancer 1989;26:131-6.

170. Kolaric K. Combination of cytostafics and radiation: a new trend in the treatment of inoperable esophageal cancer. Prog Clin Biot Res 1985;201:259-82.

171. Smith TJ, Ryan LM, Douglass HO Jr, Haller DG, DayalY, Kirkwood J, et al. Com- bined chemoradiotherapy vs radiotherapy alone for early stage squamous cell carcinoma of the esophagus: a study of the Eastern Cooperative Oncology Group. Int J Radiat Onc01 Biol Phys 1998;42:269-76.

172. Dinshaw KA, Sharma V, Pendse AM, Telang CS, Vege SS, Malliat MK, et al. The role of intraluminal radiotherapy and concurrent 5-fluorouracil infusion in the management of carcinoma esophagus: a pilot study. J Surg Oncol 1991;47:155-60.

173. Roussel A, Bleiberg H, Dalesio O, Jacob JH, Haegele P, Jung GM, et al. Palliative therapy of inoperable oesophageal carcinoma with radiotherapy and methotrexate: final results of a controlled clinical trial. Int J Radiat Oncol Biol Phys 1989; 16:67-72.

174. Zhou JC. Randomized trial of combined chemotherapy including high dose cisplatin and radiotherapy for esophageal cancer [Chinese]. Chung Hua Chung Liu Tsa Chih 1991;13:291-4.

175. Hatlevoll R, Hagen S, Hansen HS, Hultborn R, Jakobsen A, Mantyla M, et al. Bleomycirdcis-platin as neoadjuvant chemotherapy before radical radiotherapy in localized, inoperable carcinoma of the esophagus: A prospective randomized multicentre study. The second Scandinavian trial in esophageal cancer. Radiother Oncol 1992;24:114-6.

176. Cooper JS, Guo MD, Herskovic A, Macdonald JS, Martenson JA, al-Sarraf M, et al. Chemoradiotherapy of locally advanced esophageal cancer: long term follow-up of a prospective randomized trial RTOG 85-01. JAMA 1999;281:1623-7.

177. Slabber CF, Nel JS, Schoeman L, Burger W, Falkson G, Falkson CI. A ranodmized study of radiotherapy alone versus radiotherapy plus 5-Fluorouracil and platinum


in patients with inoperable, locally advnaced squamous cancer of the esophagus. Am J Clin Oncol 1998;21:462-5.

178. Kaneta T, Takai Y, Nemoto K, Kakuto Y, Ogawa Y, Ariga H, et al. Effect of combination chemotherapy with daily low dose CDDP for esophageal cancer: results of a randomized trial. Jpn J Cancer Chemother 1997;24:2099-104.

179. Roussel A, Haegele P, Paillot B, Gignoux M, Marinus A, Sahmoud T, et al. Results of the EORTC-GTCCG Phase III trial of irradiation vs irradiation and CDDP in inoperable esophageal cancer [abstract]. Proc Annu Meet Am Soc Clin Oncol 1994;13:A583.

180. Araujo CM, Souhami L, Gil RA, Carvalho R, Garcia JA, Froimtchuk MJ, et al. A randomized trial comparing radiation therapy versus concomitant radiation therapy and chemotherapy in carcinoma of the thoracic esophagus. Cancer 1991 ;67:2258- 61.

181. Andersen AR Berdal P, Edsmyr F, Hagen S, Hatlevoll R, Nygaard K, et al. Irradi- ation, chemotherapy and surgery in esophageal cancer: a randomized clinical study. The first Scandinavian trial in esophageal cancer. Radiother Oncol 1984;2:179-88.

182. Zhang Z. Radiation combined with bleomycin for esophageal carcinoma: a randomized study of 99 patients. Chung Hua Chung Liu Tsa Chih 1984;6:372-4.

183. Earle JD, Gelber RD, Moertel CG, Hahn RG. A controlled evaluation of combined radiation and bleomycin therapy for squamous cell carcinoma of the esophagus. Int J Radiat Oncol Biol Pbys 1980;6:821-6.

184. Kolaric K, Roth A, Dujmovic I. The value of two combined chemoradiotherapy approaches in the treatment of inoperable esophageal cancer. Tumori 1984;70:69-75.

185. Kolaric K, Zupanc D, Tometic Z. Radiation alone vs radiation + chemotherapy (DDP + 5FU) in locoregionally advanced esophageal cancer: preliminary report of a prospective randomized study [abstract]. Ann Oncol 1990;1:43.

186. Kolaric K, Zupanc D, Zivkovic M. Radiation alone vs radiochemotherapy (DDP + 5FU) in locoregionally advanced esophageal cancer: report of a prospective randomized study [abstract]. Ann Oncol 1992;3:68.

187. Kolaric K, Zupanc D, Zivkovic M. Chemoradiotherapy vs radiation alone in locoregionally advanced esophageal cancer: report of a prospective randomized study [abstract]. Presented at: Eighth Mediterranean Congress of Chemotherapy; 1992 May 24-29; Athens, Greece.

188. Kolaric K, Zupanc D, Zivkovic M. Radiation alone vs radiochemotherapy (DDP + 5FU) in locoregionally advanced esophageal cancer: interim report of a prospective randomized study [abstract]. Proc Annu Meet Am Soc Clin Oncol 1992;11:A516.

189. Kolaric K, Zupanc D, Tometic Z. Radiation alone vs radiation + claemotherapy (DDP + 5FU) in locoreginally advanced esophageal cancer: preliminary report of a prospective randomized study [abstract]. Presented at: Third International Congress on the Neo-adjuvant Chemotherapy; 1991 ..o; oo..

190. Okawa T, Dokiya T, Nishio M, Hishikawa Y, Morita K. Multi-institutional randomized trial of external radiotherapy with and without intraluminal brachytherapy for esophageal cancer in Japan. Japanese Society of Therapeutic Radiology and Oncology (JASTRO) Study Group. Int J Radiat Oncol Biol Phys 1999;45:623-8.

191. Adam A, Ellul J, Watkinson AF, Tan BS, Morgan RA, Saunders MR et al. Pallia- tion of inoperable esophageal carcinoma: a prospective randomized trial of laser therapy and stent placement. Radiology 1997;202:344-8.

192. De Palma GD, di Matteo E, Romano G, Fimmano A, Rondinone G, Catanzano C. Plastic prosthesis versus expandable metal stents for palliation of inoperable


esophageal thoracic carcinoma: a controlled prospective study. Gastrointest Endosc 1996;43:478-82.

193. Siersema PD, Hop WC, Dees J, Tilanus HW, van Blankenstein M. Coated self- expanding metal stents versus latex prostheses for esophagogastric cancer with special reference to prior radiation and chemotherapy: a controlled, prospective study. Gastrointest Endosc 1998;47:113-20.

194. Sanyika C, Corr R Haffejee A. Palliative treatment of oesophageal carcinoma-- efficacy of plastic versus self-expandable stents. S Afr Med J 1999;89:640-3.

195. Knyrim K, Wagner HJ, Bethge N,Keymling M, Vakil N. A controlled trial of an expansile metal stent for palliation of esophageal obstruction due to inoperable cancer. N Engl J Med 1993;329:1302-7.

196. Reed CE, Marsh WH, Carlson LS, Seymore CH, Kratz JM. Prospective, randomized trial of palliative treatment for unresectable cancer of the esophagus. Ann Tho- rac Surg 1991;51:552-5.

197. Sargeant IR, Tobias JS, Blackman G, Thorpe S, Glover JR, Bown SG. Radiother- apy enhances laser palliation of malignant dysphagia: a randomised study. Gut 1997;40:362-9.

198. Kolaric K, Maricic Z, Roth A, Dujmovic I. Combination of bleomycin and Adri- amycin with and without radiation in the treatment of inoperable esophageal cancer: a randomized study. Cancer 1980;45:2265-73.

199. Schmid EU, Alberts AS, Greeff F, Terblanche APS, Schoeman L, Burger W, et al. The value of radiotherapy or chemotherapy after intubation for advanced esophageal carcinoma-A prospective randomzied trial. Radi0ther Oncol 1993;28:27-30.

200. Jensen DM, Machicado G, Randall G, Tung LA, English-Zych S. Comparison of low-power YAG laser and BICAP tumor probe for palliation of esophageal cancer strictures. Gastroenterol 1988;94:1263-70.

201. Kharadi MY, Qadir A, Khan FA, Khuroo MS. Comparative evaluation of therapeutic approaches in stage III and IV squamous cell carcinoma of the thoracic esophagus with conventional radiotherapy and endoscopic treatment in combination and endoscopic treatment alone: a randomized prospective trial. Int J Radiat Oncol Biol Phys 1997;39:309-20.

202. Sur RK, Donde B, Levin VC, Mannell A. Fractionated high dose rate intraluminal brachytherapy in palliation of advanced esophageal cancer. Int J Radiat Oncol Biol Phys 1998;40:447-53.

203. Tan CC, Freeman JG, Holmes GK, Benghiat A. Laser therapy combined with brachytherapy for the palliation of malignant dysphagia. Singapore Med J 1998; 39:202-7.

204. Low DE, Pagliero KM. Prospective randomized clinical trial comparing brachytherapy and laser photoablation for palliation of esophageal cancer. J Thorac Cardiovasc Surg 1992; 104:173-8.

205. Sander R, Hagenmueller F, Sander C, Riess G, Classen M. Laser versus laser plus afterloading with iridium-192 in the palliative treatment of malignant stenosis of the esophagus: a prospective, randomized, and controlled study. Gastrointest Endosc 1991;37:433-40.

206. Ries G, Topfer M, Hagenmuller F, Sander C, Sander R. Palliative treatment ~n malignant stenoses of esophagus and cardia: laser therapy versus laser + high-dose- rate-iridium-192 afterloading therapy: a prospective randomized study. Strahlen- ther Onkol 1989; 165:584-6.

207. Levard H, Pouliquen X, Hay JM, Fingerhut A, Langlois-Zantain O, Huguier M, et


al. 5-Fluorouracil and cisplatin as palliative treatment of advanced oesophageal squamous cell carcinoma: a multicentre randomised controlled trial. The French Associations for Surgical Research. Eur J Surg 1998;164:849-57.

208. Mannell A, Becker PJ, Melissas J, Diamantes T. Intubation v. dilatation plus bleomycin in the treatment of advanced oesophageal cancer: the results of a prospective randomized trial. S Afr J Surg 1986;24:15-9.

209. Andersen AP, Berdal R Edsmyr F, Hagen S, Hatlevoll R, Nygaard K, et al. Irradi- ation, chemotherapy and surgery in esophageal cancer: a randomized clinical study. The first Scandinavian trial in esophageal cancer. Radiother Oncol 1984;2:179-88.

210. Kolaric K, Roth A, Dujmovic I. The value of two combined chemoradiotherapy approaches in the treatment of inoperable esophageal cancer. Tumori 1984;70:69-75.

211. Ezdinli EZ, Gelber R, Desai DV, Falkson G, Moertel CG, Hahn RG. Chemother- apy of advanced esophageal carcinoma: Eastern Cooperative Oncology Group experience. Cancer 1980;46:2149-53.

212. Webb A, Cunningham D, Scarffe JH, Harper P, Norman A, Joffe JK, et al. Ran- domized trial comparing epirubicin, cisplatin, and fluorouracil versus fluorouracil, doxorubicin, and methotrexate in advanced esophagogastric cancer. J Clin Oncol 1997;15:261-7.

213. Ancona E, Bardini R, Ruol A, Andreotti F, Cusumano A, Spreafico G, et al. Immunostimulation with levamisole in inoperable immunostimulation with levamisole in inoperable cancer of the esophagus. Min Med 1983;74:1623-983.

214. Alberts AS, Burger W, Greeff F, Schoeman L, Friediger D, Nel J, et al. Severe complications of 5 FU and cisplatin with concomitant radiotherapy in inoperable non- metastatic squamous cell oesophagus cancer after intubation: early termination of a prospective randomized trial. Eur J Cancer 1992;28A: 1006-7.

215. Herskovic A, Martz K, al-Sarraf M, Leichman L, Brindle J, Vaitkevicius V, et al. Combined chemotherapy and radiotherapy compared with radiotherapy alone in patients with cancer of the esophagus. N Engl J Med 1992;326:1593-8.

216. Coia LR, Minsky BD, John MJ, Haller D, Landry J, Pisansky TM, et al. Patterns of care study decision tree and management guidelines for esophageal cancer. Radiat Med 1998;16:321-7.

217. NCCN practice guidelines for upper gastrointestinal carcinomas. National Com- prehensive Cancer Network. Oncology 1998;12:179-223.

218. Ginsberg R, Roth J, Fergusson M. Esophageal cancer surgical practice guidelines. Esophageal Cancer Practice Guideline Committee [published erratum appears in Oncology (Huntingt) 1997;11:1323]. Oncology (Huntingt) 1997; 11:1059-62.

219. Gaspar LE, Nag S, Herskovic A, Mantravadi R, Speiser B. American Brachyther- apy Society (ABS) consensus guidelines for brachytherapy of esophageal, cancer. Clinical Research Committee, American Brachytherapy Society, Philadelphia, PA. Int J Radiat Oncol Biol Phys 1997;38:127-32.

220. Mannell A, Murray W. Oesophageal cancer in South Africa: a review of 1926 cases. Cancer 1989;64:2604-8.

221. Oliver SE, Robertson CS, Logan RF. Oesophageal cancer: a population-based study of survival after treatment. Br J Surg 1992;79:1321-5.

222. Daly JM, Karnell LH, Menck HR. National Cancer Data Base report on esophageal carcinoma. Cancer 1996;78:1820-8.

223. Coia LR, Minsky BD, John MJ, Haller DG, Landry J, Pisansky TM, et al. Tile evaluation and treatment of patients receiving radiation therapy for carcinoma of the esophagus: results of the 1992-1994 Patterns of Care Study. Cancer 1999;85:2499-505.


Esophageal cancer: A systematic review

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