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10.1245/s10434-006-9216-4
Annals of Surgical Oncology 14:1439-1448 (2007)
© 2007 Society of Surgical Oncology
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Original Article

Treatment of the Adenocarcinoma of the Esophagogastric Junction at a Single Institution in Mexico

Luis F. Oñate-Ocaña, MD1, Gonzalo Milán-Revollo, MD1, Vincenzo Aiello-Crocifoglio, MD1, José F. Carrillo, MD1, Dolores Gallardo-Rincón, MD2, Rocío Brom-Valladares, MD, MPH3, Roberto Herrera-Goepfert, MD4 and Alfonso Dueñas-González, MD, PhD5

1 Clínica de Neoplasias Gástricas, Gastroenterology Department, Surgery Division, Instituto Nacional de Cancerología, México D.F., México
2 Medical Oncology Department, Internal Medicine Division, Instituto Nacional de Cancerología, México D.F., México
3 Tomography, Ultrasound and Magnetic Resonance Department, Instituto Nacional de Cancerología, México D.F., México
4 Pathology Department, Instituto Nacional de Cancerología, México D.F., México
5 Unidad de Investigación Biomédica en Cancer, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Instituto Nacional de Cancerología, México D.F., México

Correspondence: Address correspondence and reprint requests to: Luis F. Oñate-Ocaña, MD. Gastroenterology Department, Instituto Nacional de Cancerología, San Fernando 22, México D.F., 14080, México; E-mail: lfonate{at}gmail.com


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: Adenocarcinoma of the esophagogastric junction (EGJ) is rapidly increasing in the west. Our aim is to define the prognostic factors and treatment of EGJ carcinoma in Mexico, particularly the location after the Siewert’s classification.

Methods: A retrospective cohort of patients suffering from EGJ adenocarcinoma treated from 1987 to 2000. The Kaplan-Meier and the Cox’s models were used to define prognostic factors.

Results: Two hundred and thirty-four patients were included, 90 females and 144 males. Surgical resection was possible in 68 cases only (29%). Significant prognostic factors were tumor node metastasis (TNM) stage [stages I–II: risk ratio (RR) is 1; stage III RR is 1.3, 95% confidence interval (CI) 0.75–2.4; stage IV RR, 2.04, 95% CI 1.1–3.7], gender (male RR = 1.47, 95% CI 1.05–2.05), metastatic lymph node ratio (no resection: RR = 1; ratio 0.2–1 RR=0.67, 95% CI 0.39–1.14; ratio 0–0.19 RR = 0.42, 95% CI 0.23–0.76) and seralbumin (3 mg/dL or less RR = 2.05 95% CI 1.3–3.2; 3.1–3.4 mg/dL RR = 1.9 95% CI 1.2–3.03; 3.5–3.8 mg/dL RR = 1.3 95% CI 0.8–1.9; 3.9 mg/dL or more: RR = 1) (model P = 0.0001).

Conclusions: EGJ adenocarcinoma is a highly lethal neoplasia and the location after the Siewert’ classification is not a prognostic factor. In Mexico, TNM clinical stage, serum albumin, gender, surgical resection and metastatic lymph node ratio are significant prognostic factors. Curative treatment is infrequent but radical resection is associated to longer survival. Consequently, the management must consider quality of life and surgical morbidity.

Key Words: prognostic factors • adenocarcinoma • esophageal cancer • gastric cancer • esophagogastric junction


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
In the last 30 years, the death rates from adenocarcinoma of the esophagus and esophagogastric junction (EGJ) have risen steadily from 3 to 6 per 100 000 and from 1.5 to 3 per 100 000 inhabitants in the United Kingdom, respectively.1 These figures represent the most rapidly increasing malignancy in the west, with marked regional differences in epidemiology and incidence,2 explained in part by recent improvements in site classification.3

In Mexico, esophageal and gastric carcinomas represent the eighth and the first gastrointestinal malignancies, respectively.4,5 However, no specific information regarding incidence and prognostic factors for EGJ adenocarcinoma in our country are available yet.

Siewert et al. proposed an anatomic-topographic classification for cancer of the EGJ: type I, with the tumor center in the distal esophagus; type II, arising at the cardias properly; and type III, subcardial cancer.6

Some reports addressed the usefulness of this classification7–9 and many controversial issues have arisen.10 Therefore, the aim of this study was to review the results of the adoption of this classification in our institution. In addition, we aimed to define the clinical prognostic factors and compare the outcomes in patients grouped and treated according to the Siewert’s classification.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patients
This is a retrospective cohort study of consecutive patients suffering from EGJ adenocarcinoma and treated in the Gastroenterology Department from the "Instituto Nacional de Cancerología" at Mexico City from January 1987 to December 2000. Inclusion criteria were patients of any age or gender, with endoscopy and computed tomography (CT) imaging demonstrating the location in the EGJ according to the Siewert classification.6 In addition, biopsy-proven adenocarcinoma was required in all cases.

Clinical records were reviewed and data regarding clinical history, blood tests, chest X-ray reports and tumor markers were registered. CT images and pathology slides were reviewed prospectively. For type I tumors, the classification for the clinical staging of esophageal carcinoma described in the sixth edition of the tumor (T), node (N), metastasis (M) staging system by the American Joint Committee on Cancer (AJCC) was used.11 For types II and III tumors, the classification for the clinical staging of gastric carcinoma was used.11

In the case of patients undergoing surgical resection, the surgical pathology study of the resected specimen permitted to use the pTNM stage classification. Among those patients with unresectable tumors, the CT scan was used along with all clinical information to define the clinical TNM staging, including thoracotomy, laparoscopy or laparotomy. Patients with insufficient or inadequate data to define the cTNM stage (particularly thoracic or abdominal CT scan) were excluded from the study.

Pretherapeutic serum albumin was measured using the bromocresol purple method in all cases.12 The Siewert’s classification was defined by the Esophago-Gastro-Duodenal series, endoscopy (with orthograde and retrograde visions of the EGJ), thoracoabdominal CT scan, surgical findings and the surgical pathology examination of the resected specimen as previously reported.6

Statistic Analysis
The differences between groups defined by the Siewert’s classification were analyzed by analysis of variance (ANOVA) or by the chi-squared test for continuous or categorical variables, respectively. Continuous variables were categorized dividing all values into four groups by quartiles.13

Variables tested and their coding were: age (quartiles 1 to 4); gender (0 = female, 1 = male); socioeconomic status (0 = good or moderate; 1 = poor); body mass index (0 = 25 or more, 1 = 20–24.9, 2 = 19.9 or less); differentiation degree (1 = well, 2 = moderately, 3 = poor); Laurén classification (1 = intestinal type, 2 = diffuse type, 3 = mixed type); Siewert classification (1 = type I, 2 = type II, 3 = type III, 4 = undefined type); basal hemoglobin level (quartiles 1 to 4); basal albumin level (quartiles 1 to 4); basal lymphocyte count (quartiles 1 to 4); surgical resection (0 = no resection, 1 = resection); T classification (1 = T1, 2 = T2, 3 = T3, 4 = T4); N classification (0 = negative lymph nodes, 1 = positive lymph nodes); metastatic lymph node ratio (MLNR), defined as the number of metastatic nodes resected divided by the total number of lymph nodes resected (0 = no resection or MLNR unknown, 1 = MLNR from 0.2 to 1, 2 = MLNR from 0 to 0.19); M classification (0 = M0, 1 = M1); residual status (0 = no resection, 1 = R2 disease, 2 = R1 disease, 3 = R0); TNM stage (1 = stages I and II, 2 = stage III, 3 = stage IV).

Bivariate analyses of survival were performed using the Kaplan-Meier method14 and differences in survival were tested using the log-rank method.15 Stratified Kaplan-Meier analysis was performed for serum albumin quartiles using clinical TNM stages as strata.

Overall survival times were calculated from the day of diagnosis of cancer to the last visit recorded on the clinical charts or until death. Operative mortality was considered as an event. All patients lost to follow-up were located by phone to define their final status.

All variables with a significant association with survival or with a probability value of 0.2 or less in the bivariate analysis were included in the multivariate analysis.

The Cox’s proportional hazards model was used for the multivariate analysis of survival. Risk ratios (RR) with 95% CIs were obtained as a measure of association.16 The maximum likelihood criteria were used to define the final model. Proportionality assumptions and interaction terms were checked as described previously.16 All probability values of 0.05 or less were considered as significant and two-tail statistics were considered in all calculations. The SPSS for Windows version 10.0 (1999) software (SPSS, Inc., Chicago, IL) was used for all computations.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Two hundred and thirty-four Mexican patients were included in our database (90 were females and 144 were males). Mean age of the cohort was 56.9 years (standard deviation 13.8 years).

There were 23 cases (9.8%) of type I EGJ adenocarcinoma, 84 cases (35.9%) of type II and 109 (46.6%) of type III, respectively. Clinical, endoscopic and tomographic information was insufficient to define the Siewert’s classification because bulky tumors did not permit to define the mass epicenter in 18 cases (7.7%) even when the EGJ location was well defined.

Demographic and pathologic characteristics associated to each tumor location are shown in Table 1Go and treatment chosen is depicted in Table 2Go. Sixty-eight patients (29.1%) were treated by radical resection and 166 (70.9 %) patients underwent palliative non-surgical treatments only. Surgical morbidity occurred in 17 (25 %) cases and surgical mortality in 7 (10.3 %).


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  		TABLE 1. Demographic and pathological characteristics of all patients in the cohort
 

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  		TABLE 2. Selected treatments depending on the Siewert’s classification
 
Recurrences were recorded in 22 patients; 12 were loco-regional and 10 distant. The most frequent sites of recurrence were loco-regional in the mediastinum or celiac trunk in 11 cases, peritoneal carcinomatosis in 4, liver metastasis in 3 cases, lung metastasis in 2 and left supraclavicular lymph node in 2.

Neither adjuvant chemotherapy nor adjuvant chemoradiation was used routinely in the period of this study.

Age, hemoglobin, hematocrit, absolute lymphocyte count, serum albumin and globulin values were categorized by quartiles (Table 3Go).


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  		TABLE 3. Bivariate analysis of overall survival
 
Pretherapeutic serum albumin levels were categorized by quartiles. "High" albumin values were 3.9 g/dL or more; "medium" values were from 3.5 to 3.89 g/dL; "low" values were from 3.1 to 3.49 g/dL and "very low" values were 3 g/dL or less.

Median overall survival of the cohort was 0.44 years (95% CI 0.34–0.53). Median overall and disease-free survival of the subgroup of patients with surgical resection was 1.34 years (95% CI 0.91–1.77) and 1.25 years (95% CI 0.94–1.56), respectively.

The association of each relevant clinical factor with overall survival is analyzed in Table 3Go. Survival curves by Siewert’s type, clinical stage, serum albumin levels and by surgical resection are depicted in Fig. 1Go to 4GoGoGo, respectively.


Figure 1
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  		FIG. 1. Overall survival curves by Siewert’s classification ("+" represents censored cases; log-rank P = 0.48).

 

Figure 2
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  		FIG. 2. Overall survival curves by tumor node metastasis (TNM) clinical stage ("+" represents censored cases; log-rank P = 0.0002).

 

Figure 3
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  		FIG. 3. Overall survival curves by pretherapeutic serum albumin level ("+" represents censored cases; log-rank P = 0.0008; high values are 3.9 g/dL or more; medium values are from 3.5 to 3.89 g/dL; low values are from 3.1 to 3.49 g/dL; very low values are 3 g/dL or less).

 

Figure 4
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  		FIG. 4. Overall survival curves by surgical resection or best medical care ("+" represents censored cases; log-rank P = 0.00001).

 
Stratified Kaplan-Meier analysis of survival depending on serum albumin levels using clinical TNM stages or by surgical resection as strata are depicted in Fig. 5Go and 6Go, respectively.


Figure 5
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  		FIG. 5. Stratified Kaplan-Meier analysis of overall survival by serum albumin levels using clinical tumor node metastasis (TNM) stages as stratum: (A) stages I and II; (B) stage III; (C) stage IV ("+" represents censored cases; log-rank P = 0.0026; high values are 3.9 g/dL or more; medium values are from 3.5 to 3.89 g/dL; low values are from 3.1 to 3.49 g/dL; very low values are 3 g/dL or less).

 

Figure 6
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  		FIG. 6. Stratified Kaplan-Meier analysis of overall survival by serum albumin levels using surgical resection status as stratum: (A) no resection and (B) surgical resection ("+" represents censored cases; log-rank P = 0.0106; high values are 3.9 g/dL or more; medium values are from 3.5 to 3.89 g/dL; low values are from 3.1 to 3.49 g/dL; very low values are 3 g/dL or less).

 
All variables with a possible association with survival in the bivariate survival analysis were used in the multivariable survival analysis to define prognostic factors. Clinical TNM stage, pretherapeutic serum albumin level, gender and resection with metastatic lymph node ratio were significant prognostic factors in the final model (P = 0.00001). The estimators of these factors are listed in Table 4Go. The model was tested for interaction terms but none was found.


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  		TABLE 4. Multivariate analysis of factors associated to overall survival
 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
In the western world, the incidence of adenocarcinoma of the EGJ is rising at an alarming rate,1–3 including the United States.10 However, the borderline location of the EGJ between the esophagus and stomach makes difficult to define EGJ adenocarcinoma as a clinical entity.

Many discrepancies exist in the literature regarding the etiology, physiopathology and treatment strategy for these tumors. This is reflected by the great heterogeneity of surgical approaches and long-term survival rates after surgical resection reported in the literature.10,17,18

The Siewert’s classification has received now worldwide acceptance and has been adopted by the International Society for Diseases of the Esophagus and the International Gastric Cancer Association.17,18 This classification permits to compare the results of different studies. However, some controversial issues limit the validity and interpretation of the available evidence. These issues are the significance of the anatomical classification itself, the clinical staging and the treatment strategy for the specific types.

In this study, we present the results of the adoption of this classification in our Institution on the management of 234 patients with EGJ adenocarcinoma. In addition to the TNM clinical staging, the prognostic roles of pretherapeutic serum albumin level in association with gender, surgical resection and MLNR are outstanding.

In Mexico, this study represents the only information available on the problem until date: frequently, patients were classified in the past as having esophageal or gastric adenocarcinoma.

The value of pretherapeutic serum albumin as prognostic factor is well known for a wide range of benign and malignant diseases, and even in healthy population. In the case of gastric carcinoma, the relationship between pretherapeutic serum albumin and survival has been described.19 Recently, serum albumin has been reported as a significant prognostic factor in adenocarcinoma of the gastric cardia.20 However, this report does not show a clear dose–response effect nor defines the lesion according to the Siewert’s classification, neither describes whether included patients with type II EGJ adenocarcinoma only or if types I and III were also included under the nomination of "gastric cardia."20

It is unclear whether the prognostic effect of low pretherapeutic serum albumin value simply reflects nutritional status or inflammation or if there is an independent effect of albumin. Many biological mechanisms could be responsible for this association in patients with gastric cancer. We did an intentional statistical adjustment for different factors associated to malnutrition including socioeconomic status, absolute lymphocyte count, body mass index, blood hemoglobin and found none significant. Therefore, we believe that the prognostic effect of serum albumin is not related to malnutrition.

Elevation of cytokines represents another potential mechanism through which disease severity could confound the relationship between serum albumin and EGJ carcinoma-related survival. Tumor necrosis factor and interleukin-2 have been found to be elevated and associated with poor prognosis in patients with gastric cancer.21

Serum interleukin-6 is increased in acute or chronic inflammation situations, is associated with hypoalbuminemia,22 and the development of lymph node and liver metastases in gastric cancer.23

A potentially important protective role of serum albumin is enhancement of removal of reactive oxygen species, which are implicated in the pathogenesis of many diseases, including cancer.24 However, this mechanism has not been evaluated in EGJ adenocarcinoma.

In our work, significance of MLNR as a prognostic factor in multivariate analyses was found, which has been suggested in previous trials on esophageal and gastric adenocarcinoma.25,26 In addition, an important prognostic significance for MLNR has been reported in a small series of patients with EGJ adenocarcinoma.27 Therefore, an extended lymphadenectomy in EGJ adenocarcinoma could increase the survival of patients with metastases to lymph nodes by decreasing the MLNR.

We choose a cutoff point of 0.2 because our previous data on the issue in patients with gastric carcinoma.28 However, other groups suggest 0.1 or 0.15 as the best cut-off point.25,26

EGJ adenocarcinomas are often grouped together as one single entity even when strong evidence is available supporting that these tumors differ biologically depending on the anatomical relationship to the EGJ.29 Accordingly, the clinical classification and surgical management should be different.

Our study shows important epidemiological, clinical and pathological differences between type I and type III EGJ adenocarcinomas; type I adenocarcinomas are most likely to be originated on a Barrett’s mucosa of the distal portion of the esophagus, whereas type III tumors arise from a damaged gastric mucosa in the proximal third of the stomach. However, our data are insufficient to define if type II tumors simply represent an overlapping between these two well-defined neoplasms or a distinct nosological entity. According to international literature, prognosis is better for type I tumors.18 However, in our multivariate analysis this difference corresponds to a higher frequency of advanced stages in type III tumors and the relative frequency of other prognostic factors, not to the location in the EGJ by itself. Moreover, this difference can be explained by the different staging methods used for the TNM clinical staging of these malignancies.

Type I tumors must be staged using the esophageal cancer classification and type III tumors must be staged using the gastric cancer classification. However, which classification must be used for type II tumors?30 Both, esophageal and gastric cancer staging systems are inappropriate for staging type II (and maybe for type III also) EGJ adenocarcinomas and revision of this issue is urgently needed by the AJCC and the UICC.

On the other hand, controversy exists regarding the best surgical treatment for each tumor type, even when the only curative treatment is complete surgical resection.

There is a general agreement to treat type I tumors with total esophagectomy as esophageal tumors. Some evidence supports to treat type II and III tumors in the same way, with a total gastrectomy and distal esophagectomy.17,18 However, other groups support that types I and II tumors are true esophageal adenocarcinomas and must be treated the same way.31–33 In the absence of adequate phase III trials addressing these problems, we believe that the existing data support application of procedures that are tailored to individual patients.34

In type I EGJ adenocarcinoma, a recent randomized clinical trial showed that transhiatal esophagectomy was associated with lower morbidity (but not mortality) than transthoracic esophagectomy with lymphadenectomy. Median overall and disease-free survival did not differ statistically between both procedures, but there was a trend toward improved long-term survival at 5 years with the radical transthoracic approach.35

Only one randomized controlled trial showed evidence of a small survival benefit of preoperative chemoradiation (5-fluorouracil-cisplatin plus radiotherapy) as compared with surgery alone in localized esophageal adenocarcinoma.36 Accordingly, multimodal treatment based on preoperative chemoradiation in esophageal adenocarcinoma is controversial and still should be considered under clinical evaluation.

In our study, there were only 23 patients with type I EGJ adenocarcinoma. The only conclusion derived from our data is that patients with favorable prognostic factors should probably be considered for transthoracic esophagectomy and poor risk patients for transhiatal esophagectomy or even for only palliative treatments.

In type III EGJ adenocarcinomas, extended total gastrectomy is the treatment of choice. Controversy exists regarding the best multimodal strategy besides the surgical resection ant the extent of lymph node resection. A randomized clinical trial demonstrated survival benefit of adjuvant chemoradiation after completely resected gastric carcinoma, including EGJ adenocarcinoma.37 On the other hand, a recent randomized clinical trial demonstrated a survival benefit of perioperative chemotherapy with etoposide, cisplatin and 5-fluorouracil.38

The best therapeutic strategy for type II EGJ adenocarcinoma is controversial and the information available in the medical literature is scarce, but most authors prefer to treat it with total extended gastrectomy as in the case of type III EGJ adenocarcinoma.17,18

In Mexico, EGJ adenocarcinoma is a highly lethal neoplasia as reported in the world literature. The Siewert’s classification is not a significant prognostic factor, but differences in survival could be explained by the TNM stage and by different methods used for clinical staging, by the event of complete surgical resection, the basal serum albumin level, gender, surgical resection and by the MLNR. However, the Siewert’s classification is by now the best classification available for the selection of the surgical treatment.

Curative treatment is infrequent but surgical resection is associated to longer survival regardless of the location of EGJ cancer. Consequently, the best management must consider quality of life and surgical morbidity and mortality.


   ACKNOWLEDGMENTS
 
Many thanks to Ms Blanca Rosas Rosas and to Maria Esther Briones Trejo for their invaluable help with the logistics of this research. Many thanks also to Alejandra García Hubard for her help in the writing of the manuscript and to Maggie Brunner, M.A. for her English language editorial review.

Received for publication May 23, 2006. Accepted for publication August 3, 2006.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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