Abstract
Esophagogastric junction (EGJ) carcinomas often require access to two compartments of the body for good margin and lymphadenectomy. Whether it is required to do so in all patients is debatable. We analyzed outcomes of patients who underwent surgeries for EGJ carcinomas in terms of margin status and survival. This is a retrospective analysis of a prospectively maintained database of patients with EGJ adenocarcinomas operated between January 2014 and December 2016. Type of surgery performed and its impact on margin status and survival were assessed. Follow-up was for a minimum of 5 years. Ninety-four patients with EGJ carcinomas were operated on during the study period. Eight (8.51%) had involved proximal margin, and 2 of these had positive distal margin also. None had distal margin alone involved. Seventeen (18.09%) and 5 (5.32%) had a close proximal and distal margin, respectively. Radial margin was close/involved in 6 (6.38%) patients. Five-year overall survival and disease-free survival for the cohort was 38% and 30.8%, respectively. Proximal gastrectomy had a higher proximal margin positivity. Positive proximal or distal margin and a close/involved radial margin were detrimental to disease free survival and overall survival. Proximal gastrectomy is associated with a higher likelihood of proximal margin positivity. Positive margin leads to lower survival. Whether involvement of margins is just a surrogate marker of aggressive tumor or is an error in assessing extent tumor needs to be studied. Large-scale prospective studies in this regard are desirable.
Keywords: Esophagogastric junction carcinomas, Surgery, Margin
Introduction
Cancers of the esophagus and stomach are two of common malignancies of the upper digestive tract. They are also an important cause of disease-related mortality [1, 2]. The incidence of adenocarcinoma of the lower esophagus and gastric cardia is increasing in many regions of the world [3, 4].
Gastroesophageal junction (GEJ) borders two adjacent organs and cancers of this region are often difficult to manage. This is mainly because of the anatomical location. Optimal surgical approach, extent of lymphadenectomy and margins of resection have very well been defined for esophageal and stomach cancers. However, in case of GE junction tumors, surgical decision making is difficult because of two reasons. The first is that, in order to address the primary and its first echelon lymph nodal territory, the esophagus and stomach need to be resected at varying lengths. This often necessitates access to both thorax as well as abdomen. Secondly, the stomach is the most commonly used and preferred conduit after esophagectomy. This may prompt the surgeon to compromise on the extent of resection in order to conserve part of either of the two organs resulting in compromise of margins. There is a tendency to avoid thoracic component of surgery for GE junction tumors and to manage via only transabdominal approach, especially in patients with advanced age and compromised nutritional and health status. Whether it is worthwhile to enter the thorax to achieve that extra margin, thereby increasing the extent of surgery and the complexity of reconstruction is largely pondered upon.
We reviewed our cases of gastroesophageal junction adenocarcinomas who underwent surgery with curative intent, with special emphasis on the surgical approach used, margin status, and survival.
Aims and Objectives
To determine the effect of proximal surgical margin status on recurrence and survival.
To determine the correlation between margin status and type of surgical approach used.
Methodology
This is a retrospective analysis of a prospectively maintained database of patients who got operated for cancer of the gastroesophageal junction with curative intent at a single institution over a period of 3 years from January 2013 to December 2015. Their follow-up data till 31 July 2022 was retrieved and analyzed.
Details like age, gender, performance status, and use of adjuvant chemotherapy or chemo-radiation were collected. Details of type of surgery done (Ivor Lewis esophagectomy, McKeown esophagectomy, transhiatal esophagectomy, total gastrectomy, and proximal gastrectomy), type of lymphadenectomy performed, stage of tumor on histopathology, nodal yield, and presence or absence of pathological complete response were noted.
Distal, proximal, and radial margin status were looked into. Margins were classified as “free” (more than 1 cm clearance for proximal or distal margins; more than 1 mm clearance for circumferential margin), “close” (less or equal to 1 cm clearance, but more than 1 mm clearance for proximal or distal margins), and “involved” (tumor at margin or less than or equal 1 mm clearance for proximal, distal, and circumferential margins) based on gross and macroscopic examination specimen after resection [5, 6].
Follow-up data of all patients was looked into. Recurrences were noted and classified as local, regional, and systemic. Status of patient at last follow-up was noted, and overall survival and disease-free survival were calculated.
Statistical Methods
The categorical variables were summarized using frequencies and percentages. The continuous variables were presented using mean and standard deviation. The association between two categorical variables was assessed using Chi-square or Fisher’s exact test. The survival probabilities were estimated using Kaplan-Meier method, and the comparison between survival curves was done using a log-rank test. The risk for survival was done using univariate and multivariate Cox regression analysis. A p value < 0.05 is considered to be significant.
Results
There were 94 patients with adenocarcinoma of the gastroesophageal junction who underwent surgery with curative intent during the study period.
The median age at diagnosis was 58 years (range 25–74 years). The male to female ratio was 75: 19 (79.8 % Vs 20.2%).
Seventeen (18.09%) patients had an abnormal PFT and were taken up for surgery with increased pulmonary risk. Eighty-nine (94.68%) patients received neoadjuvant chemotherapy, 2 (2.13%) patients had received neoadjuvant chemoradiation (NACTRT), and 3 (3.19%) patients did not receive any preoperative therapy. The procedures done were Ivor Lewis procedure, 34(36.17%); proximal gastrectomy, 30 (31.92%); transhiatal resection, 13 (13.82%); total gastrectomy, 12 (12.77%); and McKeown, 5(5.32%).
Of the 39 patients who required thoracic access, open thoracotomy was done in 35 (89.74%) patients and thoracoscopy was used in 4 (10.26%) patients. Out of 94 patients, open access to the abdomen was used in 84 (89.36%) patients and laparoscopic assisted surgery was done in 10 (10.64%)patients.
Following surgery, one patient developed very early relapse in the peritoneum and died of rapidly progressive disease during the month following surgery. There was no treatment-related mortality within 30 days of surgery.
Of the 91 patients who received neoadjuvant therapy (89 chemotherapy and 2 chemo-radiation), pathological complete response (pCR) was attained in 13 (13.83%) patients. Both patients received chemo-radiotherapy and attained pCR.
Eight (8.51%) patients had involved proximal margin, and out of these, 2 had positive distal margin also. None of the patients had a distal margin alone involved.
Seventeen patients (18.09 %) had a close proximal margin. Five patients (5.32%) had a close distal margin (Table 1).
Table 1.
Patient, surgery-related, and tumor-related characteristics
| Number | Percentage | ||
|---|---|---|---|
| Gender | Male | 75 | 79.8 |
| Female | 19 | 20.2 | |
| Surgical procedure | Ivor Lewis esophagectomy | 34 | 36.17 |
| McKeown esophagectomy | 5 | 5.32 | |
| Transhiatal Esophagectomy | 13 | 13.82 | |
| Total gastrectomy | 12 | 12.77 | |
| Proximal gastrectomy | 30 | 31.92 | |
| Extend of nodal dissection | 2 Field | 49 | 52.13 |
| Extended 2 Field | 6 | 6.38 | |
| Abdominal only | 39 | 41.49 | |
| Median lymph node harvest | 8 ( 0-27) | ||
| LVI | Present | 11 | 11.70 |
| Absent | 83 | 88.30 | |
| Proximal margin | Free | 69 | 73.40 |
| Close < 1 cm | 17 | 18.09 | |
| Involved | 8 | 8.51 | |
| Distal margin | Free | 87 | 92.55 |
| Close < 1 cm | 5 | 5.32 | |
| Involved | 2 | 2.13 | |
| Radial margin | Free | 88 | 93.62 |
| Close or involved | 6 | 6.38 | |
| pT status | 0 | 14 | 14.89 |
| 1 | 2 | 2.13 | |
| 2 | 24 | 25.53 | |
| 3 | 35 | 37.23 | |
| 4 | 19 | 20.22 | |
| pN status | 0 | 46 | 48.93 |
| 1 | 21 | 22.34 | |
| 2 | 16 | 17.02 | |
| 3 | 11 | 11.71 | |
| Pathological stage—AJCC 8 | 0 = PCR | 13 | 13.83 |
| I | 16 | 17.02 | |
| II | 13 | 13.83 | |
| III | 35 | 37.23 | |
| IV | 17 | 18.09 | |
| Neo adjuvant treatment | Not received | 3 | 3.19 |
| CT | 89 | 94.68 | |
| CT RT | 2 | 2.13 | |
| PCR | Attained | 13 | 13.83 |
| Residual disease | 81 | 86.17 | |
| Adjuvant treatment | Not received | 6 | 6.38 |
| CT | 81 | 86.17 | |
| CT RT | 7 | 7.45 |
Radial margin was either close or involved in 6 patients (6.38%).
A total of 25 (26.60%) patients had close (n = 17) or involved (n = 8) proximal margin. Out of these 25 patients, 15 (60%)had undergone proximal gastrectomy, 6 (24%) underwent Ivor Lewis esophagectomy, and 4 (16%) patients underwent total gastrectomy. Thus, the proximal margin was more likely to be close (n = 11) or positive (n = 4) when the surgery performed was proximal gastrectomy (p = 0.023) (Table 2).
Table 2.
Margins in different types of surgery and survival
| Surgery | Free (n = 69) | Close (n = 17) | Involved (n = 8) | p value | |
|---|---|---|---|---|---|
| Proximal margin | Ivor Lewis | 28 | 4 | 2 | 0.023* |
| McKeown | 5 | 0 | 0 | ||
| Transhiatal | 13 | 0 | 0 | ||
| Total gastrectomy | 8 | 2 | 2 | ||
| Proximal gastrectomy | 15 | 11 | 4 | ||
| 5-year OS in % (SE in %) | 28.5 (5.5) | 40.3 (12.1) | 12.5 (11.7) | 0.148 | |
| 5-year DFS | 27.4 (5.8) | 40.3(12.1) | 12.5 (11.7) | 0.181 | |
| Surgery | Free (n = 87) | Close (n = 5) | Involved (n = 2) | p value | |
| Distal margin | Ivor Lewis | 33 | 0 | 1 | 0.151 |
| McKeowen | 5 | 0 | 0 | ||
| THE | 10 | 3 | 0 | ||
| Total gastrectomy | 12 | 0 | 0 | ||
| Proximal gastrectomy | 27 | 2 | 1 | ||
| 5-year OS in % (SE in %) | 28.6 (4.9) | 50.0 (25.0) | 0.0 (0.0) | 0.217 | |
| 5-year DFS | 27.9 (5.1) | 50.0 (25.0) | 0.0 (0.0 ) | 0.253 | |
| Surgery | Free (n = 88) | Close/involved (n = 6) | p value | ||
| Radial margin (esophagus) | Free | Close/involved | |||
| Ivor Lewis | 32 | - | 2 | 0.602 | |
| McKeowen | 4 | - | 1 | ||
| THE | 12 | - | 1 | ||
| Total gastrectomy | 12 | - | 0 | ||
| Proximal gastrectomy | 28 | - | 2 | ||
| 5-year OS in % (SE in %) | 31.1 (5.1) | 0.0 (0.0) | 0.023* | ||
| 5-year DFS | 30.1 (5.2) | 0.0 (0.0) | 0.143 |
Seven (7.44%) patients had close (n = 5) or involved (n = 2) distal margin. Out of these 7 patients, 3 (42.86%) had undergone transhiatal esophagectomy, 3 (42.86%) had undergone proximal gastrectomy, and 1 (14.29%) patient underwent Ivor Lewis surgery. There was no statistically significant difference between the occurrence of positive or close distal margin and type of surgery that the patient underwent (p = 0.151) (Table 2).
Radial margin was close/involved in 6 (6.38%) patients. There was no statistically significant difference between occurrence of positive or close radial margin and type of surgery that the patient underwent (p = 0.602) (Table 2).
Median follow-up period was 72 months. During this period, 15 patients had local recurrence (15.95%), 3 had regional recurrence (3.19%), and 28 (29.78%) had systemic recurrence. Of the patients with locoregional recurrence, 13 had a positive margin. Of these, 28 patients with systemic metastasis, 11 had liver metastasis, 6 had lung metastasis, 3 had brain metastasis, and 4 had peritoneal metastasis, and 4 patients had metastases in non-regional nodes.
At the end of the follow-up period, 49 patients (52.13%) were alive without any disease.
There were 46 (48.94%) patients who had recurrences. Out of these, 18 (39.13%) patients had locoregional recurrences, 28 (60.87%) patients had systemic recurrences. Amongst these, 9 (25%) patients had both locoregional as well as systemic recurrences (Table 3).
Table 3.
Recurrences in different types of surgery
| Surgery | N | Recurrences (%) | p value | |
|---|---|---|---|---|
| Total recurrence 36 (9-both locoregional and systemic) | ||||
| Locoregional recurrence (17) | Ivor Lewis | 4 | 29.41 | 0.737 |
| McKeowen | 0 | 0 | ||
| THE | 3 | 17.65 | ||
| Total gastrectomy | 2 | 17.65 | ||
| Proximal gastrectomy | 6 | 35.29 | ||
| Systemic recurrence (28) | Ivor Lewis | 7 | 25 | 0.082 |
| McKeowen | 1 | 3.57 | ||
| THE | 3 | 10.72 | ||
| Total gastrectomy | 2 | 7.14 | ||
| Proximal gastrectomy | 15 | 53.57 | ||
Out of the 17 patients who had local recurrences, 6 (35.29%) had undergone proximal gastrectomy, 5 (29.41%)had undergone Ivor Lewis surgery, and 3 (17.65%) each had undergone transhiatal esophagectomy and total gastrectomy
There was no significant difference in occurrence of local or regional recurrence among different surgeries performed, but both locoregional and systemic recurrence was more likely to occur in patients undergoing proximal gastrectomy .
Local recurrences were found to be more when proximal, distal, or radial margins were involved. The difference however did not reach a level of statistical significance.
The 5-year overall survival for the whole group was 38% with a median survival of 36 months.
Overall, the type of surgical procedure did not significantly affect survival.
The 5-year DFS for the whole group was 30.8%. The median DFS was 27 months.
An involved proximal (n = 8) or distal margin (n = 2) led to a trend towards reduced overall survival and disease-free survival at 5 years.
Close or involved radial margin led to significantly reduced 5-year overall survival (31.1 v/s 0.0%, p = 0.023).
None of those who had an involved distal (n = 2) or close or involved radial margin (n = 6) were disease free at 5 years. Thus, proximal, distal, or circumferential margin positivity was detrimental to disease-free survival, although the difference did not attain a level of statistical significance.
Discussion
The decision regarding what is the optimum surgical approach for esophagogastric junction tumors is quite challenging and has to take into consideration multiple factors like patients performance status, desired margins of resection, lymphadenectomy and feasibility of options of reconstruction. Whether to enter both the thorax as well as the abdomen, thereby increasing radicality of surgery to achieve a good margin of resection and radical lymphadenectomy is a matter worth pondering upon.
The long-term results of Japanese JCOG 9502 trial favored transabdominal approach for tumors invading less than 3 cm of distal esophagus [7]. Similarly, the results of the Dutch trial of limited transhiatal versus extended transthoracic resections for adenocarcinomas of mid and distal esophagus, by Omloo et al. revealed that while there is a survival benefit of transthoracic approach for type 1 tumors, the type of surgical approach does not affect survival in type 2 tumors [8]. In this study, in patients with limited nodes positive (1–8), extended transthoracic approach seemed to have a survival advantage [8]. This probably indicates that tumor biology dictates survival more than the type of surgery alone, and it justifies more radical approaches in patients with better tumor biology.
In our study, firstly, proximal margin was most likely to be positive when the surgery performed was proximal gastrectomy. There is an increase in locoregional recurrence, though not reaching a level of statistical significance in patients undergoing proximal gastrectomy. This highlights the importance of achieving negative margins for the purpose of achieving better oncological outcomes.
In the study of H Ito et al., proximal margin infilteration by tumor was a function T stage of tumor [9]. Similarly, in a retrospective review of patients undergoing surgery for adenocarcinoma of the cardia by J G Shen et al., it was seen that the proximal margin positivity was determined by size of the tumor and depth of invasion. The authors concluded that a positive margin is more of an indicator of advanced disease rather than an independent prognostic factor for survival [10]. Likewise, in our study also, the fact that systemic recurrences were significantly high in the proximal gastrectomy group where margin positivity was also high. This might point towards the biological aggressive nature of tumors.
An involved margin was detrimental to overall survival. However, amongst patients in whom proximal or distal margin was not directly involved [i.e., was either close (< 1 cm), but free or was wide], margin status did not affect survival.
Margin positivity also led to drop in disease-free survival. This however did not reach a level of statistical significance. This was probably due to less number of patients with positive margins.
Submucosal spread of tumor might be an important factor leading to false judgement of a negative margin by surgeon on endoscopy and intraoperatively leading to margin positivity. This needs to be looked into. Intraoperative frozen section analysis for margins might be beneficial and desirable in this aspect.
Though margin status was routinely assessed by surgeons on fresh specimens, the frozen section was not routinely used to assess margins due to logistics involved. Whether this would have helped to bring down the margin positivity rates needs to be studied.
It is possible that there has been selection bias in this study in view of its retrospective nature. Surgeon would have chosen the best possible approach for the patient considering his/her general condition and disease status.
Lastly, It will be worthwhile to do a prospective and a preferably randomized study. We also need to study different subsets of esophagogastric junction tumors separately.
Conclusion
It is more common to have a positive proximal margin when proximal gastrectomy has been done for OGJ tumors. A positive margin leads to drop in survival in esophagogastric junction tumors.
There is an increase in locoregional recurrence, though not statistically significant, and a significantly high incidence of systemic recurrences in patients undergoing proximal gastrectomies.
Margin positivity could be due to an aggressive disease rather than due to failure of judgment. So, whether an increase in radicality of surgery in such cases will have any survival advantage is largely unknown. A large-scale prospective trial in this regard is desirable.
Declarations
Ethics Approval
This study was cleared by the institutional ethics committee (IEC); vide number 11/2019/04. This article does not contain any studies with animals performed by any of the authors.
Consent to Participate
Informed consent was obtained from all individual participants included in the study for retrospective usage of data related to them from our prospectively based database.
Conflict of Interest
The authors declare no competing interests.
Footnotes
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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