Recurrence risk after Ivor Lewis oesophagectomy for cancer

Oesophageal cancer is a major public health concern as it is the fourth cause of cancer death after lung, colorectal and prostate cancers. Without contraindication of resectability or operability, surgery is the standard treatment of curative intent. However, in spite of optimal R0 resection, overall 5-year survival is poor, about 20 to 30%, because of frequent tumor recurrence [1]. Thus, exclusive chemoradiotherapy has become an alternative to surgical treatment, with a comparable overall survival in locally advanced squamous cell carcinoma [2, 3]. However, ratio between adenocarcinoma and squamous cell carcinoma incidence is changing with an increasing incidence of adenocarcinoma developed on Barrett oesophagus in Western countries [4]. Regarding adenocarcinoma, combination of neo-adjuvant treatment seems to provide improved survival despite of its own morbi-mortality [5]. Study of tumor relapse could therefore allow adaptation and targeting perioperative treatment to patients with high risk of recurrence. The aim of this study was to analyze the profile of tumor recurrence in a homogenous group of patients operated on for cancer of oesophagogastric junction or oesophagus by Ivor-Lewis oesophagectomy.

From January 1999 to December 2008, 120 consecutive patients underwent an Ivor-Lewis oesophagectomy for cancer at a single institution. Their clinical records were reviewed retrospectively for age, sex, Body Mass Index (BMI), nutritional factors, American Society of Anesthesiologists (ASA) score, symptoms at diagnosis, preoperative treatment, details of the surgical procedure, pathological findings, postoperative course, recurrence and long term survival. The research was carried out in compliance with the Helsinki Declaration and approved by the Comité de Protection des Personnes (CPP) Sud Ouest (Toulouse, France).

Several studies have identified different risk factors of tumor recurrence after surgery of oesophageal cancer. Positive lymph node status is the most frequent factor identified [7–9]. It is also highlighted as an independent risk factor in our study. However, the impact of lymph node involvement can be refined by studying the prognostic role of lymph node ratio ie ratio between positive lymph nodes and resected lymph nodes. Ratios varying from 0.1 to 0.5 have already been discussed [8, 10]. In this study, ratio was set at 0.2, low enough to be discriminating. It turns out to be an independent major risk factor for relapse free survival that can be illustrated by a 5-year RFS of 67% with a ratio ≤ 0.2 versus 0% with a ratio > 0.2. An interesting finding of our study is the independency of lymph node ratio as a risk factor, particularly independent from lymph node positivity what could have been a confusing factor.

Other authors have also identified the number of involved nodes as a prognostic factor [9, 11]. These studies show the importance of node involvement as a quantitative and not only qualitative factor and are behind the recent changes to the 2009 UICC TNM classification. This last distinguishes nowadays different stages of nodal involvement for oesophageal cancer, superimposed on the oesophagogastric junction cancer classification, whereas it included only a single stage of nodal involvement in the previous version [12].

Unfortunately, information on the presence of this major prognostic factor is only obtained retrospectively on specimen examination. It does not allow optimal adaptation of neo-adjuvant treatment. Current diagnostic methods combining computed tomography, EUS and endoscopy permit an appropriate staging in 56% of cases and adjunction of PET does not provide better sensitivity for the preoperative lymph node diagnosis compared to EUS or computed tomography (sensitivity of 0.57 vs 0.8 and 0.5 resp.) [13, 14].

Indication of adjuvant treatment after oesophageal surgery is not recommended even in case of lymph node involvement but may be discussed if the patient is healthy, demanding, and informed. However, lymph node invasion seems to be a very accurate predictor of relapse free survival and may be used to identify patients requiring adjuvant chemotherapy or chemoradiotherapy to treat systemic metastases developing after primary resection [15].

Tumor depth, defined with pT stage, was also found as an independent prognostic factor in our study. Depth invasion has also been described in several other studies as a prognostic factor independent of nodal status [16, 17]. Similarly, the importance of tumor length or its development location have been described [18].

Preoperative tumor stenosis was found in our study to be an independent risk factor of local relapse that, to our knowledge, has never been previously reported. This is the main new factor identified in our study. The interest of this factor, simply defined on endoscopic and/or barium swallow criteria, is its preoperative availability. Despite its clear clinical correlation with a high pT stage, quality of resection but also with nutritional status, it appears, statistically, to be an independent risk for local relapse and not for distant relapse. It could represent an additional argument in the discussion of either preoperative chemoradiotherapy or in the indication of transthoracic vs transhiatal approach to get an optimal local disease control. Indeed, there is evidence that preoperative chemoradiotherapy increases the rate of complete resection i.e. local control for patients with locally advanced disease even if this was not always translated into a survival benefit in individual studies [19, 20]. Similarly, transthoracic approach allows greater lymphadenectomy (eight more lymph node retrieved compared with transhiatal approach) [21] that might provide increased local control and disease free survival [22].

Several other risk factors of recurrence, very different, have been described as circumferential margin involvement [23, 24], involvement of subcarinal and lower paraoesophageal lymph nodes [25], tumor-stroma ratio [26], endoscopic tumor length [27], good performance status of the patient [28]. Even if tumor stage and lymph node ratio are probably the most relevant risk factors of recurrence, this kind of studies, as ours, are necessary to refine oesophagus cancer prognosis and to help in the decision for adjuvant therapy.

Locoregional recurrence has been described with longer survival than distant or disseminated recurrence particularly in case of cervical recurrence [29, 30]. On the other hand, Bhansali et al. [31] reported no difference in different types of recurrence. In our report, survival in case of local recurrence was surprisingly 3 months shorter than for distant recurrence. This is probably due to differences in treatment protocol after relapse.

Half of our patients presented with pT < 3 or negative preoperative lymph node status. That partly explains our low rate of patient who received preoperative treatment (30%). Moreover, the length of our study, begun in 1998, is another explanation, first main studies of neo-adjuvant treatment still not published at that time. Finally, low rate of 50% of preoperative EUS performed may have led to a preoperative downstaging and also explains the rate of preoperative treatment.

A same approach was performed with overall survival and brought similar results. As our study focused on recurrence risk, these results are not detailed here. Five year overall survival estimated by Kaplan Meier method was 49% in our survey. This result, higher than OS reported in literature [1], may be due to our high rate of low stage tumors and drastic patient selection for surgical treatment.

Adenocarcinoma and squamous cell carcinoma were both included in this study that may be a bias. Indeed, Siewert et al.[32] reported two different diseases with different pathogenesis, epidemiology, tumor biology and prognosis requiring different therapeutic strategies. However, focusing on relapse and survival, several studies comparing adenocarcinoma and squamous cell carcinoma have reported worse, similar or better survival according to histopathology [33–35]. In our study, histopathology doesn’t appear to be correlated to RFS and OS and multivariate analysis allowed us to statistically study all of our patients in the same cohort. Signet ring cell adenocarcinoma is well known to have poorer prognosis [36]. Our number of patient and particularly with signet ring cell was too small to study it as a risk factor.

This study might initiate thinking for patients who received neoadjuvant treatment as indicated in guidelines, if they could benefit, in presence of these risks factors, of post-operative treatment or of a more intensive clinical or radiological follow-up. Moreover, recurrence risk is directly correlated with the number of positive risk factors (pN stage, pT stage and lymph node ratio), creating a risk score of recurrence, what may ponder discussion according to this score. Our score has to be confirmed by others studies but strongly argue for adjuvant therapy in case of cumulated risks, particularly in case of tumor regression after preoperative treatment.

Limitations of this study are numerous. The main is it retrospective type, while conducted on a homogeneous group of patients, that has led to heterogeneity in preoperative administrated treatments. These results have to be confirmed in a prospective one with standardized protocols. Then, monocentric aspect of the study allowed us to analyze patients with standardized practices but represents also a bias as the results must be confirmed in multicentric studies. Besides, our department is not a high volume center for oesophageal surgery, due to a low incidence of oesophageal cancer in our county, but belongs to the university hospital and is experienced in oesophago-gastric surgery.

Finally, our study demonstrates that preoperative tumor stenosis is the only prognostic factor associated with an increased risk of local relapse. Concerning relapse free survival, pT stage > 2, positive lymph node status and lymph node ratio > 0.2 are independent prognostic factors of recurrence after Ivor-Lewis surgery for cancer. Furthermore, addition of these risk factors is correlated with an increasing risk of recurrence. Thus, a routine postoperative treatment or reinforced follow-up should probably be considered in patients combining these risk factors.