Histological Regression of Squamous Esophageal Carcinoma Assessed by Percentage of Residual Viable Cells after Neoadjuvant Chemoradiation is an Important Prognostic Factor

From 1995 to 2007, 183 patients who had squamous cell esophageal carcinoma and who received neoadjuvant chemoradiation followed by surgery at the Queen Mary Hospital, The University of Hong Kong, were included in this study. Neoadjuvant chemoradiation treatment was given as part of a randomized controlled trial comparing neoadjuvant chemoradiation versus surgical resection alone or when locally advanced tumor or nonregional metastatic nodal spread was present. In these situations, a R0 resection was judged not probable and thus chemoradiation was used upfront. Patients with systemic organ metastases were not selected for surgical treatment and thus were excluded. Only patients who had R0 resections were included in this study because patients who had incomplete tumor resection invariably would have a poor prognosis. Tumors located at the cardia or nonsquamous cell cancers were excluded.

For all patients, staging investigations included upper endoscopy, endoscopic ultrasound (EUS) and bronchoscopy, ultrasound of the neck with or without fine-needle aspiration cytology of suspected nodes, computer tomography (CT), or positron emission tomography fusion with computer tomography (PET/CT) imaging (PET/CT scan was available since 2003). Chemoradiation therapy was given in a concurrent manner. The chemotherapy regime comprised cisplatin at 100 mg/m² on day 1 and then day 22 and continuous infusion of 5-fluorouracil (5-FU) at 500 mg/m² per day for 5 days from days 1 to 5 and days 22 to 26. Radiotherapy was given at a dosage of 40–46 Gy at 2 Gy per fraction. It was delivered through anterior and posterior opposing fields to the primary esophageal tumor covering at least 1-cm lateral margins and 3-cm axial margins. Postchemoradiation evaluation was performed 4 weeks after the date of finishing the treatment course, and surgery carried out soon after.

The choice of surgical approach was governed by the location of the tumor. For tumors located in the middle and lower thirds of the esophagus a Lewis-Tanner esophagectomy through an abdominal-right thoracotomy approach was preferred, but three-phase esophagectomy and minimally invasive techniques using thoracoscopic ± laparoscopic approaches have been increasingly employed in recent years. Two-field lymph node dissection was performed. Bilateral cervical nodal dissection was not routine because evidence was not strong enough to demonstrate clear benefits over two-field lymphadenectomy but with potentially increased morbidities.14,15

Of the 183 patients who had chemoradiation followed by surgery, 175 had total tumor clearance (R0) achieved and were included in this study. Among these patients, 149 were men and the median age was 65 (range, 38–82). The median follow-up was 20 months (range, 1–143). The demographic data of these patients are shown in Table 1.

In this study, we have shown that in patients who underwent neoadjuvant chemoradiation therapy before surgical resection, percentage of viable cells in the primary tumor, nodal status, and gender were prognostic factors on multivariate analysis. ypV stage could potentially replace ypT stage. Nodal status is however even more important; positive nodal metastasis incurs a poor prognosis even in the presence of complete response in the primary tumor.

The beneficial effects of neoadjuvant chemoradiation therapy, although gaining popularity, have not been consistently shown in randomized trials.3,4,17‐21 However, patients who have pathological complete response (ypT0N0M0) after neoadjuvant chemoradiation therapy have repeatedly been shown to have better survival compared with those with incomplete response.22‐25 In our group of patients, chemoradiation had substantial effects; 75.4% of patients were downstaged, and 31.4% achieved complete response. Consistent with other reports, the long-term survival of the complete responders was significantly longer than those patients with residual tumor.4,19,26 The 3-year and 5-year survival rates in ypCR patients were 72.1% and 61.6%, respectively.

Pretherapeutic clinical TNM stage had no impact on survival. This is not unexpected since long-term prognosis would depend on the response to neoadjuvant treatment. This is also consistent with the findings from other similar studies.8,27 It is however controversial whether postsurgical ypTNM stage is of prognostic significance or not. The relevance of ypTNM has been variably reported by different investigators.10 Swisher and associates identified ypTNM as an independent prognostic factor on multivariate analysis, while data from the Memorial Sloan Kettering Center did not find it of value.9 Our data could not demonstrate the significance of ypTNM stage on multivariate analysis. ypT stage was not prognostic on multivariate analysis, only ypN was useful. The reason that ypTNM stage was not prognostic may be related to an altered relationship between ypT and ypN stage. In our previous study, we have shown that while in patients who had surgical resection alone without prior treatment there was a linear relationship between the chance of nodal metastasis and pT stage, this clear association was lost in those who had had chemoradiation.7 Response in the primary tumor does not necessarily imply equal response in the lymph nodes. The metastatic cells may behave differently, or they may be located outside the irradiation field.

There are difficulties assigning ypT stage in patients who had prior treatment. The conventional TNM classification denotes a pT stage according to the deepest layer of the esophageal wall that is infiltrated by the tumor. After neoadjuvant treatment, this simple gradation is lost. Often only small clusters of residual viable cells are found in the deep layer of the esophagus, with the superficial layers sterilized. It is not clear if assigning a ypT stage according to this layer is appropriate. Instead, looking at the percent of residual viable tumor may be a better way to measure the severity of disease status.

Different grading systems have been reported to assess the degree of primary tumor response after neoadjuvant therapy (Table 4). Mandard and associates first reported the importance of taking into account the degree of tumor regression as an important survival prognostic factor.28 The grading system was based on the amount of residual viable cells and posttherapeutic fibrosis. Schneider divided the percent of viable cells into 0%, <10%, 10%–50%, and >50%.11 Chirieac used slightly different dividing points as 0%, 1%–50%, and >50%.8 The Japanese Society for Esophageal Disease published a guideline to assess the degree of primary tumor response by dividing the proportions of viable cell into thirds.16 From our data, it seems certain that ypV is of prognostic significance both as a continuous or a categorical variable (Tables 2 and 3). For the ease of daily clinical application, the ability to divide ypV into discrete grades could be useful. A clear trend is seen in survival from ypV0 to ypV3 (Fig. 2e). However, the choice of different categories is arbitrary. Consistently reproducible categories are not yet available in the literature. This may in part be related to different ways of assessing histological regression. One potential limitation on assessing the percent of viable cells is that spontaneous tumor necrosis can occur in any tumor, particularly if the necrosis is confined to the center of a large tumor cell clump, and this may not be related to treatment effect. Distinction between the two mechanisms is not possible by histological examination. A scar area is presumed to have developed after tumor necrosis. However, scarring might occur without prior tumor’s presence.

Undoubtedly, nodal status is an important prognostic factor. The ypN stage is shown in the present study as an important factor. Gaca et al. demonstrated in 101 patients who had chemoradiation that the ypN status was the only prognostic factor for disease-free survival.29 Similar findings were reported by Reynolds et al.27 It is important to note that in our patients who had ypN0 disease, ypV0 patients survived longer than those who had ypV+ disease. This difference was not significant in patients who had nodal metastases (ypN+). This is not unexpected as the importance of metastatic disease overrides the status of the primary tumor.

In summary, we have shown that the pretherapeutic clinical TNM stage has no prognostic value in patients who had neoadjuvant chemoradiation. Gender, nodal status, and the percent of residual viable cells in the primary tumor were independent prognostic factors. ypV assessment should replace conventional ypT stage as a prognostic factor.