Clinical Investigation
Initial Stage Affects Survival Even After Complete Pathologic Remission is Achieved in Locally Advanced Esophageal Cancer: Analysis of 70 Patients With Pathologic Major Response After Preoperative Chemoradiotherapy

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Purpose

To analyze outcomes and factors predictive for recurrence and survival in patients with operable esophageal carcinoma who achieved pathologic complete response (PCR) or microscopic residual disease (MRD) after preoperative chemoradiotherapy (CRT).

Materials and Methods

Outcomes were assessed in 70 patients with locally advanced esophageal cancer who achieved pathologic major response (53 with PCR and 17 with MRD) after preoperative CRT.

Results

At a median follow-up of 38.6 months for surviving patients, 17 of 70 patients (24.3%) experienced disease recurrence and 31 (44.3%) died. Clinical stage (II vs III; p = 0.013) and pathologic response (PCR vs. MRD; p = 0.014) were independent predictors of disease recurrence. Median overall survival (OS) was 99.6 months (95% CI, 44.1–155.1 months) and the 5-year OS rate was 57%. Median recurrence-free survival (RFS) was 71.5 months (95% CI, 39.5–103.6 months) and the 5-year RFS rate was 51.3%. Median OS of patients with Stage II and Stage III disease was 108.8 months and 39.9 months, respectively, and the 5-year OS rates were 68.2% and 27.0%, respectively (p = 0.0003). In a subgroup of patients with PCR, median OS and RFS were also significantly different according to clinical stage. Multivariate analysis showed that clinical stage was an independent predictor of RFS (p = 0.01) and OS (p = 0.008).

Conclusions

Even though patients achieved major response after preoperative CRT, pretreatment clinical stage is an important prognostic marker for recurrence and survival. Patients with MRD have an increased recurrence risk but similar survival compared with patients achieved PCR.

Introduction

Concurrent chemoradiotherapy (CRT) followed by esophagectomy has become a standard treatment option in patients with operable esophageal cancer 1, 2, 3, 4, 5. In our institution, all patients with operable Stage ≥II esophageal cancer undergo preoperative CRT 6, 7, 8, 9. We have previously reported that the 5-year overall survival (OS) rate of patients who do and do not achieve a pathologic complete response (PCR) was significantly different (57% and 33%, respectively) (10). Several studies have also demonstrated that pathologic complete responses to preoperative CRT are important predictors of survival (11). However, some patients who achieve PCR subsequently experience tumor recurrence or death, whereas few studies have assessed the prognostic factors for survival or recurrence in these patients.

It is well known that the degree of histomorphologic regression after preoperative CRT correlates with clinical outcome of patients 12, 13. However, several researchers have reported that the OS of patients who achieved major histologic response after preoperative CRT was similar to the survival of patients who achieved PCR 14, 15, 16. We have found that some patients who achieved significant pathologic regression after preoperative CRT retained residual small tumor foci, with these patients designated as having microscopic residual disease (MRD) 6, 17. Comparative analysis of clinical outcomes of patients that have achieved PCR or MRD has not yet been reported. We hypothesized that although OS may be similar in patients with PCR and MRD, the recurrence rate or recurrence-free survival (RFS) may differ between these two groups of patients.

We therefore analyzed clinical outcomes in patients with operable esophageal cancer who achieved pathologic major response (PMR, either PCR or MRD) in three clinical trials of preoperative CRT. We sought to determine the factors that predict survival and recurrence among patients with PMR, and have assessed whether the recurrence rate and survival differed between patients who achieved PCR and had MRD after preoperative CRT.

Section snippets

Patients

Beginning in March 1993, we performed three prospective clinical trials on a total of 268 patients with locally advanced but resectable esophageal cancer 6, 7, 8, 9, 10. Of these 268 patients, 180 patients were treated with preoperative CRT, including 129 who also underwent esophagectomy. Of the 129 patients, 58 patients achieved PCR and 17 had MRD; of these 75 patients, 5 (6.6%) patients died of perioperative mortality and were excluded from the analysis of recurrence and survival. Ultimately,

Patient and treatment characteristics

Fifty-three patients who achieved PCR at the time of surgery and 17 patients who had MRD were enrolled in the analysis. Patient characteristics are summarized in Table 1. The 70 patients consisted of 60 men and 10 women, with a median age of 63 years (range, 43–71 years). Histologically, all of the primary tumors were squamous cell carcinomas. Forty-two patients (60%) had Stage II disease and 28 patients (40%) had Stage III carcinomas. Fifty-four patients (77%) underwent EUS and 35 patients

Discussion

Although uncertainty remains regarding whether multimodal therapy is superior to surgery in patients with esophageal cancer, we have found that subgroups of patients who have achieved PMR clearly benefit from preoperative CRT. Although PCR may be an excellent predictor of outcome, not all patients have the same outcome. To identify the prognostic factors for tumor recurrence and patient survival, we retrospectively reviewed outcomes in 70 patients who had achieved PMR after preoperative CRT.

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    Conflict of interest: none.

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