Abstract
Background: Histopathological tumor regression grade is applied not to lymph nodes but primary tumors modified by preoperative treatments. This study focused on patients whose pathological examination at the time of surgery showed no residual tumor after chemo(radio)therapy in the primary lesion (ypT0) or lymph nodes (ypN0). Patients and Methods: A total of 87 patients with clinical stage II/III thoracic esophageal cancer underwent esophagectomy following preoperative treatments to evaluate significances between pathological response and clinical outcomes; 51 patients with clinically definitive lymph node metastasis (cN+) were analyzed as a subgroup. Results: ypT0 rates were 20.7% and 23.5%, and ypN0 rates were 47.1% and 27.5% in the whole cohort and in the cN+ subgroup, respectively. Disease-free survival, from surgery to relapse or death, was significantly influenced by ypN status (p=0.035) but not by ypT status in the 51 patients with definitive cN+ disease. Preoperative chemoradiation was an independent favorable factor for achievement of ypN0 in the 51 patients (odds ratio=0.09; p=0.007). Conclusion: ypN status was a predictive factor for DFS in patients treated with docetaxel plus low-dose 5-fluorouracil and cisplatin combined chemotherapy, superior to ypT status, especially in patients with definitive cN+ disease.
Preoperative chemotherapy has been a standard treatment in the therapy of clinical stage (cStage) II/III thoracic esophageal squamous cell carcinomas based on the randomized phase III trial, JCOG9907, in which a cisplatin and 5-fluorouracil combined chemotherapeutic regimen was adopted (1). Furthermore, the three-arm phase III trial JCOG1109 is ongoing to evaluate the superiority of docetaxel with cisplatin plus 5-fluorouracil over cisplatin plus 5-fluorouracil, and the superiority of cisplatin plus 5-fluorouracil with chemoradiotherapy (41.4 Gy/23 fractions) over cisplatin plus 5-fluorouracil as preoperative therapy for squamous cell carcinoma of the esophagus (2). Multidisciplinary treatment is expected to improve both response and survival.
Following the development of multidisciplinary treatment, almost all histopathological examinations are carried out on resected specimens after therapy of patients with preoperative treatments; therefore, additional anticancer treatments or follow-up schedules should be individualized according to the histopathological findings following preoperative treatment. However, the clinical impact of pathological examination at the time of surgery showing no residual tumor in primary lesions and lymph nodes (ypT0 and ypN0) is still unknown.
Individualized management for patients with clinical stage (cStage) II/III diagnosed by the Japanese Classification of Esophageal Cancer (3) is currently considered based on the findings of initial histopathological examinations and imaging before preoperative treatments, including enhanced multi-detector row computed tomography.
Histopathological evaluation of the number of metastatic lymph nodes is a crucial prognostic factor (4). Additionally, tumor regression grading of primary tumors and the possibility of complementary prognostic factors associated with tumor regression grading of lymph nodes have been reported (5-7).
Regarding histopathological findings affected by preoperative treatment, TNM staging and histopathological diagnoses of primary tumors and lymph nodes are expected to be different from those based on clinical findings. Therefore, we evaluated the prognostic influence of ypT and ypN status in a total of 87 patients with esophageal squamous cell carcinoma (ESCC), including those with definitive cN-positive status.
Patients and Methods
Patients with ESCC treated with more than one course of preoperative combined chemotherapy using docetaxel and cisplatin plus 5-fluorouracil as an initial treatment were evaluated. Combined chemotherapy was 25 mg/m2 of docetaxel for 30 min on day 1, plus 370 mg/m2 5-fluorouracil for 22 h, and 7 mg/m2 cisplatin for 30 min on days 1-5 per week (DFP), intravenously administered; one course of this regimen consisted of 4 weeks with/without 1-week interval after 2 weeks of administration (8).
Clinical TNM category was assigned according to the eighth edition of the Union for International Cancer Control TNM classification (9). Tumor regression grades were assigned according to the histopathological criteria of antitumor effects after radiotherapy or chemotherapy (3).
The therapeutic strategy in patients with cStage II/III ESCC is to ensure curative resection (R0 resection). Based on this strategy, a second course of DFP was conducted in patients with multiple lymph node metastases, and chemoradiation following primary DFP was applied for those with locally advanced disease such as cT3/4 borderline disease.
Histopathological examinations were performed on the resected specimens modified by preoperative treatments including chemotherapy and/or chemoradiotherapy.
Additionally, relationships between complete regression (ypN0) in the dissected regional lymph nodes and survival were investigated in the patients diagnosed as having clinicalIy definitive lymph node metastases (cN+) before treatment.
For example, a patient may be diagnosed with a primary lesion and two lymph node metastases prior to initial treatment. After preoperative chemotherapy or chemoradiotherapy, patients with ypT0 status with residual nodal disease or ypN0 with residual cancer cells in the primary tumor are identified in responding patients with advanced disease. This study evaluated the proportions and the prognostic impact of ypT0 and ypN0 status after preoperative treatment. Application of histopathological diagnoses were investigated retrospectively in the subgroup of patients with cN+ disease confirmed by multi-detector row computed tomography at our Institute.
One course of DFP was defined as 4 weeks of administration. Second-line treatment was esophagectomy, or two courses of DFP therapy alone or with chemoradiotherapy, which consisted of DFP therapy and radiation of 40-50.4 Gy (at 1.8-2.0 Gy per fraction) following the first chemotherapy, as shown in Figure 1.
The three different therapeutic schedules used in this study. DFP: Weekly docetaxel plus low-dose 5-fluorouracil and cisplatin combined chemotherapy (8); DFP+RT, chemoradiotherapy combined with DFP; OP: esophagectomy.
Overall survival (OS) and disease-free survival (DFS) from the initial treatments were estimated by Kaplan–Meier method according to the second-line treatment. Additionally, predictive factors for OS and DFS were investigated in the patients with ypN0, in those who at the time of surgery showed pathological complete response in a primary lesion (ypT0) or pathological complete response (pCR, ypT0N0), which was defined as no residual cancer cells in lymph nodes as well as primary lesions.
Histopathological findings were diagnosed by more than two pathologists from the Division of Pathology of our hospital.
This clinical research was approved by the Ethical Review Board of the Tokushima University of Biomedical Science (no. 3672) and performed in accordance with the ethical standards established in the 1964 Declaration of Helsinki and later amendments. All patients provided informed consent for the use of their data and materials.
Statistical methods. Fisher’s exact test and Student’s t-test were used to evaluate the association between clinical factors. Survival curves were estimated using the Kaplan–Meier method and comparisons among groups using the log-rank test. Univariate and multivariate logistic regression analyses assessed and calculate odds ratios associated with the selected variables. Significance was defined as a p-value of less than 0.05. All statistical analyses were carried out using SPSS version 20.0 for Windows (IBM, Armonk, NY, USA).
Results
A total of 114 patients were diagnosed as having cStage II/III ESCC and treated with DFP therapy as an initial treatment from 2009 to 2018 at our hospital. Overall, 87 patients who underwent esophagectomy following primary chemotherapy were investigated to evaluate significance differences in pathological response and clinical outcomes, after excluding 27 patients treated without surgery (Figure 2). These 87 patients were divided into two groups with 51 and 36 patients having clinically definitive lymph node metastases or not, respectively. Furthermore, the prognostic value of ypN0 status (n=14) was compared to non-ypN0 status (n=37) in these 51 patients with definitive cN+ disease.
Study patient population. DFP: Weekly docetaxel plus low-dose 5-fluorouracil and cisplatin combined chemotherapy (8); ESCC: esophageal squamous cell carcinoma; cN+: clinical lymph node metastasis; definitive cN+: lymph node metastasis confirmed by imaging examination.
Histopathological examinations of the resected specimens demonstrated that the proportion of patients with ypT0 and pCR were 21.8% and 12.6%, respectively, considering the 87 patients with cStage II/III ESCC. The ypN0 rate was 27.5% (n=14/51) in patients with definitive cN+ disease; 14 patients had an average of two nodal metastases (range=1-7). Furthermore, these 14 patients had no metastatic disease in any other dissected lymph nodes. Clinicopathological characteristics of subgroups were listed in Table I.
Patient characteristics.
Patients with advanced esophageal cancer with multi-nodal metastasis who responded to one course of DFP received an additional course of DFP. Chemoradiotherapy following one course of DFP was applied to patients with advanced esophageal cancer at risk of microscopic (R1) or macroscopic (R2) residual tumor even after one course of DFP as preoperative treatment. Based on these backgrounds, groups of patients undergoing additional chemo(radio)therapy tended to be in a higher cT- or cN-category than the group which received one course of DFP followed by surgery.
The 87 patients were divided into three groups in terms of the second-line treatments that were performed after a course of DFP. Proportions of ypT0, ypN0 and ypStage0 as well as responses to primary chemotherapy of DFP are given in Table II. Adverse events of all grades/≥3 were identified as neutropenia in 29%/8%, anemia in 11%/0%, thrombocytopenia in 6%/0%, anorexia in 80%/17%, diarrhea in 76%/18%, stomatitis in 42%/4% and fever/infection in 20%/0% according to Common Terminology Criteria for Adverse Events v3.0 (10).
Clinical features according to the three types of second-line treatment in 87 patients with stage II/III esophageal cancer.
There was no significant difference in OS and DFS by the three different second-line treatments following one course of DFP (Figure 3).
Kaplan–Meier curves for overall (OS) (A) and disease-free (DFS) (B) survival of 87 patients with clinical stage II/III esophageal cancer by the three different second-line treatments following one course of therapy. DFP: Weekly docetaxel plus low-dose 5-fluorouracil and cisplatin combined chemotherapy (8); RT: radiotherapy.
Prognostic significance of ypT0 tended to be similar to that of ypN0 considering the whole patient cohort (Figure 4).
Kaplan–Meier curves for overall (OS) (A) and disease-free (DFS) (B) survival of 87 patients with clinical stageII/III esophageal cancer according to pathological T status (ypT) (left) and pathological N status (ypN) (right) after preoperative chemo(radio)therapy.
Focusing on the 51 patients with definitive cN+ status, there was no significant survival difference by ypT status. On the other hand, ypN+ status was associated with poorer OS and significantly poorer DFS (Figure 5). Furthermore, survival significance considering all of the 87 patients with stage II/III disease, i.e., including those with clinical N0 disease, was different from that of the 51 patients with definitive cN+ disease who had a poor prognostic factor. For example, ypN0 in 87 patients treated with preoperative chemo(radio)therapy, which includes those with cN0, and ypN0, did not indicate complete response in the dissected lymph nodes. In contrast, ypN0 in 51 patients with definitive cN+ disease practically showed cancer cells had completely disappeared under preoperative treatments. Patient background, Response Evaluation Criteria in Solid Tumors criteria before second treatments and ypTNM of resected specimens are shown in Table II according to therapy group. A status of ypN0 in the 51 patients with definitive cN+ disease was achieved in 17.5%, 25.0% and 66.7% in those treated with DFP, two courses of DFP, or DFP with chemoradiotherapy, respectively, then surgery. Survival curves according to pCR/non-pCR were similar to those of ypN0/non-ypN0.
Kaplan–Meier curves for overall (OS) (A) and disease-free (DFS) (B) survival of 51 patients with definitive clinical nodal-positive stage II/III esophageal cancer according to pathological T status (ypT) (left) and pathological N status (ypN) (right) after preoperative chemo(radio)therapy.
A comparison of characteristics in patients with ypN0 status (n=14) and non-ypN0 status (n=37) is given in Table I. Patients with clinically N-positive status were then categorized by the number of metastatic lymph nodes into two groups with only one or with two or more metastatic lymph nodes. Two or more metastatic lymph nodes and chemoradiotherapy following primary chemotherapy were identified as predictive factors in univariate logistic regression analysis for patients with ypN0. Additionally, multivariate analysis was performed for the factors with a significance level of <0.10. Multivariate analysis indicated that an independent factor associated with achieving ypN0 was chemoradiotherapy following primary chemotherapy (Table III).
Logistic regression analysis of predictive factors in ypN0 (n=51).
Clinicopathological features of the ypN0 and the non-ypN0 groups in the 51 definitive cN+ cases were investigated. As a result, there were significant differences in pathological T-status and tumor regression grade in primary tumor after preoperative treatments compared to the results of the 87 patients including cN0, and no patient in the group with ypN0 (n=14) developed recurrence in a lymph node as well as a local site.
Discussion
Preoperative chemotherapy and chemoradiotherapy are expected to demonstrate survival benefits in cStage II/III ESCC (1, 11). The number of lymph node metastases influences survival in patients with cancer, including those with ESCC (4). Therefore, in this study, antitumor effects of preoperative treatments were investigated in patients with cStage II/III disease; we hypothesized that their effects on lymph node metastases would have significant prognostic value. Our results showed that there was no significant difference in DFS in patients with cStage II/III disease between those with pathological N0 status after preoperative treatment (ypN0) and those with non-ypN0. However, there was a significant difference in DFS between those with ypN0 and non-ypN0 in patients with cStage II/III disease who had definitive cN+ disease in our study. These findings indicate that lymph node multidisciplinary metastasis-targeted preoperative treatments such as primary chemotherapy followed by chemoradiotherapy can be recommended in patients with definitive cN+ disease. Cho et al. reported that there was no significant difference in oncological outcomes between patients with ypT0N0 and those with ypT0N+ in esophageal cancer (12). However, it seems that these survival analyses were performed including patients with cN0. We divided ypN statuses into ypN0 and non-ypN0, and prognostic factors were evaluated focusing on the patients with definitive cN+ status in our study. ypT statuses can be classified into five grades following the criteria of the Japanese Classification of Esophageal Cancer (3) or the histological criteria presented by Mandard et al. (13). Survival benefits were investigated among patients with primary tumors of grades I-III, but not grade IV, by the classification of pathological tumor regression grades I-IV, and only pCR was used as a biomarker (14-16). However, in recent reports, prognostic factors have been investigated by classification of pathological regression grades I-IV or grades 0-3 in metastatic lymph nodes as well as primary tumors in recent reports (6, 15-17).
Blackham et al. reported that residual nodal disease was identified as a prognostic factor in patients with ypT0 disease undergoing neoadjuvant chemoradiation followed by surgery (15). On the other hand, Loya et al. concluded there was no prognostic significance of micrometastases after chemotherapy in axillary lymph nodes in breast cancer (18). The opposite results have been reported in relation to lymph node micrometastases (19). We suspect that there was no significant difference in survival between patients with no residual cancer cells and those with micrometastases in the definitive clinical metastatic lymph nodes after neoadjuvant chemo(radio)therapy in esophageal cancer (Table IV).
Previous reports related to prognostic histopathological factors in patients with esophageal cancer treated with preoperative chemotherapy.
These findings indicate that the classification of antitumor effects on metastatic lymph nodes must also be defined in order to predict survival.
There was no significant difference in OS in the surgically treated group compared to the other groups with advanced disease treated with additional chemo(radio)therapy prior to surgery. This suggests that more effective systemic preoperative treatments or individual secondary treatments following primary chemotherapy provided better prognosis in patients with locally advanced esophageal cancer.
The reason why ypT0 did not result in significantly better survival than ypT+ is presumably that the absence of residual cancer cells in the regional lymph nodes is a better prognostic factor than the absence of residual cancer cells in primary tumor in cN+ cStageII/III ESCC. Indeed, we propose that a histopathological diagnosis of the definitive metastatic lymph nodes should have priority over other findings in cStage II/III ESCC. Chemoradiotherapy following primary chemotherapy yielded high rates of ypN0 in our study. Therefore, chemoradiotherapy prior to surgery for resectable diseases would seem to be a promising preoperative treatment approach, as suggested in previous reports (11, 20).
In the future, individual perioperative multidisciplinary treatments should be designed by evaluating histopathological tumor regression grade in definitively metastatic lymph nodes as well as in the primary tumor after preoperative treatments including neoadjuvant chemoradiation in the future.
This study had some limitations. This analysis was retrospective in design and performed on a small number of patients and at a single institution. There were selection biases in decision-making in regard to the three different types of therapeutic strategy according to individual clinical factors. Finally, in order to evaluate the prognostic impact of ypN0 compared to ypT0, a longer follow-up time is necessary.
In conclusion, ypN0 after preoperative chemo(radio) therapy was a predictive factor in patients with clinical stage II/III ESCC with definitive clinical lymph node metastases. Our findings indicated that evaluation of residual metastatic disease in patients with definitive cN+ status should have priority in histopathological examinations for prognosis.
Footnotes
Authors’ Contributions
T.Y. and A.T. designed the study. T.N., M.G., S.I., S.F. and T.Y. diagnosed clinical TNM classifications, and performed data collection, analysis and interpretation. H.U. and Y.B. diagnosed histopathological examinations. A.T., H.T. and T.Y. wrote the original article and made the decision to submit for publication.
Conflicts of Interest
All Authors have no conflicts of interest associated with this study.
- Received July 10, 2021.
- Revision received October 5, 2021.
- Accepted October 22, 2021.
- Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.