Abstract
Background/Aim: Squamous cell carcinoma antigen (SCC) is widely used as a tumor marker for esophageal cancer. In this study, we investigated the relationship between SCC and long-term outcomes in patients with esophageal squamous cell carcinoma after neoadjuvant chemotherapy (NAC) followed by minimally invasive esophagectomy (MIE). Patients and Methods: Between 2010 and 2018, 124 patients with ESCC who underwent MIE after NAC (cisplatin plus 5-fluorouracil) were included. Patients were divided into low and high groups based on their pre-NAC SCC level, according to the cut-off value determined using a receiver operating characteristic curve. These two patient groups were further divided into subgroups by receiver operating characteristics according to whether SCC was low or high after NAC. Results: For overall survival (OS), the cut-off value for SCC pre-NAC was 0.9 ng/ml. Ninety-six patients were in the high SCC group (≥0.9 ng/ml) and 28 patients were in the low SCC group (<0.9 ng/ml) prior to NAC. The patients were then divided into pre-NAC/post-NAC SCC subgroups accordingly: low/low SCC (n=7), low/high SCC (n=21), high/low SCC (n=53), and high/high SCC (n=43). The 5-year OS rates were 100%, 66.7%, 50.9%, and 32.6%, respectively. In the multivariate analysis for OS, a high/high pre-NAC/post-NAC SCC status was an independent prognostic factor for poorer OS, along with pathological N stage. Conclusion: For patients with esophageal squamous cell carcinoma treated with NAC followed by MIE, a high SCC level prior to NAC which was also high after NAC was an independent prognostic factor and might contribute to deciding the need for adjuvant therapy.
- Esophageal squamous cell carcinoma
- minimally invasive esophagectomy
- neoadjuvant chemotherapy
- squamous cell carcinoma antigen
- tumor marker
Esophageal squamous cell carcinoma (ESCC) is the seventh most common cancer and the sixth leading cause of cancer-related deaths worldwide (1). In Asian countries, at least 90% of patients with esophageal cancer have ESCC, an aggressive tumor characterized by rapid growth and early metastasis (2). Esophagectomy is the preferred treatment for patients with locally advanced tumors. However, this is an invasive procedure associated with serious morbidity and mortality (3, 4). To reduce the invasiveness of the procedure, minimally invasive esophagectomy (MIE) using a thoracoscopic or laparoscopic approach to remove esophageal tumors through small incisions in the chest or abdomen has been developed (5-10). This approach is less invasive than open esophagectomy and shows reduced morbidity and mortality (11).
Esophagectomy with neoadjuvant chemotherapy (NAC) or chemoradiotherapy is the predominant treatment for esophageal cancer (12). In Japan, NAC, consisting of cisplatin and 5-fluorouracil (CF), is one of the standard therapies (13). However, some patients who undergo esophagectomy and receive NAC still have a poor prognosis. Therefore, it is crucial to predict which cases will have a poor prognosis to initiate suitable treatment.
Tumor markers are substances produced by cancer cells or other cells in the body in response to cancer or certain benign conditions (14). Tumor markers allow for a convenient and noninvasive assessment of prognosis. They provide information about the cancer, such as how aggressive it is, what kind of treatment to which it may respond, or whether it is responding to treatment. The association between tumor markers and prognosis in certain cancer types has been consistently confirmed. The squamous cell carcinoma antigen (SCC) is commonly used to predict the prognosis of patients with ESCC (15-17). However, this assay lacks sufficient sensitivity and specificity for early detection and progression of ESCC (15). A cutoff value of 1.5 ng/ml for SCC has long been used; however, this value is not specific for a particular disease or purpose, and is therefore not clinically useful for diagnosis, prognosis, estimation, and recurrence monitoring (17-20). Consequently, surgical resection was not indicated for patients based on these findings.
The use of a standard cut-off value without sufficient validation may lead to an underestimation of the performance of serum SCC concentration for prognostication of ESCC. Moreover, only a few studies have focused on the relationship between serum SCC concentration before and after NAC and long-term outcomes in the era of neoadjuvant treatment. Therefore, using a composite evaluation consisting of the optimal cut-off value for serum SCC concentration before and after NAC, we clarified the easy prognostic factors for patients with ESCC treated with NAC followed by MIE.
Patients and Methods
Selection of patients. This study retrospectively examined 309 patients with thoracic ESCC (excluding cervical and abdominal ESCC) who underwent MIE after NAC at Kobe University Hospital between April 2010 and May 2018. Patients with clinical stages I-III (excluding cT1N0 and cT4b) or IV ESCC due to supraclavicular lymph node metastasis received NAC. In this population, 42 patients underwent incomplete (R1/R2) resection, seven underwent MIE in the left lateral position, eight underwent open esophagectomy, one underwent bypass surgery but not esophagectomy, and 39 had missing records. Patients who underwent salvage esophagectomy after definitive chemotherapy were excluded. Patients who underwent adjuvant chemotherapy with CF, neoadjuvant chemoradiotherapy, or neoadjuvant therapy with CF plus docetaxel (DCF), or those who did not undergo NAC were excluded. Finally, 124 patients were included in this study. We retrospectively calculated the SCC concentration from the hematological data of each patient before and after NAC.
SCC cut-off values pre- and post-NAC for overall survival (OS) were calculated using the receiver operating characteristic (ROC) curve to divide the 124 patients treated with NAC into two groups (21). We investigated the association between pre-NAC SCC status, clinicopathological characteristics, and surgical outcomes. The clinical stage was determined by esophagogastroduodenoscopy and computed tomography before and after NAC and evaluated according to the eighth edition of the Union for International Cancer Control guidelines (22). Postoperative complications, such as anastomotic leakage, recurrent nerve paralysis, and postoperative pneumonia were evaluated according to the Clavien–Dindo classification (23). A Clavien–Dindo classification of grade II or higher was considered to indicate postoperative morbidity.
To assess the impact of changes in SCC during NAC on OS, patients were further categorized into four groups according to the level of SCC post-NAC. Subsequently, clinicopathological factors and OS were compared between the low (<0.9 ng/ml) and high (≥0.9 ng/ml) SCC groups pre-NAC and post-NAC. In addition, we examined independent prognostic factors for OS using the pre-NAC/post-NAC SCC status.
Treatment and follow-up. NAC therapy with cisplatin (80 mg/m2/day, day 1) and 5-fluorouracil (800 mg/m2/day, days 15) twice every 3 weeks, which was the standard preoperative treatment for ESCC in Japan until 2021 (13), was performed for participants in this study. The patients underwent MIE in the prone position with systematic lymphadenectomy according to the tumor location, and the reconstruction method was at the surgeon’s discretion.
As a clinical practice in Japan, postoperative follow-up surveillance includes esophagogastroduodenoscopy every year and computed tomography every 6 months after surgery. OS was calculated from the day of surgery to the day of last follow-up.
Statistical analysis. The cut-off SCC concentration for OS was calculated using the ROC curve (21). Chi-squared tests were performed to evaluate SCC associations with clinicopathological factors. Continuous variables were compared using analysis of variance. Survival curves were generated based on SCC using the Kaplan–Meier method and compared using the log-rank test. Multivariate analysis using Cox proportional hazards models was performed to identify the independent prognostic factors for OS. A value p<0.05 was considered as significant. All analysis were carried out using JMP® 14.2 (SAS Institute Inc., Cary, NC, USA).
Results
Analysis of SCC before NAC for 124 patients who underwent MIE following NAC for ESCC. According to the ROC curve, the pre-NAC SCC cut-off for OS was 0.9 ng/mL (Figure 1A) as was that of post-NAC SCC (Figure 1B). Prior to NAC, 96 patients were in the high SCC group (≥0.9 ng/ml) and 28 patients were in the low SCC group (<0.9 ng/ml). Table I shows the baseline characteristics of the two groups. We found that pre-NAC, the high SCC group (≥0.9 ng/ml) included significantly more men (p=0.009; Table I). The survival curve for the group with a high SCC level (≥0.9 ng/ml) pre-NAC was significantly worse than that of the low SCC group (<0.9 ng/ml). The 5-year OS rates were 42.7% and 75.0%, respectively (p=0.003; Figure 2).
Receiver operating characteristics curves generated to analyze the relationship of squamous cell carcinoma antigen (SCC) concentration pre (A) and post (B) neoadjuvant chemotherapy (NAC) with overall survival (OS) in 124 patients who received NAC. The pre-NAC SCC cutoff value for OS was determined to be 0.9 ng/ml, resulting in an area under the curve of 0.686; the post-NAC SCC cut-off value for OS was also determined to be 0.9 ng/ml, resulting in an area under the curve of 0.693.
Characteristics of 124 patients divided according to the cut-off for squamous cell carcinoma antigen (SCC) concentration before neoadjuvant chemotherapy (NAC).
Kaplan–Meier curves for analyzing the overall survival differences according to the level of squamous cell carcinoma antigen (SCC) prior to neoadjuvant chemotherapy (NAC). The patients in the group with a high level of SCC pre-NAC (≥0.9 ng/ml) exhibited significantly worse overall survival than those in the group with a low level of SCC (p=0.003). The 5-year overall survival rates were 42.7% and 75.0%, respectively.
Analyses for effect of changes of SCC during NAC on OS. The patients in these two groups were further divided into pre-NAC/post-NAC SCC subgroups accordingly: low/low (n=7), low/high (n=21), high/low (n=53), and high/high (n=43). In the group with low SCC pre-NAC (<0.9 ng/ml), we found that high SCC post-NAC was associated with greater age and intrathoracic operative time (p=0.011 and 0.007, respectively) (Table II). There were no significant differences in the clinicopathological factors between the two groups with high SCC pre-NAC (≥0.9 ng/ml) (Table III). The 5-year OS rates were 100%, 66.7%, 50.9% and 32.6% for the low/low, low/high, high/low and high/high groups, respectively (p=0.001). There were significant differences in the Kaplan–Meier curves among the four groups, with high SCC being associated with poorer OS (p=0.001; Figure 3).
Characteristics of 28 patients with low squamous cell carcinoma antigen (SCC) concentration before neoadjuvant chemotherapy (NAC) (<0.9 ng/ml) divided into two groups according to their post-NAC SCC level.
Characteristics of 96 with high squamous cell carcinoma antigen (SCC) concentration before neoadjuvant chemotherapy (NAC) (≥0.9 ng/ml) divided into two groups according to their post-NAC SCC level.
Kaplan–Meier curves for analyzing the overall survival differences according to the level of squamous cell carcinoma antigen (SCC) prior to and after neoadjuvant chemotherapy (NAC). Using a cut-off of ≥0.9 ng/ml for pre-/post NAC SCC, the patients were divided into groups with low/low, low/high, high/low and high/high levels. The overall survival rates differed significantly and were 100%, 66.7%, 50.9%, and 32.6%, respectively, at 5 years (p=0.001).
Multivariate analyses to examine independent risk factor for OS in 124 patients treated with MIE following NAC for ESCC. In the multivariate analysis for OS, having a high/high pre-/post-NAC SCC status was an independent risk factor, along with pathological N stage (p≤0.001 and p<0.001, respectively) (Table IV).
Multivariate analysis using the Cox proportional hazard model in 124 patients to determine independent prognostic factors for overall survival.
Discussion
In this study, we identified a high/high pre-/post-NAC SCC status as being an independent prognostic factor for poor OS. This means that a high/high pre-/post-NAC SCC status reflects a condition in which the tumor is very aggressive and does not respond to NAC, leading to poor prognosis. Moreover, this implies that assessing changes in SCC during NAC is more valuable than considering pre-NAC SCC or post-NAC SCC in isolation. Additionally, pN stage (≥pN2) was identified as an independent prognostic factor for OS. This means that the risk associated with the high/high pre-/post-NAC SCC status, which can be identified preoperatively, is similar to the risk associated with having three or more pathological lymph nodes metastases. The major difference is that the pre-/post-NAC SCC status can be determined preoperatively unlike pN stage, making it easier to plan adjuvant therapy and to select less invasive surgery, such as partially omitting prophylactic lymph node dissection, performing a two-stage segmental resection followed by adjuvant therapy and reconstructive surgery, or avoiding surgery in high-risk patients so that they can be quickly transferred to adjuvant therapy. Consequently, the usefulness of evaluating the changes in SCC during NAC is obvious.
It is important to note that our findings were specific to patients treated with NAC and MIE. Some patients treated with NAC and MIE may be considered for adjuvant therapy due to the risk of recurrence. According to the CheckMate 577 trial, patients who underwent neoadjuvant chemoradiotherapy and resection of esophageal or gastroesophageal junction cancer had significantly longer disease-free survival when treated with adjuvant therapy using nivolumab as an immune checkpoint inhibitor than those who received placebo (24). The efficacy and safety of nivolumab in patients receiving NAC was not clear in the CheckMate 577 study (24). Guidelines for the diagnosis and treatment of esophageal carcinoma indicate that the efficacy and safety of nivolumab in patients undergoing NAC cannot be recommended at the moment (25, 26). However, in clinical practice, immune checkpoint inhibitors have been used as an adjuvant therapy in some patients treated with NAC and esophagectomy. An easy biomarker that makes it possible to decide on the introduction of adjuvant therapy for patients with ESCC is needed. Consequently, a simple tumor marker assay could be advantageous for identifying high-risk patients and should be conducted before and after NAC. The high/high pre-/post-NAC SCC status can be predictive of cases requiring adjuvant therapy. Furthermore, while pathological factors are known to be useful prognostic indicators, a predictive system using preoperative SCC may be useful in predicting the need for adjuvant therapy prior to MIE.
SCC was discovered primarily as a tumor marker in uterine cervical squamous cell carcinoma (27). Increased SCC levels have been observed not only in benign disease, including pulmonary and skin disease, but also in squamous cell carcinoma of the head and neck, esophagus, skin, lung, urothelium, anal canal, and vulva (27). Although SCC is produced in the normal epithelium and epithelial tissues, patients with squamous cell cancer have an abnormally high quantity of this antigen. Several studies have suggested that SCC levels can predict advanced tumor stage, recurrence, and survival in patients with ESCC (18, 28). The gradual increase in SCC concentrations associated with increasing tumor size and progression may be caused by excess SCC produced by numerous cancer cells in patients with advanced carcinoma. Accordingly, physicians should monitor changes in SCC concentrations before and after treatment.
SCC assays frequently yield false-positive results, especially after surgery (20). However, our Institution routinely measures SCC concentrations in patients with ESCC before treatment. Therefore, we retrospectively analyzed the data to determine the optimal SCC cut-off for predicting the prognosis of ESCC. The proposed cut-off for SCC in this study was 0.9 ng/ml, which is lower than the conventional value of 1.5 ng/ml. This suggests that an SCC value of 0.9 ng/ml or higher might result in adverse outcomes, even if it falls below the traditional cut-off value.
According to a previous report, the optimal cut-off value for preoperative SCC concentration that predicted recurrence after curative resection of squamous cell carcinoma of the esophagus was 1.1 ng/ml (28). Although there are limited reports discussing the link between SCC post-NAC and long-term prognosis, our study demonstrated that a high level of pre-/post-NAC SCC serves as a prognostic factor.
This study had some limitations. Firstly, as with all retrospective studies, there may have been selection bias. Secondly, this study had a small sample size, and it was conducted only at a single center. Therefore, a larger prospective multicenter trial is required to confirm our findings. Finally, all the patients received NAC consisting of CF, which is the standard in Japan (29, 30). However, the JCOG1109 trial demonstrated significantly improved OS in the group receiving neoadjuvant DCF compared to the CF group (31). Future verification is necessary when more cases in the neoadjuvant DCF group have been accumulated and an optimal cutoff value for SCC for patients receiving NAC consisting of DCF therapy will be required.
In conclusion, our study suggests that a high/high pre-/post-NAC SCC status is an independent prognostic factor and might contribute to deciding the introduction of adjuvant therapy for patients with ESCC treated with NAC followed by MIE. SCC concentrations before and after NAC should be measured in clinical practice to predict patient prognosis.
Acknowledgements
The Authors thank the members of the Department of Gastrointestinal surgery, Kobe University for their valuable insight and technical guidance.
Footnotes
Authors’ Contributions
Rikuya Torigoe, Taro Oshikiri, Hironobu Goto, and Yoshihiro Kakeji designed the study. Hitoshi Harada, Naoki Urakawa, and Shingo Kanaji interpreted the study data. Ryuichiro Sawada, Hiroshi Hasegawa, Kimihiro Yamashita, and Takeru Matsuda analyzed the data. All Authors revised and commented on the article and approved the final version.
Conflicts of Interest
The Authors declare no conflicts of interest.
- Received October 8, 2024.
- Revision received October 23, 2024.
- Accepted October 24, 2024.
- Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).
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