Abstract
Background: The clinical significance of neoadjuvant chemoradiotherapy (NACRT) for potentially resectable esophageal squamous cell carcinoma (ESCC) is unclear. Patients and Methods: Patients with clinical stage II-III ESCC were classified into an NACRT group (n=76) and surgery alone group (n=92). The prognosis and the incidence of postoperative complications were retrospectively investigated. The pathological response to NACRT and patient prognosis were also analyzed. Results: The 5-year survival rate was 47.7% in the surgery alone group and 56.5% in the NACRT group (p=0.4831). The 5-year survival rates of patients in whom NACRT was markedly effective was clearly better than that of the other patients (ineffective/slightly effective: 36.9%, moderately effective: 53.8%, markedly effective: 100%). The incidence of postoperative complications was 31.5% in the surgery alone group and 40.8% in the NACRT group (p=0.2121). Conclusion: A pathological complete response to NACRT is critical for improving the survival of patients with clinical stageII-III ESCC.
- Esophageal squamous cell carcinoma
- neoadjuvant chemoradiotherapy
- pathological response
- complication
- prognosis
Since the majority of patients with esophageal cancer still tend to have widespread disease at the time of detection, esophageal cancer remains one of the most difficult malignancies in the digestive tract to control by surgery alone (1). Neoadjuvant chemoradiotherapy (NACRT) has been applied for esophageal cancer, mainly at advanced stages, for the purpose of reducing the main tumor and control of microscopic metastases. However, the clinical usefulness of NACRT for potentially resectable esophageal cancer still remains controversial. Some randomized studies and meta-analyses have emphasized the superiority of the clinical results in NACRT plus surgery to those of surgery alone (2, 3), whereas other reports have shown that the difference was not significant (4-6). With regard to postoperative complications, NACRT for esophageal cancer was reported to increase their incidence (7, 8). However, others have reported that the incidence of complications was similar to that in the patients who received surgery without NACRT (9-11).
In Japan, the clinical significance of NACRT for resectable advanced esophageal squamous cell carcinoma (ESCC) still remains controversial. In this study, we retrospectively evaluated the usefulness of NACRT for clinical stage II-III (cStageII-III) ESCC. We also examined the relationship between NACRT and the development of postoperative complications.
Patients and Methods
Patients. An esophagectomy was performed in 168 patients with cStageII-III ESCC between 1998 and 2007 in the Department of Surgery and Science at Kyushu University, Japan. Among these patients, NACRT had been performed for 76 patients, while surgery alone was indicated for 92 patients. For cStageII-III patients, NACRT was principally administered between 1998 and 2002. However, since NACRT was found to demonstrate no substantial survival benefit, surgery without neoadjuvant therapy was performed between 2003 and 2007. Therefore, this study is retrospective, without randomization, but is based on historical controls.
The clinicopathological backgrounds according to the administration of NACRT are shown in Table I. There were some differences in the clinical backgrounds between the two groups: the incidence of clinical T1b was significantly lower in the NACRT group than in the surgery alone group (p<0.05). The incidence of pathological T1 and pathological N (+) was also significantly lower in the NACRT group than in that of surgery alone (p<0.05 and p<0.0005, respectively). The pathological stage (pStage) was significantly more advanced in the NACRT group than in that of surgery alone (p<0.05). There were no differences in factors such as age, gender, location of the tumor, clinical N factor, cStage and curability.
Clinicopathological background according to NACRT.
For NACRT, 30-42 Gy of radiation for the primary tumor and metastatic lymph nodes was administered preoperatively. The chemotherapy regimen was low-dose cisplatin and 5-fluorouracil (5-FU) (cisplatin: 5 mg/m2/day, 5-FU: 250 mg/m2/day, administered on weekdays, repeated every 3-4 weeks).
Staging of the tumor and pathological effectiveness of NACRT. The staging of the tumor and the effects of NACRT were assessed based on the criteria in the Guidelines for the Clinical and Pathologic Studies on Carcinoma of the Esophagus by the Japanese Society for Esophageal Diseases (12). The details of pathological evaluations are as follows: markedly effective (grade 3), all cancer cells were destroyed with no evidence of viable cancer cells; moderately effective (grade 2), most (more than two-thirds) of the cancer cells were damaged, despite the continued presence of viable cancer cells. In this study, slightly effective cases (grade 1) and ineffective cases (grade 0) were regarded as ineffective. The pStage was determined not only based on the viable cancer cells but also on the scar tissue affected by NACRT.
We compared the clinicopathological features, as well as the prognosis, of the patients according to the effects of NACRT. We divided the patients into two groups, those whose pathological effects were grade 3 (n=16) and those who were grade 0-2 (n=60), because the outcome of the patients was clearly different between the groups.
Statistical analysis. The differences in distribution frequencies among the groups were evaluated using Fisher's exact test or unpaired t-test. The survival curves were plotted according to the Kaplan-Meier method and any differences were analyzed using the log-rank test. Differences were considered to be significant if the p-value was less than 0.05.
The survival curves of cStageII-III ESCC patients in the surgery alone group and in the NACRT group. The 5-year survival rate was 56.5% in the NACRT group and 47.7% in the surgery alone group, which was not significantly different (p=0.4831).
Results
Outcome of NACRT in patients with cStageII-III ESCC. The survival curves of cStageII-III ESCC patients in the surgery alone group and the NACRT group are shown in Figure 1. The 3-year and 5-year survival rate was 61.5% and 56.5% in the NACRT group and 50.1% and 47.7% in the surgery alone group (p=0.4831). As shown in Figure 2, there were no significant differences in the prognosis between the patients in the surgery alone group and the NACRT group, regardless of disease stage (cStageII, p=0.7387, cStageIII, p=0.4370).
Pathological effects of NACRT and prognosis. Among the 76 patients who received NACRT, grade 3 and grade 2 responses were observed in 16 (21.1%) and 26 patients (34.2%), respectively. In the other 34 (44.7%) patients, the pathological effects of NACRT were grade 0/1.
No significant differences were observed with regard to clinical background between the patients with grade 0-2 and grade 3 responses (Table II). The survival of patients whose pathological effects were grade 3 was clearly better than those with grade 2 or grade 0/1: the 5-year survival rate was 100%, 53.8% and 36.9%, respectively (Figure 3). The log-rank test was inapplicable because no events were observed in the patients with grade 3 responses.
NACRT and postoperative complications. Table III shows the postoperative complications and hospital mortality of each group. The incidence of postoperative complications was 31.5% in the surgery alone group and 40.8% in the NACRT group (p=0.2121). Pulmonary complications developed in 12.0% of patients in the surgery alone group and in 19.7% of patients in the NACRT group (p=0.1621). Anastomotic leakage developed in 17.4% of the surgery alone patients and in 25.0% of the NACRT patients (p=0.2268). Regarding in-hospital mortality, there were no significant differences between the groups: the incidence was 3.3% in the surgery alone group and 0% in the NACRT group (p=0.1122).
The survival curves of cStageII (a) and cStageIII (b) ESCC patients in the surgery alone group and the NACRT group. The 5-year survival rates were not significantly different (cStageII: p=0.7387, cStageIII: p=0.4370).
Discussion
For surgically resectable esophageal cancer, whether or not NACRT actually increases long-term survival remains controversial. Urba et al. (4) reported that in randomized trial, NACRT versus surgery alone for patients with potentially resectable esophageal carcinoma did not demonstrate a statistically significant survival difference. Burmeister et al. (5) reported that NACRT with cisplatin and 5-FU did not significantly improve progression-free or overall survival for patients with resectable esophageal cancer compared with surgery alone, however, the subgroup analysis showed that patients with ESCC had better progression-free survival with NACRT than did those with non-squamous carcinomas. In randomized trials in Western countries, the patients usually have different pathological types (i.e. adenocarcinoma and ESCC). No clearly recommended protocols have so far been established regarding either the radiation dose and field, or the chemotherapy regimen for the treatment of surgically resectable esophageal cancer. We therefore need to pay careful attention when we introduce new treatments based on evidence from Western countries to our practice in Japan. In this study, there was no significant difference between the patients with and without NACRT, thus suggesting that NACRT has no clinical significance for patients with cStageII-III ESCC. However, the incidence of clinical T1b was significantly lower in the NACRT group than in the surgery alone group. As a result, this incidence may have affected the clinical results of NACRT in this study.
Clinical background according to the pathological effect of NACRT.
Overall survival after esophagectomy according to the pathological effectiveness of NACRT in patients with ESCC who underwent NACRT. Each grade indicates the pathological effectiveness (grade 0, 1: ineffective or slightly effective; grade 2: moderately effective; and grade 3: markedly effective). The 5-year survival rate of patients in whom the response to NACRT was grade 3 (100%) was clearly better than that of patients whose pathological response was grade 2 (53.8%), or grade 0/1 (36.9%).
In Japan, a recent randomized trial of postoperative adjuvant chemotherapy with cisplatin and 5-FU versus neoadjuvant chemotherapy for cStageII-III ESCC (JCOG 9907) rendered a dramatic change in the daily practice of esophageal surgery (13). Preoperative chemotherapy with cisplatin and 5-FU followed by surgery improved overall survival without additional serious adverse events in the treatment for cStage II-III ESCC. Preoperative chemotherapy with cisplatin and 5-FU is, therefore, regarded as a new standard treatment for cStage II-III ESCC. However, preoperative cisplatin and 5-FU-induced down-staging and R0 resection were reported to be less beneficial in cStage III than in cStage II disease. This suggests that a more powerful preoperative treatment than the cisplatin and 5-FU regimen may be necessary for patients with cStage III ESCC. We retrospectively evaluated the effectiveness of NACRT as a treatment for cStage II-III ESCC in this study. However, we need to make efforts to conduct further prospective randomized trials including NACRT in order to clarify its usefulness.
In terms of the long-term survival after NACRT followed by surgery for esophageal cancer, the response to NACRT has been reported to be the most important factor. Swisher et al. (14) emphasized that pathologic response is an independent risk factor for survival and proposed revision of the esophageal cancer staging system to accommodate pathologic response following NACRT. However, factors associated with pathological complete response are still unclear. We had previously performed a multivariate analysis, and the depth of invasion was found to be an independent factor associated with the clinical response to NACRT (15). In this study, no differences were observed in the background between the patients with grade 3 and those with grade 0-2 responses. It is thought to be clinically difficult to predict the effect of NACRT before treatment.
Mortality and morbidity according to NACRT.
Regarding anticancer drugs, combination chemotherapy using cisplatin and 5-FU with radiation has been proven to be superior to radiation alone according to the RTOG 85-01 study (16). Our previous study supported the idea that pre-operative cisplatin and 5-FU administration improved patient prognosis, as well as the response to NACRT (15). Thus, in this study, we focused on the patients who received cisplatin and 5-FU regimens as NACRT in order to avoid a mixture of subjects having different treatment backgrounds.
The current study examining NACRT did not reveal NACRT to be associated with postoperative complications, including pulmonary complications. However, we have reported the clinical results of esophagectomy for 1,000 cases with esophageal cancer in our institute, and we found preoperative radiotherapy to be an independent risk factor for postoperative pulmonary complications (1). Regarding the mechanism of this increase in postoperative complications, suppression of immune function has been reported to be significant (17). In our previous report, multiple immunological measures in patients with esophageal cancer revealed that preoperative treatment induced significant reductions in the total lymphocyte count, phytohemagglutinin response, and natural killer cell activity, as well as a significant gradual decrease in the CD4+/CD8+ ratio (18). It has also been reported that NACRT for patients with ESCC results in the suppression of T-lymphocyte functions (19). Since NACRT induces a pronounced influence on the immune function, perioperative immunonutritional management might play a key role in reducing postoperative complications after NACRT.
NACRT for esophageal cancer must be associated with improvement in patient survival. Our current study strongly supports the notion that the patients who achieve pathological complete response show a better prognosis than non-responders, suggesting that strict determination of the indications for NACRT is important in order to avoid performing unnecessary NACRT. One approach to improving the outcome after NACRT is the use of molecular biological assessment of particular characteristics of the tumor. To identify biomarkers that predict the response of esophageal cancer to NACRT, gene expression analysis of pretreatment cancer biopsies from patients with esophageal cancer has been demonstrated to be significant (20).
The current study confirms that achievement of a pathological complete response is the most significant factor underlying the efficacy of NACRT. It is important not only to clarify the most useful diagnostic strategy for prediction of the effectiveness of NACRT, but also to identify the molecular markers associated with the effects of NACRT.
Acknowledgements
We thank Brian Quinn for assisting with the preparation of the manuscript.
- Received May 5, 2011.
- Revision received June 14, 2011.
- Accepted June 15, 2011.
- Copyright© 2011 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved
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