Trimodality therapy of esophagectomy plus neoadjuvant chemoradiotherapy improves the survival of clinical stage II/III esophageal squamous cell carcinoma patients

The prognosis of advanced esophageal cancer patients is poor. Trimodality therapy of surgical resection plus neoadjuvant chemoradiotherapy (CRT) has been developed to improve survival through locoregional control, leading to prevention of micrometastasis. We investigated whether or not neoadjuvant CRT led to survival benefits in TNM stage II/III esophageal cancer patients. We retrospectively reviewed 62 patients with stage II or III esophageal squamous cell carcinoma (ESCC) treated with neoadjuvant CRT. All patients received esophagectomy 4–7 weeks after CRT consisting of 40 Gy irradiation and chemotherapy (5-FU, 500 mg/m2/day, days 1–5 and cisplatin, 10–20 mg/body, days 1–5). Clinical response and survival rates were analyzed using Kaplan-Meier methods, with P<0.05 considered as significant. The clinical effect rate of CRT for both primary tumors and metastatic nodes was 82.3%. Operative and hospital mortality rates were 1.65 and 6.5%, respectively. The 3-year overall survival (OS) and disease-free survival (DFS) rates were 52.6 and 49.2%, respectively. A significant difference was noted between stages II and III for both OS and DFS. The 5-year OS rates were 64.2% for stage II, 33.1% for stage III (T4 and non-T4) and 46.9% for stage III (non-T4 only) patients. The depth of tumor invasion (T3 vs. T4), resectability (R0 vs. R1, R2), lymph node metastasis (positive vs. negative), and the effect of CRT were proven to be independent prognostic factors for univariate analysis, with resectability and the effect of CRT for multivariate analysis. These data suggest that CRT in stage II/III (non-T4) ESCC patient contributed to tumor shrinkage, leading to higher resectability and longer survival. Neoadjuvant CRT appears to be a promising option for these patients.


Introduction
Esophageal cancer is one of the most aggressive malignancies and is associated with a poor prognosis because of early metastasis to lymph nodes as well as distant organs (1)(2)(3). Esophageal squamous cell carcinomas (ESCCs) are far more common in Asian countries including Japan, whilst adenocarcinomas of the lower third of the esophagus are often seen in Western countries. In 2005, 11,182 Japanese died from esophageal cancer according to the Japanese Ministry of Health, Labour and Welfare. Surgery has been considered the treatment of choice for patients with locoregionally confined esophageal carcinoma. However, the 5-year survival rate is less than 25% worldwide (4)(5)(6).
In Japan, the survival rate has been improving during the past two decades since three field lymphadenectomy was advocated by Isono et al (7) and Akiyama et al (8) and it is now widely performed. According to the comprehensive registry of esophageal cancer in Japan (3rd edition) (9), the current survival rates of clinical stage IIA, IIB and III patients categorized by UICC (10) are reportedly 47.5, 45.1 and 33.3%, respectively. These results were rather disappointing in spite of vigorous lymphadenectomy. The bottom-line in esophageal cancer treatment is locoregional control, and the locoregional failure rate after esophagectomy has been reported to be approximately 30% for patients who received R0 resection (11). Likewise, the locoregional recurrence rate (which included persistent disease and locoregional recurrence) is 50-55% after definitive chemoradiotherapy (CRT) without surgery (12,13).
To resolve these locoregional failures, multimodality therapy involving the combination of surgery and CRT has been developed. The most common approach is preoperative CRT followed by esophagectomy, called trimodality therapy (14,15). This approach offers the potential advantage of tumor downstaging, less dissemination of malignant cells during surgery and prevention of micrometastasis. Nine randomized trials have been performed in patients with locoregionally confirmed esophageal cancer who received preoperative CRT compared with surgery alone (15)(16)(17)(18)(19)(20)(21)(22)(23). Two of these 9 studies showed an improved outcome despite a small number of Trimodality therapy of esophagectomy plus neoadjuvant chemoradiotherapy improves the survival of clinical stage II/III esophageal squamous cell carcinoma patients patients (15), while the other studies showed no survival benefits in the trimodality therapy group. Therefore, the benefits of preoperative CRT are still controversial.
There is no randomized study ongoing or being planned related to preoperative CRT of ESCC in Japan because of technical difficulties both in surgery and radiotherapy. Since 1996, we have introduced preoperative CRT using 5-fluorouracil (5-FU) and cisplatin (CDDP) combined with radical surgery for the treatment of advanced esophageal cancers, and have reported increased resectability, a reduced incidence of both local recurrence and distant metastasis, and a more favorable prognosis for CRT responders (24). In the present study, we re-evaluated the feasibility and efficacy of preoperative CRT and investigated whether a survival benefit was obtained for stage II/III ESCC patients receiving neoadjuvant CRT.

Patients and methods
Patients. We performed a retrospective review of 80 consecutive patients with esophageal cancer who received esophagectomy after neoadjuvant CRT between August 1997 and October 2007 at the Department of Surgery, Hyogo College of Medicine, Japan. Sixty-two of the 80 patients had clinical stage II or III disease based on the UICC TNM Classification of Malignant Tumors (5th edition) (10), as determined by CT scan and/or endoscopic ultrasound examination findings, and underwent concurrent CRT followed by esophagectomy.
The eligibility criteria of this study were as follows: <80 years old, adequate organ function (WBC≥3500, Hb≥10 g/dl, ALT/AST≤2x upper limit of normal, platelets ≥100,000, serum creatinine≤1.3), and a performance status (Eastern Cooperative Oncology Group) of <2 at the time of admission (Table I).
Preoperative radiotherapy was performed for 5 days per week (Monday to Friday, 2 Gy/day) using a linear accelerator (Mevatron KD2; Siemens, Germany). The radiation field encompassed the primary tumor volume (as defined by endoscopy, esophagography and CT scan) with a 3-cm margin in each cephalad and caudal direction and 4-cm horizontal margins. If the lymph nodes metastasis was detected by a CT scan, the radiation field was extended to include the primary tumor and metastatic lesions. The patients received 20 fractions of 2 Gy for a total of 40 Gy of radiation. Concurrent chemotherapy consisted of 5-FU (500 mg/m 2 /day) administration for a 120-h continuous intravenous infusion starting on Day 1 and CDDP (15-20 mg/day) for a 2-h intravenous infusion on Days 1-5, repeated after 3 weeks.
Two to three weeks after the completion of radiotherapy, the effects of CRT on the primary tumor and metastatic nodes were assessed using chest CT scanning, barium esophagography, and/or upper gastrointestinal endoscopy. The response to therapy was defined as confirmed by esophagography or esophagoscopy and CT scans according to the criteria of the Japanese Society of Esophageal Disease (9th edition) (25): i) complete response (CR), 100% regression of cancer; ii) partial response (PR), >50% regression of the primary tumor and metastatic nodes; iii) progressive disease (PD), defined as increase of 25% in the size of the primary tumor or metastatic nodes or the appearance of new lesions; and iv) no change (NC) defined as a decrease of <50% in the size of the primary tumor and metastatic nodes and no evidence of tumor progression.
Esophagectomy was planned for 4-7 weeks after the completion of CRT. Most patients underwent thoracotomy, laparotomy, and cervicotomy to perform esophagectomy with 2-or 3-fields lymphadenectomy, and gastroesophageal anastomosis at the left side of the neck. Radical resection (R0) was defined as the removal of all macroscopic tumors, no evidence of distant metastasis, the absence of a microscopic residual tumor, free resection margins, and lymphadenectomy extending beyond the involved nodes. Resection was defined as non-radical when a microscopic (R1) or macroscopic (R2) residual tumor was found according to the TNM criteria (10). Informed consents were obtained in all patients.
Statistical analysis. Overall survival (OS) was defined as the time from the data of initial treatment to patient death or the data of the last available information on the vital status. Disease-free survival (DFS) was defined as the length of time after treatment during which no cancer was found. Differences between the cumulative survival rates of the patient groups were calculated by the log-rank test for comparison using Kaplan-Meier survival curves. Statistical significance was considered at values of P<0.05. Univariate analyses were used to examine the patients' characteristics and other prognostic factors. Multivariate analyses were employed for the identification of prognostic factors with the Cox proportional hazard model. Statistical analyses were carried out using the Statistica software, version 06J (StatSoft, Tulsa, OK, USA), and SPSS version 16 (SPSS, Tokyo, Japan).

Results
Patient characteristics. The patient characteristics of this study are summarized in Table I. All tumors were histologically confirmed to be ESCC. The gender was biased toward males (male/female, 50:12). The mean age was 60.83 years   Table IV. Lymph node metastasis, depth of tumor invasion and resectability showed significant differences in the prognostic value (P<0.01). Furthermore, the patients who were CRT responders showed significantly longer OS compared to those who were not (P<0.001). Using multivariate analysis, resectability and the effect of CRT were independent prognostic factors for OS (Table V).

Discussion
We have previously reported that preoperative CRT contributes to improve the resectability in patients with ESCC, and     that surgical esophagectomy remains the standard therapy for CRT responders (24). In this study, we focused on the characteristics of the UICC stage II/III ESCC, and analyzed whether this trimodality therapy combined with neoadju-vant CRT and esophagectomy improved the outcome of the patients.
This retrospective study showed that the 5-year OS rates of cstage II/III esophageal cancer patients were 64.2 and 33.1%, respectively. On the other hand, those of UICC clinical stage II/III patients after esophagectomy were reported to be from 47.5% (stage IIA) to 33.3% (stage III) by the Comprehensive Registry of Esophageal Cancer in Japan (9). These data suggest that the addition of neoadjuvant CRT is beneficial regarding the outcome of stage II patients. We failed to show the survival benefit of neoadjuvant CRT in stage III patients. However, this is thought to be due to the biased demographics in our study; more advanced T4 patients comprised approximately 50% in stage III patients. Actually, subgroup analysis showed that trimodality therapy improved the outcome of T3 more than T4 patients in stage III.
Notably, a large-scale study by Burmeister et al revealed that 5-FU/CDDP (FP) plus radiation (35 Gy) followed by esophagectomy for ESCC improves DFS, but not for all patients including those with adenocarcinoma (22). This report has encouraged us to continue trimodality therapy for ESCC in Japan. In any case, it is difficult to evaluate these randomized studies unitarily, because all these randomized phase III reports have flaws due to their wide variation in CRT protocols, short follow-up duration, different histological types, different stages, and different operative procedures. Moreover, we are urged to standardize the regimen of chemotherapeutic agents and radiation dose. Courrech Staal et al systematically reviewed the benefits and risks of neoadjuvant CRT for esophageal cancer, and reported that FP was the widely used mainstay in CRT regimens all over the world (27). Therefore, it sounds reasonable that the standard chemotherapeutic regimen needs to be established based on FP regimen in Asia as well as in Western countries. The standard regimen of definitive CRT advocated by Intergroup INT0123 (RTOG9405) consists of 2 cycles of 5-FU (1,000 mg/m 2 /24 h for 4 days) and CDDP (100 mg/m 2 /bolus on Day 1) with 50.4 Gy irradiation (13). In Japan, the regimen of neoadjuvant CRT should also be determined on the basis of the INT123 study, and the concurrent radiation dose should be discussed considering the safety of surgery. In this study, CRT consists of 5-FU (500 mg/m 2 /24 h for 5 days) and CDDP (15-20 mg/bolus for 5 days) with 40 Gy irradiation as a result of discussion with radiologists. The chemotherapeutic and radiation doses in our regimen were lower than those in the INT0123 study, but our setting dose was sufficient to show the efficacy and safety with tolerability. Hospital mortality after esophagectomy following CRT was reported to be 5.2% in Courrech Staal's review, which was compatible with that in our study (27). The clinical response rates were assessed in this study. Those of the primary tumor ranged from 59 to 87% in previous preoperative randomized or non-randomized studies (17,18,21,28,29). Meanwhile, our study showed that the clinical response rate using the Japanese Guidelines for Esophageal Disease was 83.9% for the primary tumor and 70% for metastatic nodes.
Regarding the radiation field, the optimal radiation field design remains controversial (30)(31)(32)(33)(34). Hsu et al (30) compared the patients with AJCC stage II/III ESCC undergoing preoperative CRT (median, 36 Gy) followed by radical esophagectomy with or without elective nodal irradiation (ENI). As a result, ENI reduced the M1a failure rate, but was not associated with improved outcomes in the patients undergoing preoperative CRT. Zhao et al (33) also evaluated 3D-CRT (irradiating only the primary tumor and positive lymph nodes) for ESCC, and concluded that the omission of elective nodal irradiation was not associated with a significant failure in lymph node regions not included in the planned target volume. In our study, we planned a radiation field including both the primary tumor and metastatic lymph nodes which were identified by an enhanced CT scan. Namely, we planned the irradiation field minimally to prevent operative and postoperative complications. Consequently, CRT minimized postoperative complications as we expected and improved the prognosis beyond our expectations, especially with the marked clinical response for metastatic nodes. In China, Zhao et al also used the same radiation field setting (33). In this way, the minimum setting for the primary tumor and metastatic nodes may be promising to achieve fewer complications and more prognostic benefits.
A recent meta-analysis revealed that a significant survival benefit for neoadjuvant CRT was evident for patients with resectable esophageal cancer with no increase in the morbidity rate [hazard ratio (HR), 0.81], and that definitive CRT did not demonstrate any survival benefit over other curative strategies (35). Intriguingly, neoadjuvant chemotherapy (without radiation) did not show any survival benefit (HR, 0.93). In Japan, preoperative chemotherapy with FP has been regarded as the standard treatment for patients with stage II/III (non-T4) ESCC by the JCOG 9204 and 9907 trials (36,37). However, some critical problems were pointed out in these prospective randomized studies. First, there was a significant difference in subject numbers between pre-and postoperative chemotherapy groups (P= 0.04) Secondly, patients with the pN0 status did not undergo postoperative chemotherapy in reality. Therefore, future clinical trials should resolve these above-mentioned problems. The 5-year OS in stage II/III (T3) patients in our study was higher than that in the JCOG study (63.3 vs. 55%, respectively). We strongly propose that preoperative CRT be included in the next JCOG study to evaluate the efficacy of CRT more objectively in Japan.
In conclusion, preoperative CRT for cstage II/III (non-T4) ESCC patients contributed to high response rates for both the primary tumor and metastatic nodes and showed satisfactory outcome with tolerable morbidity and mortality. A phase II study is needed to better clarify the standard neoadjuvant CRT regimen through a large prospective randomized trial.