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10.1245/s10434-006-9075-z
Annals of Surgical Oncology 13:1724-1731 (2006)
© 2006 Society of Surgical Oncology
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Original Article

REG I Expression Predicts Long-term Survival among Locally Advanced Thoracic Squamous Cell Esophageal Cancer Patients Treated with Neoadjuvant Chemoradiotherapy Followed by Esophagectomy

Satoru Motoyama, MD1, Toshihiro Sugiyama, MD2, Yasuharu Ueno, MD2, Hiroshi Okamoto, MD3, Shin Takasawa, MD4, Hiroshi Nanjo, MD5, Hitoshi Watanabe6, Kiyotomi Maruyama, MD1, Manabu Okuyama, MD1 and Jun-ichi Ogawa, MD1

1 Department of Surgery, Akita University School of Medicine, Akita, Japan
2 Department of Biochemistry, Akita University School of Medicine, Akita, Japan
3 Department of Advanced Biological Sciences for Regeneration (Kotobiken Medical Laboratories), Tohoku University Graduate School of Medicine, Sendai, Japan
4 Department of Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan
5 Department of Pathology, Akita University School of Medicine, Akita, Japan
6 Central Research Laboratory, Akita University School of Medicine, Akita, Japan

Correspondence: Address correspondence and reprint requests to: Satoru Motoyama, MD; E-mail: motoyama{at}doc.med.akita-u.ac.jp


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: The prognosis for patients with locally advanced thoracic esophageal cancer is extremely unfavorable. We have been administering neoadjuvant chemoradiotherapy (CRT) followed by esophagectomy to these patients and studying whether REG I expression in untreated endoscopic biopsy specimens is predictive of patient responsiveness to CRT and/or survival after treatment.

Methods: Between 1992 and 2003, 47 patients with T4 (direct invasion of adjacent organs) thoracic esophageal cancers were administered neoadjuvant CRT followed by esophagectomy. REG I expression was assessed in untreated endoscopic biopsy specimens and correlated with clinical and histological responses and survival in 37 patients who had also undergone curative surgery.

Results: Among the 37 cases that received CRT followed by surgery, the therapeutic response rate for neoadjuvant CRT was 68%, and a complete histological response in resected specimens from the primary lesion was achieved in 8 (22%) patients. These clinical and histological responses to neoadjuvant CRT did not significantly correlate with survival, however. By contrast, 9 patients were judged REG-positive based on analysis of their untreated endoscopic biopsy specimens, and their cumulative survival rate was significantly higher than that of the 28 REG-negative patients (P = 0.0073). Univariate analysis showed REG I expression to be a prognostic factor (P = 0.0386) that increased the risk of death 8.4-fold.

Conclusions: Evaluation of REG I expression in untreated endoscopic biopsy specimens may provide a basis for new treatments of locally advanced thoracic squamous cell esophageal cancers.

Key Words: Esophageal cancer • Chemoradiotherapy • Esophagectomy • REG I • Prognosis


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Thoracic esophageal cancer is one of the most malignant of tumors, so that even among patients with resectable cancers the 5-year survival rate is poor.1–3 Furthermore, the prognosis of patients with locally advanced (T4; direct invasion to adjacent organs) thoracic esophageal cancer is even more unfavorable. Because curative resection is impossible in T4 patients, chemoradiotherapy (CRT) is employed as the first line therapy.4 In that regard, thoracic esophageal cancer patients often show good responses to CRT.4–5 Nevertheless, we have been unable to obtain a good survival rate among patients with T4 thoracic esophageal cancer using only CRT. Therefore, to improve survival among these patients, since 1992 we have been using neoadjuvant CRT in these patients to diminish the direct invasion of adjacent organs prior to esophagectomy with extensive lymph node dissection. Still, we often see early recurrence among these patients, though there are some who achieve long-term survival after surgery. This prompts us to question, what is the key to long-term survival following multimodal treatment of locally advanced thoracic esophageal cancer: CRT sensitivity, surgery or some other factor affecting thoracic esophageal cancer malignancy? To address this question, we evaluated the pathological chemoradiosensitivity in a group of T4 thoracic esophageal cancer patients who were treated with CRT prior to esophagectomy. Although the number of patients in the study was small, the survival data may provide a clue to a useful new strategy for treating locally advanced esophageal cancer.

The REG gene was first identified in regenerating pancreatic islets, and its product has long been known to be a specific mitogen for islet ß cells.6–7 However, recent advances in our understanding of the REG I gene has made it clear that some members play important roles in the proliferation of gastrointestinal tumors, including colon, hepatocellular and gastric carcinomas.8–11 This led us to hypothesize that REG I expression in endoscopic biopsy specimens of primary tumors from untreated patients with T4 thoracic esophageal cancer might be predictive of the sensitivity to CRT and/or patient survival after treatment. To test this idea, we assessed (i) the expression of REG I protein in untreated thoracic esophageal cancer specimens, (ii) the pathological response observed in resected esophageal tumors and (iii) survival after esophagectomy to determine which, if any, correlated with the clinical behavior of the tumor.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patients
Between 1992 and 2003, 392 consecutive patients with thoracic esophageal cancer underwent esophagectomy with extensive lymph node dissection at Akita University Hospital, Japan. Among these patients, 47 (12%) were diagnosed with T4 cancers (showing direct invasion to adjacent organs) without distant organ metastasis and received CRT preoperatively. Thereafter, transthoracic esophagectomy was carried out. These patients were then evaluated using esophagography, esophagoscopy, bronchoscopy, computed tomography (CT) and ultrasonography, and staging was carried out according to the tumor-node-metastasis (TNM) classification proposed by the International Union Against Cancer. In 7 of the patients, we were unable to perform curative surgery (R2); 1 patient was treated using a different CRT; 1 received surgery 3 months after CRT; and 1 was without an untreated endoscopic paraffin biopsy block. Ultimately, therefore, we enrolled 37 patients who had received more than 35 Gy irradiation and concurrent cisplatin- and 5-fluorouracil-based chemotherapy followed by curative surgery (R0 operation). All of the participants provided informed consent and signed a human subject institutional review board consent form. The clinicopathological background factors and clinical stage estimates are summarized in Table 1Go. Among the 37 patients, 3 died of operation-related causes within 3 months. Following CRT, adjacent T4 organs were partially resected in 10 patients (4 pericardia, 3 lungs, the membrane portion of 2 tracheas, the adventitia of 2 descending aortas, 2 pulmonary veins and 1 subclavian artery). Endoscopic biopsy specimens were obtained from all patients before the start of CRT and were used to assess REG I protein expression.


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  		TABLE 1. The clinical background factors
 
Chemoradiotherapy
Patients received CRT that included three cycles of continuous 5-fluorouracil at a dose of 250–300 mg/m2 per day, 5 days/week (total: 3750–4500 mg/m2). This was combined with four cycles of cisplatin at a dose of 25 mg/m2 per day (total: 100 mg/m2) or three cycles of 3 mg/m2 per day, 5 days/week (total: 45 mg/m2), along with concomitant radiotherapy (daily dose, 1.8–2.0 Gy; total dose, 35–40 Gy). If invasion of surrounding organs by the T4 esophageal tumor was still evident, the irradiation was increased to 60 Gy.

The responses to CRT were evaluated by three clinicians on the basis of the results of esophagography, esophagoscopy, bronchoscopy, CT and ultrasonography. The effectiveness was classified into four categories according to the Guidelines for the Clinical and Pathologic Studies on Carcinoma of the Esophagus of the Japanese Society for Esophageal Diseases12: complete response (CR), partial response (PR), no change (NC) and progression of disease (PD). CR was defined as 100% regression of all tumors, PR as a 50% reduction in the sum of the longest diameters of the tumors after 4 weeks, NC as less than 50% reduction in the tumor, and PD as a 25% enlargement of the tumor or the appearance of a new tumor. Surgical resection was considered to be indicated when there was down-staging of the tumor from T4 to T3. Surgery was performed approximately 4 weeks after the final dose of radiotherapy and, on the basis of the histological findings, the resected specimens were classified by pathologists into three categories according to the following guidelines12: grade 3, no viable cancer cells in the resected specimens; grade 2, viable cancer cells accounting for less than one-third of the tumor tissue; grade 1, viable cancer cells accounting for more than one-third of the tumor tissue; grade 0, no effect of CRT on the cancer cells and tissues. The patients were followed up in outpatient clinics, where diagnostic examinations consisting of chest X-ray, esophagography, endoscopy, CT and ultrasonography were performed every 6 months to detect recurrence. The longest follow-up period was 152 months, the median 22 months.

Immunohistochemistry
Deparaffinized sections of endoscopic biopsy specimens of esophageal cancer were incubated overnight at 4° C in phosphate-buffered saline containing anti-REG I monoclonal antibody (1:400 dilution), after which they were incubated for 20 min with Envision (Dako Corporation, Copenhagen, Denmark). The REG I antigen was then visualized by incubating the specimens for 1 min with diaminobenzidine solution (Dako) and hydrogen peroxide. Negative controls were treated with the same procedures except that the primary antibody was omitted.

We used the following criteria to assess the immunohistochemical results. The area of REG I staining received a score of 1 if 10% or more but less than 50% of tumor cells were stained, a score of 2 if 50% or more but less than 90% were stained, and a score of 3 if 90% or more were stained; if less than 10% of tumor cells were stained, the sample received a score of 0. We also scored the REG staining intensity from 1 to 3 and then calculated a REG index (0–9) as REG-positive area (0–3) x REG intensity (1–3). The evaluation of REG staining was done by a pathologist and a surgeon.

Analysis
Values are expressed as means ± SD. Categorical data were compared using the chi-squared test and Fisher’s exact test. Survival rates were estimated using the Kaplan-Meier method, and statistical analysis was carried out using the Log rank test for equality of the survival curves (Stat View J-5.0, Abacus Concepts, Berkeley, CA). For the univariate analyses, independent prognostic factors were determined using a Cox proportional hazards model (Stat View J-5.0). Values of P < 0.05 were considered significant.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
CRT Response
Of the 37 patients who received neoadjuvant CRT followed by surgery, the responses of 4 patients were graded as CR and those of 21 were graded PR, making the therapeutic response rate (CR + PR = 25) 68%. A complete histological response (grade 3) in resected specimens from the primary lesion was achieved in 8 (22%) patients, but 3 were histologically positive for lymph node metastasis after neoadjuvant CRT. Grade 2 was achieved in 16 cases, 11 were grade 1 and 2 were grade 0. Seven patients are alive without recurrence of their esophageal cancer, the longest survival being 152 months. Notably, the 25 patients showing a therapeutic neo-adjuvant CRT response (CR + PR) did not show significantly longer survival than those who did not respond (NC) (Fig. 1Go). Likewise, patients with histological CRT responses (grade 2–3) did not show significantly longer survival than those who did not respond (grade 0–1) to neoadjuvant CRT followed by surgery (Fig. 2Go).


Figure 1
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  		FIG. 1 A, B. Overall (A) and esophageal cancer-specific (B) 5-year survival rates among patients found to be clinically responsive to chemoradiotherapy (complete response + partial response; CR + PR) and those that were not responsive (NC).

 

Figure 2
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  		FIG. 2 A, B. Overall (A) and esophageal cancer-specific (B) 5-year survival rates among patients found to be histologically chemoradiotherapy responsive (grade 3–2) and those that were not responsive (grade 1–0).

 
REG I Expression in Endoscopic Biopsy Specimens
Immunohistochemical analysis of REG I protein expression and subsequent calculation of REG indexes enabled us to determine that the biopsy specimens fell into two groups: those with indexes of 6 or higher and those with indexes of 2 or lower (Figs. 3Go and 4Go). We defined the former group as positive and the latter as negative. Figure 4Go shows the REG indexes of the 37 patients; 9 were judged positive ( ≥ 6), while 28 were negative ( ≤ 2). The clinicopathological status did not differ between these two groups (Table 2Go), but the overall survival rate among the 9 patients with a positive REG index was significantly higher than that among the 28 patients with a negative REG index (5-year survival rates were 62% and 10%, respectively; P = 0.0073; Fig. 5AGo). Moreover, the esophageal cancer-specific survival rate among patients with a positive REG index was also significantly higher than among those with a negative index (5-year survival rates were 88% and 30%, respectively; P = 0.0128; Fig. 5BGo). Thus, REG I expression did not correlate with the clinical and histological CRT responses or with tumor differentiation (Table 2Go).


Figure 3
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  		FIG. 3 A, B. Immunohistochemical analysis showing REG I expression in a REG-positive (A index = 9) and a REG-negative (B index = 0) specimen.

 

Figure 4
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  		FIG. 4. REG indexes (0–9) calculated as REG-positive area (0–3) x REG intensity (1–3). See Materials and Methods.

 

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  		TABLE 2. The clinicopathological factors, tumor differentiation and chemoradiosensitivity between REG positive and negative groups
 

Figure 5
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  		FIG. 5. A, B. Overall (A) and esophageal cancer-specific (B) 5-year survival rates among REG-positive and REG-negative patients.

 
To determine the prognostic factors affecting esophageal cancer-specific 5-year survival, we carried out univariate analyses, taking into consideration the following 9 co-variates: age, gender, REG I expression (negative versus positive), tumor differentiation (well versus not well), clinical stage (stage IV versus stage III), clinical response for CRT (NC versus CR-PR), pathological response for CRT (grade 0–1 versus grade 2–3), pathological lymph node metastasis (positive versus negative), number of pathological lymph node metastases ( ≥ 3 versus < 3) (Table 3Go). The univariate analysis indicated that REG I expression (P = 0.0386) and the number of pathological lymph node metastases (P = 0.0012) were significant prognostic factors affecting esophageal cancer-specific 5-year survival, which respectively increased the risk of death 8.4- and 5.1-fold (Hazard ratio; Table 3Go).


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  		TABLE 3. Univariate analysis for esophageal cancer-specific 5-year survival
 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
In this study, we have been able to show that patients with locally advanced thoracic squamous esophageal cancer and expressing REG I protein in untreated endoscopic biopsy specimens achieved long-term survival when treated with neoadjuvant CRT followed by esophagectomy. This is the first report of a correlation between esophageal cancer survival and REG expression.

We administer CRT as the first line therapy for most T4 thoracic esophageal cancer patients; however, the clinical benefits of neoadjuvant CRT in patients with thoracic esophageal cancer is controvercial.13–15 The subjects receiving neoadjuvant CRT ( < 40 Gy irradiation, whenever possible) in the present study were limited to T4 patients; the purpose of the CRT in these cases was to down-stage the tumor and, thus, improve its resectability. All too often, however, the CRT is ineffective, valuable time is wasted and patients experience severe toxicity (nausea, esophagitis and leucopenia).4 Some patients, though, who respond to neoadjuvant CRT and then undergo their planned surgery, achieve long-term survival. If, therefore, we had some indicator with which to predict the CRT sensitivity and the prognosis after treatment, perhaps we could optimize the treatment protocols for T4 esophageal cancer patients, whose prognoses are typically very poor.

Recent investigations have shown that the status of p53 and p16 expression or the Ki-67 are predictive of the responsiveness to CRT and survival,16 and that there is a significant correlation between the CRT response and survival.16–17 Among our patients, by contrast, clinical and histological responses to CRT were not associated with significantly better survival than was seen among the non-responders. Perhaps this reflects the fact that we excluded patients who did not respond to CRT and, thus, did not receive surgery; all of the participants in the present study clinically down-staged from T4 to T3 and were then treated with esophagectomy. Among this group of patients, the CRT response was not predictive of who would most benefit from neoadjuvant CRT followed by surgery and who would be better off receiving definitive CRT without surgery.

It has been reported that overexpression of ATP7B in ovarian carcinoma is correlated with unfavorable clinical outcomes in patients treated with cisplatin-based chemotherapy.18 We therefore determined whether ATP7B expression could be considered a predictive marker of chemoradioresistance to cis-platin-based CRT. We did not, however, find a significant correlation between ATP7B expression and CRT sensitivity or survival. Apparently, ATP7B would not be a useful therapeutic target for improving the outcomes of patients with thoracic squamous cell carcinoma.

One important question is whether identification of these molecular markers present in small pretreatment endoscopic biopsy specimens reflects the characteristics of the whole tumor. To address that question, Takeuchi et al. compared the molecular markers in endoscopic biopsy specimens with those in primary esophageal squamous cell carcinomas resected without neoadjuvant CRT.16 They found that p53 and p16 staining of the biopsy specimens coincided with that in resected tumors in more than 75% the cases.

The REG gene family has four members (REG I–IV) and there is reportedly a clear association between REG I expression and islet cell replication.6,19 REG expression also has been detected in colon, pancreatic and gastric adenocarcinomas, but not in esophageal squamous cell carcinoma;20 ours is the first report of REG expression in that tumor type. Macadam et al. reported that expression of REG mRNA is associated with a poor prognosis in patients with colon carcinoma and that the REG mRNA status was the only variable in a Cox proportional hazards model that independently predicted tumor recurrence. Those authors proposed that REG mRNA expression may be a good marker for colon carcinoma.21 In addition, Yonemura et al. reported that REG mRNA and protein are expressed in some gastric tumors and are closely linked to an infiltrative growth pattern and to signet ring cell and poorly differentiated adenocarcinomas, which have poor prognoses.10 They suggested that inhibition of apoptotic signaling through a regenerative response mediated by REG protein may be partly responsible for the poor survival rate among patients with REG mRNA-positive tumors. However, Harada et al. reported that REG I plays a role in biliary carcinogenesis, which has good prognosis, probably via an effect on cell proliferation.22 We speculated that, in our patients’ REG-positive tumors, neoadjuvant CTR suppressed micrometastasis to distant organs and infiltration of surrounding lymph nodes and vessels, thereby enhancing local control by radiation therapy. The subsequent surgery completed local control, enabling some patients to achieve long-term survival. Further experimental and clinical studies will be needed to test this hypothesis, however.

Although the present study does not enable us to definitively conclude that REG I expression correlates with long-term survival of esophageal cancer patients following multimodal therapy, our REG-positive T4 patients generally achieved long-term survival (88% esophageal cancer-specific 5-year survival) when treated with neoadjuvant CRT followed by planned surgery. By contrast, REG-negative patients had poor survival (30%), even with effective CRT and surgery. This is particularly noteworthy because esophagectomy after definitive CRT often fails to be curative, and the patients are then subject to a variety postoperative complications and mortality.23–25 Even among patients that do not experience severe toxicity with definitive CRT, the survival rate is not good.4–5 This study may, thus, provide a useful new strategy for treating locally advanced esophageal cancer. The results suggest that patients with REG-positive endoscopic biopsy specimens may be best treated with neoadjuvant CRT and subsequent esophagectomy, whereas REG-negative patients may be best treated with definitive CRT without surgery. However, larger randomized studies will be needed to confirm the predictive values of REG I expression in tumors.

Received for publication March 25, 2006. Accepted for publication May 19, 2006.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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