© 2007 Foundation for Promotion of Cancer Research
Epidermal Growth Factor Receptor is a Possible Predictor of Sensitivity to Chemoradiotherapy in the Primary Lesion of Esophageal Squamous Cell Carcinoma
Department of Internal Medicine II, Osaka Medical College, Takatsuki, Osaka Japan
For reprints and all correspondence: Masahiro Gotoh, Department of Internal Medicine II, Osaka Medical College, 2-7 Daigakumachi, Takatsuki, Osaka 569-0802, Japan E-mail: in2030{at}poh.osaka-med.ac.jp
Received October 23, 2006; accepted May 28, 2007
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Abstract |
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 TOP Abstract INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONConflict of interest statementReferences |
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Background: Chemoradiotherapy (CRT) is currently performed for patients with esophageal squamous cell carcinoma (SCC). Some reports have revealed that patients who responded well to CRT had favorable outcomes, whereas poor responders conversely showed a worse prognosis. The aim of this study was to identify molecular markers predicting sensitivity to CRT.
Methods: We reviewed 62 patients with T3-4, N-any, and M-any esophageal SCC treated with definitive CRT. The regimen comprised protracted 5-fluorouracil infusion and a 2-h infusion of cisplatinum combined with radiation therapy (2 Gy/day) at a total radiation dose of 60 Gy. The expressions of epidermal growth factor receptor (EGFR), vascular endothelial growth factor, cyclin D1, and proliferating cell nuclear antigen were investigated immunohistochemically in biopsy specimens obtained before treatment from all 62 patients. The immunoreactivities were compared with responsiveness to CRT, as evaluated by endoscopy.
Results: The complete response rate of the primary tumor estimated by endoscopy was 62% (13/21) in patients in the EGFR-positive group. The difference in the CR rate between EGFR-positive and -negative groups was significant (p = 0.037). The immunoreactivities of the other molecular markers did not show a significant correlation with the responsiveness of the primary lesion to CRT. Multiple logistic regression analysis revealed that positive immunostaining for EGFR was significantly correlated with primary CR for CRT in esophageal SCC.
Conclusion: Among 62 patients with esophageal SCC, differences in the responsiveness of primary lesions to CRT were correlated with EGFR immunoreactivity assessed in the biopsy specimens. These results suggest that EGFR may help to predict the response of primary sites to definitive CRT in esophageal SCC, although the results should be confirmed in a larger, more homogeneous series.
Key Words: esophageal cancer • chemoradiotherapy • epidermal growth factor receptor
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INTRODUCTION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONConflict of interest statementReferences |
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Esophageal cancer is a typical refractory cancer with a poor prognosis among malignant tumors of the gastrointestinal tract. Even in operable cases, the outcomes of surgical treatment alone are poor in Western countries, and the 5-year survival rate has been reported to be 6–24% (1). However, as a local complete response (cCR) is obtained by radical chemoradiotherapy (CRT) in 40–60% of patients (2), CRT is also beginning to be performed widely for resectable esophageal cancers. While there has been no randomized comparative study of esophagectomy and radical CRT for operable esophageal cancers, a retrospective study reported that a survival rate comparable to that after esophagectomy was obtained by radical CRT (3). The prognosis of advanced localized esophageal cancer invading multiple organs has been considered very poor. Otsu et al., however, reported an overall CR (complete disappearance of the tumor) rate of 33% (18/54) and a 3-year survival rate of 23% after CRT without surgery in 54 patients with esophageal cancer clinically staged before treatment as T4/M1LYM (4), suggesting that even locally advanced esophageal cancer can be cured by radical CRT. Recently, important comparative studies of preoperative CRT vs radical CRT for locally advanced esophageal cancer (T3–4) were also performed almost simultaneously in Germany and France (5–7) The French study considered that definitive radiochemotherapy may be regarded as a standard treatment in responders. The German study was designed to perform surgery after CRT (40 Gy) in one group and to perform radical CRT (at least 65 Gy) in another group with chemotherapy before CRT in both groups. Since the 3-year survival rate exceeded 50% in the responders to chemotherapy in both groups (58% in the surgery group and 55% in the radical CRT group), it was concluded that surgery may not be necessary in these patients. On the other hand, the 3-year survival rate was low in the non-responders to chemotherapy in both groups (17.9% in the surgery group and 9.4% in the radical CRT group), but some patients in the surgery group survived for a long period after surgery, because the tumor could be resected completely while they did not respond to chemotherapy. Therefore, the study concluded that whether surgery should be performed after CRT or radical CRT for advanced localized esophageal cancer depends on the response to induction chemotherapy or induction chemo-radiotherapy. Therefore, if factors that allow prediction of the effect of CRT are found, a more effective therapeutic strategy can be expected. However, whether primary CR can be achieved by CRT is an important point if CRT is intended to be a radical treatment. Owing to the recent development of molecular biology, various target molecules related to the proliferation, infiltration and metastasis of cancer cells have been identified, and their relations with chemo- or radiosensitivity and the prognosis have been evaluated (8–11).
In this study, we investigated the relationships between the clinical effect (primary CR) of definitive CRT on the primary lesions of advanced esophageal cancer and molecular markers considered to be involved in cell proliferation and angiogenesis by examining biopsy specimens, and evaluated whether these molecular markers are useful as predictors of the effectiveness of treatment.
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PATIENTS AND METHODS |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONConflict of interest statementReferences |
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Subjects
The source of the study data was a database of esophageal cancer patients who received definitive CRT between July 1994 and July 2003 at Osaka Medical College. Sixty-two patients fulfilled the following criteria: (a) histologically proven esophageal squamous cell carcinoma; (b) no previous treatment; (c) PS on Eastern Cooperative Oncology Group scale 0–2; (d) those with an endoscopically evaluable primary lesion; (e) patients with adequate organ, bone marrow, liver, and renal functions; (f) patients with no severe complications; (g) clinically diagnosed T3-4, N-any, and M-any on the International Union Against Cancer tumor-node-metastasis (TNM) classification; and (h) informed consent was obtained before treatment. All patients were given the same regimen of definitive CRT.
Treatment Schedule
The treatment comprised protracted 5-fluorouracil (5-FU) infusion (400 mg/m2/day on days 1–5 and 8–12), and a 2 h infusion of cisplatinum (CDDP 40 mg/m2 on days 1 and 8) combined with radiation therapy (2 Gy/day) delivered for 3 weeks (5 days/week). These schedules were repeated twice every 4–5 weeks and the total radiation dose was 60 Gy. For patients who showed an objective response to treatment, additional chemotherapy was administered and consisted of a protracted infusion of 5-FU (800 mg/m2/day) on days 1–5 and a 2 h infusion of CDDP (80 mg/m2/day) on day 1. This treatment was repeated every 4 weeks for two courses. No further treatment was administered if no disease progression was observed.
Evaluation of Response Concerning the Primary Site and Survival
We assessed the primary site by way of the endoscopic response criteria proposed by Tahara et al. (12). Response at the primary site was evaluated as CR (primary-CR) by endoscopic examination when all of the following criteria were satisfied under observation of the entire esophagus: (a) disappearance of the tumor lesion; (b) disappearance of ulceration; and (c) absence of cancer cells in biopsy specimens. When these criteria were not satisfied, a non-CR was designated. Existence of an erosion, ulcer scar, and lugol-voiding lesion did not preclude a CR evaluation. The first evaluation was performed 1 month after the completion of CRT to determine whether or not disease progression was present. Although repeat assessments were not essential to confirm primary-CR after the criteria for a response were first met, endoscopic examinations were performed every 2 or 3 months. All 62 patients were reviewed according to the above criteria. Survival time was measured from the initiation of the first course of treatment to the date of death or the final date of survival confirmation.
Immunohistochemical Staining Methods
Pretreatment endoscopic biopsy specimens from 62 patients were assessed for epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), cyclin D1, and proliferating cell nuclear antigen (PCNA) expression. Immunohistochemical staining was carried out with the labeled streptavidin biotin (LSAB) method using a Dako LSAB kit (Dako, Carpinteria, CA, USA). Primary antibodies used for the immunohistochemical staining were as follows: anti-EGFR rabbit polyclonal antibody (1005; Santa Cruz Biotechnology Inc., Santa Cruz, CA, USA, dilution 1:100), anti-Cyclin D1 mouse monoclonal antibody (DOS-6; Novocasta, dilution 1:50), anti- PCNA mouse monoclonal antibody (PC-10; DAKO, Glostrup, Denmark, dilution 1:200), and anti-VEGF rabbit polyclonal antibody (A-20; Santa Cruz Biotechnology, Inc., Santa Cruz, CA, USA, dilution 1:100).
Formalin-fixed, paraffin-embedded biopsy materials were cut into 4 µm sections. After deparaffinization with three changes of xylene, and then dehydration in a graded alcohol series, the sections were heated in a microwave at 500 W for 5 min three times in 10 mM citrate buffer solution for the retrieval of antigenicity. Endogenous peroxide activity was blocked with 3% hydrogen peroxide at room temperature for 10 min. After being rinsed with phosphate-buffered saline (PBS), the sections were incubated with 10% normal bovine serum albumin (blocking buffer) in PBS for 30 min in order to reduce nonspecific background staining. Sections were then drained off and incubated overnight at 4°C with primary antibodies. After six rinses in PBS, sections were incubated with the secondary biotinylated anti-mouse antibodies for cyclin D1 and PCNA, and anti-rabbit antibodies for EGFR and VEGF for 20 min at room temperature. The primary antibodies were localized by the sequential application of biotinylated anti-mouse–rabbit IgG gout immunoglobins, streptavidin–peroxide conjugate (Dako, Carpinteria, CA, USA). Immunostaining was visualized by developing the slides in diaminobenzidine (DAB) and counterstaining with Meyer-hematoxylin. Finally, the sections were subjected to alcohol and xylene baths, and then mounted for examination. For negative controls, the primary antibody solutions were replaced by the blocking buffer.
Staining Evaluation
Immunohistochemical staining was evaluated by two authors without prior knowledge of the endoscopic response. The immunoreactivity of EGFR was graded into four groups according to the intensity of cell membrane EGFR staining in the whole tumor: high (markedly stronger staining than normal esophageal epithelium), medium (moderately stronger staining), low (the same staining level as normal epithelium), and negative (fainter staining). Strong and moderate staining groups were defined as positive for EGFR expression, in agreement with previous interpretations of EGFR in esophageal squamous cell carcinoma (10,13,14). VEGF staining was graded as follows: (a) +, staining intensity in cancer cells was stronger than that in stromal cells; (b) ±, staining intensity in cancer cells was equal to that in stromal cells; and (c) –?, staining intensity in cancer cells was weaker than that in stromal cells. The cases graded as + were defined as positive, as described in previous reports (15). The percentages of cyclin D1-positive tumor cells were calculated by counting the number of brown-stained tumor nuclei/total number of cancer cells in the most highly stained area on a high-power view (x400). Cut-off values were determined by the following estimation: cyclin D1-positive judgment was a more than 30% labeling index (16). The PCNA index was the percentage of nuclei staining positive (17). A PCNA score greater than 40 was taken as PCNA-positive.
Statistical Analysis
The 
2 test and Student's t-test were used to evaluate the association between the response of primary lesions and clinical variables. A logistic regression analysis was used to control for possible confounding factors. Survival curves of the patients excluding M1 disease were calculated by the Kaplan–Meier method and analyzed by the log rank test. Significance was defined as P < 0.05. Statistical analyses were conducted with the Stat View software (5.0 version)
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RESULTS |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONConflict of interest statementReferences |
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Patient Characteristics and Response
From July 1994 to July 2003, 62 patients fulfilled the inclusion criteria of our study, and their characteristics are presented in Table 1. There were 54 males and eight females with a median age of 68 years (range, 43–85 years). Twenty-one patients had tumors in the lower third of the esophagus, 28 in the middle third, and 13 in the upper third. All had histologically proven squamous cell carcinoma. In terms of the T stage, 49 patients had T3 invasion and 13 had T4 invasion. In terms of the N stage, 10 had N0 disease, and 52 patients had N1 disease. Twenty two cases of M1 disease were as follows: M1 LYM (n = 6), liver (n = 9), lung (n = 4), liver and lung (n = 2), and liver and bone (n = 1). Sixty-five percent (40/62) belonged to TNM stage II/III and the other 22 to stage IV. Primary-CR to CRT was seen in 44% (27/62) of patients. Primary-CR rates in patients with T3 and T4 were 47% (23/49) and 31% (4/13), respectively.
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Immunoreactivity
All 62 specimens were immunohistochemically evaluated for EGFR, cyclin D1, VEGF, and PCNA. Positive cyclin D1,PCNA immunoreactivities were detected in nuclei, whereas VEGF immunoreactivities were observed in the cytoplasm. EGFR expression was seen both on the cell membrane and in the cytoplasm (Figure 1). Positivity for EGFR, cyclin D1, VEGF, and PCNA was observed in 21, 21, 24, and 27 of 62 cases (34, 34, 39, and 44%), respectively. Table 2 shows the correlation between the immunohistochemical study and endoscopic response. Thirteen (62%) of the 21 patients with EGFR positivity achieved primary tumor CR. In contrast, 14 (34%) of the 41 EGFR-negative patients achieved primary tumor CR. The CR of the primary tumors tended to be higher in the EGFR-positive than -negative group, and the difference between the CR of the EGFR-positive and -negative groups was significant (P = 0.037). These results suggest that the immunoreactivity of EGFR in biopsy specimens has a significant correlation with the sensitivity to CRT. Other immunohistochemical markers do not show significant correlations with the sensitivity to CRT. Table 3 shows the correlation between each T stage and immunohistochemical markers. In T3 stages, similar results were obtained concerning EGFR (P = 0.07). However, there were no significant correlations between immunohistochemical markers and each T stage. On multiple logistic regression analysis, only EGFR was shown to be a significant predictor of primary CR in T3-4 esophageal SCC (Table 4).
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Survival
Patients with local disease (M0) comprised 40 cases. With a median follow-up of 11 months, the median survival time (MST) of all patients with T3-4M0 esophageal cancer given CRT was 16 months. Figure 2 shows the survival curves according to EGFR expression using Kaplan–Meier analysis. The MST of the EGFR-positive group was 18 months, and the MST of the EGFR-negative group was 19 months. There was no difference between the groups concerning EGFR expression (P = 0.645). Seven patients are still alive. The causes of death in the 33 patients who died consisted of 21 cases of locoregional disease (EGFR+, 6; EGFR–, 15), 11 cases of distant disease (EGFR+, 6; EGFR–, 5), and one case of treatment-related death due to radiation pneumonitis. There were no significant differences in the EGFR status and relapse site (P = 0.518).
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DISCUSSION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONConflict of interest statementReferences |
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In this study, we evaluated the usefulness of molecular biological markers for the prediction of the effectiveness of definitive CRT in patients with advanced esophageal cancer (T3–4). In patients with esophageal cancer, definitive CRT is often performed as a radical treatment, and whether primary CR can be achieved is very important. This study focused on the relationships between molecular biological markers and primary CR. Therefore, even M1 patients who underwent CRT for the primary lesion and in whom the responses were evaluable were included in the subjects. In this study, EGFR positive patients correlated with primary CR on multivariate analysis. However, the expression of cyclin D1, VEGF, or PCNA was not correlated with the response to CRT. By nature, EGFR is not only involved in the proliferation of tumor cells when stimulated by EGF, but also involved in their infiltration, metastasis, and angiogenesis. If tumor vessels are generated more vigorously in deep areas of the tumor in EGFR-positive patients among those with T3-4 highly invasive esophageal cancer, tumor cell proliferation is considered to contribute to high radiosensitivity, because cells are reported to be three times more radiosensitive in the presence of oxygen than in a severely hypoxic condition (22). Since the distribution of the drug to the lesion increases if more vessels are supplying the tumor, the increase in oxygen and drug transport to the lesion in the EGFR-positive patients may contribute to high radio-chemosensitivity. However, when the relationship between the EGFR expression and outcome was examined in 40 patients, excluding those with distant metastasis (M1), the median survival period was 18 months in the EGFR-positive group and 19 months in the EGFR-negative group, with no significant difference (P = 0.65). Also, no difference was observed in the first relapse site between the two groups.
There have been reports on the relationship between the outcome of surgically treated esophageal cancer and EGFR overexpression in surgical specimens (8,9,11), and the outcomes of tumors over-expressing EGFR were poor in all these reports. In particular, Kitagawa et al. reported that the median survival period was 9 months in patients with EGFR gene amplification but 42 months in those without EGFR gene amplification in 107 patients (P < 0.01) after radical surgery for esophageal cancer, and concluded that EGFR gene amplification is an independent prognostic factor. In our study, the survival rate of EGFR-positive patients appeared better by radical CRT, while positive EGFR has been regarded as a poorer prognostic factor after surgery. Local recurrence and distant metastasis were observed regardless of the EGFR expression, so that EGFR expression may not be a prognostic factor in radical CRT for locally advanced esophageal cancer.
Recently, various therapeutic strategies incorporating CRT such as neoadjuvant chemotherapy and radical CRT have been evaluated to improve the therapeutic results in esophageal cancer. There have been various opinions put forward regarding preoperative adjuvant CRT. The survival rate improved significantly with preoperative CRT compared with surgery alone in some reports (18), but no significant difference was noted in other reports (19,20), and its significance remains controversial. There is also a report that the outcomes were better in those who obtained a pathologic complete response (pCR) by preoperative CRT than in those who did not (21). Concerning the curability of treatment for advanced localized esophageal cancer, there was no clear difference between surgery and radical CRT, and even local advanced esophageal cancer impossible to curatively resection has been reported to be cured by CRT alone in some patients (3,4). Therefore, if predictive factors of the effectiveness of CRT can be found, more appropriate design of treatment for each patient may become possible, leading to an improvement in the outcome. In our present study, a close correlation was observed between the EGFR expression of biopsy specimens from primary lesions of esophageal cancer before treatment and primary-CR with CRT, but the high probability of recurrence even after CR cannot be ignored. Even in patients who are expected to respond markedly to CRT, salvage surgery must always be considered. On the other hand, surgery without CRT may be a better option in some patients who are not expected to respond sufficiently to CRT to avoid treatment-related death such as radiation pneumonitis. We hope that EGFR helps with the selection of treatment in the future and contributes to improvement in the outcome through optimization of individualized treatment. However, further studies including prospective ones are considered to be necessary to establish the usefulness of this biologic marker.
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Conflict of interest statement |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONConflict of interest statementReferences |
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None declared.
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References |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONConflict of interest statementReferences |
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1 Roth JA, Putnam JB Jr. Surgery for cancer of the esophagus. Semin Oncol (1994) 21(4):453–61.[Web of Science][Medline]
2 Brenner B, Ilson DH, Minsky BD. Treatment of localized esophageal cancer. Semin Oncol (2004) 31(4):554–65.[CrossRef][Web of Science][Medline]
3 Hironaka S, Ohtsu A, Boku N, Muto M, Nagashima F, Saito H, et al. Nonrandomized comparison between definitive chemoradiotherapy and radical surgery in patients with T(2–3)N(any) M(0) squamous cell carcinoma of the esophagus. Int J Radiat Oncol Biol Phys (2003) 57(2):425–33.[CrossRef][Web of Science][Medline]
4 Ohtsu A, Boku N, Muro K, Chin K, Muto M, Yoshida S, et al. Definitive chemoradiotherapy for T4 and/or M1 lymph node squamous cell carcinoma of the esophagus. J Clin Oncol (1999) 17(9):2915–21.
5 Stahl M, Stuschke M, Lehmann N, Meyer HJ, Walz MK, Seeber S, et al. Chemoradiation with and without surgery in patients with locally advanced squamous cell carcinoma of the esophagus. J Clin Oncol (2005) 23(10):2310–7.
6 Bedenne LPM, Bouche O, Triboulet J-P, Conroy T, Pezet D, Roullet B, Seitz J-F, Lacourt J, Milan C, Service d'Hepato, Gastroenterologie Chu, Le Bocage, Dijon Cedex, France CHU Charles-Nicolle, Rouen France, CHU Robert-Debre, Reims France, CHU Claude-Huriez, Lille France, Centre Alexis Vautrin, Nancy France, CHU Hotel-Dieu, Clermont-Ferrand France, CHU Dupuytren, Limoges France CHU, la Timone, Marseille France, Clinique Sainte-Marie, Chalon sur Saone, France FCD Statistical Center, Dijon France. Randomized phase III trial in locally advanced esophageal cancer: radiochemotherapy followed by surgery versus radiochemotherapy alone (FFCD 9102). Proc Am Soc Clin Oncol (2002) 21:130a.
7 Bonnetain F, Bouche O, Michel P, Mariette C, Conroy T, Pezet D, et al. A comparative longitudinal quality of life study using the Spitzer quality of life index in a randomized multicenter phase III trial (FFCD 9102): chemoradiation followed by surgery compared with chemoradiation alone in locally advanced squamous resectable thoracic esophageal cancer. Ann Oncol (2006) 17(5):827–34.
8 Ozawa S, Ueda M, Ando N, Shimizu N, Abe O. Prognostic significance of epidermal growth factor receptor in esophageal squamous cell carcinomas. Cancer (1989) 63(11):2169–73.[CrossRef][Web of Science][Medline]
9 Mukaida H, Toi M, Hirai T, Yamashita Y, Toge T. Clinical significance of the expression of epidermal growth factor and its receptor in esophageal cancer. Cancer (1991) 68(1):142–8.[CrossRef][Web of Science][Medline]
10 Itakura Y, Sasano H, Shiga C, Furukawa Y, Shiga K, Mori S, et al. Epidermal growth factor receptor overexpression in esophageal carcinoma. An immunohistochemical study correlated with clinicopathologic findings and DNA amplification. Cancer (1994) 74(3):795–804.[CrossRef][Web of Science][Medline]
11 Kitagawa Y, Ueda M, Ando N, Ozawa S, Shimizu N, Kitajima M. Further evidence for prognostic significance of epidermal growth factor receptor gene amplification in patients with esophageal squamous cell carcinoma. Clin Cancer Res (1996) 2(5):909–14.[Abstract]
12 Tahara M, Ohtsu A, Hironaka S, Boku N, Ishikura S, Miyata Y, et al. Clinical impact of criteria for complete response (CR) of primary site to treatment of esophageal cancer. Jpn J Clin Oncol (2005) 35(6):316–23.
13 Yano H, Shiozaki H, Kobayashi K, Yano T, Tahara H, Tamura S, et al. Immunohistologic detection of the epidermal growth factor receptor in human esophageal squamous cell carcinoma. Cancer (1991) 67(1):91–8.[CrossRef][Web of Science][Medline]
14 Gibault L, Metges JP, Conan-Charlet V, Lozac'h P, Robaszkiewicz M, Bessaguet C, et al. Diffuse EGFR staining is associated with reduced overall survival in locally advanced oesophageal squamous cell cancer. Br J Cancer (2005) 93(1):107–15.[CrossRef][Web of Science][Medline]
15 Boku N, Chin K, Hosokawa K, Ohtsu A, Tajiri H, Yoshida S, et al. Biological markers as a predictor for response and prognosis of unresectable gastric cancer patients treated with 5-fluorouracil and cis-platinum. Clin Cancer Res (1998) 4(6):1469–74.[Abstract]
16 Samejima R, Kitajima Y, Yunotani S, Miyazaki K. Cyclin D1 is a possible predictor of sensitivity to chemoradiotherapy for esophageal squamous cell carcinoma. Anticancer Res (1999) 19(6C):5515–21.[Web of Science][Medline]
17 Jain S, Filipe MI, Hall PA, Waseem N, Lane DP, Levison DA. Prognostic value of proliferating cell nuclear antigen in gastric carcinoma. J Clin Pathol (1991) 44(8):655–9.
18 Walsh TN, Noonan N, Hollywood D, Kelly A, Keeling N, Hennessy TP. A comparison of multimodal therapy and surgery for esophageal adenocarcinoma. New Engl J Med (1996) 335(7):462–7.
19 Bosset JF, Gignoux M, Triboulet JP, Tiret E, Mantion G, Elias D, et al. Chemoradiotherapy followed by surgery compared with surgery alone in squamous-cell cancer of the esophagus. New Engl J Med (1997) 337(3):161–7.
20 Urba SG, Orringer MB, Turrisi A, Iannettoni M, Forastiere A, Strawderman M. Randomized trial of preoperative chemoradiation versus surgery alone in patients with locoregional esophageal carcinoma. J Clin Oncol (2001) 19(2):305–13.
21 Rohatgi P, Swisher SG, Correa AM, Wu TT, Liao Z, Komaki R, et al. Characterization of pathologic complete response after preoperative chemoradiotherapy in carcinoma of the esophagus and outcome after pathologic complete response. Cancer (2005) 104(11):2365–72.[CrossRef][Web of Science][Medline]
22 Chapman JD, Dugle DL, Reuvers AP, Meeker BE, Borsa J. Letter: Studies on the radiosensitizing effect of oxygen in Chinese hamster cells. Int J Radiat Biol Relat Stud Phys Chem Med (1974) 26(4):383–9.[Medline]
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