Ann Surg Oncol DOI 10.1245/s10434-014-3688-4
ORIGINAL ARTICLE – GASTROINTESTINAL ONCOLOGY
The Usefulness of Neoadjuvant Chemoradiation Therapy for Locally Advanced Esophageal Cancer with Multiple Lymph-Node Metastases Hiroshi Okumura, MD, PhD1, Yasuto Uchikado, MD, PhD1, Itaru Omoto, MD1, Yoshiaki Kita, MD, PhD1, Ken Sasaki, MD, PhD1, Takaaki Arigami, MD, PhD1, Yoshikazu Uenosono, MD, PhD1, Daisuke Matsushita, MD1, Yoshiyuki Hiraki, MD, PhD2, Tetsuhiro Owaki, MD, PhD3, Sumiya Ishigami, MD, PhD1, and Shoji Natsugoe, MD, PhD1 1
Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medical Sciences, Kagoshima University, Kagoshima, Japan; 2Department of Radiology, Graduate School of Medical Sciences, Kagoshima University, Kagoshima, Japan; 3Education Center for Doctors in Remote Islands and Rural Areas, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan
ABSTRACT Background. The prognosis of patients with esophageal squamous-cell cancer (ESCC) and multiple lymph-node metastases is quite poor. We examined whether neoadjuvant chemoradiation therapy (CRT) has a beneficial effect in such patients. Methods. A total of 50 consecutive patients with T3–4 tumors and without organ metastases were prospectively enrolled. Of those patients, 20, who had four or more nodal metastases, underwent neoadjuvant CRT (CRT group), and the remaining 30 patients, who had three or fewer nodal metastases, underwent surgery alone (surgery group). CRT consisted of 5-fluorouracil plus cisplatin and 40 Gy of radiation. The groups’ clinical outcomes were compared. Results. Surgery was performed in 48 patients: all enrolled patients except for 2 who had organ metastasis after CRT. In the CRT group, the number of patients with pathological complete response was observed in 8 patients (44 %), mean nodal metastases number was changed from 8.2 to 2.6 and 9 patients had pN0. The 3-year survival rate was 76 % in the CRT group (4 patients relapsed) and 68 % in the surgery group (8 patients relapsed), which is not a statistically significant difference (P = 0.61).
Conclusions. Neoadjuvant CRT is beneficial for locally advanced ESCC with four or more lymph-node metastases.
The prognosis is poor for patients with esophageal squamous-cell cancer (ESCC) with multiple lymph-node metastases. In particular, the prognosis in patients with four or more lymph-node metastases is significantly poorer than in those with three or fewer.1 Preoperative endoscopic ultrasonography (EUS) is useful to diagnose clinical lymph-node metastases, with results that correlate well with pathological diagnoses.1,2 Chemoradiation therapy (CRT) has been investigated since the 1980s for the treatment of ESCC and is one of the most useful treatments available; however, it remains controversial whether neoadjuvant CRT provides a significant advantage.3–5 We hypothesized that neoadjuvant CRT might be less useful for those patients who could be cured with surgery alone. In this study, we examined the effect of neoadjuvant CRT on patients with ESCC and four or more lymph-node metastases and compared the outcome with that of patients with three or fewer nodal metastases treated with surgery alone. MATERIALS AND METHODS Patients
Ó Society of Surgical Oncology 2014 First Received: 30 January 2014 H. Okumura, MD, PhD e-mail: [email protected]
The study included 130 consecutive ESCC patients who were treated at the Department of Surgical Oncology and Digestive Surgery of Kagoshima University Hospital
H. Okumura et al. TABLE 1 Pretreatment clinicopathologic features Characteristics
CRT group (n = 20)
Surgery group (n = 30)
P value
Gender (male/female)
20/0
30/0
NS NS
Age (years)
64.0 ± 7.1
66.4 ± 9.0
cT3/T4
16/4
29/1
0.05
cN0/N1/N2/N3
0/0/12/8
7/8/15/0
\0.001
c-Number of metastatic LN
8.2 ± 5.3
1.9 ± 1.2
\0.001
cM0/M1
11/9
25/5
0.03
cStage II/III/IV
0/11/9
9/16/5
0.008
CRT chemoradiation therapy, NS not significant, c clinical
between January 2010 and December 2012. All patients had been preoperatively diagnosed and staged by esophagoscopy with biopsy, barium study, computed tomography (CT) scan of the neck, chest and abdomen, ultrasonography (US) of the neck and abdomen, EUS, and positron emission tomography (PET). Of these 130 patients, 50 had a T3 or T4 tumor without organ metastasis: 20 of these patients had four or more lymph-node metastases and underwent neoadjuvant CRT followed by curative surgery (CRT group); the other 30 patients, who had three or fewer lymph-node metastases, were treated with curative surgery only (surgery group). Patients in both groups underwent esophagectomy with lymph-node dissection, and the reconstruction was performed by cervical esophagogastric anastomosis using a gastric tube. In the CRT group, surgery was performed 4–6 weeks after completing CRT. After all patients had given their informed consent, the resected specimens were collected. The specimens were classified according to the International Union against Cancer tumor-node-metastasis (TNM) classification system.6 Patients in the CRT group did not undergo adjuvant chemotherapy because their immune system was weakened by multimodal treatment; however, 17 patients who had pathological lymph nodes metastases in the surgery group underwent adjuvant chemotherapy consisting of docetaxel, cisplatin plus 5-fluorouracil. All patients were followed up with CT every 3 months after discharge, US every 6 months, and endoscopy every 6–12 months. Follow-up data after surgery were available for all patients, with a median follow-up period of 21 months (range 7–37 months). Mode of recurrence was categorized as lymph node, hematogenous, or local. For patients whose disease relapsed, CRT or chemotherapy was performed according to the relapse site and condition of patients. The pretreatment clinicopathologic features of the study group are summarized in Table 1. All M1 tumors were due to distant lymph-node metastases. The mean number of lymph-node metastases in the CRT group and the surgery
group was 8.2 and 1.9, respectively. Thus, the CRT group had significantly more lymph-node metastases and more advanced stage. The CRT group also tended to have cT4 tumors. In the surgery group, 1 patient with cT4 had suspected tracheal invasion, but that was curatively removed and final diagnosis was pT3. There were 2 patients with pT4 invaded to lung and pleura that were curatively resected. The study was approved by the Institutional Review Board of Kagoshima University and performed according to the Helsinki Declaration.
Chemoradiation Therapy A total radiation dose of 40 Gy was applied: 2 Gy fractions were delivered 5 days per week for 4 weeks to the mediastinum and neck. Supraclavicular to lower mediastinal lymph-node as well as cardiac to celiac lymph-node areas were irradiated as a long T-shaped field for upper to lower thoracic tumors, and perigastric LN areas were additionally irradiated for lower tumors. In the same period, chemotherapy was performed intravenously using 2 anticancer agents: cisplatin (7 mg/m2 over 2 h) and 5-FU (350 mg/m2 over 24 h).1 Tumor response was evaluated by the Response Evaluation Criteria in Solid Tumors version 1.1.7 The clinical response to CRT was evaluated by the findings of esophagography, esophagoscopy, US, EUS, CT, and PET for the lymph-node metastases. The clinical criteria for the response of target lesions were: complete response (CR), the disappearance of all target lesions as well as secondary changes associated with the tumors; partial response (PR), at least a 30 % decrease in the sum of the greatest dimensions of target lesions, relative to the baseline sum of greatest dimensions; progressive disease (PD), at least a 20 % increase in the sum of greatest dimensions of target lesions, relative to the smallest sum of greatest dimensions recorded since the treatment started; and stable disease (SD), neither PR nor PD. The histological criteria for the response of CRT were: grade 0, neither necrosis nor cellular or structural changes can be seen throughout the lesion; grade 1, necrosis or disappearance of the tumor is present in no more than two-thirds of the whole lesion; grade 2, necrosis or disappearance of the tumor is present in more than two-thirds of the whole lesion but viable tumor cells remain; and grade 3, the whole lesion falls into necrosis and/or is replaced by fibrosis, with or without granulomatous changes. No viable tumor cells are observed.8,9 CRT was judged to be effective in patients whose histological response was grade 2 or 3, but ineffective in patients whose histological response was grade 0 or 1. Adverse events were diagnosed according to Common Terminology Criteria for Adverse Events v4.0.
The Usefulness of CRT in ESCC
Statistical Analysis Statistical analysis of group differences was performed using the v2 test and t test. The Kaplan–Meier method was used for survival analysis, and differences in survival were estimated using the log-rank test. The P values in this study were 2-sided, and P \ 0.05 was considered to indicate statistical significance. All statistical analyses were performed using the software package StatView version 5.0 (Abacus Concepts, Berkeley, CA, USA).
TABLE 2 Pathological diagnoses Characteristics
CRT group (n = 18)
Surgery group (n = 30)
P value
pT0/T1/T2/T3/T4
8/4/0/6/0
0/7/4/17/2
0.001
pN0/N1/N2/N3
9/4/4/1
13/9/3/5
NS
p-Number of metastatic LN
2.6 ± 4.4
2.4 ± 3.6
NS
pM0/M1
15/3
26/4
NS
pStage 0/I/II/III/IV
5/2/1/7/3
0/4/12/11/3
0.008
CRT chemoradiation therapy, NS not significant, p pathological
RESULTS
Of the 50 patients, surgical treatment was performed in 48, excluding 2 patients from the CRT group with bone or liver metastasis, although all 20 patients in the CRT group completed CRT. Grade 3 adverse effects comprised appetite loss (n = 1), leukopenia (n = 2), and anemia (n = 1). No serious complications requiring cessation of CRT were encountered. The number of patients with CR, PR, SD, and PD after CRT was 2, 11, 4, and 3, respectively. The number of patients with grades 1, 2, and 3 histological response was 8, 2, and 8, respectively. Pathological Findings Table 2 summarizes the pathological diagnoses for the study groups. There were no significant differences in pN, p-number of lymph-node metastasis, and pM between the CRT group and the surgery group. Unlike the pretreatment diagnoses reported in Table 1, the tumors in the surgery group had deeper wall invasion and more advanced stage than those in the CRT group. The mean number of nodal metastases in the CRT group changed from 8.2 to 2.6 after CRT and 9 patients became pN0; the surgery group did not see a significant change (from 1.9 to 2.4) (Tables 1, 2). Clinical Outcome No hospital deaths were reported in the study. Anastomotic leakage was found in 3 patients (16 %) from the CRT group and in 4 (13 %) from the surgery group. Serious pneumonia with mechanical ventilation was reported in 1 patient (6 %) from the CRT group, and thoracic empyema was experienced by 1 patient (3 %) from the surgery group. The incidence of morbidity was not significantly different between the 2 groups. Relapses occurred in 4 patients (22 %) in the CRT group and in 8 patients (26 %) in the surgery group. The mode of initial recurrence in the CRT group was lymph node (n = 1), hematogenous (n = 2), and local (n = 1). In the surgery group, mode of recurrence was lymph node
TABLE 3 Mode of initial recurrence CRT group (n = 18)
Surgery group (n = 30)
4
8
Lymph node
1
4
Hematogenous
2
3
Local
1
1
Number of recurrence Mode of recurrence
1.0 CRT group: 76.4% 0.8
Survival rate
Effects of Chemoradiotherapy
0.6
Surgery group: 68.2%
0.4 0.2 P = 0.61 0 0
5
10
15
20
25
30
35
40
months after surgery FIG. 1 Survival analyses. The 3-year survival ratios were 76.4 and 68.2 % for the CRT group and surgery group, respectively. There was no significant difference between the 2 groups
(n = 4), hematogenous (n = 3), and local (n = 1) (Table 3). During the study period, 3 patients died of relapsed disease and 1 in the CRT group died of pneumonia. In the surgery group, all 8 patients with recurrence died of esophageal cancer. The 3-year survival rate was 76.4 % in the CRT group and 68.2 % in the surgery group (P = 0.61) (Fig. 1). Furthermore, the survival rate of patients underwent surgery in Ref.1 that we previously reported was estimated and compared with that of CRT group. The 3-year survival rates of patients with three and fewer and four or more lymph nodes metastases diagnosed by ultrasound and endoscopic ultrasound before surgery
H. Okumura et al.
were 54.9 and 16.0 %, respectively, that were significantly worse than that of the CRT group in this study. DISCUSSION Lymph-node metastasis is the most important prognostic factor for esophageal cancer, so its accurate diagnosis prior to surgical treatment is indispensable.1,10 There is a significant difference in 5-year survival between patients with three or fewer and those with four or more metastases.1 Therefore, we usually determine the number of lymphnode metastases using US and EUS, whose results correlate well with pathological diagnoses.1,2,11 For ESCC patients treated with CRT, it is important to correctly diagnose clinical nodal status in order to ensure that an appropriate radiation field is set for CRT and subsequently to perform surgical treatment.10,11 Although many surgeons, radiologists, and oncologists have made efforts to improve the survival of ESCC patients, survival benefit of neoadjuvant CRT remains controversial. Some retrospective studies have shown prognosis to be improved due to the effects of neoadjuvant CRT, while some randomized controlled studies have found no significant survival difference between treatment with neoadjuvant CRT and surgery alone.3,12–17 In our previous study, pN0 patients had better survival even when they had clinical lymph-node metastases.10 Taken together, these results suggest that neoadjuvant CRT might be less useful for patients with a few lymph-node metastases, who could be cured by surgery alone, and more useful for the patients with four or more lymph-node metastases who cannot be cured with surgery alone and need multimodal treatment. In this prospective trial, neoadjuvant CRT succeeded in decreasing the number of lymph-node metastases: there was no statistically significant difference in survival between the CRT group and the surgery group, which indicates an improvement in survival in the CRT group. Accurate preoperative lymph-node diagnosis enables ESCC patients to receive targeted treatment to reduce multiple lymph-node metastases and thus allows curative surgery. Of the 4 patients who had hematogenous recurrent disease in the CRT group, 1 was judged as CR. Previous experience has shown that pN0 patients tend to have hematogenous rather than lymph-node recurrence.10 Meguid et al.18 also reported that most recurrences of esophageal cancer after neoadjuvant therapy and surgery are distant, even in patients with complete pathologic response. This is one of the most important problems facing clinicians performing CRT on esophageal cancer patients, and we should clarify the mechanisms by which good responders have hematogenous relapses and investigate how to modify the treatment strategy to avoid this problem.
Nowadays, preoperative neoadjuvant chemotherapy is recommended for patients with cStage II or III ESCC patients in Japan; the 5-year overall survival was 55 % in patients who received preoperative chemotherapy with cisplatin plus 5-fluorouracil, which was superior to 43 % in patients who received postoperative chemotherapy.19 However, survival rate was still unsatisfactory; therefore, we are exploring a new treatment strategy by trying to modify the use of CRT, which has a powerful tumorshrinking effect, in order to improve the survival of ESCC patients. In conclusion, neoadjuvant CRT was beneficial for patients with locally advanced esophageal cancer with four or more lymph-node metastases.
REFERENCES 1. Natsugoe S, Yoshinaka H, Shimada M, Sakamoto F, Morinaga T, Nakano S, et al. Number of lymph node metastases determined by presurgical ultrasound and endoscopic ultrasound is related to prognosis in patients with esophageal carcinoma. Ann Surg. 2001;234:613–8. 2. Natsugoe S, Yoshinaka H, Shimada M, Shirao K, Nakano S, Kusano C, et al. Assessment of cervical lymph node metastasis in esophageal carcinoma using ultrasonography. Ann Surg. 1999;229:62–6. 3. Natsugoe S, Okumura H, Matsumoto M, Uchikado Y, Setoyama T, Yokomakura N, et al. Randomized controlled study on preoperative chemoradiotherapy followed by surgery versus surgery alone for esophageal squamous cell cancer in a single institution. Dis Esophagus. 2006;19:468–72. 4. John MJ, Flam MS, Mowry PA, Podolsky WJ, Xavier AM, Wittlinger PS, et al. Radiotherapy alone and chemoradiation for nonmetastatic esophageal carcinoma. A critical review of chemoradiation. Cancer. 1989;632:397–403. 5. Naunheim KS, Petruska P, Roy TS, Andrus CH, Johnson FE, Schlueter JM, et al. Preoperative chemotherapy and radiotherapy for esophageal carcinoma. J Thorac Cardiovasc Surg. 1992;103:887–93. 6. Sobin LH, Gospodarowicz MK, Wittekind Ch, eds. International Union against Cancer (UICC) TNM classification of malignant tumors. 7th ed. Oxford, UK: Wiley-Blackwell; 2009. 7. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45:228–47. 8. Japan Esophageal Society. Japanese Classification of Esophageal Cancer, tenth edition: part I. Esophagus. 2009;6:1–25. 9. Japan Esophageal Society. Japanese Classification of Esophageal cancer, tenth edition: parts II and III. Esophagus. 2009;6:71–94. 10. Okumura H, Uchikado Y, Matsumoto M, Owaki T, Kita Y, Omoto I, et al. Prognostic factors in esophageal squamous cell carcinoma patients treated with neoadjuvant chemoradiation therapy. Int J Clin Oncol. 2013;18:329–34. 11. Owaki T, Matsumoto M, Okumura H, Uchicado Y, Kita Y, Setoyama T, et al. Endoscopic ultrasonography is useful for monitoring the tumor response of neoadjuvant chemoradiation therapy in esophageal squamous cell carcinoma. Am J Surg. 2012;203:191–7. 12. Yeh AM, Mendenhall WM, Morris CG, Zlotecki RA, Desnoyers RJ, Vogel SB. Factors predictive of survival for esophageal
The Usefulness of CRT in ESCC
13.
14.
15.
16.
carcinoma treated with preoperative radiotherapy with or without chemotherapy followed by surgery. J Surg Oncol. 2003;83: 14–23. Vogel SB, Mendenhall WM, Sombeck MD, Marsh R, Woodward ER. Downstaging of esophageal cancer after preoperative radiation and chemotherapy. Ann Surg. 1995;221:685–93. Liao Z, Zhang Z, Jin J, Ajani JA, Swisher SG, Stevens CW, et al. Esophagectomy after concurrent chemoradiotherapy improves locoregional control in clinical stage II or III esophageal cancer patients. Int J Radiat Oncol Biol Phys. 2004;60:1484–93. Lee JL, Park SI, Kim SB, Jung HY, Lee GH, Kim JH, et al. A single institutional phase III trial of preoperative chemotherapy with hyperfractionation radiotherapy plus surgery versus surgery alone for resectable esophageal squamous cell carcinoma. Ann Oncol. 2004;15:947–54. Malthaner RA, Wong RK, Rumble RB, Zuraw L. Neoadjuvant or adjuvant therapy for resectable esophageal cancer: a systematic review and meta-analysis. BMC Med. 2004;2:35.
17. 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;19:305–13. 18. Meguid RA, Hooker CM, Taylor JT, Kleinberg LR, Cattaneo SM II, Sussman MS, et al. Recurrence after neoadjuvant chemoradiation and surgery for esophageal cancer: does the pattern of recurrence differ for patients with complete response and those with partial or no response? J Thorac Cardiovasc Surg. 2009;138:1309–17. 19. Ando N, Kato H, Igaki H, Shinoda M, Ozawa S, Shimizu H, et al. A randomized trial comparing postoperative adjuvant chemotherapy with cisplatin and 5-fluorouracil versus preoperative chemotherapy for localized advanced squamous cell carcinoma of the thoracic esophagus (JCOG9907). Ann Surg Oncol. 2012;19:68–74.
ORIGINAL ARTICLE – GASTROINTESTINAL ONCOLOGY
The Usefulness of Neoadjuvant Chemoradiation Therapy for Locally Advanced Esophageal Cancer with Multiple Lymph-Node Metastases Hiroshi Okumura, MD, PhD1, Yasuto Uchikado, MD, PhD1, Itaru Omoto, MD1, Yoshiaki Kita, MD, PhD1, Ken Sasaki, MD, PhD1, Takaaki Arigami, MD, PhD1, Yoshikazu Uenosono, MD, PhD1, Daisuke Matsushita, MD1, Yoshiyuki Hiraki, MD, PhD2, Tetsuhiro Owaki, MD, PhD3, Sumiya Ishigami, MD, PhD1, and Shoji Natsugoe, MD, PhD1 1
Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medical Sciences, Kagoshima University, Kagoshima, Japan; 2Department of Radiology, Graduate School of Medical Sciences, Kagoshima University, Kagoshima, Japan; 3Education Center for Doctors in Remote Islands and Rural Areas, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan
ABSTRACT Background. The prognosis of patients with esophageal squamous-cell cancer (ESCC) and multiple lymph-node metastases is quite poor. We examined whether neoadjuvant chemoradiation therapy (CRT) has a beneficial effect in such patients. Methods. A total of 50 consecutive patients with T3–4 tumors and without organ metastases were prospectively enrolled. Of those patients, 20, who had four or more nodal metastases, underwent neoadjuvant CRT (CRT group), and the remaining 30 patients, who had three or fewer nodal metastases, underwent surgery alone (surgery group). CRT consisted of 5-fluorouracil plus cisplatin and 40 Gy of radiation. The groups’ clinical outcomes were compared. Results. Surgery was performed in 48 patients: all enrolled patients except for 2 who had organ metastasis after CRT. In the CRT group, the number of patients with pathological complete response was observed in 8 patients (44 %), mean nodal metastases number was changed from 8.2 to 2.6 and 9 patients had pN0. The 3-year survival rate was 76 % in the CRT group (4 patients relapsed) and 68 % in the surgery group (8 patients relapsed), which is not a statistically significant difference (P = 0.61).
Conclusions. Neoadjuvant CRT is beneficial for locally advanced ESCC with four or more lymph-node metastases.
The prognosis is poor for patients with esophageal squamous-cell cancer (ESCC) with multiple lymph-node metastases. In particular, the prognosis in patients with four or more lymph-node metastases is significantly poorer than in those with three or fewer.1 Preoperative endoscopic ultrasonography (EUS) is useful to diagnose clinical lymph-node metastases, with results that correlate well with pathological diagnoses.1,2 Chemoradiation therapy (CRT) has been investigated since the 1980s for the treatment of ESCC and is one of the most useful treatments available; however, it remains controversial whether neoadjuvant CRT provides a significant advantage.3–5 We hypothesized that neoadjuvant CRT might be less useful for those patients who could be cured with surgery alone. In this study, we examined the effect of neoadjuvant CRT on patients with ESCC and four or more lymph-node metastases and compared the outcome with that of patients with three or fewer nodal metastases treated with surgery alone. MATERIALS AND METHODS Patients
Ó Society of Surgical Oncology 2014 First Received: 30 January 2014 H. Okumura, MD, PhD e-mail: [email protected]
The study included 130 consecutive ESCC patients who were treated at the Department of Surgical Oncology and Digestive Surgery of Kagoshima University Hospital
H. Okumura et al. TABLE 1 Pretreatment clinicopathologic features Characteristics
CRT group (n = 20)
Surgery group (n = 30)
P value
Gender (male/female)
20/0
30/0
NS NS
Age (years)
64.0 ± 7.1
66.4 ± 9.0
cT3/T4
16/4
29/1
0.05
cN0/N1/N2/N3
0/0/12/8
7/8/15/0
\0.001
c-Number of metastatic LN
8.2 ± 5.3
1.9 ± 1.2
\0.001
cM0/M1
11/9
25/5
0.03
cStage II/III/IV
0/11/9
9/16/5
0.008
CRT chemoradiation therapy, NS not significant, c clinical
between January 2010 and December 2012. All patients had been preoperatively diagnosed and staged by esophagoscopy with biopsy, barium study, computed tomography (CT) scan of the neck, chest and abdomen, ultrasonography (US) of the neck and abdomen, EUS, and positron emission tomography (PET). Of these 130 patients, 50 had a T3 or T4 tumor without organ metastasis: 20 of these patients had four or more lymph-node metastases and underwent neoadjuvant CRT followed by curative surgery (CRT group); the other 30 patients, who had three or fewer lymph-node metastases, were treated with curative surgery only (surgery group). Patients in both groups underwent esophagectomy with lymph-node dissection, and the reconstruction was performed by cervical esophagogastric anastomosis using a gastric tube. In the CRT group, surgery was performed 4–6 weeks after completing CRT. After all patients had given their informed consent, the resected specimens were collected. The specimens were classified according to the International Union against Cancer tumor-node-metastasis (TNM) classification system.6 Patients in the CRT group did not undergo adjuvant chemotherapy because their immune system was weakened by multimodal treatment; however, 17 patients who had pathological lymph nodes metastases in the surgery group underwent adjuvant chemotherapy consisting of docetaxel, cisplatin plus 5-fluorouracil. All patients were followed up with CT every 3 months after discharge, US every 6 months, and endoscopy every 6–12 months. Follow-up data after surgery were available for all patients, with a median follow-up period of 21 months (range 7–37 months). Mode of recurrence was categorized as lymph node, hematogenous, or local. For patients whose disease relapsed, CRT or chemotherapy was performed according to the relapse site and condition of patients. The pretreatment clinicopathologic features of the study group are summarized in Table 1. All M1 tumors were due to distant lymph-node metastases. The mean number of lymph-node metastases in the CRT group and the surgery
group was 8.2 and 1.9, respectively. Thus, the CRT group had significantly more lymph-node metastases and more advanced stage. The CRT group also tended to have cT4 tumors. In the surgery group, 1 patient with cT4 had suspected tracheal invasion, but that was curatively removed and final diagnosis was pT3. There were 2 patients with pT4 invaded to lung and pleura that were curatively resected. The study was approved by the Institutional Review Board of Kagoshima University and performed according to the Helsinki Declaration.
Chemoradiation Therapy A total radiation dose of 40 Gy was applied: 2 Gy fractions were delivered 5 days per week for 4 weeks to the mediastinum and neck. Supraclavicular to lower mediastinal lymph-node as well as cardiac to celiac lymph-node areas were irradiated as a long T-shaped field for upper to lower thoracic tumors, and perigastric LN areas were additionally irradiated for lower tumors. In the same period, chemotherapy was performed intravenously using 2 anticancer agents: cisplatin (7 mg/m2 over 2 h) and 5-FU (350 mg/m2 over 24 h).1 Tumor response was evaluated by the Response Evaluation Criteria in Solid Tumors version 1.1.7 The clinical response to CRT was evaluated by the findings of esophagography, esophagoscopy, US, EUS, CT, and PET for the lymph-node metastases. The clinical criteria for the response of target lesions were: complete response (CR), the disappearance of all target lesions as well as secondary changes associated with the tumors; partial response (PR), at least a 30 % decrease in the sum of the greatest dimensions of target lesions, relative to the baseline sum of greatest dimensions; progressive disease (PD), at least a 20 % increase in the sum of greatest dimensions of target lesions, relative to the smallest sum of greatest dimensions recorded since the treatment started; and stable disease (SD), neither PR nor PD. The histological criteria for the response of CRT were: grade 0, neither necrosis nor cellular or structural changes can be seen throughout the lesion; grade 1, necrosis or disappearance of the tumor is present in no more than two-thirds of the whole lesion; grade 2, necrosis or disappearance of the tumor is present in more than two-thirds of the whole lesion but viable tumor cells remain; and grade 3, the whole lesion falls into necrosis and/or is replaced by fibrosis, with or without granulomatous changes. No viable tumor cells are observed.8,9 CRT was judged to be effective in patients whose histological response was grade 2 or 3, but ineffective in patients whose histological response was grade 0 or 1. Adverse events were diagnosed according to Common Terminology Criteria for Adverse Events v4.0.
The Usefulness of CRT in ESCC
Statistical Analysis Statistical analysis of group differences was performed using the v2 test and t test. The Kaplan–Meier method was used for survival analysis, and differences in survival were estimated using the log-rank test. The P values in this study were 2-sided, and P \ 0.05 was considered to indicate statistical significance. All statistical analyses were performed using the software package StatView version 5.0 (Abacus Concepts, Berkeley, CA, USA).
TABLE 2 Pathological diagnoses Characteristics
CRT group (n = 18)
Surgery group (n = 30)
P value
pT0/T1/T2/T3/T4
8/4/0/6/0
0/7/4/17/2
0.001
pN0/N1/N2/N3
9/4/4/1
13/9/3/5
NS
p-Number of metastatic LN
2.6 ± 4.4
2.4 ± 3.6
NS
pM0/M1
15/3
26/4
NS
pStage 0/I/II/III/IV
5/2/1/7/3
0/4/12/11/3
0.008
CRT chemoradiation therapy, NS not significant, p pathological
RESULTS
Of the 50 patients, surgical treatment was performed in 48, excluding 2 patients from the CRT group with bone or liver metastasis, although all 20 patients in the CRT group completed CRT. Grade 3 adverse effects comprised appetite loss (n = 1), leukopenia (n = 2), and anemia (n = 1). No serious complications requiring cessation of CRT were encountered. The number of patients with CR, PR, SD, and PD after CRT was 2, 11, 4, and 3, respectively. The number of patients with grades 1, 2, and 3 histological response was 8, 2, and 8, respectively. Pathological Findings Table 2 summarizes the pathological diagnoses for the study groups. There were no significant differences in pN, p-number of lymph-node metastasis, and pM between the CRT group and the surgery group. Unlike the pretreatment diagnoses reported in Table 1, the tumors in the surgery group had deeper wall invasion and more advanced stage than those in the CRT group. The mean number of nodal metastases in the CRT group changed from 8.2 to 2.6 after CRT and 9 patients became pN0; the surgery group did not see a significant change (from 1.9 to 2.4) (Tables 1, 2). Clinical Outcome No hospital deaths were reported in the study. Anastomotic leakage was found in 3 patients (16 %) from the CRT group and in 4 (13 %) from the surgery group. Serious pneumonia with mechanical ventilation was reported in 1 patient (6 %) from the CRT group, and thoracic empyema was experienced by 1 patient (3 %) from the surgery group. The incidence of morbidity was not significantly different between the 2 groups. Relapses occurred in 4 patients (22 %) in the CRT group and in 8 patients (26 %) in the surgery group. The mode of initial recurrence in the CRT group was lymph node (n = 1), hematogenous (n = 2), and local (n = 1). In the surgery group, mode of recurrence was lymph node
TABLE 3 Mode of initial recurrence CRT group (n = 18)
Surgery group (n = 30)
4
8
Lymph node
1
4
Hematogenous
2
3
Local
1
1
Number of recurrence Mode of recurrence
1.0 CRT group: 76.4% 0.8
Survival rate
Effects of Chemoradiotherapy
0.6
Surgery group: 68.2%
0.4 0.2 P = 0.61 0 0
5
10
15
20
25
30
35
40
months after surgery FIG. 1 Survival analyses. The 3-year survival ratios were 76.4 and 68.2 % for the CRT group and surgery group, respectively. There was no significant difference between the 2 groups
(n = 4), hematogenous (n = 3), and local (n = 1) (Table 3). During the study period, 3 patients died of relapsed disease and 1 in the CRT group died of pneumonia. In the surgery group, all 8 patients with recurrence died of esophageal cancer. The 3-year survival rate was 76.4 % in the CRT group and 68.2 % in the surgery group (P = 0.61) (Fig. 1). Furthermore, the survival rate of patients underwent surgery in Ref.1 that we previously reported was estimated and compared with that of CRT group. The 3-year survival rates of patients with three and fewer and four or more lymph nodes metastases diagnosed by ultrasound and endoscopic ultrasound before surgery
H. Okumura et al.
were 54.9 and 16.0 %, respectively, that were significantly worse than that of the CRT group in this study. DISCUSSION Lymph-node metastasis is the most important prognostic factor for esophageal cancer, so its accurate diagnosis prior to surgical treatment is indispensable.1,10 There is a significant difference in 5-year survival between patients with three or fewer and those with four or more metastases.1 Therefore, we usually determine the number of lymphnode metastases using US and EUS, whose results correlate well with pathological diagnoses.1,2,11 For ESCC patients treated with CRT, it is important to correctly diagnose clinical nodal status in order to ensure that an appropriate radiation field is set for CRT and subsequently to perform surgical treatment.10,11 Although many surgeons, radiologists, and oncologists have made efforts to improve the survival of ESCC patients, survival benefit of neoadjuvant CRT remains controversial. Some retrospective studies have shown prognosis to be improved due to the effects of neoadjuvant CRT, while some randomized controlled studies have found no significant survival difference between treatment with neoadjuvant CRT and surgery alone.3,12–17 In our previous study, pN0 patients had better survival even when they had clinical lymph-node metastases.10 Taken together, these results suggest that neoadjuvant CRT might be less useful for patients with a few lymph-node metastases, who could be cured by surgery alone, and more useful for the patients with four or more lymph-node metastases who cannot be cured with surgery alone and need multimodal treatment. In this prospective trial, neoadjuvant CRT succeeded in decreasing the number of lymph-node metastases: there was no statistically significant difference in survival between the CRT group and the surgery group, which indicates an improvement in survival in the CRT group. Accurate preoperative lymph-node diagnosis enables ESCC patients to receive targeted treatment to reduce multiple lymph-node metastases and thus allows curative surgery. Of the 4 patients who had hematogenous recurrent disease in the CRT group, 1 was judged as CR. Previous experience has shown that pN0 patients tend to have hematogenous rather than lymph-node recurrence.10 Meguid et al.18 also reported that most recurrences of esophageal cancer after neoadjuvant therapy and surgery are distant, even in patients with complete pathologic response. This is one of the most important problems facing clinicians performing CRT on esophageal cancer patients, and we should clarify the mechanisms by which good responders have hematogenous relapses and investigate how to modify the treatment strategy to avoid this problem.
Nowadays, preoperative neoadjuvant chemotherapy is recommended for patients with cStage II or III ESCC patients in Japan; the 5-year overall survival was 55 % in patients who received preoperative chemotherapy with cisplatin plus 5-fluorouracil, which was superior to 43 % in patients who received postoperative chemotherapy.19 However, survival rate was still unsatisfactory; therefore, we are exploring a new treatment strategy by trying to modify the use of CRT, which has a powerful tumorshrinking effect, in order to improve the survival of ESCC patients. In conclusion, neoadjuvant CRT was beneficial for patients with locally advanced esophageal cancer with four or more lymph-node metastases.
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