ORIGINAL ARTICLE
Clinical Importance of Supraclavicular Lymph Node Metastasis After Neoadjuvant Chemotherapy for Esophageal Squamous Cell Carcinoma Hiroshi Miyata, MD, Makoto Yamasaki, MD, Yasuhiro Miyazaki, MD, Tsuyoshi Takahashi, MD, Yukinori Kurokawa, MD, Kiyokazu Nakajima, MD, Shuji Takiguchi, MD, Masaki Mori, MD, and Yuichiro Doki, MD
Objective: To examine the clinical implications of supraclavicular (SC) lymph node (LN) metastasis in patients with esophageal squamous cell carcinoma (ESCC) who receive neoadjuvant chemotherapy, followed by surgery. Background: Indications for surgery for esophageal cancer often do not include cases with SCLN metastasis because the latter is considered distant metastasis. However, neaodjuvant therapy may change the clinical importance of SCLN metastasis. Methods: In 323 patients with ESCC who underwent neoadjuvant chemotherapy, the correlations between SCLN metastasis and clinicopathological factors including survival were examined. Results: The incidence of SCLN metastasis was 17.6% before therapy and 14.6% after therapy. In patients with SCLN metastasis at baseline, the incidence of posttherapy SCLN metastasis was significantly lower in major responders to chemotherapy than in minor responders. The total number of metastatic LNs was significantly higher in patients with posttherapy SCLN metastasis than in patients with metastatic LN but no SCLN (10.9 vs 3.9; P ≤ 0.001). Survival was shorter in patients with SCLN metastasis than in those with metastatic LN without SCLN (3-year overall survival rate; 20.1% vs 45.7%; P = 0.003). However, there was no significant difference in survival between patients with SCLN metastasis before but not after therapy and patients without SCLN metastasis before and after chemotherapy (3-year overall survival rate; 64.9% vs 58.2%; P = 0.2071). Conclusions: This study showed that SCLN metastasis in ESCC reflects the number of metastatic LNs. SCLN metastasis should not be considered as contraindication to curative surgery in multimodal treatment of ESCC because preoperative treatment can change SC nodal status. Keywords: esophageal cancer, lymph node metastasis, neoadjuvant chemotherapy, neoadjuvnat therapy, supraclavicular (Ann Surg 2015;262:280–285)
E
sophageal cancer is one of the most aggressive gastrointestinal cancers because it spreads to regional and distant lymph nodes (LNs) at relatively early stage.1,2 More than half of advanced esophageal cancers are diagnosed with LN metastasis, and the presence of large number of metastatic LNs is an important, poor prognostic factor in patients with esophageal cancer.3–6 In the cancer staging system of the International Union Against Cancer (UICC), Seventh Edition, LN status is classified into N0–N3 based on the number of regional lymph node metastases.7 Furthermore, in the UICC-TNM classification, LNs in the esophageal drainage area, including celiac From the Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan. Disclosure: The authors declare no conflicts of interest. Reprints: Hiroshi Miyata, MD, Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan. E-mail: [email protected]. C 2014 Wolters Kluwer Health, Inc. All rights reserved. Copyright ISSN: 0003-4932/14/26202-0280 DOI: 10.1097/SLA.0000000000000933
280 | www.annalsofsurgery.com
axis nodes and paraesophageal nodes in the neck, are defined as regional LNs whereas supraclavicular (SC) LNs are defined as distant LNs. Esophageal cancer with SCLN metastasis is classified as stage IV cancer. Thus, esophageal cancer with SCLN metastasis is often excluded from indications for curative surgery, especially in Western countries.8–10 Preoperative therapy, including preoperative chemoradiotherapy and preoperative chemotherapy, was recently considered to be the standard treatment of advanced esophageal cancer. Preoperative therapy helps in downstaging esophageal cancer, thus enhancing the chance of curative resection and improving the prognosis of patients with esophageal cancer.11–17 In other words, a more extensive application of preoperative therapy can change the clinical importance of the initial cancer staging. We should perhaps also reconsider the clinical importance of SCLN metastasis in the overall treatment strategy of preoperative therapy, followed by surgery, for esophageal cancer. In this study, we examined the clinical importance of SCLN metastasis in patients with esophageal squamous cell carcinoma (ESCC) who underwent preoperative chemotherapy, followed by surgery.
MATERIALS AND METHODS Patients and Pretreatment Protocols Between October 2000 and December 2011, a total of 623 patients with thoracic esophageal cancers underwent surgery at the Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University. Among them, 323 patients underwent esophagectomy after neoadjuvant chemotherapy for thoracic esophageal cancer. In our hospital, preoperative chemotherapy, followed by surgery, was selected during the time of the study for patients with clinical stage IB, II, III, or IV with distant LN metastasis, including SCLN metastasis. All 323 patients received a diagnosis of squamous cell carcinoma of the thoracic esophagus using pretreatment biopsy samples. All patients were younger than 80 years; had adequate cardiac, hepatic, renal, and bone marrow reserve; and could tolerate both planned chemotherapy and the subsequent surgical procedures. Before treatment (baseline), the neoplastic disease of all 323 patients was staged by computed tomography (CT) and endoscopy, together with 18-fluorodeoxy glucose (18 F-FDG)-positron emission tomography (PET) when possible (n = 279; 86.4%). In our hospital, endoscopic ultrasonography (US) was not routinely used for staging of advanced esophageal cancers, although it was used in staging superficial esophageal cancers. LNs were considered metastasispositive on CT scan if they were spherical and larger than 1.0 cm in maximum transverse diameter or if focal major 18 F-FDG uptake, compared with normal mediastinal activity, was detected on the PET scan. LNs visible but smaller than 1.0 cm on the long axis on the CT scan were regarded as metastasis-positive only if prominent 18 F-FDG uptake was detected. The neoadjuvant chemotherapy regimen used in our hospital consisted of 5-fluorouracil (5-FU) and cisplatin plus adriamycin (ACF) or 5-FU and cisplatin plus docetaxel (DCF), as described Annals of Surgery r Volume 262, Number 2, August 2015
Copyright © 2014 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Annals of Surgery r Volume 262, Number 2, August 2015
previously.18 In the ACF regimen, cisplatin was administered at 70 mg/m2 , adriamycin at 35 mg/m2 by rapid intravenous infusion on day 1, and 5-FU at 700 mg/m2 administered by continuous intravenous infusion on days 1 to 7. Two courses of chemotherapy were used, separated by a 4-week interval. Since July 2008, patients with a clinical diagnosis of T3–T4 tumors often received the DCF regimen instead of ACF. In the DCF regimen, cisplatin was administered at 70 mg/m2 , docetaxel at 70 mg/m2 by rapid intravenous infusion on day 1, and 5-FU at 700 mg/m2 administered by continuous intravenous infusion on days 1 to 5. Two courses of chemotherapy were administered, separated by a 3-week rest period. Consequently, among 323 patients who underwent neoadjuvant chemotherapy, 265 patients received the ACF therapy whereas the remaining 58 patients received DCF therapy. The study protocol was approved by the Human Ethics Review Committee of Osaka University Graduate School of Medicine.
Surgical Treatment Surgical resection was performed 3 to 5 weeks after completion of the chemotherapy. Our standard procedures consisted of subtotal esophagectomy with mediastinal lymphadenectomy via right thoracotomy, upper abdominal lymphadenectomy, reconstruction of the gastric tube, and anastomosis in the cervical incision. In our hospital, cervical lymphadenectomy was performed for patients with upper thoracic esophageal cancer and for those with middle or lower thoracic esophageal cancer with SCLN metastases or recurrent laryngeal nerve LN metastasis diagnosed by radiological imaging. Patients with middle or lower thoracic esophageal cancer without SCLN or recurrent laryngeal nerve LN metastasis underwent cervical lymphadenectomy only if recurrent laryngeal nerve LNs were determined as metastatic by intraoperative genetic diagnosis using real-time reverse transcription-polymerase chain reaction.19 Thus, of the 323 patients, 198 underwent 3-field lymphadenectomy whereas 125 patients underwent 2-field lymphadenectomy.
Pathological Response to Chemotherapy The degree of histopathological tumor regression in the surgical specimen was classified into 5 categories.20,21 The extent of viable residual carcinoma at the primary site was assessed semiquantitatively, based on the estimated percentage of viable residual carcinoma in relation to the macroscopically identifiable tumor bed that was evaluated histopathologically. The percentage of viable residual tumor cells within the entire cancerous tissue was assessed as follows: grade 3, no viable residual tumor cells (pathological complete response); grade 2, less than one-third residual tumor cells; grade 1b, one-third to two-third residual tumor cells; grade 1a, more than two-third residual tumor cells; grade 0, no significant response to preoperative therapy.20,21 The histopathological findings were classified according to the UICC-TNM classification.7
Statistical Analysis Differences in clinicopathological factors were compared between patients with SCLN metastases and those with metastatic LN but without SCLN (LN+ /SCLN− ), using the χ 2 , Mann-Whitney, and Student t tests. Overall survival was calculated from the date of neoadjuvant therapy to the occurrence of the event or to the last known date of follow-up. Actual survival was calculated by the Kaplan-Meier method and statistically evaluated by the log-rank test. In all analyses, a P value of less than 0.05 was accepted as statistically significant. All analyses were carried out using the JMP (version 9.0) software (SAS Institute Inc., Cary, NC). C 2014 Wolters Kluwer Health, Inc. All rights reserved.
Supraclavicular LN in Esophageal Cancer
RESULTS Relationship Between Status of SCLN Metastasis and Other Clinicopathological Factors The characteristics of 323 patients enrolled in this study are listed in Table 1. Before preoperative chemotherapy, 57 (17.6%) of 323 patients had a clinical diagnosis of SCLN metastasis. After such treatment, 107 (33.1%) of 323 patients had no LN metastasis, 169 patients (52.3%) had metastatic LN+ /SCLN− , and 47 patients (14.6%) had SCLN metastasis. Comparison of the clinicopathological factors of the LN+ /SCLN− and LN+ /SCLN+ groups showed no significant difference in age, sex, tumor depth, and pathological response to preoperative chemotherapy. With regard to tumor location, SCLN metastasis was more common in upper third esophageal cancers and less common in lower third esophageal cancers, compared with that of the LN+ /SCLN− group (P = 0.005). The proportion of pN3 cases was only 14.2% among patients of the LN+ /SCLN− group, whereas it was 55.3% in the LN+ /SCLN+ group. Thus, the incidence of SCLN metastasis correlated significantly with advanced nodal status (P < 0.001). Moreover, the mean number of metastatic LNs was significantly higher in patients of the LN+ /SCLN+ group than in those of the LN+ /SCLN− group (10.9 vs 3.9; P ≤ 0.001). In subclass analysis according to tumor location, significantly more metastatic LNs were present in patients with SCLN metastasis than those of the LN+ /SCLN− group in case of middle and lower third esophageal cancers, although the difference did not reach statistical significance in upper third esophageal cancers (Table 2).
TABLE 1. Characteristics of Patients LN Metastasis Positive Negative n 107 Age, yr 64.7±8.5 Sex (male/female) 92/15 Tumor location Upper third 14 (13) Middle third 54 (50) Lower third 39 (37) Tumor depth pT0 17 (16) pT1 26 (24) pT2 22 (21) pT3 38 (35) pT4 4 (4) Nodal status pN0 107 pN1 0 pN2 0 pN3 0 No. metastatic LNs 0 LN dissection 3-field 58 (54) 2-field 49 (46) Pathological response Grade 0 8 (7) Grade 1 58 (54) Grade 2 23 (22) Grade 3 18 (17) Pretherapy SCLN status Negative 94 (88) Positive 13 (12)
SCLN−
SCLN+
P
169 63.7 ± 8.3 145/24
47 63.1 ± 7.9 37/10
0.662 0.239
18 (11) 70 (41) 81 (48)
12 (26) 23 (48) 12 (26)
0.005
4 (2) 29 (17) 34 (20) 94 (56) 8 (5)
2 (4) 7 (15) 8 (17) 27 (58) 3 (6)
0.693
0 (0) 91 (54) 54 (32) 24 (14) 3.9 ± 5.9
0 (0) 10 (21) 11 (23) 26 (56) 10.9 ± 11.2
Clinical Importance of Supraclavicular Lymph Node Metastasis After Neoadjuvant Chemotherapy for Esophageal Squamous Cell Carcinoma Hiroshi Miyata, MD, Makoto Yamasaki, MD, Yasuhiro Miyazaki, MD, Tsuyoshi Takahashi, MD, Yukinori Kurokawa, MD, Kiyokazu Nakajima, MD, Shuji Takiguchi, MD, Masaki Mori, MD, and Yuichiro Doki, MD
Objective: To examine the clinical implications of supraclavicular (SC) lymph node (LN) metastasis in patients with esophageal squamous cell carcinoma (ESCC) who receive neoadjuvant chemotherapy, followed by surgery. Background: Indications for surgery for esophageal cancer often do not include cases with SCLN metastasis because the latter is considered distant metastasis. However, neaodjuvant therapy may change the clinical importance of SCLN metastasis. Methods: In 323 patients with ESCC who underwent neoadjuvant chemotherapy, the correlations between SCLN metastasis and clinicopathological factors including survival were examined. Results: The incidence of SCLN metastasis was 17.6% before therapy and 14.6% after therapy. In patients with SCLN metastasis at baseline, the incidence of posttherapy SCLN metastasis was significantly lower in major responders to chemotherapy than in minor responders. The total number of metastatic LNs was significantly higher in patients with posttherapy SCLN metastasis than in patients with metastatic LN but no SCLN (10.9 vs 3.9; P ≤ 0.001). Survival was shorter in patients with SCLN metastasis than in those with metastatic LN without SCLN (3-year overall survival rate; 20.1% vs 45.7%; P = 0.003). However, there was no significant difference in survival between patients with SCLN metastasis before but not after therapy and patients without SCLN metastasis before and after chemotherapy (3-year overall survival rate; 64.9% vs 58.2%; P = 0.2071). Conclusions: This study showed that SCLN metastasis in ESCC reflects the number of metastatic LNs. SCLN metastasis should not be considered as contraindication to curative surgery in multimodal treatment of ESCC because preoperative treatment can change SC nodal status. Keywords: esophageal cancer, lymph node metastasis, neoadjuvant chemotherapy, neoadjuvnat therapy, supraclavicular (Ann Surg 2015;262:280–285)
E
sophageal cancer is one of the most aggressive gastrointestinal cancers because it spreads to regional and distant lymph nodes (LNs) at relatively early stage.1,2 More than half of advanced esophageal cancers are diagnosed with LN metastasis, and the presence of large number of metastatic LNs is an important, poor prognostic factor in patients with esophageal cancer.3–6 In the cancer staging system of the International Union Against Cancer (UICC), Seventh Edition, LN status is classified into N0–N3 based on the number of regional lymph node metastases.7 Furthermore, in the UICC-TNM classification, LNs in the esophageal drainage area, including celiac From the Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan. Disclosure: The authors declare no conflicts of interest. Reprints: Hiroshi Miyata, MD, Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan. E-mail: [email protected]. C 2014 Wolters Kluwer Health, Inc. All rights reserved. Copyright ISSN: 0003-4932/14/26202-0280 DOI: 10.1097/SLA.0000000000000933
280 | www.annalsofsurgery.com
axis nodes and paraesophageal nodes in the neck, are defined as regional LNs whereas supraclavicular (SC) LNs are defined as distant LNs. Esophageal cancer with SCLN metastasis is classified as stage IV cancer. Thus, esophageal cancer with SCLN metastasis is often excluded from indications for curative surgery, especially in Western countries.8–10 Preoperative therapy, including preoperative chemoradiotherapy and preoperative chemotherapy, was recently considered to be the standard treatment of advanced esophageal cancer. Preoperative therapy helps in downstaging esophageal cancer, thus enhancing the chance of curative resection and improving the prognosis of patients with esophageal cancer.11–17 In other words, a more extensive application of preoperative therapy can change the clinical importance of the initial cancer staging. We should perhaps also reconsider the clinical importance of SCLN metastasis in the overall treatment strategy of preoperative therapy, followed by surgery, for esophageal cancer. In this study, we examined the clinical importance of SCLN metastasis in patients with esophageal squamous cell carcinoma (ESCC) who underwent preoperative chemotherapy, followed by surgery.
MATERIALS AND METHODS Patients and Pretreatment Protocols Between October 2000 and December 2011, a total of 623 patients with thoracic esophageal cancers underwent surgery at the Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University. Among them, 323 patients underwent esophagectomy after neoadjuvant chemotherapy for thoracic esophageal cancer. In our hospital, preoperative chemotherapy, followed by surgery, was selected during the time of the study for patients with clinical stage IB, II, III, or IV with distant LN metastasis, including SCLN metastasis. All 323 patients received a diagnosis of squamous cell carcinoma of the thoracic esophagus using pretreatment biopsy samples. All patients were younger than 80 years; had adequate cardiac, hepatic, renal, and bone marrow reserve; and could tolerate both planned chemotherapy and the subsequent surgical procedures. Before treatment (baseline), the neoplastic disease of all 323 patients was staged by computed tomography (CT) and endoscopy, together with 18-fluorodeoxy glucose (18 F-FDG)-positron emission tomography (PET) when possible (n = 279; 86.4%). In our hospital, endoscopic ultrasonography (US) was not routinely used for staging of advanced esophageal cancers, although it was used in staging superficial esophageal cancers. LNs were considered metastasispositive on CT scan if they were spherical and larger than 1.0 cm in maximum transverse diameter or if focal major 18 F-FDG uptake, compared with normal mediastinal activity, was detected on the PET scan. LNs visible but smaller than 1.0 cm on the long axis on the CT scan were regarded as metastasis-positive only if prominent 18 F-FDG uptake was detected. The neoadjuvant chemotherapy regimen used in our hospital consisted of 5-fluorouracil (5-FU) and cisplatin plus adriamycin (ACF) or 5-FU and cisplatin plus docetaxel (DCF), as described Annals of Surgery r Volume 262, Number 2, August 2015
Copyright © 2014 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Annals of Surgery r Volume 262, Number 2, August 2015
previously.18 In the ACF regimen, cisplatin was administered at 70 mg/m2 , adriamycin at 35 mg/m2 by rapid intravenous infusion on day 1, and 5-FU at 700 mg/m2 administered by continuous intravenous infusion on days 1 to 7. Two courses of chemotherapy were used, separated by a 4-week interval. Since July 2008, patients with a clinical diagnosis of T3–T4 tumors often received the DCF regimen instead of ACF. In the DCF regimen, cisplatin was administered at 70 mg/m2 , docetaxel at 70 mg/m2 by rapid intravenous infusion on day 1, and 5-FU at 700 mg/m2 administered by continuous intravenous infusion on days 1 to 5. Two courses of chemotherapy were administered, separated by a 3-week rest period. Consequently, among 323 patients who underwent neoadjuvant chemotherapy, 265 patients received the ACF therapy whereas the remaining 58 patients received DCF therapy. The study protocol was approved by the Human Ethics Review Committee of Osaka University Graduate School of Medicine.
Surgical Treatment Surgical resection was performed 3 to 5 weeks after completion of the chemotherapy. Our standard procedures consisted of subtotal esophagectomy with mediastinal lymphadenectomy via right thoracotomy, upper abdominal lymphadenectomy, reconstruction of the gastric tube, and anastomosis in the cervical incision. In our hospital, cervical lymphadenectomy was performed for patients with upper thoracic esophageal cancer and for those with middle or lower thoracic esophageal cancer with SCLN metastases or recurrent laryngeal nerve LN metastasis diagnosed by radiological imaging. Patients with middle or lower thoracic esophageal cancer without SCLN or recurrent laryngeal nerve LN metastasis underwent cervical lymphadenectomy only if recurrent laryngeal nerve LNs were determined as metastatic by intraoperative genetic diagnosis using real-time reverse transcription-polymerase chain reaction.19 Thus, of the 323 patients, 198 underwent 3-field lymphadenectomy whereas 125 patients underwent 2-field lymphadenectomy.
Pathological Response to Chemotherapy The degree of histopathological tumor regression in the surgical specimen was classified into 5 categories.20,21 The extent of viable residual carcinoma at the primary site was assessed semiquantitatively, based on the estimated percentage of viable residual carcinoma in relation to the macroscopically identifiable tumor bed that was evaluated histopathologically. The percentage of viable residual tumor cells within the entire cancerous tissue was assessed as follows: grade 3, no viable residual tumor cells (pathological complete response); grade 2, less than one-third residual tumor cells; grade 1b, one-third to two-third residual tumor cells; grade 1a, more than two-third residual tumor cells; grade 0, no significant response to preoperative therapy.20,21 The histopathological findings were classified according to the UICC-TNM classification.7
Statistical Analysis Differences in clinicopathological factors were compared between patients with SCLN metastases and those with metastatic LN but without SCLN (LN+ /SCLN− ), using the χ 2 , Mann-Whitney, and Student t tests. Overall survival was calculated from the date of neoadjuvant therapy to the occurrence of the event or to the last known date of follow-up. Actual survival was calculated by the Kaplan-Meier method and statistically evaluated by the log-rank test. In all analyses, a P value of less than 0.05 was accepted as statistically significant. All analyses were carried out using the JMP (version 9.0) software (SAS Institute Inc., Cary, NC). C 2014 Wolters Kluwer Health, Inc. All rights reserved.
Supraclavicular LN in Esophageal Cancer
RESULTS Relationship Between Status of SCLN Metastasis and Other Clinicopathological Factors The characteristics of 323 patients enrolled in this study are listed in Table 1. Before preoperative chemotherapy, 57 (17.6%) of 323 patients had a clinical diagnosis of SCLN metastasis. After such treatment, 107 (33.1%) of 323 patients had no LN metastasis, 169 patients (52.3%) had metastatic LN+ /SCLN− , and 47 patients (14.6%) had SCLN metastasis. Comparison of the clinicopathological factors of the LN+ /SCLN− and LN+ /SCLN+ groups showed no significant difference in age, sex, tumor depth, and pathological response to preoperative chemotherapy. With regard to tumor location, SCLN metastasis was more common in upper third esophageal cancers and less common in lower third esophageal cancers, compared with that of the LN+ /SCLN− group (P = 0.005). The proportion of pN3 cases was only 14.2% among patients of the LN+ /SCLN− group, whereas it was 55.3% in the LN+ /SCLN+ group. Thus, the incidence of SCLN metastasis correlated significantly with advanced nodal status (P < 0.001). Moreover, the mean number of metastatic LNs was significantly higher in patients of the LN+ /SCLN+ group than in those of the LN+ /SCLN− group (10.9 vs 3.9; P ≤ 0.001). In subclass analysis according to tumor location, significantly more metastatic LNs were present in patients with SCLN metastasis than those of the LN+ /SCLN− group in case of middle and lower third esophageal cancers, although the difference did not reach statistical significance in upper third esophageal cancers (Table 2).
TABLE 1. Characteristics of Patients LN Metastasis Positive Negative n 107 Age, yr 64.7±8.5 Sex (male/female) 92/15 Tumor location Upper third 14 (13) Middle third 54 (50) Lower third 39 (37) Tumor depth pT0 17 (16) pT1 26 (24) pT2 22 (21) pT3 38 (35) pT4 4 (4) Nodal status pN0 107 pN1 0 pN2 0 pN3 0 No. metastatic LNs 0 LN dissection 3-field 58 (54) 2-field 49 (46) Pathological response Grade 0 8 (7) Grade 1 58 (54) Grade 2 23 (22) Grade 3 18 (17) Pretherapy SCLN status Negative 94 (88) Positive 13 (12)
SCLN−
SCLN+
P
169 63.7 ± 8.3 145/24
47 63.1 ± 7.9 37/10
0.662 0.239
18 (11) 70 (41) 81 (48)
12 (26) 23 (48) 12 (26)
0.005
4 (2) 29 (17) 34 (20) 94 (56) 8 (5)
2 (4) 7 (15) 8 (17) 27 (58) 3 (6)
0.693
0 (0) 91 (54) 54 (32) 24 (14) 3.9 ± 5.9
0 (0) 10 (21) 11 (23) 26 (56) 10.9 ± 11.2
