Ann Surg Oncol (2014) 21:3739–3743 DOI 10.1245/s10434-014-3929-6
ORIGINAL ARTICLE – THORACIC ONCOLOGY
Treatment of Clinical T2N0M0 Esophageal Cancer Thomas J. Hardacker, BA, DuyKhanh Ceppa, MD, Ikenna Okereke, MD, Karen M. Rieger, MD, Shadia I. Jalal, MD, Julia K. LeBlanc, MD, John M. DeWitt, MD, Kenneth A. Kesler, MD, and Thomas J. Birdas, MD Section of Thoracic Surgery, Indiana University School of Medicine, Indianapolis, IN
ABSTRACT Background. Management of clinical T2N0M0 (cT2N0M0) esophageal cancer remains controversial. We reviewed our institutional experience over 21 years (1990–2011) to determine clinical staging accuracy, optimal treatment approaches, and factors predictive of survival in this patient population. Methods. Patients with cT2N0M0 esophageal cancer determined by endoscopic ultrasound (EUS) were identified through a prospectively collected database. Demographics, perioperative data, and outcomes were examined. Cox regression model and Kaplan–Meier plots were used for statistical survival analysis. Results. A total of 731 patients underwent esophagectomy, of whom 68 cT2N0M0 patients (9 %) were identified. Fifty-seven patients (84 %) had adenocarcinoma. Thirty-three patients (48.5 %) were treated with neoadjuvant chemoradiation followed by surgery, and 35 underwent surgical resection alone. All resections except one included a transthoracic approach with two-field lymph node dissection. Thirty-day operative mortality was 2.9 %. Only 3 patients (8.5 %) who underwent surgery alone had T2N0M0 disease identified by pathology: the disease of 15 (42.8 %) was found to be overstaged and 17 (48.5 %) understaged after surgery. Understaging was more common in poorly differentiated tumors (p = 0.03). Nine patients (27.2 %) had complete pathologic response after chemoradiotherapy. Absence of lymph node metastases (pN0) was significantly more frequent in the neoadjuvant group (29 of 33 vs. 21 of 35, p = 0.01). Median follow-up was 44.2 months. Overall 5-year survival was 50.8 %. On multivariate analysis, adenocarcinoma (p = 0.001) and
Ó Society of Surgical Oncology 2014 First Received: 1 April 2014; Published Online: 22 July 2014 T. J. Hardacker, BA e-mail: [email protected]
pN0 after resection (p = 0.01) were significant predictors of survival. Conclusions. EUS was inaccurate in staging cT2N0M0 esophageal cancer in this study. Poorly differentiated tumors were more frequently understaged. Adenocarcinoma and absence of lymph node metastases (pN0) were independently predictive of long-term survival. pN0 status was significantly more common in patients undergoing neoadjuvant therapy, but long-term survival was not affected by neoadjuvant therapy. A strategy of neoadjuvant therapy followed by resection may be optimal in this group, especially in patients with disease likely to be understaged.
Esophageal adenocarcinoma has the fastest-rising incidence of any neoplasm in the Western world.1Though treatment of early and late-stage esophageal tumors has been well established, therapeutic protocols for clinical-stage T2N0M0 tumors (cT2N0M0) as determined by endoscopic ultrasound (EUS) are still somewhat controversial, in part because of the relative inaccuracy of EUS in these earlystage lesions. Although it is generally accepted that locally advanced tumors are best treated with neoadjuvant chemotherapy or chemoradiation followed by surgical resection, and early-stage tumors are best treated with surgery alone, the management of cT2N0M0 tumors is currently a subject of debate, with limited available literature on the topic. Treatment decisions are typically determined by clinical tumor staging, utilizing imaging studies and EUS. Clinical staging is not without limitations, however. Zuccaro et al.2 observed that EUS incorrectly assessed pathologic T status approximately 45 % of the time and N status in 25 % of cases. In studies specifically examining cT2N0M0 tumors, Rice et al.3 and Zhang et al.4 observed 13 and 28 % accuracy, respectively. Without dependable presurgical staging, treatment algorithms must be developed for cT2N0M0 cancers with the knowledge that the final pathologic diagnosis will often differ.5
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T. J. Hardacker et al.
Though several studies have examined whether surgical resection versus neoadjuvant therapy produces better survival in cT2N0M0 cases, there is not yet strict agreement on the most effective modality.3,4,6 The intent of this study was to examine the outcomes of cT2N0M0 esophageal cancer patients and identify prognostic factors that might influence treatment decisions, in particular the use of neoadjuvant therapy. It is also important to consider that treatment decisions must be made in the setting of somewhat unreliable clinical staging, done using EUS.
20
Count
15
METHODS All patients undergoing esophagectomy at Indiana University are entered in a prospectively collected database. After institutional review board approval, patients who underwent esophagectomy between 1990 and 2011 and who had disease staged clinically as cT2N0M0 by EUS and crosssectional imaging were identified. Demographic variables, perioperative outcomes, and long-term follow-up were obtained from review of hospital records and office charts. Survival information was obtained from our records as well as the Social Security Death Index. Data were analyzed with respect to operative mortality and length of stay as well as pathological staging after operation, disease recurrence, and overall survival. Univariate and multivariate analysis was performed to identify factors significantly affecting outcomes. A p level of less than 0.05 was considered significant. Statistical analysis was performed by IBM SPSS Statistics 20 Software (IBM Corp., Armonk, NY). RESULTS A total of 731 patients underwent esophagectomy at our institution between 1990 and 2011, with 68 of those patients (9 %) having disease staged as cT2N0M0. Of these, there were 54 distal tumors (82 %) and 57 adenocarcinomas (84 %). Neither tumor length nor tumor differentiation differed significantly between the surgery and neoadjuvant treatment groups. Median age was 61.5 years, and the group included 55 men and 13 women. Thirty-three patients (48.5 %) were treated with neoadjuvant chemoradiation followed by surgical resection; the remaining 35 underwent surgery alone. The use of preoperative therapy became more frequent in the most recent years in our study (Fig. 1), a finding likely attributed to wider acceptance of preoperative therapy in patients with locally advanced esophageal cancer.7 All resections except one were done by a transthoracic approach with two-field lymph node dissection (60 Ivor-Lewis, 7 three port, 1 transhiatal). The 30-day operative mortality was 2.9 %, and median follow-up was 44.2 months. Patient data are summarized in Table 1.
Neoadjuvant treatment N Y
10
5
0 1990-1995
1996-2000
2001-2005 2006-present
Time period
FIG. 1 Treatment choice trends at our institution for cT2N0M0 esophageal cancer over time. Initially the standard of care in the 1990s, surgical resection alone has gradually declined as a treatment modality in recent years. Neoadjuvant therapy has been used more frequently since the early 2000s and is the more common treatment approach today TABLE 1 Patient data for surgery and neoadjuvant treatment groups Characteristic
Surgery (n = 35)
Neoadjuvant p (n = 33)
Age
62.5
60.9
0.55
Gender, F/M
6/29
7/26
–
Distal location
26
28
–
Incomplete resection
2
2
–
Hospital death
1
1
–
Length of stay, d
17.5
12
0.05
Anastomotic leak
3
3
–
Squamous histology
6
5
–
Lymph nodes
13.1 ± 8.0 12.1 ± 6.1
–
Positive lymph nodes
1.2 ± 3.2
0.3 ± 1
–
Follow-up, monthsa
–
–
44.2 months
Pathologic complete response
–
9/33
–
pN0
21/35
29/33
0.013
Adjuvant therapy
3
1
–
Tumor length
2.58
2.24
0.27
Poorly differentiated, %
48.5
51.7
0.40
a
Follow-up was 44.2 months
Of patients in the surgery group, only 3 had disease accurately staged as pT2N0 by preoperative EUS (8.5 %; Table 2). The disease of 15 patients was overstaged (42.8 %; 1 T0N0, 14 T1N0) and 17 was understaged (48.5 %; 3 T2N1, 10 T3N1, 3 T3N0, 1 T4N1). Of patients
cT2N0M0
3741
TABLE 2 Pathologic staging of surgery and neoadjuvant treatment groups Group
T0N0
T1N0
T2N0
T3N0
T4N0
T2N1
T3N1
T4N1
Total
Surgery
1
14
3
3
0
3
10
1
35
Neoadjuvant
9
7
5
7
1
1
3
0
33
Survival Functions 1.0
pN0 N Y N-censored Y-censored
Cum Survival
0.8
0.6
0.4
0.2
0.0
In an attempt to identify risk factors for understaging by EUS, we examined the patients in the surgery-only group. The date of diagnosis did not have a correlation with understaging, meaning that the disease of earlier patients in our series was just as likely to be understaged as in later patients. Mean length of tumor was higher in the understaged group (3.1 vs. 2.4 cm, p = 0.35). Importantly, poor tumor differentiation at pathologic examination was significantly more frequent in understaged disease (70.6 vs. 33.3 %, p = 0.03). Surgery patients with poor tumor differentiation showed a trend toward decreased survival, with a mean survival of 38.4 months, as opposed to 49.1 months for patients with well or moderate differentiation (p = 0.26). DISCUSSION
0
12
24
36
48
60
72
Survival
FIG. 2 Patient survival as a factor of pathologic nodal positivity. Patients in this study without metastasis to regional lymph nodes (pN0; yellow line) experience a significant increase in survival over 72 months as compared to pN1? patients (blue line)
found to be understaged in the surgery group, 14 (40 % of the entire surgery group) were found to have lymph node metastases at the time of surgery. In contrast to the surgery group, only 4 patients (12 %) were found to have lymph node metastases in the neoadjuvant group. In addition, the disease 9 patients in the neoadjuvant treatment group (27.2 %) was found to exhibit complete pathologic response. Four patients received postoperative adjuvant therapy, 3 from the surgery group and 1 from the neoadjuvant group. Of these 4 patients, 3 were found to have nodal disease at pathologic examination. Five-year survival in the neoadjuvant group was 50.9 versus 44.8 % for the surgery group (p = 0.21). Overall, 5year survival in both groups was 50.8 %. Patients with no nodal metastases in the final pathology specimen (pN0) had a 5-year survival of 59.8 %, while patients with nodal disease (pN1?) had a 25.9 % survival (p = 0.01; Fig. 2). The pN0 finding was significantly more frequent in the neoadjuvant group (29 of 33 vs. 21 of 35; p = 0.01). Patients with adenocarcinoma had a 56 % 5-year survival, compared to 11.4 % in patients with squamous cell carcinoma (p = 0.001). On multivariate analysis, only adenocarcinoma and pN0 after resection were found to be significant predictors of 5-year survival.
The management of esophageal cancer has evolved significantly over the past 30 years. EUS has been an indispensable tool in the staging and management of esophageal cancer.8,9 Tumors clinically staged as T1N0 are typically treated with surgery. The use of neoadjuvant chemoradiation followed by surgery in locally advanced esophageal cancer (cT3 and above or any nodal disease by EUS) has been studied extensively in several phase 2 and phase 3 clinical trials.10 Despite continued debate, it has been accepted widely, primarily in the United States, as the preferred approach. Use of this strategy in earlier stage tumors is much more controversial, with far fewer published studies available. Tumors staged clinically as T2N0M0 present a challenging problem. Some reports suggest that these patients be managed similar to cT1N0M0 patients and undergo surgical resection. Rice et al. suggested that surgical resection alone is appropriate, followed by adjuvant therapy if the cancer is pathologically more advanced than the suspected clinical stage.3These researchers noted that 5year survival in cT2N0M0 patients treated with surgery alone was better than in patients treated with both surgery and postoperative adjuvant therapy, though 10-year survival was still low (30 %). Eight patients who were treated with neoadjuvant chemotherapy all did poorly, with one death resulting from toxicity and the remaining due to cancer recurrence. It should be noted that the majority (63 %) of instances of cT2N0M0 disease were overstaged in this study, with pT1 tumors in most cases. It is possible that because the disease of many patients was overstaged,
3742
surgical resection may have been a more favorable treatment modality and possibly could have produced better results in this population. Other studies have advocated the routine use of preoperative therapy, typically combination chemoradiotherapy, followed by esophagectomy. Kountourakis et al.6 found that 10-year survival was 60 % for patients with cT2N0M0 adenocarcinoma who were treated with neoadjuvant chemoradiation before surgical resection. Zhang et al.4 did not find a significant difference between neoadjuvant and surgery-only groups with regard to 5-year survival rates (53.8 vs. 49.5 %, respectively; p = 0.652). Interestingly, the majority of these patients had disease that was clinically understaged, and as a result, they suggest that neoadjuvant therapy be provided to all cT2N0M0 patients. Rohatgi et al.11 found that approximately 68 % of cT2N0M0 esophageal cancers were understaged; they echoed this treatment strategy. A recurring theme in many reports is the inaccuracy of EUS with respect to cT2N0M0 staging. Rice et al.3 found that the disease of only approximately 13 % of patients with cT2N0M0 esophageal cancer was correctly staged by EUS. Similar findings were reported by Crabtree et al.12,who found that only 6 % of disease was truly pT2N0 after resection. In a more recent analysis using the Society of Thoracic Surgeons database, Crabtree et al.5 found that 46.7 % of the disease of cT2N0M0 patients who underwent surgical resection alone were understaged. Although this study underscores the increased rate of understaging and the need for neoadjuvant therapy in these patients, the authors note that factors such as tumor differentiation increase the likelihood for understaging and should be taken into consideration. In the current study, EUS correctly predicted pathologic T status 17 % of the time (6 of 35) and N status 51 % (18 of 35) in the surgery group. In comparison, preoperative staging by EUS for the 26 cT1N0 tumors during this span was found to be 61.6 % accurate in assessing T status and 88.5 % accurate in assessing N status, with only 11.5 % of these tumors being understaged. As such, we cannot expect that a cT2N0M0 diagnosis will consistently result in a pT2N0M0 finding. Given this lack of confidence in EUSdriven cT2N0M0 findings, we assessed additional tumor features, specifically tumor length and differentiation, as possible factors for use in guiding treatment decisions. Although increased tumor length showed a trend toward understaging, this was not statistically significant. However, poor tumor differentiation had a statistically significant correlation with understaging by EUS in our study and could be a useful tool in decision making. We identified two factors—adenocarcinoma histology and absence of nodal metastases in the resected specimen (pN0)—that significantly improved long-term survival.
T. J. Hardacker et al.
The impact of histology on survival is consistent with other reports.6 Patients with cT2N0M0 disease are commonly found to have lymph node metastases, approximately 40 % of the time in our findings and up to 55 % in other studies.13 The significance of pN0 status is intriguing, primarily because we noted that this finding was significantly more frequent in patients who received preoperative treatment compared to the surgery-only group. It would be reasonable to view pN0 status as a surrogate for long-term survival. Despite that, we were not able to directly demonstrate significantly improved survival with the use of preoperative chemoradiation. This study has several strengths and limitations. It is a single-institution study of retrospectively analyzed data, although it was based on a prospectively collected database. The patient sample size was relatively small, but the distribution of patients was fairly balanced. The study extends over a significant period of time, and evolution in EUS technology and experience might confound the results. Still, the date of diagnosis was not found to affect outcomes. Finally, positron emission tomography results were not available in all patients. In summary, the current study underscores the inaccuracy of EUS and the need for better clinical staging modalities in this patient population. Given the significant rates of understaging in this group, we think that neoadjuvant therapy followed by surgery in patients with cT2N0M0 esophageal cancer may be beneficial, as reflected by the higher rates of pathologically negative nodal status in the neoadjuvant group. This strategy may be particularly indicated in patients with poor tumor differentiation, as the disease of patients was much more likely to be understaged by EUS, and it ought to be explored further in a prospective trial. DISCLOSURE
The authors declare no conflict of interest.
REFERENCES 1. Pohl H, Welch HG. The role of overdiagnosis and reclassification in the marked increase of esophageal adenocarcinoma incidence. J Natl Cancer Inst. 2005;97:142–6. 2. Zuccaro G Jr, Rice TW, Vargo JJ, et al. Endoscopic ultrasound errors in esophageal cancer. Am J Gasteroenterol. 2005;100: 601–6. 3. Rice TW, Mason DP, Murthy SC, et al. T2N0M0 esophageal cancer. J Thorac Cardiovasc Surg. 2007;133:317–24. 4. Zhang JQ, Hooker CM, Brock MV, et al. Neoadjuvant chemoradiation therapy is beneficial for clinical stage T2 N0 esophageal cancer patients due to inaccurate preoperative staging. Ann Thorac Surg. 2012;93:429–35. 5. Crabtree TD, Kosinski AS, Puri V, et al. Evaluation of the reliability of clinical staging of T2 N0 esophageal cancer: a review of the Society of Thoracic Surgeons database. Ann Thorac Surg. 2013;96:382–90.
cT2N0M0 6. Kountourakis P, Correa AM, Hofstetter WL, et al. Combined modality therapy of cT2N0M0 esophageal cancer: the University of Texas MD Anderson Cancer Center experience. Cancer. 2011;117:925–30. 7. Kesler KA, Helft PR, Werner EA, et al. A retrospective analysis of locally advanced esophageal cancer patients treated with neoadjuvant chemoradiation therapy followed by surgery or surgery alone. Ann Thorac Surg. 2005;79:1116–21. 8. Chandawarkar RY, Kakegawa T, Fujita H, Yamana H, Toh Y, Fujitoh H. Endosonography for preoperative staging of specific nodal groups associated with esophageal cancer. World J Surg. 1996;20:700–2. 9. DeWitt J, Kesler K, Brooks JA, et al. Endoscopic ultrasound for esophageal and gastroesophageal junction cancer: impact of increased use of primary neoadjuvant therapy on
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10. 11.
12.
13.
preoperative locoregional staging accuracy. Dis Esophagus. 2005;18:21–7. Campbell NP, Villaflor VM. Neoadjuvant treatment of esophageal cancer. World J Gastroenterol. 2010;16:3793–803. Rohatgi A, Naji S, Hamouda A, et al.: Effect of understaging of early oesophageal cancers on treatment. J Clin Oncol. 2009;27(suppl):15572. Crabtree TD, Yacoub WN, Puri V, et al. Endoscopic ultrasound for early stage esophageal adenocarcinoma: implications for staging and survival. Ann Thorac Surg. 2011;91:1509–15. Stiles BM, Mirza F, Coppolino A, et al. Clinical T2–T3N0M0 esophageal cancer: the risk of node positive disease. Ann Thorac Surg. 2011;92:491–6.
ORIGINAL ARTICLE – THORACIC ONCOLOGY
Treatment of Clinical T2N0M0 Esophageal Cancer Thomas J. Hardacker, BA, DuyKhanh Ceppa, MD, Ikenna Okereke, MD, Karen M. Rieger, MD, Shadia I. Jalal, MD, Julia K. LeBlanc, MD, John M. DeWitt, MD, Kenneth A. Kesler, MD, and Thomas J. Birdas, MD Section of Thoracic Surgery, Indiana University School of Medicine, Indianapolis, IN
ABSTRACT Background. Management of clinical T2N0M0 (cT2N0M0) esophageal cancer remains controversial. We reviewed our institutional experience over 21 years (1990–2011) to determine clinical staging accuracy, optimal treatment approaches, and factors predictive of survival in this patient population. Methods. Patients with cT2N0M0 esophageal cancer determined by endoscopic ultrasound (EUS) were identified through a prospectively collected database. Demographics, perioperative data, and outcomes were examined. Cox regression model and Kaplan–Meier plots were used for statistical survival analysis. Results. A total of 731 patients underwent esophagectomy, of whom 68 cT2N0M0 patients (9 %) were identified. Fifty-seven patients (84 %) had adenocarcinoma. Thirty-three patients (48.5 %) were treated with neoadjuvant chemoradiation followed by surgery, and 35 underwent surgical resection alone. All resections except one included a transthoracic approach with two-field lymph node dissection. Thirty-day operative mortality was 2.9 %. Only 3 patients (8.5 %) who underwent surgery alone had T2N0M0 disease identified by pathology: the disease of 15 (42.8 %) was found to be overstaged and 17 (48.5 %) understaged after surgery. Understaging was more common in poorly differentiated tumors (p = 0.03). Nine patients (27.2 %) had complete pathologic response after chemoradiotherapy. Absence of lymph node metastases (pN0) was significantly more frequent in the neoadjuvant group (29 of 33 vs. 21 of 35, p = 0.01). Median follow-up was 44.2 months. Overall 5-year survival was 50.8 %. On multivariate analysis, adenocarcinoma (p = 0.001) and
Ó Society of Surgical Oncology 2014 First Received: 1 April 2014; Published Online: 22 July 2014 T. J. Hardacker, BA e-mail: [email protected]
pN0 after resection (p = 0.01) were significant predictors of survival. Conclusions. EUS was inaccurate in staging cT2N0M0 esophageal cancer in this study. Poorly differentiated tumors were more frequently understaged. Adenocarcinoma and absence of lymph node metastases (pN0) were independently predictive of long-term survival. pN0 status was significantly more common in patients undergoing neoadjuvant therapy, but long-term survival was not affected by neoadjuvant therapy. A strategy of neoadjuvant therapy followed by resection may be optimal in this group, especially in patients with disease likely to be understaged.
Esophageal adenocarcinoma has the fastest-rising incidence of any neoplasm in the Western world.1Though treatment of early and late-stage esophageal tumors has been well established, therapeutic protocols for clinical-stage T2N0M0 tumors (cT2N0M0) as determined by endoscopic ultrasound (EUS) are still somewhat controversial, in part because of the relative inaccuracy of EUS in these earlystage lesions. Although it is generally accepted that locally advanced tumors are best treated with neoadjuvant chemotherapy or chemoradiation followed by surgical resection, and early-stage tumors are best treated with surgery alone, the management of cT2N0M0 tumors is currently a subject of debate, with limited available literature on the topic. Treatment decisions are typically determined by clinical tumor staging, utilizing imaging studies and EUS. Clinical staging is not without limitations, however. Zuccaro et al.2 observed that EUS incorrectly assessed pathologic T status approximately 45 % of the time and N status in 25 % of cases. In studies specifically examining cT2N0M0 tumors, Rice et al.3 and Zhang et al.4 observed 13 and 28 % accuracy, respectively. Without dependable presurgical staging, treatment algorithms must be developed for cT2N0M0 cancers with the knowledge that the final pathologic diagnosis will often differ.5
3740
T. J. Hardacker et al.
Though several studies have examined whether surgical resection versus neoadjuvant therapy produces better survival in cT2N0M0 cases, there is not yet strict agreement on the most effective modality.3,4,6 The intent of this study was to examine the outcomes of cT2N0M0 esophageal cancer patients and identify prognostic factors that might influence treatment decisions, in particular the use of neoadjuvant therapy. It is also important to consider that treatment decisions must be made in the setting of somewhat unreliable clinical staging, done using EUS.
20
Count
15
METHODS All patients undergoing esophagectomy at Indiana University are entered in a prospectively collected database. After institutional review board approval, patients who underwent esophagectomy between 1990 and 2011 and who had disease staged clinically as cT2N0M0 by EUS and crosssectional imaging were identified. Demographic variables, perioperative outcomes, and long-term follow-up were obtained from review of hospital records and office charts. Survival information was obtained from our records as well as the Social Security Death Index. Data were analyzed with respect to operative mortality and length of stay as well as pathological staging after operation, disease recurrence, and overall survival. Univariate and multivariate analysis was performed to identify factors significantly affecting outcomes. A p level of less than 0.05 was considered significant. Statistical analysis was performed by IBM SPSS Statistics 20 Software (IBM Corp., Armonk, NY). RESULTS A total of 731 patients underwent esophagectomy at our institution between 1990 and 2011, with 68 of those patients (9 %) having disease staged as cT2N0M0. Of these, there were 54 distal tumors (82 %) and 57 adenocarcinomas (84 %). Neither tumor length nor tumor differentiation differed significantly between the surgery and neoadjuvant treatment groups. Median age was 61.5 years, and the group included 55 men and 13 women. Thirty-three patients (48.5 %) were treated with neoadjuvant chemoradiation followed by surgical resection; the remaining 35 underwent surgery alone. The use of preoperative therapy became more frequent in the most recent years in our study (Fig. 1), a finding likely attributed to wider acceptance of preoperative therapy in patients with locally advanced esophageal cancer.7 All resections except one were done by a transthoracic approach with two-field lymph node dissection (60 Ivor-Lewis, 7 three port, 1 transhiatal). The 30-day operative mortality was 2.9 %, and median follow-up was 44.2 months. Patient data are summarized in Table 1.
Neoadjuvant treatment N Y
10
5
0 1990-1995
1996-2000
2001-2005 2006-present
Time period
FIG. 1 Treatment choice trends at our institution for cT2N0M0 esophageal cancer over time. Initially the standard of care in the 1990s, surgical resection alone has gradually declined as a treatment modality in recent years. Neoadjuvant therapy has been used more frequently since the early 2000s and is the more common treatment approach today TABLE 1 Patient data for surgery and neoadjuvant treatment groups Characteristic
Surgery (n = 35)
Neoadjuvant p (n = 33)
Age
62.5
60.9
0.55
Gender, F/M
6/29
7/26
–
Distal location
26
28
–
Incomplete resection
2
2
–
Hospital death
1
1
–
Length of stay, d
17.5
12
0.05
Anastomotic leak
3
3
–
Squamous histology
6
5
–
Lymph nodes
13.1 ± 8.0 12.1 ± 6.1
–
Positive lymph nodes
1.2 ± 3.2
0.3 ± 1
–
Follow-up, monthsa
–
–
44.2 months
Pathologic complete response
–
9/33
–
pN0
21/35
29/33
0.013
Adjuvant therapy
3
1
–
Tumor length
2.58
2.24
0.27
Poorly differentiated, %
48.5
51.7
0.40
a
Follow-up was 44.2 months
Of patients in the surgery group, only 3 had disease accurately staged as pT2N0 by preoperative EUS (8.5 %; Table 2). The disease of 15 patients was overstaged (42.8 %; 1 T0N0, 14 T1N0) and 17 was understaged (48.5 %; 3 T2N1, 10 T3N1, 3 T3N0, 1 T4N1). Of patients
cT2N0M0
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TABLE 2 Pathologic staging of surgery and neoadjuvant treatment groups Group
T0N0
T1N0
T2N0
T3N0
T4N0
T2N1
T3N1
T4N1
Total
Surgery
1
14
3
3
0
3
10
1
35
Neoadjuvant
9
7
5
7
1
1
3
0
33
Survival Functions 1.0
pN0 N Y N-censored Y-censored
Cum Survival
0.8
0.6
0.4
0.2
0.0
In an attempt to identify risk factors for understaging by EUS, we examined the patients in the surgery-only group. The date of diagnosis did not have a correlation with understaging, meaning that the disease of earlier patients in our series was just as likely to be understaged as in later patients. Mean length of tumor was higher in the understaged group (3.1 vs. 2.4 cm, p = 0.35). Importantly, poor tumor differentiation at pathologic examination was significantly more frequent in understaged disease (70.6 vs. 33.3 %, p = 0.03). Surgery patients with poor tumor differentiation showed a trend toward decreased survival, with a mean survival of 38.4 months, as opposed to 49.1 months for patients with well or moderate differentiation (p = 0.26). DISCUSSION
0
12
24
36
48
60
72
Survival
FIG. 2 Patient survival as a factor of pathologic nodal positivity. Patients in this study without metastasis to regional lymph nodes (pN0; yellow line) experience a significant increase in survival over 72 months as compared to pN1? patients (blue line)
found to be understaged in the surgery group, 14 (40 % of the entire surgery group) were found to have lymph node metastases at the time of surgery. In contrast to the surgery group, only 4 patients (12 %) were found to have lymph node metastases in the neoadjuvant group. In addition, the disease 9 patients in the neoadjuvant treatment group (27.2 %) was found to exhibit complete pathologic response. Four patients received postoperative adjuvant therapy, 3 from the surgery group and 1 from the neoadjuvant group. Of these 4 patients, 3 were found to have nodal disease at pathologic examination. Five-year survival in the neoadjuvant group was 50.9 versus 44.8 % for the surgery group (p = 0.21). Overall, 5year survival in both groups was 50.8 %. Patients with no nodal metastases in the final pathology specimen (pN0) had a 5-year survival of 59.8 %, while patients with nodal disease (pN1?) had a 25.9 % survival (p = 0.01; Fig. 2). The pN0 finding was significantly more frequent in the neoadjuvant group (29 of 33 vs. 21 of 35; p = 0.01). Patients with adenocarcinoma had a 56 % 5-year survival, compared to 11.4 % in patients with squamous cell carcinoma (p = 0.001). On multivariate analysis, only adenocarcinoma and pN0 after resection were found to be significant predictors of 5-year survival.
The management of esophageal cancer has evolved significantly over the past 30 years. EUS has been an indispensable tool in the staging and management of esophageal cancer.8,9 Tumors clinically staged as T1N0 are typically treated with surgery. The use of neoadjuvant chemoradiation followed by surgery in locally advanced esophageal cancer (cT3 and above or any nodal disease by EUS) has been studied extensively in several phase 2 and phase 3 clinical trials.10 Despite continued debate, it has been accepted widely, primarily in the United States, as the preferred approach. Use of this strategy in earlier stage tumors is much more controversial, with far fewer published studies available. Tumors staged clinically as T2N0M0 present a challenging problem. Some reports suggest that these patients be managed similar to cT1N0M0 patients and undergo surgical resection. Rice et al. suggested that surgical resection alone is appropriate, followed by adjuvant therapy if the cancer is pathologically more advanced than the suspected clinical stage.3These researchers noted that 5year survival in cT2N0M0 patients treated with surgery alone was better than in patients treated with both surgery and postoperative adjuvant therapy, though 10-year survival was still low (30 %). Eight patients who were treated with neoadjuvant chemotherapy all did poorly, with one death resulting from toxicity and the remaining due to cancer recurrence. It should be noted that the majority (63 %) of instances of cT2N0M0 disease were overstaged in this study, with pT1 tumors in most cases. It is possible that because the disease of many patients was overstaged,
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surgical resection may have been a more favorable treatment modality and possibly could have produced better results in this population. Other studies have advocated the routine use of preoperative therapy, typically combination chemoradiotherapy, followed by esophagectomy. Kountourakis et al.6 found that 10-year survival was 60 % for patients with cT2N0M0 adenocarcinoma who were treated with neoadjuvant chemoradiation before surgical resection. Zhang et al.4 did not find a significant difference between neoadjuvant and surgery-only groups with regard to 5-year survival rates (53.8 vs. 49.5 %, respectively; p = 0.652). Interestingly, the majority of these patients had disease that was clinically understaged, and as a result, they suggest that neoadjuvant therapy be provided to all cT2N0M0 patients. Rohatgi et al.11 found that approximately 68 % of cT2N0M0 esophageal cancers were understaged; they echoed this treatment strategy. A recurring theme in many reports is the inaccuracy of EUS with respect to cT2N0M0 staging. Rice et al.3 found that the disease of only approximately 13 % of patients with cT2N0M0 esophageal cancer was correctly staged by EUS. Similar findings were reported by Crabtree et al.12,who found that only 6 % of disease was truly pT2N0 after resection. In a more recent analysis using the Society of Thoracic Surgeons database, Crabtree et al.5 found that 46.7 % of the disease of cT2N0M0 patients who underwent surgical resection alone were understaged. Although this study underscores the increased rate of understaging and the need for neoadjuvant therapy in these patients, the authors note that factors such as tumor differentiation increase the likelihood for understaging and should be taken into consideration. In the current study, EUS correctly predicted pathologic T status 17 % of the time (6 of 35) and N status 51 % (18 of 35) in the surgery group. In comparison, preoperative staging by EUS for the 26 cT1N0 tumors during this span was found to be 61.6 % accurate in assessing T status and 88.5 % accurate in assessing N status, with only 11.5 % of these tumors being understaged. As such, we cannot expect that a cT2N0M0 diagnosis will consistently result in a pT2N0M0 finding. Given this lack of confidence in EUSdriven cT2N0M0 findings, we assessed additional tumor features, specifically tumor length and differentiation, as possible factors for use in guiding treatment decisions. Although increased tumor length showed a trend toward understaging, this was not statistically significant. However, poor tumor differentiation had a statistically significant correlation with understaging by EUS in our study and could be a useful tool in decision making. We identified two factors—adenocarcinoma histology and absence of nodal metastases in the resected specimen (pN0)—that significantly improved long-term survival.
T. J. Hardacker et al.
The impact of histology on survival is consistent with other reports.6 Patients with cT2N0M0 disease are commonly found to have lymph node metastases, approximately 40 % of the time in our findings and up to 55 % in other studies.13 The significance of pN0 status is intriguing, primarily because we noted that this finding was significantly more frequent in patients who received preoperative treatment compared to the surgery-only group. It would be reasonable to view pN0 status as a surrogate for long-term survival. Despite that, we were not able to directly demonstrate significantly improved survival with the use of preoperative chemoradiation. This study has several strengths and limitations. It is a single-institution study of retrospectively analyzed data, although it was based on a prospectively collected database. The patient sample size was relatively small, but the distribution of patients was fairly balanced. The study extends over a significant period of time, and evolution in EUS technology and experience might confound the results. Still, the date of diagnosis was not found to affect outcomes. Finally, positron emission tomography results were not available in all patients. In summary, the current study underscores the inaccuracy of EUS and the need for better clinical staging modalities in this patient population. Given the significant rates of understaging in this group, we think that neoadjuvant therapy followed by surgery in patients with cT2N0M0 esophageal cancer may be beneficial, as reflected by the higher rates of pathologically negative nodal status in the neoadjuvant group. This strategy may be particularly indicated in patients with poor tumor differentiation, as the disease of patients was much more likely to be understaged by EUS, and it ought to be explored further in a prospective trial. DISCLOSURE
The authors declare no conflict of interest.
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