Original Paper Received: December 9, 2013 Accepted: June 4, 2014 Published online: September 4, 2014
Digestion 2014;90:98–107 DOI: 10.1159/000365073
Prediction of Survival by Tumor Area on Endosonography after Definitive Chemoradiotherapy for Locally Advanced Squamous Cell Carcinoma of the Esophagus Choong Nam Shim a Mi Kyung Song b Hye Sun Lee b Hyunsoo Chung a Hyuk Lee a Sung Kwan Shin a Sang Kil Lee a Yong Chan Lee a Jun Chul Park a a Department of Internal Medicine, Institute of Gastroenterology, and b Biostatistics Collaboration Unit, Yonsei University College of Medicine, Seoul, Korea
Key Words Esophageal cancer · Endosonography · Tumor area · Definitive chemoradiotherapy · Progression-free survival
Abstract Background: Definitive chemoradiotherapy (CRT) is a reasonable approach for patients with locally advanced esophageal cancer who are not surgical candidates. This study was performed to investigate whether endosonography (EUS) assessment of tumor area response is a useful prognostic marker in patients with squamous cell carcinoma (SCC) of the esophagus who receive definitive CRT. Methods: A total of 33 patients who received definitive CRT for locally advanced esophageal SCC were enrolled. The maximal transverse cross-sectional area of the tumor was measured before and after definitive therapy. EUS response was defined as a ≥50% reduction of the tumor area after definitive CRT. Results: Based on EUS evaluation, there were 20 nonresponders (60.6%) and 13 responders (39.4%). The median progression-free survival (PFS) was significantly longer in EUS responders than EUS nonresponders (p = 0.005). However, there was no statistical significance in overall survival according to EUS response (p = 0.120). During multivariate
© 2014 S. Karger AG, Basel 0012–2823/14/0902–0098$39.50/0 E-Mail [email protected] www.karger.com/dig
analysis, EUS response to definitive CRT was the only significant factor associated with PFS (p = 0.045), whereas EUS response to definitive CRT was not associated with overall survival (p = 0.221). Conclusions: A reduction of the maximal cross-sectional tumor area measured by EUS correlates with a superior prognosis in patients with locally advanced SCC of the esophagus after definitive CRT. © 2014 S. Karger AG, Basel
Introduction
The mainstay of contemporary treatment for locally advanced esophageal cancer is multimodality therapy including neoadjuvant chemotherapy followed by surgical resection [1]. However, outcomes from this treatment remain unsatisfactory, with only 30–45% patients surviving 2 years after radical resection [1, 2]. In addition, esophagectomy is associated with high postoperative morbidity and mortality rates: 30–40 and 5–10%, respectively [3–8]. Furthermore, only 25–45% of patients are selected to undergo radical esophagectomy, since over 60% of individuals have unresectable disease at presentation [9–11]. Some individuals who present with a theoretically operJun Chul Park, MD Department of Internal Medicine, Institute of Gastroenterology Yonsei University College of Medicine 134 Shinchon-dong, Seodaemun-gu, Seoul 120-752 (Korea) E-Mail junchul75 @ yuhs.ac
able tumor do not undergo surgery because of substantial comorbid disorders, old age, or tumor in the cervical esophagus. Therefore, for those who are not surgical candidates because of advanced tumor stage as well as postoperative morbidity, definitive chemoradiotherapy (CRT) has been suggested as a strategy to both prolong survival and provide symptomatic relief. The outcomes of definitive CRT are similar to those achieved with surgery [12–15]. Endosonography (EUS) is widely performed for the regional assessment of esophageal carcinoma prior to initiating therapy [16–19]. Large series have reported accuracies of 85 and 75% for EUS determination of tumor (T) classification and node (N) classification, respectively, in patients undergoing surgical resection without prior neoadjuvant therapy [20–22]. In contrast, EUS cannot accurately evaluate the T stage after neoadjuvant CRT [23– 29], because inflammation, necrosis, and fibrosis associated with CRT lead to disintegration and blurring of anatomic structures. Moreover, since we cannot obtain accurate histopathologic stage information after definitive CRT, prognosis prediction in these patients is extremely difficult, and there are no well-established prognostic factors for esophageal cancer after definitive CRT. Previous studies have attempted to determine the prognostic role of EUS for esophageal cancer treated with CRT by measuring the radial tumor thickness [30], total disease length [31], tumor volume [32] or tumor area [16, 29, 33–35]. In particular, a reduction in the cross-sectional area of tumor measured by EUS predicts the histopathologic response and prognosis in patients with esophageal cancer treated by neoadjuvant CRT [16, 29, 33–35]. However, no studies have attempted to evaluate the relation between prognosis and the reduction of esophageal cross-sectional tumor area on EUS after definitive CRT. Therefore, the purpose of this study is to evaluate the prognostic implications of a decrease in EUS maximum transverse tumor area after definitive CRT in patients with locally advanced squamous cell carcinoma (SCC) of the esophagus.
6), multiple synchronous esophageal cancers (n = 14), and stenotic tumor to be crossed with the EUS probe (n = 26) were excluded. Thus, a total of 33 patients treated with definitive CRT for locally advanced, histologically confirmed SCC in the esophagus were enrolled in the present study (fig. 1). Enrolled patients were categorized into two groups, EUS nonresponders (n = 20) and EUS responders (n = 13), based on the absence or presence of EUS response to definitive CRT. EUS response was defined as a ≥50% reduction of the maximal transverse cross-sectional area (MAX) of the esophageal cancer after definitive CRT. This cutoff percentage was evaluated using receiver operating characteristic (ROC) analysis. Typical EUS images of nonresponders and responders are shown in figure 2. Pre-therapeutic evaluations involved upper endoscopy with biopsies, EUS, computed tomography, and whole-body fluorodeoxyglucose-positron emission tomography scans for all patients, plus bronchoscopy or laparoscopy, if considered appropriate. A baseline EUS was performed during the initial staging, within 2 weeks of the first definitive CRT. Clinical staging was based on the seventh edition of the American Joint Committee on Cancer/Union for International Cancer Control tumor-node-metastasis classification for esophagus and esophagogastric junction [36]. Clinical response to treatment, based on the findings of esophagogastroduodenoscopy, EUS, and computed tomography, was assessed after two or three cycles of chemotherapy in accordance with the Revised Response Evaluation Criteria in Solid Tumors (RECIST version 1.1) [37]. In addition, we maintained a protocol of performance of endoscopic biopsies following completion of definitive CRT as a part of evaluating methods for clinical response, regardless of presence of EUS response. Demographic data of the enrolled patients and the clinicopathologic characteristics and outcomes of the two groups were analyzed. This study was approved by the Institutional Review Board of Yonsei University College of Medicine, Korea.
Patients Between October 2006 and August 2012, a total of 811 patients received CRT for esophageal cancer at our high-volume tertiary referral center. Patients with no baseline EUS evaluation (n = 280), no follow-up EUS evaluation after CRT (n = 380), surgical resection for esophageal cancer (n = 40), superficial esophageal cancer (n = 26), distant metastasis (n = 6), double primary cancers (n =
Tumor Area Measurement by Endosonography Standard EUS staging was performed with radial scanning echoendoscopes (EG-3679URK, Pentax, Japan, and GF-UE260, Olympus, Japan) [22]. Each tumor was staged using standard EUS criteria [21, 38]. EUS images of the tumor were obtained in the transverse plane at the area where the tumor exhibited the greatest bulk. Tumor cross-sectional area was measured by tracing the contour of the tumor mass with the aid of a cross-sectional area measurement function provided with the EUS processor. Multiple measurements of the tumor were performed, and the MAX was obtained during each EUS examination. The MAX was measured both before and after the second or third cycle of definitive CRT. Standardized measurements were recorded as the distance from the incisors in the pull-back position at baseline and after definitive CRT, to allow correlation with the principal anatomic landmarks: the proximal end of the gastric folds (gastroesophageal junction), the EUS longitudinal tumor extent, the upper limit of the aortic arch (main internal reference), and the MAX. EUS repeated after definitive CRT required realignment to the previously recorded landmarks, with emphasis on recovering the plane used for the baseline MAX examination, to obtain the response MAX measurement. In both evaluations, images from the corresponding planes with MAX measurements were assessed. Anatomic landmarks on these images were compared to optimize EUS realignment and ensure that the MAX measurement was performed at the same site, thus facilitating final data monitoring and quality assurance.
Tumor Area on EUS in Esophageal Cancer
Digestion 2014;90:98–107 DOI: 10.1159/000365073
Methods
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Patients with esophageal cancer treated by CRT (n = 811) Exclusion No baseline EUS evaluation (n = 280) No follow-up EUS evaluation after CRT (n = 380) Patients with EUS evaluations before and after CRT (n = 151) Exclusion Tumors with surgical resection (n = 40) Superficial esophageal cancers (n = 26) Tumors with distant metastasis (n = 6) Double primary cancers (n = 6) Multiple synchronous esophageal cancers (n = 14) Stenotic tumors to be crossed with the EUS probe (n = 26) Patients with locally advanced SCC of the esophagus treated by definitive CRT (n = 33)
EUS nonresponders (n = 20)
Fig. 1. Flowchart showing patient inclusion of the present study.
Fig. 2. EUS images in EUS nonresponders (a, b) and EUS responder (c, d). a, c EUS images before definitive CRT. b, d EUS im-
ages after definitive CRT.
100
Digestion 2014;90:98–107 DOI: 10.1159/000365073
EUS responders (n = 13)
a
b
c
d
Shim /Song /Lee /Chung /Lee /Shin /Lee / Lee /Park
1.0
EUS responders
0.8
0.6
0.6
OS (%)
PFS (%)
EUS responders 0.8
0.4 EUS nonresponders
0.2 0
0
Fig. 3. PFS (a) and OS (b) of patients ac-
0 20
40
p = 0.120 0
60
Time (months)
EUS nonresponders
0.2
p = 0.005
a
0.4
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1.0
b
20
40
60
Time (months)
cording to EUS response to definitive CRT.
Treatment and Survival of Patients At our institution, a multidisciplinary team of gastroenterologists, oncologists, radiation oncologists, and thoracic surgeons determines the treatment strategy of patients with esophageal cancer. Indications for definitive CRT in our center were largely based on national comprehensive cancer network guidelines for esophageal and esophagogastric junction cancers [39]. We considered definitive CRT in superficial T1b tumors with poor prognostic features, locally advanced tumors with medically unfit for surgery, and tumors located in cervical esophagus. Enrolled patients completed a definitive CRT protocol consisting of four cycles of cisplatin and 5-fluorouracil (5-FU) or cisplatin and TS-1 (an oral fluoropyrimidine anticancer agent composed of tegafur, 5-chloro-2,4-dihydroxypyridine, and potassium oxonate), with concurrent radiotherapy of 50.4–63.0 Gy in 28–35 fractions over 5 weeks. In protocol of cisplatin and 5-FU, cisplatin (80 mg/m2) was administered as a day case on day 2 of each of the four weekly cycles. 5-FU (800 mg/ m2) was daily delivered as a continuous intravenous infusion on days 1–4. In protocol of cisplatin and TS-1, cisplatin (80 mg/m2) was administered as a day case on day 1 of each of the three weekly cycles. TS-1 (70 mg/m2) was delivered daily on days 1–14 of each cycle. If necessary, the dosage of chemotherapy was adjusted for audiologic, renal, hematologic, or gastrointestinal toxicity. The survival assessments included progression-free survival (PFS) as a primary endpoint and overall survival (OS) as a secondary endpoint. PFS was defined as the time from treatment initiation to disease progression or death from any cause, whichever was earlier [40]. OS was defined as the time from treatment initiation to death from any cause.
er curve and log-rank test were performed to assess survivals according to the EUS response of the two groups. Cox regression analysis was carried out to investigate the relationship of clinicopathologic characteristics to the EUS response and survival. Characteristics with a p value 60 Gy 8 (24.2) Clinical response to definitive CRT Stable disease 2 (6.1) Partial response 25 (75.8) Complete response 5 (15.2) Progressive disease 1 (3.0) Location Proximal 6 (18.2) Middle 15 (45.5) Distal 12 (36.4) Histology Well-differentiated 4 (12.1) Moderately-differentiated 19 (57.6) Poorly-differentiated 10 (30.3)
70.5 (44.0 – 83.0) 18 (90.0) 23.4 (17.7 – 27.5) 15 (75.0) 15 (75.0)
p value
69.0 (57.0 – 79.0) 11 (84.6) 23.9 (20.7 – 25.9) 11 (84.6) 10 (76.9)
6 (30.0) 10 (50.0) 1 (5.0) 2 (10.0)
4 (30.8) 6 (46.2) 1 (7.7) 0 (0)
7 (35.0) 12 (60.0) 1 (5.0)
7 (53.8) 6 (46.2) 0 (0)
1 (5.0) 19 (95.0)
4 (30.8) 9 (69.2)
13 (65.0) 7 (35.0)
12 (92.3) 1 (7.7)
1 (5.0) 14 (70.0) 4 (20.0) 1 (5.0)
1 (7.7) 11 (84.6) 1 (7.7) 0 (0)
4 (20.0) 9 (45.0) 7 (35.0)
2 (15.4) 6 (46.2) 5 (38.5)
3 (15.0) 11 (55.0) 6 (30.0)
1 (7.7) 8 (61.5) 4 (30.8)
0.353 >0.999 0.650 0.676 >0.999 0.807
0.680
0.066 0.108 0.886
>0.999
>0.999
Data are expressed as median (range) or n (%).
in baseline characteristics, including age, sex, body mass index (BMI), alcohol, smoking, and comorbidities, were detected between the EUS nonresponders and EUS responders. In terms of clinicopathologic features, the clinical stage of lesions was primarily T 2–3 (97.0%, 32/33), with positive N (84.8%, 28/33). Most of the patients were treated with cisplatin/5-FU (78.8%, 26/33) and radiotherapy with 50.4 Gy (n = 6) or 54.0 Gy (n = 19) (75.8%, 25/33). The rest (24.2%, 8/33) completed concurrent radiotherapy of 63.0 Gy. We applied a 50.4- or 54.0-Gy radiation dose to patients with downgraded performance state during CRT or patients with 102
Digestion 2014;90:98–107 DOI: 10.1159/000365073
older age. The lesions were primarily located at the proximal to middle part of the esophagus (63.6%, 21/33) and their main histology was well- or moderately-differentiated SCC (69.7%, 23/33). No significant differences in clinicopathologic features, including clinical stage, radiation dose, clinical response to definitive CRT, location, and histology, were detected between the two groups. Prognostic Factors Related to Survival Figure 3 depicts the PFS and OS according to the EUS response to definitive CRT. The median PFS was signifiShim /Song /Lee /Chung /Lee /Shin /Lee / Lee /Park
Table 2. Cox regression analysis of prognostic factors related to PFS
Characteristic
PFS univariate
multivariate
hazard ratio (95% CI) EUS response to definitive CRT No response 1.00 (reference) Response 0.10 (0.01 – 0.77) Clinical response to definitive CRT Progressive disease 1.00 (reference) Nonprogressive disease 0.80 (0.10 – 6.16) Age ≤70 years 1.00 (reference) >70 years 0.74 (0.24 – 2.28) Sex Male 1.00 (reference) Female 0.04 (0 – 21.72) Tumor staging 2 1.00 (reference) 3 1.67 (0.50 – 5.57) 4 22.05 (1.74 – 278.78) Node metastasis Negative 1.00 (reference) Positive 28.05 (0.07 – 11,564.95) Radiation >50 and ≤60 Gy 1.00 (reference) >60 Gy 2.64 (0.86 – 8.16) Location Proximal 1.00 (reference) Middle 0.69 (0.18 – 2.77) Distal 0.59 (0.13 – 2.65) Histology Well-differentiated 1.00 (reference) Moderately-differentiated 0.62 (0.12 – 3.11) Poorly-differentiated 1.20 (0.23 – 6.20)
p value
hazard ratio (95% CI)
0.027
p value 0.045
1.00 (reference) 0.13 (0.02 – 0.95) 0.826 0.600 0.308 0.057
0.181 1.00 (reference) 1.86 (0.51 – 6.80) 10.59 (0.80 – 141.57)
0.278 0.092
0.369 1.00 (reference) 1.83 (0.49 – 6.87)
0.783
0.550
cantly longer for the EUS responders than for the EUS nonresponders (not reached vs. 13.0 months, 95% CI 3.26–22.74, p = 0.005). However, there was no statistical significance in OS according to EUS response (not reached vs. 30.0 months, 95% CI 20.49–39.52, p = 0.120). Concerning the presentation of distant metastasis, a total of 5 patients revealed the distant metastasis among enrolled patients during follow-up periods. Uni- and multivariate Cox regression analyses of prognostic factors for PFS are shown in table 2. During univariate analysis, the EUS response to definitive CRT was the only factor significantly associated with PFS (p = 0.027). Tumor staging (p = 0.057) and radiation therapy (p = 0.092) showed a tendency towards being associated with PFS. During multivariate analysis, the EUS response
to definitive CRT was the only significant prognostic factor for PFS (p = 0.045). The uni- and multivariate Cox regression analyses of prognostic factors for OS are summarized in table 3. The EUS response to definitive CRT was not significantly associated with OS.
Tumor Area on EUS in Esophageal Cancer
Digestion 2014;90:98–107 DOI: 10.1159/000365073
Discussion
This study focused on the role of EUS in predicting survivals according to the EUS response of the tumor area to definitive CRT for locally advanced SCC of the esophagus. Based on our data, the reduction in tumor MAX may be a predictive factor for prognosis of patients with this tumor after definitive CRT. 103
Table 3. Cox regression analysis of prognostic factors related to OS
Characteristic
OS univariate
multivariate
hazard ratio (95% CI) EUS response to definitive CRT No response 1.00 (reference) Response 0.31 (0.06 – 1.50) Clinical response to definitive CRT Progressive disease 1.00 (reference) Nonprogressive disease 0.45 (0 – 23,745.04) Age ≤70 years 1.00 (reference) >70 years 1.15 (0.31 – 4.30) Sex Male 1.00 (reference) Female 0.03 (0 – 41.62) Tumor staging 2 1.00 (reference) 3 0.99 (0.25 – 4.03) 4 3.95 (0.43 – 36.45) Node metastasis Negative 1.00 (reference) Positive 27.50 (0.02 – 46,903.89) Radiation >50 and ≤60 Gy 1.00 (reference) >60 Gy 2.31 (0.54 – 9.89) Location Proximal 1.00 (reference) Middle 0.99 (0.20 – 4.97) Distal 0.24 (0.02 – 2.60) Histology Well-differentiated 1.00 (reference) Moderately-differentiated 0.23 (0.04 – 1.40) Poorly-differentiated 0.98 (0.17 – 5.70)
In contrast to the accuracy of EUS determination of T and N stages prior to surgical treatment without CRT, previous studies have found poor correlation between standard EUS after CRT T-staging and pathologic findings [23–29]. Nevertheless, numerous authors have attempted to demonstrate the prognostic role of EUS in esophageal cancer treated with CRT by measuring the radial tumor thickness [30], total disease length [31], tumor volume [32], or tumor area [16, 29, 33–35]. Previous studies assessing the usefulness of EUS in predicting prognosis through measurement of tumor area arbitrarily defined a positive response on EUS as a 50% reduction in the maximal tumor cross-sectional area [16, 29, 35]. However, these studies primarily involved patients with esophageal cancer who received neoadju104
Digestion 2014;90:98–107 DOI: 10.1159/000365073
p value
hazard ratio (95% CI)
p value
0.146
0.221 1.00 (reference) 0.36 (0.07 – 1.86)
0.644 0.840 0.350 0.447
0.383 0.260 0.395
0.136
0.196 1.00 (reference) 0.34 (0.05 – 2.21) 1.45 (0.23 – 9.29)
vant CRT followed by surgical resection. Although this multimodal approach is a mainstay of current treatment for locally advanced esophageal cancer, many patients cannot follow this approach because of their advanced cancer stage or the substantial risk of postoperative morbidity. Furthermore, the prediction of prognosis in patients who receive definitive CRT is challenging because it is not possible to know the exact pathologic stage of the cancer with definitive CRT, yet pathologic stage is the most important factor related to prognosis. In the current study, we validated EUS-determined tumor measurement as a useful clinical method that is predictive of PFS in patients with esophageal cancer treated by definitive CRT. Furthermore, our study performed ROC analysis using PFS data to confirm the validity of Shim /Song /Lee /Chung /Lee /Shin /Lee / Lee /Park
using 50% as the EUS tumor area reduction percentage to differentiate EUS nonresponders and EUS responders. This 50% value is consistent with the cutoff value used in earlier studies [16, 29, 35]. When evaluating potential prognostic factors to predict survival, we found that the EUS assessment of response to definitive CRT was the only predictive factor of PFS that was significant during both uni- and multivariate analyses. However, our data did not demonstrate the statistical power for proving the association of the EUS response with OS. This might be stemming from small number of enrolled patients and study population primarily composed of patients with nodal metastasis (84.8%, 28/33). Since our results are compatible with previous reports of the prognostic importance of EUS based on the measurement of maximal cross-sectional tumor area [16, 29, 33–35], we believe that our data can help gastroenterologists predict prognosis in patients with locally advanced SCC of the esophagus after definitive CRT. Furthermore, CRT could unveil the biologic profile of esophageal cancer based on the absence or presence of EUS response to definitive CRT. More aggressive treatment to improve survival and further studies including targeted therapy may be needed in patients revealing no response of EUS. In contrast to the previous results, the lack of association between lymph node metastasis and survival was noted in this study [41–43]. We attributed this finding the selected patient population in the current study. We excluded patients with TNM stage 1, and therefore the vast majority of enrolled patients consisted of esophageal cancers with nodal metastasis. This composition may contribute to the lack of correlation between N stage and PFS. Therefore, further multicenter, prospective studies with a larger cohort of patients are warranted to determine the prognostic significance of EUS in esophageal cancer with definitive CRT. In terms of study population, we had to exclude a considerable number of esophageal patients who underwent
References
Tumor Area on EUS in Esophageal Cancer
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Disclosure Statement The authors have no conflicts of interest to disclose.
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28 Zuccaro G Jr, Rice TW, Goldblum J, Medendorp SV, Becker M, Pimentel R, Gitlin L, Adelstein DJ: Endoscopic ultrasound cannot determine suitability for esophagectomy after aggressive chemoradiotherapy for esophageal cancer. Am J Gastroenterol 1999;94:906–912. 29 Isenberg G, Chak A, Canto MI, Levitan N, Clayman J, Pollack BJ, Sivak MV Jr: Endoscopic ultrasound in restaging of esophageal cancer after neoadjuvant chemoradiation. Gastrointest Endosc 1998;48:158–163. 30 Jost C, Binek J, Schuller JC, Bauerfeind P, Metzger U, Werth B, Knuchel J, Frossard JL, Bertschinger P, Brauchli P, Meyenberger C, Ruhstaller T: Endosonographic radial tumor thickness after neoadjuvant chemoradiation therapy to predict response and survival in patients with locally advanced esophageal cancer: a prospective multicenter phase ll study by the Swiss group for clinical cancer research (SAKK 75/02). Gastrointest Endosc 2010;71:1114–1121. 31 Davies L, Mason JD, Roberts SA, Chan D, Reid TD, Robinson M, Gwynne S, Crosby TD, Lewis WG: Prognostic significance of total disease length in esophageal cancer. Surg Endosc 2012;26:2810–2816. 32 Twine CP, Roberts SA, Lewis WG, Dave BV, Rawlinson CE, Chan D, Robinson M, Crosby TD: Prognostic significance of endoluminal ultrasound-defined disease length and tumor volume (EDTV) for patients with the diagnosis of esophageal cancer. Surg Endosc 2010; 24:870–878. 33 Hirata N, Kawamoto K, Ueyama T, Masuda K, Utsunomiya T, Kuwano H: Using endosonography to assess the effects of neoadjuvant therapy in patients with advanced esophageal cancer. AJR Am J Roentgenol 1997;169: 485–491. 34 Shinkai M, Niwa Y, Arisawa T, Ohmiya N, Goto H, Hayakawa T: Evaluation of prognosis of squamous cell carcinoma of the oesophagus by endoscopic ultrasonography. Gut 2000;47:120–125. 35 Willis J, Cooper GS, Isenberg G, Sivak MV Jr, Levitan N, Clayman J, Chak A: Correlation of EUS measurement with pathologic assessment of neoadjuvant therapy response in esophageal carcinoma. Gastrointest Endosc 2002;55:655–661. 36 Edge S, Byrd D, Compton C, et al: AJCC Cancer Staging Manual, ed 7. New York, Springer, 2010, pp 103–115. 37 Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J: New response evaluation criteria in solid tumours: revised RECIST guideline, version 1.1. Eur J Cancer 2009;45:228–247. 38 Lightdale CJ: Endoscopic ultrasonography in the diagnosis, staging and follow-up of esophageal and gastric cancer. Endoscopy 1992; 24(suppl 1):297–303.
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41 Minsky BD, Pajak TF, Ginsberg RJ, Pisansky TM, Martenson J, Komaki R, Okawara G, Rosenthal SA, Kelsen DP: INT 0123 (Radiation Therapy Oncology Group 94–05) phase III trial of combined-modality therapy for esophageal cancer: high-dose versus standard-dose radiation therapy. J Clin Oncol 2002;20:1167–1174. 42 Mandard AM, Dalibard F, Mandard JC, Marnay J, Henry-Amar M, Petiot JF, Roussel A, Jacob JH, Segol P, Samama G, et al: Pathologic assessment of tumor regression after preoperative chemoradiotherapy of esophageal carcinoma. Clinicopathologic correlations. Cancer 1994;73:2680–2686. 43 Forastiere AA, Orringer MB, Perez-Tamayo C, Urba SG, Zahurak M: Preoperative chemoradiation followed by transhiatal esophagectomy for carcinoma of the esophagus: final report. J Clin Oncol 1993;11:1118–1123.
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Digestion 2014;90:98–107 DOI: 10.1159/000365073
Prediction of Survival by Tumor Area on Endosonography after Definitive Chemoradiotherapy for Locally Advanced Squamous Cell Carcinoma of the Esophagus Choong Nam Shim a Mi Kyung Song b Hye Sun Lee b Hyunsoo Chung a Hyuk Lee a Sung Kwan Shin a Sang Kil Lee a Yong Chan Lee a Jun Chul Park a a Department of Internal Medicine, Institute of Gastroenterology, and b Biostatistics Collaboration Unit, Yonsei University College of Medicine, Seoul, Korea
Key Words Esophageal cancer · Endosonography · Tumor area · Definitive chemoradiotherapy · Progression-free survival
Abstract Background: Definitive chemoradiotherapy (CRT) is a reasonable approach for patients with locally advanced esophageal cancer who are not surgical candidates. This study was performed to investigate whether endosonography (EUS) assessment of tumor area response is a useful prognostic marker in patients with squamous cell carcinoma (SCC) of the esophagus who receive definitive CRT. Methods: A total of 33 patients who received definitive CRT for locally advanced esophageal SCC were enrolled. The maximal transverse cross-sectional area of the tumor was measured before and after definitive therapy. EUS response was defined as a ≥50% reduction of the tumor area after definitive CRT. Results: Based on EUS evaluation, there were 20 nonresponders (60.6%) and 13 responders (39.4%). The median progression-free survival (PFS) was significantly longer in EUS responders than EUS nonresponders (p = 0.005). However, there was no statistical significance in overall survival according to EUS response (p = 0.120). During multivariate
© 2014 S. Karger AG, Basel 0012–2823/14/0902–0098$39.50/0 E-Mail [email protected] www.karger.com/dig
analysis, EUS response to definitive CRT was the only significant factor associated with PFS (p = 0.045), whereas EUS response to definitive CRT was not associated with overall survival (p = 0.221). Conclusions: A reduction of the maximal cross-sectional tumor area measured by EUS correlates with a superior prognosis in patients with locally advanced SCC of the esophagus after definitive CRT. © 2014 S. Karger AG, Basel
Introduction
The mainstay of contemporary treatment for locally advanced esophageal cancer is multimodality therapy including neoadjuvant chemotherapy followed by surgical resection [1]. However, outcomes from this treatment remain unsatisfactory, with only 30–45% patients surviving 2 years after radical resection [1, 2]. In addition, esophagectomy is associated with high postoperative morbidity and mortality rates: 30–40 and 5–10%, respectively [3–8]. Furthermore, only 25–45% of patients are selected to undergo radical esophagectomy, since over 60% of individuals have unresectable disease at presentation [9–11]. Some individuals who present with a theoretically operJun Chul Park, MD Department of Internal Medicine, Institute of Gastroenterology Yonsei University College of Medicine 134 Shinchon-dong, Seodaemun-gu, Seoul 120-752 (Korea) E-Mail junchul75 @ yuhs.ac
able tumor do not undergo surgery because of substantial comorbid disorders, old age, or tumor in the cervical esophagus. Therefore, for those who are not surgical candidates because of advanced tumor stage as well as postoperative morbidity, definitive chemoradiotherapy (CRT) has been suggested as a strategy to both prolong survival and provide symptomatic relief. The outcomes of definitive CRT are similar to those achieved with surgery [12–15]. Endosonography (EUS) is widely performed for the regional assessment of esophageal carcinoma prior to initiating therapy [16–19]. Large series have reported accuracies of 85 and 75% for EUS determination of tumor (T) classification and node (N) classification, respectively, in patients undergoing surgical resection without prior neoadjuvant therapy [20–22]. In contrast, EUS cannot accurately evaluate the T stage after neoadjuvant CRT [23– 29], because inflammation, necrosis, and fibrosis associated with CRT lead to disintegration and blurring of anatomic structures. Moreover, since we cannot obtain accurate histopathologic stage information after definitive CRT, prognosis prediction in these patients is extremely difficult, and there are no well-established prognostic factors for esophageal cancer after definitive CRT. Previous studies have attempted to determine the prognostic role of EUS for esophageal cancer treated with CRT by measuring the radial tumor thickness [30], total disease length [31], tumor volume [32] or tumor area [16, 29, 33–35]. In particular, a reduction in the cross-sectional area of tumor measured by EUS predicts the histopathologic response and prognosis in patients with esophageal cancer treated by neoadjuvant CRT [16, 29, 33–35]. However, no studies have attempted to evaluate the relation between prognosis and the reduction of esophageal cross-sectional tumor area on EUS after definitive CRT. Therefore, the purpose of this study is to evaluate the prognostic implications of a decrease in EUS maximum transverse tumor area after definitive CRT in patients with locally advanced squamous cell carcinoma (SCC) of the esophagus.
6), multiple synchronous esophageal cancers (n = 14), and stenotic tumor to be crossed with the EUS probe (n = 26) were excluded. Thus, a total of 33 patients treated with definitive CRT for locally advanced, histologically confirmed SCC in the esophagus were enrolled in the present study (fig. 1). Enrolled patients were categorized into two groups, EUS nonresponders (n = 20) and EUS responders (n = 13), based on the absence or presence of EUS response to definitive CRT. EUS response was defined as a ≥50% reduction of the maximal transverse cross-sectional area (MAX) of the esophageal cancer after definitive CRT. This cutoff percentage was evaluated using receiver operating characteristic (ROC) analysis. Typical EUS images of nonresponders and responders are shown in figure 2. Pre-therapeutic evaluations involved upper endoscopy with biopsies, EUS, computed tomography, and whole-body fluorodeoxyglucose-positron emission tomography scans for all patients, plus bronchoscopy or laparoscopy, if considered appropriate. A baseline EUS was performed during the initial staging, within 2 weeks of the first definitive CRT. Clinical staging was based on the seventh edition of the American Joint Committee on Cancer/Union for International Cancer Control tumor-node-metastasis classification for esophagus and esophagogastric junction [36]. Clinical response to treatment, based on the findings of esophagogastroduodenoscopy, EUS, and computed tomography, was assessed after two or three cycles of chemotherapy in accordance with the Revised Response Evaluation Criteria in Solid Tumors (RECIST version 1.1) [37]. In addition, we maintained a protocol of performance of endoscopic biopsies following completion of definitive CRT as a part of evaluating methods for clinical response, regardless of presence of EUS response. Demographic data of the enrolled patients and the clinicopathologic characteristics and outcomes of the two groups were analyzed. This study was approved by the Institutional Review Board of Yonsei University College of Medicine, Korea.
Patients Between October 2006 and August 2012, a total of 811 patients received CRT for esophageal cancer at our high-volume tertiary referral center. Patients with no baseline EUS evaluation (n = 280), no follow-up EUS evaluation after CRT (n = 380), surgical resection for esophageal cancer (n = 40), superficial esophageal cancer (n = 26), distant metastasis (n = 6), double primary cancers (n =
Tumor Area Measurement by Endosonography Standard EUS staging was performed with radial scanning echoendoscopes (EG-3679URK, Pentax, Japan, and GF-UE260, Olympus, Japan) [22]. Each tumor was staged using standard EUS criteria [21, 38]. EUS images of the tumor were obtained in the transverse plane at the area where the tumor exhibited the greatest bulk. Tumor cross-sectional area was measured by tracing the contour of the tumor mass with the aid of a cross-sectional area measurement function provided with the EUS processor. Multiple measurements of the tumor were performed, and the MAX was obtained during each EUS examination. The MAX was measured both before and after the second or third cycle of definitive CRT. Standardized measurements were recorded as the distance from the incisors in the pull-back position at baseline and after definitive CRT, to allow correlation with the principal anatomic landmarks: the proximal end of the gastric folds (gastroesophageal junction), the EUS longitudinal tumor extent, the upper limit of the aortic arch (main internal reference), and the MAX. EUS repeated after definitive CRT required realignment to the previously recorded landmarks, with emphasis on recovering the plane used for the baseline MAX examination, to obtain the response MAX measurement. In both evaluations, images from the corresponding planes with MAX measurements were assessed. Anatomic landmarks on these images were compared to optimize EUS realignment and ensure that the MAX measurement was performed at the same site, thus facilitating final data monitoring and quality assurance.
Tumor Area on EUS in Esophageal Cancer
Digestion 2014;90:98–107 DOI: 10.1159/000365073
Methods
99
Patients with esophageal cancer treated by CRT (n = 811) Exclusion No baseline EUS evaluation (n = 280) No follow-up EUS evaluation after CRT (n = 380) Patients with EUS evaluations before and after CRT (n = 151) Exclusion Tumors with surgical resection (n = 40) Superficial esophageal cancers (n = 26) Tumors with distant metastasis (n = 6) Double primary cancers (n = 6) Multiple synchronous esophageal cancers (n = 14) Stenotic tumors to be crossed with the EUS probe (n = 26) Patients with locally advanced SCC of the esophagus treated by definitive CRT (n = 33)
EUS nonresponders (n = 20)
Fig. 1. Flowchart showing patient inclusion of the present study.
Fig. 2. EUS images in EUS nonresponders (a, b) and EUS responder (c, d). a, c EUS images before definitive CRT. b, d EUS im-
ages after definitive CRT.
100
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EUS responders (n = 13)
a
b
c
d
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1.0
EUS responders
0.8
0.6
0.6
OS (%)
PFS (%)
EUS responders 0.8
0.4 EUS nonresponders
0.2 0
0
Fig. 3. PFS (a) and OS (b) of patients ac-
0 20
40
p = 0.120 0
60
Time (months)
EUS nonresponders
0.2
p = 0.005
a
0.4
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1.0
b
20
40
60
Time (months)
cording to EUS response to definitive CRT.
Treatment and Survival of Patients At our institution, a multidisciplinary team of gastroenterologists, oncologists, radiation oncologists, and thoracic surgeons determines the treatment strategy of patients with esophageal cancer. Indications for definitive CRT in our center were largely based on national comprehensive cancer network guidelines for esophageal and esophagogastric junction cancers [39]. We considered definitive CRT in superficial T1b tumors with poor prognostic features, locally advanced tumors with medically unfit for surgery, and tumors located in cervical esophagus. Enrolled patients completed a definitive CRT protocol consisting of four cycles of cisplatin and 5-fluorouracil (5-FU) or cisplatin and TS-1 (an oral fluoropyrimidine anticancer agent composed of tegafur, 5-chloro-2,4-dihydroxypyridine, and potassium oxonate), with concurrent radiotherapy of 50.4–63.0 Gy in 28–35 fractions over 5 weeks. In protocol of cisplatin and 5-FU, cisplatin (80 mg/m2) was administered as a day case on day 2 of each of the four weekly cycles. 5-FU (800 mg/ m2) was daily delivered as a continuous intravenous infusion on days 1–4. In protocol of cisplatin and TS-1, cisplatin (80 mg/m2) was administered as a day case on day 1 of each of the three weekly cycles. TS-1 (70 mg/m2) was delivered daily on days 1–14 of each cycle. If necessary, the dosage of chemotherapy was adjusted for audiologic, renal, hematologic, or gastrointestinal toxicity. The survival assessments included progression-free survival (PFS) as a primary endpoint and overall survival (OS) as a secondary endpoint. PFS was defined as the time from treatment initiation to disease progression or death from any cause, whichever was earlier [40]. OS was defined as the time from treatment initiation to death from any cause.
er curve and log-rank test were performed to assess survivals according to the EUS response of the two groups. Cox regression analysis was carried out to investigate the relationship of clinicopathologic characteristics to the EUS response and survival. Characteristics with a p value 60 Gy 8 (24.2) Clinical response to definitive CRT Stable disease 2 (6.1) Partial response 25 (75.8) Complete response 5 (15.2) Progressive disease 1 (3.0) Location Proximal 6 (18.2) Middle 15 (45.5) Distal 12 (36.4) Histology Well-differentiated 4 (12.1) Moderately-differentiated 19 (57.6) Poorly-differentiated 10 (30.3)
70.5 (44.0 – 83.0) 18 (90.0) 23.4 (17.7 – 27.5) 15 (75.0) 15 (75.0)
p value
69.0 (57.0 – 79.0) 11 (84.6) 23.9 (20.7 – 25.9) 11 (84.6) 10 (76.9)
6 (30.0) 10 (50.0) 1 (5.0) 2 (10.0)
4 (30.8) 6 (46.2) 1 (7.7) 0 (0)
7 (35.0) 12 (60.0) 1 (5.0)
7 (53.8) 6 (46.2) 0 (0)
1 (5.0) 19 (95.0)
4 (30.8) 9 (69.2)
13 (65.0) 7 (35.0)
12 (92.3) 1 (7.7)
1 (5.0) 14 (70.0) 4 (20.0) 1 (5.0)
1 (7.7) 11 (84.6) 1 (7.7) 0 (0)
4 (20.0) 9 (45.0) 7 (35.0)
2 (15.4) 6 (46.2) 5 (38.5)
3 (15.0) 11 (55.0) 6 (30.0)
1 (7.7) 8 (61.5) 4 (30.8)
0.353 >0.999 0.650 0.676 >0.999 0.807
0.680
0.066 0.108 0.886
>0.999
>0.999
Data are expressed as median (range) or n (%).
in baseline characteristics, including age, sex, body mass index (BMI), alcohol, smoking, and comorbidities, were detected between the EUS nonresponders and EUS responders. In terms of clinicopathologic features, the clinical stage of lesions was primarily T 2–3 (97.0%, 32/33), with positive N (84.8%, 28/33). Most of the patients were treated with cisplatin/5-FU (78.8%, 26/33) and radiotherapy with 50.4 Gy (n = 6) or 54.0 Gy (n = 19) (75.8%, 25/33). The rest (24.2%, 8/33) completed concurrent radiotherapy of 63.0 Gy. We applied a 50.4- or 54.0-Gy radiation dose to patients with downgraded performance state during CRT or patients with 102
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older age. The lesions were primarily located at the proximal to middle part of the esophagus (63.6%, 21/33) and their main histology was well- or moderately-differentiated SCC (69.7%, 23/33). No significant differences in clinicopathologic features, including clinical stage, radiation dose, clinical response to definitive CRT, location, and histology, were detected between the two groups. Prognostic Factors Related to Survival Figure 3 depicts the PFS and OS according to the EUS response to definitive CRT. The median PFS was signifiShim /Song /Lee /Chung /Lee /Shin /Lee / Lee /Park
Table 2. Cox regression analysis of prognostic factors related to PFS
Characteristic
PFS univariate
multivariate
hazard ratio (95% CI) EUS response to definitive CRT No response 1.00 (reference) Response 0.10 (0.01 – 0.77) Clinical response to definitive CRT Progressive disease 1.00 (reference) Nonprogressive disease 0.80 (0.10 – 6.16) Age ≤70 years 1.00 (reference) >70 years 0.74 (0.24 – 2.28) Sex Male 1.00 (reference) Female 0.04 (0 – 21.72) Tumor staging 2 1.00 (reference) 3 1.67 (0.50 – 5.57) 4 22.05 (1.74 – 278.78) Node metastasis Negative 1.00 (reference) Positive 28.05 (0.07 – 11,564.95) Radiation >50 and ≤60 Gy 1.00 (reference) >60 Gy 2.64 (0.86 – 8.16) Location Proximal 1.00 (reference) Middle 0.69 (0.18 – 2.77) Distal 0.59 (0.13 – 2.65) Histology Well-differentiated 1.00 (reference) Moderately-differentiated 0.62 (0.12 – 3.11) Poorly-differentiated 1.20 (0.23 – 6.20)
p value
hazard ratio (95% CI)
0.027
p value 0.045
1.00 (reference) 0.13 (0.02 – 0.95) 0.826 0.600 0.308 0.057
0.181 1.00 (reference) 1.86 (0.51 – 6.80) 10.59 (0.80 – 141.57)
0.278 0.092
0.369 1.00 (reference) 1.83 (0.49 – 6.87)
0.783
0.550
cantly longer for the EUS responders than for the EUS nonresponders (not reached vs. 13.0 months, 95% CI 3.26–22.74, p = 0.005). However, there was no statistical significance in OS according to EUS response (not reached vs. 30.0 months, 95% CI 20.49–39.52, p = 0.120). Concerning the presentation of distant metastasis, a total of 5 patients revealed the distant metastasis among enrolled patients during follow-up periods. Uni- and multivariate Cox regression analyses of prognostic factors for PFS are shown in table 2. During univariate analysis, the EUS response to definitive CRT was the only factor significantly associated with PFS (p = 0.027). Tumor staging (p = 0.057) and radiation therapy (p = 0.092) showed a tendency towards being associated with PFS. During multivariate analysis, the EUS response
to definitive CRT was the only significant prognostic factor for PFS (p = 0.045). The uni- and multivariate Cox regression analyses of prognostic factors for OS are summarized in table 3. The EUS response to definitive CRT was not significantly associated with OS.
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Digestion 2014;90:98–107 DOI: 10.1159/000365073
Discussion
This study focused on the role of EUS in predicting survivals according to the EUS response of the tumor area to definitive CRT for locally advanced SCC of the esophagus. Based on our data, the reduction in tumor MAX may be a predictive factor for prognosis of patients with this tumor after definitive CRT. 103
Table 3. Cox regression analysis of prognostic factors related to OS
Characteristic
OS univariate
multivariate
hazard ratio (95% CI) EUS response to definitive CRT No response 1.00 (reference) Response 0.31 (0.06 – 1.50) Clinical response to definitive CRT Progressive disease 1.00 (reference) Nonprogressive disease 0.45 (0 – 23,745.04) Age ≤70 years 1.00 (reference) >70 years 1.15 (0.31 – 4.30) Sex Male 1.00 (reference) Female 0.03 (0 – 41.62) Tumor staging 2 1.00 (reference) 3 0.99 (0.25 – 4.03) 4 3.95 (0.43 – 36.45) Node metastasis Negative 1.00 (reference) Positive 27.50 (0.02 – 46,903.89) Radiation >50 and ≤60 Gy 1.00 (reference) >60 Gy 2.31 (0.54 – 9.89) Location Proximal 1.00 (reference) Middle 0.99 (0.20 – 4.97) Distal 0.24 (0.02 – 2.60) Histology Well-differentiated 1.00 (reference) Moderately-differentiated 0.23 (0.04 – 1.40) Poorly-differentiated 0.98 (0.17 – 5.70)
In contrast to the accuracy of EUS determination of T and N stages prior to surgical treatment without CRT, previous studies have found poor correlation between standard EUS after CRT T-staging and pathologic findings [23–29]. Nevertheless, numerous authors have attempted to demonstrate the prognostic role of EUS in esophageal cancer treated with CRT by measuring the radial tumor thickness [30], total disease length [31], tumor volume [32], or tumor area [16, 29, 33–35]. Previous studies assessing the usefulness of EUS in predicting prognosis through measurement of tumor area arbitrarily defined a positive response on EUS as a 50% reduction in the maximal tumor cross-sectional area [16, 29, 35]. However, these studies primarily involved patients with esophageal cancer who received neoadju104
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p value
hazard ratio (95% CI)
p value
0.146
0.221 1.00 (reference) 0.36 (0.07 – 1.86)
0.644 0.840 0.350 0.447
0.383 0.260 0.395
0.136
0.196 1.00 (reference) 0.34 (0.05 – 2.21) 1.45 (0.23 – 9.29)
vant CRT followed by surgical resection. Although this multimodal approach is a mainstay of current treatment for locally advanced esophageal cancer, many patients cannot follow this approach because of their advanced cancer stage or the substantial risk of postoperative morbidity. Furthermore, the prediction of prognosis in patients who receive definitive CRT is challenging because it is not possible to know the exact pathologic stage of the cancer with definitive CRT, yet pathologic stage is the most important factor related to prognosis. In the current study, we validated EUS-determined tumor measurement as a useful clinical method that is predictive of PFS in patients with esophageal cancer treated by definitive CRT. Furthermore, our study performed ROC analysis using PFS data to confirm the validity of Shim /Song /Lee /Chung /Lee /Shin /Lee / Lee /Park
using 50% as the EUS tumor area reduction percentage to differentiate EUS nonresponders and EUS responders. This 50% value is consistent with the cutoff value used in earlier studies [16, 29, 35]. When evaluating potential prognostic factors to predict survival, we found that the EUS assessment of response to definitive CRT was the only predictive factor of PFS that was significant during both uni- and multivariate analyses. However, our data did not demonstrate the statistical power for proving the association of the EUS response with OS. This might be stemming from small number of enrolled patients and study population primarily composed of patients with nodal metastasis (84.8%, 28/33). Since our results are compatible with previous reports of the prognostic importance of EUS based on the measurement of maximal cross-sectional tumor area [16, 29, 33–35], we believe that our data can help gastroenterologists predict prognosis in patients with locally advanced SCC of the esophagus after definitive CRT. Furthermore, CRT could unveil the biologic profile of esophageal cancer based on the absence or presence of EUS response to definitive CRT. More aggressive treatment to improve survival and further studies including targeted therapy may be needed in patients revealing no response of EUS. In contrast to the previous results, the lack of association between lymph node metastasis and survival was noted in this study [41–43]. We attributed this finding the selected patient population in the current study. We excluded patients with TNM stage 1, and therefore the vast majority of enrolled patients consisted of esophageal cancers with nodal metastasis. This composition may contribute to the lack of correlation between N stage and PFS. Therefore, further multicenter, prospective studies with a larger cohort of patients are warranted to determine the prognostic significance of EUS in esophageal cancer with definitive CRT. In terms of study population, we had to exclude a considerable number of esophageal patients who underwent
References
Tumor Area on EUS in Esophageal Cancer
CRT due to lack of EUS evaluation before (n = 280) and after CRT (n = 380). 40 patients who showed nearly complete response after CRT were also excluded, because they underwent surgical resection. In addition, 26 patients with severe stenosis were excluded, since their EUS evaluations were limited due to no scope-passing caused by stenosis. We had a policy of EUS evaluation for routine baseline work-up in patients scheduled for CRT to treat esophageal cancer. In contrast, a substantial number of patients were transferred from other hospitals including tertiary hospitals, and they already had the EUS and radiologic evaluations in the previous hospital. In those cases, most patients were excluded in the present study due to lack of baseline EUS evaluation. Moreover, large number of patients did not have follow-up EUS evaluation after CRT. This finding was attributed to unsatisfactory accuracy of EUS in response evaluation after CRT, particularly in a neoadjuvant setting [44–46]. In addition, some patients could not have EUS follow-up due to their poor general conditions, and others chose to refuse evaluations including EUS. This study had limitations, namely (1) it was a retrospective study at a single center, (2) the number of enrolled patients was small, and (3) the chemotherapy regimens and radiotherapy doses were heterogeneous. In spite of these limitations, this is the first comparative study of EUS nonresponders versus EUS responders, according to the response to definitive CRT as determined by MAX measurements, for locally advanced esophageal cancer. In conclusion, our study adds to the growing body of evidence that EUS-determined tumor area measurements may be a useful clinical method to predict prognosis of patients with esophageal cancer.
Disclosure Statement The authors have no conflicts of interest to disclose.
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