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doi:10.1111/jgh.12683

GASTROENTEROLOGY

Response evaluation with endoscopic ultrasound and computed tomography in esophageal squamous cell carcinoma treated by definitive chemoradiotherapy Wei-Lun Chang,*,† Wen-Lun Wang,*,‡ Ta-Jung Chung,§ Forn-Chia Lin,*,¶ Chia-Jui Yen,† Wu-Wei Lai,** Hsiao-Bai Yang†† and Bor-Shyang Sheu*,† *Institute of Clinical Medicine, and Departments of †Internal Medicine, §Diagnostic Radiology, ¶Radiation Oncology and **Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, ‡Department of Internal Medicine, E-Da Hospital/I-Shou University, Kaohsiung, and ††Department of Pathology, Ton-Yen General Hospital, Hsinchu, Taiwan

Key words definitive chemoradiotherapy, esophageal squamous cell carcinoma, miniprobe endoscopic ultrasound (EUS), prognostic factors, response evaluation. Accepted for publication 10 July 2014. Correspondence Professor Bor-Shyang Sheu, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, 138 Sheng Li Road, Tainan, Taiwan. Email: [email protected]

Abstract Background and Aim: We assessed the feasibility of combined endoscopic ultrasound and computed tomography on response evaluation in patients with esophageal squamous cell carcinoma treated by definitive chemoradiotherapy, and the impact of response on prognosis. Methods: Sixty patients treated by definitive chemoradiotherapy were followed by miniprobe endoscopic ultrasound and computed tomography. The post-treatment esophageal wall thickness was measured by miniprobe endoscopic ultrasound. Metastatic tumors were evaluated by computed tomography. The correlation between post-treatment image findings and prognosis was evaluated. Results: Twenty-four patients (40%) had esophageal stricture after chemoradiotherapy, which limited complete evaluation by endoscopy. Miniprobe successfully penetrated all strictures to measure post-treatment esophageal wall thickness. Both post-treatment esophageal wall thickness < 8 mm measured by endoscopic ultrasound and no enlargement of metastatic tumor foci on computed tomography predicted good prognosis (P = 0.001). Combined evaluation with these two modalities improved survival prediction (P < 0.001). Patients who met the above two criteria after chemoradiotherapy had the longest survival compared with those who met only one or none of the criteria. The corresponding median survivals were > 30 months, 16.8 months and 7.1 months, respectively (P < 0.001). On multivariate analysis, treatment response is the strongest independent prognostic factor (hazard ratio 3.65, P = 0.006) regardless of baseline tumor-node-metastasis staging and chemoradiation regimen. Conclusions: Response evaluation by miniprobe endoscopic ultrasound and computed tomography can predict the prognosis of esophageal squamous cell carcinoma patients treated by definitive chemoradiotherapy. Those who were judged as poor responder should receive additional treatment to improve outcome.

Introduction Esophageal cancer is one of the most deadly malignancies with increasing incidence in the world. With an estimated 482000 new cases diagnosed annually, it now ranks as the eight most common cancer worldwide.1 Since nearly 50% of patients are diagnosed at advanced stages, the prognosis is very poor. The reported mortality rate/incidence rate ratio is higher than 0.8, and 5-year survival rate is less than 15%.2,3 Adenocarcinoma and squamous cell carcinoma (SCC) are two major histological types of esophageal cancer. While the incidence of adenocarcinoma is increasing in Western countries,4 SCC is still most common in endemic areas such as

Asia and Sub-Saharan Africa.5 In Taiwan, more than 95% of esophageal cancer is SCC, and more than 75% of patients are diagnosed at advanced stages (stages III and IV).6 Besides different geographic distributions between the two cancer types, their etiology and response to therapy are also different. It was generally observed that esophageal squamous cell carcinoma (ESCC) had better response to chemoradiotherapy (CRT) than adenocarcinoma. In a recent clinical trial that includes both cancer types, SCC had 49% complete pathological response rate after neoadjuvant CRT compared with 23% of that in adenocarcinoma.7 It was shown that neoadjuvant CRT increased complete resection rate and improve patient survival especially in

Journal of Gastroenterology and Hepatology 30 (2015) 463–469 © 2014 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd

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patients with ESCC.7 In addition, two randomized trials proved that CRT alone (definitive CRT) can achieve similar survival compared with neoadjuvant CRT plus surgery in patients with advanced resectable ESCC (stage T3-4N0-1M0).8,9 According to the above observation, CRT is now the preferred first-line treatment, which is potentially curative in patients with advanced ESCC. Therefore, in patients initially treated by CRT, response evaluation is an important clinical issue as to decide who can be observed safely and who should be offered additional treatment, such as salvage esophagectomy in patients with resectable disease, or novel anticancer drugs in patients with unresectable disease or unfit for surgery. Endoscopic ultrasound (EUS) and computed tomography (CT) scan are commonly used modalities for treatment response evaluation and post-treatment surveillance. EUS can identify residual submucosal tumors in the absence of superficial lesions. In addition, tumor size change or post-CRT tumor size measured by EUS correlates with pathological response and predicts local recurrence after esophagectomy.10–13 CT scan is less accurate than EUS in assessing primary tumor response, but it offers an overview from neck to abdomen to assess size change in metastatic lesions.14,15 Previous studies had focused on analyzing the accuracy of these image modalities in predicting pathological response for patients treated by neoadjuvant CRT plus surgery. However, in patients treated by CRT alone, there is no way to know their pathological response, and little is known about how to evaluate their treatment response and the impact of response on prognosis.10,11 Therefore, in this study, we evaluated the feasibility of combined EUS and CT scan for treatment response evaluation of ESCC treated by CRT alone. We suppose that response evaluation should be useful to guide further treatment decision or compare the treatment efficacies of new drugs in clinical trials.

Methods Patients and treatments. From 2008 to 2012, histologyproven ESCC patients who received definitive CRT and post-CRT EUS follow-up were prospectively enrolled. Before treatment, complete staging by EUS and CT scan was performed. All patients received radiotherapy to esophageal tumor and regional lymph nodes with 1.8 gray per day and 5 days per week to achieve a total dose of 66.6 gray. During radiotherapy, patients were given with either one of the two standard chemotherapy regimens according to the oncologist’s preference. Regimen one consisted of cisplatin (20 mg/m2 daily, on days 1–4) and fluorouracil (800 mg/m2 daily, on days 1–4) given intravenously for four cycles on day 1, 29, 57, and 85. Regimen two consisted of cisplatin (30 mg/m2), fluorouracil (2000 mg/m2), and leucovorin (200 mg/m2) given intravenously for eight cycles on day 1, 8, 15, 22, 29, 36, 43, and 50. At 4–8 weeks after completion of CRT, patients received follow-up images that included EUS and CT scan to evaluate treatment response. All patients received regular follow-up to determine overall survival. Patients whose radiotherapy doses did not achieve 50 gray or did not complete chemotherapy course due to toxicity were excluded. The study protocol was approved by the institutional review board of National Cheng Kung University Hospital. EUS protocol. The esophagus was first observed under white light endoscopic view. Esophageal stricture was defined as lumen 464

narrowing to the severity that the conventional endoscope (GIFCV260, Olympus Corp., Tokyo, Japan) could not be passed through. EUS was performed by methods as our previous publication.16 A miniprobe ultrasound catheter (20 MHz, Olympus Corp.) was inserted to measure the post-CRT esophageal wall thickness. Thickness was measured at sites where tumor was located before treatment, and wherever a mucosal defect or stricture was found. The catheter was propagated until the distal margin of lesions where normal mucosal layers were detected, and then pulled back at 1-cm intervals to measure post-CRT esophageal wall thicknesses. The maximal post-CRT esophageal wall thickness was recorded. CT protocol. All CT scans were done from neck to abdomen. They were performed with a 16 slice helical CT scanner (SOMATOM Sensation 16; Siemens Medical Systems, Malvern, PA, USA), using 5-mm section width, 5-mm reconstruction interval, 120 kVp, and automated mAs. In addition, IV contrast enhancement (injected at 3 mL/sec, total volume 100 mL) was applied to all images. The selection of contrast medium was Optiray 350 (Tyco Healthcare, Montreal, Quebec, Canada) or Xenetix 350 (Guerbet, Aulnay-sous-Bois France). The follow-up CT scan was compared with the baseline scan that was done before initiation of therapy to define treatment response of metastatic tumor foci. Progression was defined as significant enlargement of metastatic foci or development of new metastatic lesions. Patients without above findings were defined as no progression. Statistical analysis. Survival was calculated from the date of diagnosis until death. The Kaplan–Meier method was used to estimate survival in each subgroup. The significance of survival difference between subgroups was evaluated by log–rank test. Cox regression analysis was used to determine univariate and independent factors associated with prognosis. Statistical analyses were performed using SPSS Statistics 17.0 software (SPSS Inc., Chicago, IL, USA).

Results A total of 60 patients were included for analyses (Fig. 1). Their baseline demographic data and clinical features were presented in Table 1. The median follow-up time of survivors was 18.8 months. During follow-up, 30 patients died and the overall median survival time was 20.2 months (95% confidence interval [CI], 13.6–26.7). EUS assessment of treatment response. Twentyfour (40%) patients revealed esophageal stricture after CRT, which limited complete evaluation by endoscopy. Miniprobe EUS successfully penetrated all strictures to measure post-CRT esophageal wall thickness. Using univariate Cox regression model, we found that post-CRT esophageal wall thickness positively correlated with patient mortality during follow-up time. Every 1-mm increase in post-CRT esophageal wall thickness led to a 1.2-fold increase in mortality risk (hazard ratio 1.21, 95% CI 1.08–1.36, P = 0.001). Moreover, patients who survived longer than 1 year had smaller post-CRT esophageal wall thickness than those who died within 1 year (mean wall thickness 6.5 vs 8.9 mm, P = 0.025). By receiver operating characteristic (ROC) curve analysis, we found that post-


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Figure 1 Flowchart of patient enrollment. A total of 107 ESCC patients received definitive CRT during the study time. Among them, 10 did not complete the scheduled CRT course and were excluded from analysis. In the 97 patients who completed definitive CRT, 61 agreed to receive follow-up endoscopic ultrasound. Among them, one patient violated the follow-up schedule and was excluded. The remaining 60 patients were analyzed. CRT, chemoradiotherapy; ESCC, esophageal squamous cell carcinoma; EUS, endoscopic ultrasound.

Table 1

Baseline clinical features of study patients

Features

Number

Age, year (mean, range) Male/female Tumor location (upper/middle/lower)† Tumor length, cm (mean, range) Tumor thickness, cm (mean, range) TNM stage (IIb/III/IVa/IVb)‡

58.2 (34–83) 57/3 30/18/12 5.7 (1.5–15.0) 1.5 (0.7–2.5) 3/17/13/27

† Location was determined by upper margin of tumor, upper: ≤ 25 cm from incisor; middle: between 25 and 30 cm from incisor; lower: > 30 cm from incisor. ‡Clinical stage was assessed by means of endoscopic ultrasound and computed tomography, and was classified according to the International Union Against Cancer tumor-nodemetastasis (TNM) classification, 6th ed.

CRT esophageal wall thickness of 8 mm had the best sensitivity (0.735) and specificity (0.687) to predict 1-year survival (area under curve = 0.671; 95% CI, 0.493–0.849). Therefore, we divided patients into two groups using 8 mm post-CRT esophageal wall thickness as the cut-off value. Thirty-six patients had wall thickness < 8 mm after CRT, while 24 patients did not (response rate 60%). In Kaplan–Meier analysis, patient who had post-CRT esophageal wall thickness < 8 mm significantly survived longer than those who did not. The median overall survivals were 26.7 and 12.6 months, respectively (Fig. 2). CRT responder assessed by EUS had 84.7% 1-year survival rate and 56.4% 2-year survival rate compared with 50.6% and 22.8%, respectively, of that in nonresponder (P = 0.001). Figure 3 showed representative images of patients who had stricture and defective mucosa after CRT. Miniprobe EUS helped to identify good versus poor responders. CT scan assessment of treatment response. Fiftyeight patients received post-CRT CT scan follow-up. Seventeen

Figure 2 Kaplan–Meier plots of estimated overall survival according to post-chemoradiotherapy (CRT) endoscopic ultrasound (EUS) findings. Patients with post-CRT esophageal wall thickness < 8 mm measured by EUS had better overall survival compared with those with wall thickness ≥ 8 mm (P = 0.001 by log–rank test). Post-CRT EUS finding: , esophageal wall thickness < 8 mm; , esophageal wall thickness ≥ 8 mm.

patients (29.3%) showed disease progression in metastatic tumor foci, while 41 (70.7%) patients did not. Kaplan–Meier analysis showed that patient with disease progression in metastatic tumor foci had a significantly shorter survival than those without progression (P = 0.001). The median survival were 12.6 (95% CI, 10.1–15.1) and 26.5 (95% CI, 20.6–32.5) months, respectively (Fig. 4). Combined EUS and CT scan assessment of treatment response. Because both post-CRT esophageal wall thickness < 8 mm (measured by EUS) and no disease progression in metastatic tumor foci (assessed by CT scan) were favorable prognostic factors, we thus combined these two criteria to assess treatment responses. Patients could be divided into four groups according to assessments by post-CRT EUS and CT scan. Those who achieved both criteria after CRT (wall thickness < 8 mm and no metastatic progression) had best prognosis (median survival not reached during the follow-up time, Fig. 5a). Patients who achieved either one criterion had comparable survival time (both had a median survival of 16.8 months; 95% CI, 15.3–18.3 months). Patients who achieved none of these two criteria had worst prognosis (median survival 7.1 months; 95% CI, 6.7–7.5 months). Notably, these response evaluation criteria could predict prognosis in patients with different disease stages (Fig. 5b,c). The multivariate Cox regression analysis showed that treatment response assessed by combined EUS and CT scan was an independent


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a

b

c

d

Figure 3 The post-chemoradiotherapy (CRT) endoscopic images (a and b) showed esophageal stricture and defective mucosa in two patients. The miniprobe endoscopic ultrasound (c and d) successfully penetrated stricture and identify good (post-CRT esophageal wall thickness < 8 mm) versus poor (post-CRT esophageal wall thickness ≥ 8 mm) responder.

prognostic factor in ESCC patients treated by definitive CRT, irrespective of patient’s age, sex, baseline tumor-node-metastasis (TNM) stage, radiotherapy dosage, chemotherapy regimen, and diagnosis date (Table 2). Further analysis showed that chemotherapy regimen or radiation dosage was not significantly different between good and poor CRT responders (P ≥ 0.05, data not shown).

Discussion

Figure 4 Kaplan–Meier plots of estimated overall survival according to post-chemoradiotherapy (CRT) computed tomography findings. Patients who developed new lesions or showed progressive enlargement in the metastatic tumor foci had shorter overall survival compared to those without (P = 0.001 by log–rank test). Post-CRT CT finding in metastatic , no progression; , progression. tumor foci:

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CRT is the main treatment in patients with metastatic ESCC. It is also an alternative curative therapy in patients with locally advanced ESCC. Nevertheless, little is known about how to evaluate their treatment response and the impact of response on prognosis. In this prospective study, we found miniprobe EUS is useful to evaluate primary tumor response even in patients with lumen stricture after CRT. In addition, CT scan makes up for the shortage of EUS in evaluating changes in metastatic tumor foci. Combination of these two modalities provides good response evaluation criteria, which can categorize patients into three different response groups, and that the treatment response evaluated by these criteria correlated well with patient survival. Although EUS is less accurate in assessing T stage (depth of tumor invasion) after CRT owing to inflammation, fibrosis, and blurring of epithelial layers,17,18 the measurement of tumor size changes had been shown to predict pathological response on surgical specimens.12,17–20 Different measurements had been used to evaluate size changes after CRT. Some used maximal crosssectional area reduction more than 50% as good response,17,19,20


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(a)


(b)

(c)

Figure 5 Kaplan–Meier plots of estimated overall survival according to response evaluated by combined use of endoscopic ultrasound (EUS) and computed tomography (CT) in all patients (a), stage III patients (b), and stage IV patients (c). Combined evaluation with EUS and CT can divide patients into three groups with significant survival difference (P < 0.001 by log–rank test) (a). Such criteria can predict survival of patients with different stages , both (n = 28); , either (n = 21); , neither (n = 9). of esophageal cancer (b,c). (a) Wall thickness < 8 mm and no metastatic progression: (b) Wall thickness < 8 mm and no metastatic progression: , both (n = 8); , either (n = 8). (c) Wall thickness < 8 mm and no metastatic , both (n = 17); , either (n = 13); , neither (n = 9). progression:


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Table 2

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Univariate and multivariate factors correlate with prognosis

Factors

Univariate analysis

Age (≥ 57 vs < 57 years) Gender (male vs female) Baseline TNM stage‡ (IV vs ≤ III) Radiotherapy dosage† (≥ 63 G vs < 63 G) Chemotherapy regimen (PFL vs PF)§ Diagnosis date† (later vs earlier) CRT response¶ (poor vs good) †

Multivariate analysis

HR

95% CI

P

HR

95% CI

P

0.73 2.00 1.98 0.72 0.84 0.76 3.84

0.36–1.51 0.27–14.75 0.90–4.39 0.35–1.49 0.38–1.86 0.35–1.66 1.62–9.10

0.40 0.50 0.09 0.38 0.67 0.49 0.002

0.95 0.75 2.19 0.87 0.80 0.82 3.65

0.91–0.99 0.09–6.35 0.85–5.66 0.38–1.98 0.30–2.09 0.33–2.02 1.46–9.16

0.02 0.79 0.10 0.74 0.65 0.67 0.006

† Median of the variable was used as cut-off value. ‡Clinical stage was assessed by means of endoscopic ultrasound and computed tomography, and was classified according to the International Union Against Cancer tumor-node-metastasis (TNM) classification, 6th ed. §PF, cisplatin plus fluorouracil; PFL, cisplatin plus fluorouracil plus leucovorin. ¶Good response was defined as post-chemoradiotherapy (CRT) esophageal wall thickness < 8 mm on endoscopic ultrasound and no progression of metastatic tumor on computed tomography. CI, confidence interval; HR, hazard ratio.

while others used maximal tumor thickness reduction more than 30% or 50%.12,18 These studies had consistently found that tumor size reduction on EUS is predictive of pathological response on surgical specimen. However, the impact of EUS measurement on patient prognosis is less clear,19,21 especially in patients with ESCC and treated by definitive CRT. We found that cross-sectional area was difficult to measure in ESCC because ESCC often presented with a hollow cylinder shape. Measurement of cross-sectional area was even more difficult in good CRT responders when most tumor masses disappeared and only circumferential esophageal wall thickening was present. Therefore, we measured maximal esophageal wall thickness as reported by Ota et al.12 Our finding that post-CRT esophageal wall thickness more than 8 mm predicted poor survival suggests that these patients should receive additional treatment to improve outcome. If observation is decided in such patients, then more frequent follow-up is necessary to identify tumor recurrence as early as possible. Whether 8-mm esophageal wall thickness is optimal in judging treatment response and whether patients with post-CRT esophageal wall thickness ≤ 8 mm can be safely followed remained unanswered. One previous study showed that patients with complete pathological response after CRT had a mean tumor thickness of 5 mm.22 At present, no image studies can confidently say that there is no residual tumor in a given patient after CRT.23–25 Even biopsy or fine needle aspiration may have false negative results.24,26,27 Given the observation that ESCC has pretty good response to CRT,7–9 our data indicate that patients with post-CRT esophageal wall thickness ≤ 8 mm may be followed safely. Future studies applying the post-CRT EUS measurement to guide treatment options shall be in need to test the validity of these criteria. There remained some limitations in this study. First, patients with better baseline characteristics may have better CRT response and prognosis. However, we have shown in Figure 5 that our response criteria are applicable to patients with stage IV disease. In addition, multivariate Cox regression (Table 2) showed that after adjustments of baseline characteristics, CRT response remained to be the most important prognostic factor in a population mainly composed of advanced ESCC. Second, in univariate and multivariate Cox regression, TNM stage is not a significant prognostic 468

factor. This may be caused by a small case number in stage III disease or less. Future studies with bigger number of patients are warranted. In conclusion, we have shown that a single measurement of post-CRT esophageal wall thickness by miniprobe EUS is feasible for accurate evaluation of primary tumor response to CRT. This measurement is simple and easy to conduct. Post-CRT CT scan, on the other hand, can assess metastatic tumor response, which increases the preciseness of survival prediction when used in combination with EUS. Patients judged as poor responder according to our criteria should receive additional treatment to improve outcome.

Acknowledgments This study was supported by grants from National Science Council (NSC 99–2314-B-006–045-MY2), Department of Health (DOH101-TD-PB-111-TM003), and National Cheng Kung University Hospital (NCKUH-10204004), Taiwan.

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