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Toxicity and Outcomes in Patients With and Without Esophageal Stents in Locally Advanced Esophageal Cancer
Accepted Manuscript Toxicity and Outcomes in Patients with and without Esophageal Stents in Locally Advanced Esophagus Cancer Samual R. Francis, Andrew Orton, Cameron Thorpe, Greg Stoddard, Shane Lloyd, Christopher J. Anker PII:
S0360-3016(17)33523-X
DOI:
10.1016/j.ijrobp.2017.06.2457
Reference:
ROB 24391
To appear in:
International Journal of Radiation Oncology • Biology • Physics
Received Date: 31 October 2016 Revised Date:
25 May 2017
Accepted Date: 19 June 2017
Please cite this article as: Francis SR, Orton A, Thorpe C, Stoddard G, Lloyd S, Anker CJ, Toxicity and Outcomes in Patients with and without Esophageal Stents in Locally Advanced Esophagus Cancer, International Journal of Radiation Oncology • Biology • Physics (2017), doi: 10.1016/ j.ijrobp.2017.06.2457. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Title: Toxicity and Outcomes in Patients with and without Esophageal Stents in Locally Advanced Esophagus Cancer Short Title: Toxicity of Esophageal Stents in Locally Advanced Esophagus Cancer
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Keywords: esophagus cancer; esophageal cancer; esophageal stent; stents; neoadjuvant therapy; radiotherapy; chemoradiotherapy; acute toxicity Authors: Samual R. Francis1, Andrew Orton1, Cameron Thorpe1, Greg Stoddard2, Shane Lloyd1, Christopher J. Anker3 1
Radiation Oncology, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah
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Radiation Oncology, University of Vermont Cancer Center, Burlington , Vermont
Corresponding Author:
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Christopher J. Anker, MD, Division of Radiation Oncology University of Vermont Cancer Center 111 Colchester Ave, Burlington, VT 05401 Tel: (802) 847-3506 E-mail: [email protected]
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Department of Medicine, Study Design and Biostatistics Center, University of Utah, Salt Lake City, Utah
Conflict of Interest Statement:
None of the authors have any conflicts of interest or financial disclosures.
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Acknowledgments:
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The authors wish to thank Michelle Denney for her assistance in editing and preparation of the manuscript.
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Title: Toxicity and Outcomes in Patients with and without Esophageal Stents in Locally Advanced Esophagus Cancer
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Abstract
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Purpose/Objectives: Esophageal stenting is often considered to relieve dysphagia in patients with locoregionally advanced esophageal cancer. We sought to determine effects of stenting on acute toxicities and oncologic outcomes in patients treated with chemoradiotherapy (CRT).
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Materials/Methods: Patients treated with curative intent RT for locoregionally advanced esophageal cancer at our institution were retrospectively analyzed. Chi-squared or Fisher exact test was used to
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compare demographic and tumor characteristics between patients with or without esophageal stenting before RT. Univariate (UVA) and multivariate (MVA) logistic regression modeling were used to identify predictors for acute toxicities. A propensity score matched analysis with shared frailty Cox hazard regression was performed based on stent status to identify stent effect on survival. Acute toxicities were
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graded using Common Terminology Criteria for Adverse Events version 4.
Results: Between 2005-2013, 103 consecutive patients received CRT. Twenty-eight had a stent during CRT. Median dose was 50.4 Gy (Gray) for all patients. Grade ≥3 acute toxicities were seen in 71% of
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stent versus (vs.) 27% of no-stent patients (p<0.01), including esophagitis (39% vs. 20%, p=0.05), dehydration (29% vs. 13%, p=0.07), and anorexia (14% vs. 5%, p=0.13). Twenty-nine percent of stent and
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51% of no-stent patients underwent esophagectomy (p=0.05). The only significant predictor for acute toxicity on MVA was esophageal stenting (OR 8.1, p<0.01). After propensity score matching, stent patients had worse median overall survival compared to no-stent patients (11.5 vs. 22.0 months, HR 2.3 p=0.016).
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Conclusion: In patients receiving CRT with curative intent, esophageal stenting was associated with significantly increased grade ≥3 acute toxicities, fewer patients proceeding to esophagectomy, and
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worse overall survival.
Introduction
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Patients with esophageal cancer frequently present with weight loss, dysphagia, and poor nutritional status. Whether undergoing neoadjuvant or definitive chemoradiation (CRT), adequate nutritional
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support is essential to ensuring the best surgical and oncologic outcomes [13,16,31,40]. Simple oral dietary supplementation is often insufficient given advanced dysphagia; therefore, different methods have been implemented to assist with maintenance of nutritional status during treatment. Enteral feeding is preferred to parenteral nutrition given reduced costs and fewer infectious complications [41].
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Nasogastric tubes are uncomfortable and have a higher rate of failure than percutaneous tube placement [19], while gastrostomy and jejunostomy tubes have a risk of infection and surgical complications [17,48].
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Esophageal stenting has emerged as an attractive means to relieve malignant dysphagia. While esophageal stenting consistently relieves dysphagia, it is not without risk. Commonly, patients
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experience chest discomfort or pain and frequent stent migration [2,8,10,24,42]. Less common, but serious side effects include esophageal perforation, fistula, abscess, and death [12,24,27]. While initially used in the palliative setting [9,36], esophageal stenting is being increasingly used in the curative setting and as a bridge to surgery [2,8,10,12,24,27,34,39,44]. Chemoradiation, either definitive or neoadjuvant, remains the standard of care for locoregionally advanced esophageal cancer, yet there is insufficient data regarding the safety and benefit of esophageal stenting in this setting. Therefore, we sought to
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determine the effect of esophageal stenting on acute toxicities and oncologic outcomes in patients
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treated with curative intent CRT.
Methods
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Patients
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After approval by the institutional review board, patients treated with chemoradiotherapy (CRT) with curative intent for locally advanced esophageal cancer (T3-T4 or node positive) at XXXX were identified and their charts were retrospectively analyzed. Only patients with either squamous cell carcinoma or adenocarcinoma histologies were included. Patients were not included if they: had metastatic disease at presentation, had ≥1 primary at presentation, received adjuvant radiotherapy after surgery, received
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only single-agent 5-FU chemotherapy, and/or were treated with palliative intent. The primary indication for esophageal stenting at our institution was malignant dysphagia. Dysphagia
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was scored on a 0-4 scale as follows: 0=no dysphagia, 1=dysphagia to normal solids, 2=dysphagia to soft solids, 3=dysphagia to liquids, and 4=aphagia. Performance status was measured using Karnofsky
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performance scale (KPS). Acute toxicities were defined as those occurring within 90 days of completing radiation treatment and prior to surgery for patients undergoing esophagectomy. We included gross tumor volume (GTV) length in the analysis, which we used as a surrogate for esophageal dose since esophageal dosimetry would be dependent on GTV length. Pre-RT weight loss was based on the patient reported pre-symptom weight and weight at the initial consultation. In the patients for which esophagectomy was performed, it was always done after CRT. Types of esophagectomy included IvorLewis, transhiatal, laparoscopic transhiatal, and minimally invasive esophagectomy. Tumor position was 4
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defined based on the American Joint Committee on Cancer (AJCC) version 7 guidelines by proximal tumor edge distance from incisors as follows: cervical 15 centimeter (cm), upper 20 cm, middle 25 cm,
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lower 30 cm, gastroesophageal junction (GEJ) 40 cm [1]. Statistical Analysis
A chi-squared test was used to compare binary patient characteristics of the stent and no-stent groups,
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as long as three expected cell frequencies were at least 5 and the fourth one was at least 1; otherwise, Fisher’s exact test was used. For unordered categorical data with more than two categories, the chi-
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squared test was used if more than 20% of the expected cell frequencies were at least 5 and no expected cell frequency was less than 1; otherwise, the Fisher-Freeman-Halton test was used. Ordered categorical data were compared using Wilcoxon-Mann-Whitney (WMW) test. Student’s t-test was used to analyze continuous variables for two independent groups and Kruskal-Wallis analysis of variance
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(ANOVA) was used to analyze three or more independent groups.
Univariate (UVA) and multivariate (MVA) analyses via logistic regression modeling were used to identify predictors for acute toxicities, reported as odds ratios (ORs). The MVA regression model was created by
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including covariates with a P-value <0.2 on UVA and those felt to be clinically relevant to acute toxicity outcomes. For categorical covariates, if one of the covariate levels in comparison to the reference level
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had a p<0.2, then it was included in the final model [11,28]. Acute toxicities were graded using Common Terminology Criteria for Adverse Events (CTCAE) version 4. The primary oncologic outcome of interest was overall survival (OS), which was defined as time from initiation of radiotherapy to date of death or last follow-up. Propensity scores (PS) predicting for stent placement were generated for each patient using a model including age, gender, clinical stage, T-stage, N-stage, initial KPS, tumor position, tumor grade, histology,
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radiation dose, type of chemotherapy, and hospitalization ≤30 days prior to CRT according to the method previously described by Rosenbaum and Rubin [5,6,26]. One-to-one matching was performed using a nearest-neighbor algorithm assuming independent observations, fixed weights, and the
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assumption that the variance of the outcome does not depend on the PS. Pairing between cases was limited to the region of common support. Caliper width was narrowed in a step-wise fashion until the covariate distributions were balanced after matching [7]. After matching, a UV shared frailty Cox
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proportional hazard regression was used to estimate the effect of esophageal stents on OS. KaplanMeier survival analysis was performed both before and after PS analysis to generate OS curves. All
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analyses were performed using the Stata version 14.2 statistical package (Stata-Corp, College Station, TX).
Patient Characteristics
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Results
One hundred three consecutive patients who received CRT between the years 2005-2013 at XXXX met
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inclusion for analysis (Table 1). Median follow-up was 13.7 months (range 1.9 – 99.9 months).
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Twenty-eight patients had a stent during CRT comprising the stent group. Sixty-one percent of the stent group received a metal stent, and 39% received a plastic stent. Sixty-eight percent of stent patients had complications related to stenting (Supplemental Table A1). There were no significant differences in complications between plastic and metal stents. Most common complications included 39% with pain, 32% stent migration, and 14% reflux. Four patients had stent migration with stent exchange before starting CRT. Four patients had the stent removed during radiation. One of these patients was restented. Reasons for removal include migration in 3 patients and migration and pain in 1 patient. Eight
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patients had stents removed endoscopically after CRT: 5 due to migration, 1 due to stricture, and 2 for unknown reasons. The median time to stent migration after placement was 15.5 days (range 3-88 days). Significant complications included 3 patients with esophageal perforation, 2 of which required emergent
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surgical repair, and 1 patient with hematemesis that was treated conservatively.
The most common prescription dose for all patients was 50.4 Gy (Gray) in 28 fractions. While both groups received the same median dose, the stent group had more patients that received a lower total
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dose than the no-stent group (Table 2). The majority of patients were treated with 3D conformal radiation, and most commonly a 4-field technique was used. All patients received concurrent
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chemotherapy, with the most common regimen being cisplatin and fluorouracil (5FU) (55%) and the second most common regimen used was cisplatin and paclitaxel (18%) (Table 2). Patients listed as receiving “other” chemotherapy include: 3 patients who received cisplatin, paclitaxel, and 5FU; 1 patient who received paclitaxel, carboplatin, and cetuximab; 1 patient who received cisplatin; 1 patient who
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received paclitaxel and 5FU; and 1 patient who received cisplatin and irinotecan. Stent patients had a lower pre-treatment KPS than no-stent patients (Median KPS 80 [range 70-90] stent versus [vs.] 80 [range 70-100] no-stent, p=0.03). For both groups, the most common histology was adenocarcinoma
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(96% stent and 89% no-stent, p=0.26) and the most common location was the lower third of the
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esophagus (93% stent and 89% no-stent, p=0.62). Fourteen percent of no-stent compared to 33% of stent patients had pre-treatment dysphagia scores ≥2 (p=0.10). Before starting CRT stent patients lost a median of 12% (interquartile range [IQR] 7 – 19%) of their body weight and no-stent patients lost a median of 5% (IQR 0 – 11%) (p<0.01). One-hundred percent of stent patients had T3 tumors compared to 83% of no-stent patients (p=0.05). The median GTV was 96.0 cm3 (IQR 60.3 – 136.8 cm3) vs. 55.6 cm3 (IQR 34.6 – 93.5 cm3) in the stent and no-stent
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groups, respectively (p<0.01). Seventy-four percent of patients in the stent group reported a lower dysphagia score one-week post-stent.
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Sixty-four percent of stent patients and 67% of no-stent patients were treated with neoadjuvant CRT with a plan for surgery (Table 2). Of these, 39% of stent patients compared to 66% of no-stent patients underwent esophagectomy (p=0.05). The most common type of surgery was a transhiatal technique (63% of no-stent and 88% of stent patients, respectively). The median time from completion of CRT to
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surgery was 59 days (IQR 49 – 78 days). The most common reasons neoadjuvant intent patients did not receive surgery were due to development of metastatic disease (3 stent vs. 7 no-stent patients), poor
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functional status associated with poor nutritional intake, worsened comorbid conditions, and/or difficulty with activities of daily living (4 stent vs. 3 no-stent patients), unresectable (3 stent vs. 1 nostent patients), or patient declined (1 stent vs. 5 no-stent patients).There was no significant difference in the rate of 30-day post-operative complications between the two groups (55% no-stent vs. 50% stent,
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p=1.00). Three no-stent patients and 1 stent patient died within 30 days after discharge postesophagectomy.
Thirty-two percent of no-stent patients and 29% of stent patients were treated with definitive CRT. Five
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patients in the no-stent group and 1 in the stent group had salvage esophagectomy. The median time to
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salvage surgery after completing definitive CRT was 132 days (range 68 – 706 days). After salvage surgery, 3 patients died within 2 years, and the other 3 were lost to follow-up.
Acute Toxicity Analysis
Grade ≥3 acute toxicities were seen in 71% of the stent group compared to 27% of no-stent patients (p<0.01), including esophageal toxicity (39% vs. 20%, p=0.05), dehydration (29% vs. 13%, p=0.07), and
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anorexia (14% vs. 5%, p=0.13), respectively (Table 3). Overall 28% of patients had an acute thromboembolic event. Additionally, performance status improved after radiation in 13% of no-stent patients compared to 4% of stent patients (p=0.03). Additionally, more stent patients had a decrease in
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KPS of >20 after treatment (14% stent vs. 4% no-stent, p=0.03). On subset analysis, the association between stent and grade ≥3 toxicity remained significant for patients receiving neoadjuvant CRT (72% stent vs. 24% no-stent, p<0.01) but not for those receiving definitive CRT (63% stent vs. 33% no-stent,
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p=0.22). There was no statistical difference between rates of toxicities between metal or plastic stents, but both groups had higher rates of toxicity than the no-stent group (Supplemental Table A2). There was
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a trend towards worse post-CRT KPS for the metal stents compared to plastic stent (p=0.06). From start to finish of radiation, no-stent patients lost a median of 8% (IQR 5 – 10%) of body weight, and stent patients lost 9% (IQR 4 – 15%) of body weight (p=0.45). Prior to radiation, albumin levels were low (<3.4 g/dL) in 7% of no-stent and 6% of stent patients (p=1.00). After radiation, albumin levels were low in
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46% of no-stent and 67% of stent patients (p=0.33). For those patients treated with neoadjuvant intent, 36% of no-stent compared to 75% of stent patients had low albumin after radiation (p=0.18). Feeding tubes were placed before or during RT in 20% of no-stent and 54% of stent patients (p<0.01).
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On UVA logistic regression, we found that esophageal stenting (OR 6.9, p<0.01) and pre-CRT KPS (OR 2.1, p=0.02) were significant predictors for grade ≥3 acute toxicity. We did not find an association
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between acute toxicity and esophageal (i.e. GTV length), heart, or lung dose. On MVA logistic regression, we found that esophageal stenting (OR 8.1, p<0.01) was the only significant factor associated with grade ≥3 acute toxicity (Table 4). Even after excluding from analysis patients with > grade 1 dysphagia prior to starting CRT, stenting remained the sole predictor of toxicity (MVA OR 14.3, p<0.01). Survival Analysis
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The median OS for the entire cohort was 15.7 months (95% Confidence Interval [CI], 11.7 – 19.1 months). On subset analysis, the no-stent group had a longer median OS (16.8 months, 95% CI 12.4 – 23.4 months) compared to the stent group (9.1 months, 95% CI 7.8 – 16.4 months, log-rank p=0.026)
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(Figure 1, A).
After PS matching, a matched cohort of 25 no-stent and 25 stent patients was available for analysis. Patient characteristics were balanced between no-stent and stent groups (Supplemental Table A3). The
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median OS for no-stent patients was 22.0 months(95% CI,12.4 – 66.5 months) vs. 11.5 months (95% CI,7.9 – 16.8 months) for stent patients (Figure 1, B). On shared frailty UV Cox regression, stenting was
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associated with worse overall survival (Hazard Ratio [HR] 2.33; 95% CI, 1.17 – 4.62; p=0.016). Given that esophagectomy was not a baseline characteristic, it was not controlled for in our propensity analysis; however, on independent Cox UVA, esophagectomy was associated with improved survival (HR
Sensitivity Analysis
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0.41, p<0.01).
Strictly speaking, esophagectomy is not a confounder in the stenting-overall survival association, as it
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occurs after stenting. This makes it an intermediate variable and so should not be included in the model. Still, as a type of sensitivity analysis, we added it to our PS matched shared frailty Cox regression
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model as a time-varying covariate (not part of the propensity score but as a predictor variable, along with stenting as a predictor variable). In this model, stenting remained associated with worse overall survival (HR 2.3; 95%CI, 1.1 – 4.5, p=0.019).
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Discussion Our findings suggest that esophageal stent placement prior to neoadjuvant CRT is associated with worse
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acute toxicities and survival. In this retrospective analysis of esophageal cancer patients treated with curative intent, we found that esophageal stents placed prior to radiotherapy were associated with significantly increased ≥3 acute toxicities, particularly esophageal toxicity, as well as decreased overall
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survival.
As has been noted in prior studies [3,8,10,12,20,23,24,27,33,34,39,42-44], we also found that
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esophageal stent placement is effective at rapid improvement of dysphagia. However, stent placement is not without risks, as the majority of patients studied experienced complications, which commonly included significant pain or reflux. Stent migration was experienced by almost one-third of patients, which some may consider an expected outcome secondary to response to treatment and not necessarily a complication. In our series feeding tubes were placed in significantly more patients with stents and
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post-treatment albumin levels were low in more stent patients, though this was not significant. Additionally, even though stents improve dysphagia, the effectiveness of stenting to improve nutritional status remains unclear. In one series of 11 patients who received stents, all were malnourished at
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diagnosis [29]. The group had a mean dysphagia score of 2.6 prior to stenting which improved to 0.5
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after stenting. One patient had a perforation, 4 had stent migration, 3 required nasogastric feeding tube placement, and 1 required total parenteral nutrition (TPN). Only 4 patients had stabilization of weight and nutritional status and went to surgery. Given high complication rates and poor impact on improving nutritional status, further recruitment of patients for stenting was halted [29]. Additionally, a comprehensive review of the literature by Jones et al., did not show any consistency of benefit on nutritional status, serum albumin, or weight following stent placement [22]. They found that chest discomfort and stent migration were common complications among the studies included, which
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required frequent reintervention. Other uncommon, but life threatening complications, included esophageal perforation, mediastinitis, aortic erosion, and trachea-esophageal fistula. An update of their
supported based on current evidence in the neoadjuvant setting [22].
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summary table is provided in Table 5. Ultimately, they concluded that the use of stents could not be
We also found an association between esophageal stents and worse OS. These findings are consistent with recent findings by Mariette et al., who reported that self-expanding metal stents worsen R0
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resection rates, have increased peri-operative morbidity, lead to increased cancer recurrence, and decrease overall survival [32]. We also found that proceeding to esophagectomy was associated with an
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improved OS and that fewer patients with stents received surgery compared to those without stents. Possible mechanisms for increased toxicity from stents include dosimetric studies which have found that metal stents increase backscatter and thereby increase mucosal dose [4,25]. Additionally, stent placement has been found to significantly increase the target volumes for a patient, as well as increase
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dose to the heart, liver, and lungs [18]. However, in our study, we did not find a significant association between stent material, radiation dose, or tumor size and risk of toxicity. While patients who received stents did have larger tumor volumes (GTVs), higher T-stage, and worse pre-treatment KPS, after
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of toxicity.
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controlling for these factors on MVA, we found that esophageal stenting was an independent predictor
Our study contains typical limitations of retrospective data analyses, including incomplete medical records and lack of standardized follow-up. Additionally, it is possible that some unobserved covariate that was not accounted for may be contributing to the worse outcomes and toxicities associated with esophageal stents. Furthermore, our study was limited to analyzing stent effects on acute toxicity as our long-term toxicity data was incomplete and we did not have a cause of death on many patients, and thus assessing cause-specific survival was not possible. In spite of these limitations, with rigorous 12
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statistical analyses, we have demonstrated a clear association between esophageal stent placement prior to radiation and increased risk of significant toxicities as well as worse survival. This is the first study that we are aware of to report the association between toxicity outcomes in a comparative
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fashion for stent and no-stent patients. Our data, in addition to previously cited data [32], raise concerns about the safety and efficacy of esophageal stents used in the non-palliative setting for esophageal cancer patients being treated with curative intent. Esophageal stenting in the curative setting ideally
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should be evaluated in the setting of a randomized clinical trial to definitively determine the impact on patient outcomes.
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For optimal nutritional management we suggest a multidisciplinary approach with individualized nutritional evaluation and dietetic advice prior to initiating CRT. The goal should be to maximize oral nutrition intake, and may require supplementary enrichment of diet and/or modification of consistency and quantities of foods as indicated. For patients unable to intake adequate nutrition orally, enteral
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tube feeding, rather than parenteral nutrition, should be used [15,31,41]. A recent systematic review of 11 randomized controlled studies found that percutaneous endoscopy gastrostomy (PEG) was associated with lower probability of intervention failure compared with nasogastric tubes (NGT) in
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patients with swallowing disturbances [19]. While concerns regarding PEG tubes in the neoadjuvant setting have included compromising the future gastric conduit and limiting surgical options for
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neoesophagus reconstruction [38,45], several studies have shown PEG tubes to be safe and without a statistically increased risk of esophagectomy complications [30,47,48] although power could have been an issue[48]. Due to some persisting concerns for increased operative time, complexity, and complications [48], as supported by the NCCN guidelines we recommend first considering jejunostomy tube (J-tube) placement when surgery is a possibility, especially as J-tube placement is often performed routinely as part of an esophagectomy [37,48], reserving PEG tubes for those patients where surgery is not planned. Diagnostic laparoscopy may be considered for the detection of radiographically occult 13
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disease in select patients with distal (e.g. Siewart II or III) esophageal tumors [35,37], and therefore a Jtube could be considered at the time of laparoscopy to streamline patient care [46,48]. Furthermore, while not an immediate effect, chemotherapy and radiation have both been shown to improve
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malignant dysphagia by reducing tumor burden [14,21]. In the palliative setting, Hanna et al found time to improvement in dysphagia slower with RT as compared to stents (50% vs 85% at 2 weeks), but it was more durable (90% vs 80% at 10 weeks)[21]. Given these effective alternatives for nutritional support,
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and concerns about detrimental effect of stents, we do not recommend routine stent use in the curative
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setting outside of a clinical trial.
Conclusion: Esophageal stenting is associated with significantly increased grade ≥3 acute toxicities and worse OS in patients receiving CRT therapy with curative intent. For those unable to maintain adequate oral nutrition before starting CRT, rather than a stent we instead recommend J-tubes for potentially
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operable patients and PEG tubes for those not planning on surgery.
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This research did not receive any specific grant from funding agencies in the public, commercial, or not-
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for-profit sectors.
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Griffiths EA, et al. The use of biodegradable (sx-ella) oesophageal stents to treat dysphagia due to benign and malignant oesophageal disease. Surg Endosc 2012;26:2367-2375. Hanna WC, et al. What is the optimal management of dysphagia in metastatic esophageal cancer? Curr Oncol 2012;19:e60-66. Jones CM Griffiths EA. Should oesophageal stents be used before neo-adjuvant therapy to treat dysphagia in patients awaiting oesophagectomy? Best evidence topic (bet). International journal of surgery (London, England) 2014;12:1172-1180. Krokidis M, et al. The use of biodegradable stents in malignant oesophageal strictures for the treatment of dysphagia before neoadjuvant treatment or radical radiotherapy: A feasibility study. Cardiovasc Intervent Radiol 2013;36:1047-1054. Langer FB, et al. Temporary placement of self-expanding oesophageal stents as bridging for neoadjuvant therapy. Annals of surgical oncology 2010;17:470-475. Li XA, et al. Radiotherapy dose perturbation of metallic esophageal stents. International Journal of Radiation Oncology* Biology* Physics 2002;54:1276-1285. Little RJ Rubin DB. Causal effects in clinical and epidemiological studies via potential outcomes: Concepts and analytical approaches. Annu Rev Public Health 2000;21:121-145. Lopes TL Eloubeidi MA. A pilot study of fully covered self-expandable metal stents prior to neoadjuvant therapy for locally advanced esophageal cancer. Diseases of the esophagus : official journal of the International Society for Diseases of the Esophagus / I.S.D.E 2010;23:309-315. Maldonado G Greenland S. Simulation study of confounder-selection strategies. Am J Epidemiol 1993;138:923-936. Mao-de-Ferro S, et al. Stents in patients with esophageal cancer before chemoradiotherapy: High risk of complications and no impact on the nutritional status. European journal of clinical nutrition 2016;70:409-410. Margolis M, et al. Percutaneous endoscopic gastrostomy before multimodality therapy in patients with esophageal cancer. Ann Thorac Surg 2003;76:1694-1697; discussion 1697-1698. Mariette C, De Botton ML Piessen G. Surgery in esophageal and gastric cancer patients: What is the role for nutrition support in your daily practice? Annals of surgical oncology 2012;19:21282134. Mariette C, et al. Self-expanding covered metallic stent as a bridge to surgery in esophageal cancer: Impact on oncologic outcomes. Journal of the American College of Surgeons 2015;220:287-296. Martin R, et al. The use of self-expanding silicone stents in esophageal cancer care: Optimal pre-, peri-, and postoperative care. Surg Endosc 2009;23:615-621. Martin RC, 2nd, et al. Evaluation of quality of life following placement of self-expanding plastic stents as a bridge to surgery in patients receiving neoadjuvant therapy for esophageal cancer. The oncologist 2014;19:259-265. Mehta K, et al. Minimally invasive staging of esophageal cancer. Ann Cardiothorac Surg 2017;6:110-118. Mougey A Adler D. Esophageal stenting for the palliation of malignant dysphagia. The journal of supportive oncology 2008;6:267. Network NCC. Esophageal and esophagogastric junction cancers (version 1.2017). Ohnmacht GA, et al. Percutaneous endoscopic gastrostomy risks rendering the gastric conduit unusable for esophagectomy. Diseases of the esophagus : official journal of the International Society for Diseases of the Esophagus / I.S.D.E 2006;19:311-312. Pellen MG, et al. Safety and efficacy of self-expanding removable metal esophageal stents during neoadjuvant chemotherapy for resectable esophageal cancer. Diseases of the esophagus
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[43] [44]
[45] [46]
[47]
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[48]
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[42]
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[40]
: official journal of the International Society for Diseases of the Esophagus / I.S.D.E 2012;25:4853. Schiesser M, et al. The correlation of nutrition risk index, nutrition risk score, and bioimpedance analysis with postoperative complications in patients undergoing gastrointestinal surgery. Surgery 2009;145:519-526. Seres DS, Valcarcel M Guillaume A. Advantages of enteral nutrition over parenteral nutrition. Therapeutic advances in gastroenterology 2013;6:157-167. Siddiqui AA, et al. Self-expanding plastic esophageal stents versus jejunostomy tubes for the maintenance of nutrition during neoadjuvant chemoradiation therapy in patients with esophageal cancer: A retrospective study. Diseases of the esophagus : official journal of the International Society for Diseases of the Esophagus / I.S.D.E 2009;22:216-222. Siddiqui AA, et al. Expandable polyester silicon-covered stent for malignant esophageal strictures before neoadjuvant chemoradiation: A pilot study. Dig Dis Sci 2007;52:823-829. Siddiqui AA, et al. Placement of fully covered self-expandable metal stents in patients with locally advanced esophageal cancer before neoadjuvant therapy. Gastrointest Endosc 2012;76:44-51. Singh A Gelrud A. Adverse events associated with percutaneous enteral access. Gastrointest Endosc Clin N Am 2015;25:71-82. Siow SL, et al. Laparoscopic t-tube feeding jejunostomy as an adjunct to staging laparoscopy for upper gastrointestinal malignancies: The technique and review of outcomes. BMC Surg 2017;17:25. Stockeld D, et al. Percutaneous endoscopic gastrostomy for nutrition in patients with oesophageal cancer. Eur J Surg 2001;167:839-844. Wright GP, Foster SM Chung MH. Esophagectomy in patients with prior percutaneous endoscopic gastrostomy tube placement. American journal of surgery 2014;207:361-365; discussion 364-365.
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Figure Legends
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Figure 1. Kaplan-Meier curves showing overall survival (OS) based on stent placement. A: Shows OS for the pre-propensity score match cohort. B: Shows OS for the post-propensity score match cohort.
19
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Table 1. Patient Demographics and Clinical Characteristics Stent During RT N %
Total N %
Age [years]
0.77†
63.2 58.0-70.7
2 (3) (27) (40) (20) (11) (100)
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2 20 30 15 8 75
18 8 26
(77) (23) (100)
5 7 62 1 75
0 1 13 13 1 28
(7) (9) (83) (1) (100)
SC
56 17 73 2
(4) (96) (100)
(7) (93) (100)
5 98 103
(5) (95) (100)
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No Yes Total Unknown Stage
2 26 28
(69) (31) (100)
74 25 99
0.44‡
(75) (25) (100)
4
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3 72 75
T1 T2 T3 T4 Total
63.3 57.0-70.7
0.61‡
Female Male Total Current Tobacco Use
IIA IIB IIIA IIIB IIIC Total T Stage
63.8 55.3-70.1
EP
Median IQR Gender
P-value
RI PT
No Stent N %
(0) (4) (46) (46) (4) (100)
0.02¥ 2 21 43 28 9 103
(2) (20) (42) (27) (9) (100) 0.05¥
0 0 28 0 28
(0) (0) (100) (0) (100)
5 7 90 1 103
(5) (7) (87) (1) (100)
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N Stage (17) (39) (36) (8) (100)
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18 40 37 8 103
80 70-90
Grade 1 Grade 2 Grade 3 Total Unknown Tumor Volume [cm3]
2 32 33 67 8
Median IQR Tumor Length [cm]
55.6 34.6-93.5
27 1 28
(89) (11) (100) (3) (48) (49) (100)
(96) (4) (100)
0 12 13 25
(0) (43) (46) (100)
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3
6.5 5.5-8.0
18.7 15.5-21.5
80 70-100
SC
80 70-100 67 8 75
Median IQR Tumor Position
(4) (46) (46) (4) (100)
0.03†
Adenocarcinoma Squamous Cell Carcinoma Total Tumor Grade
Median IQR PTV Length [cm]
1 13 13 1 28
(23) (36) (32) (9) (100)
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Median Range Tumor Histology
17 27 24 7 75
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N0 N1 N2 N3 Total KPS Pre-treatment
0.22¥
96.0 60.3-136.8
94 9 103 2 44 46 92
0.26•
(91) (9) (100) 0.73¥
(2) (43) (45) (100)
11 <0.01† 67.2 40.8 – 110.9 0.20†
7.8 6.0-9.0
7.0 5.5-8.5 0.13†
19.8 17.4 -21.6
19.3 16.8-21.5 0.62¥
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(2) (8) (90) (100)
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2 8 93 103
NA
(5.4) (0 – 11.2)
Low (<3.4 g/dL) Normal Total Unknown Hospitalization ≤30 Days before RT
2 25 27 48
(25) (61) (7) (7) (0) (100)
(12.2) (7.2-18.7)
(7) (93) (100)
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18 44 5 5 0 72 3
66 9 75
(39) (7) (54) (100)
5 14 7 1 1 28 0
(88) (12) (100)
1 15 16 12
11 2 15 28
(39) (7) (54) (100)
SC
11 2 15 28
NA NA NA NA
0 1 2 3 4 Total Unknown Albumin Level Pre-RT
No Yes Total
(4) (4) (93) (100)
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Pre-RT Weight Loss [%] Median IQR Pre-RT Dysphagia Score*
1 1 26 28
(1) (9) (89) (100)
(18) (50) (25) (4) (4) (100)
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Plastic Stent Partially Covered Metal Stent Fully Covered Metal Stent Total
1 7 67 75
EP
Upper Third Mid Third Lower Third Total Stent Type
<0.01†
8.3 (1.1-15.6)
23 58 12 6 1 100 3
0.10¥
(23) (58) (12) (6) (1) (100) 1.00‡
(6) (94) (100)
3 40 43 60
(7) (93) (100)
0.23• 22 6 28
(79) (21) (100)
88 15 103
(85) (15) (100)
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Abbreviations: N= number; RT=radiotherapy; cm=centimeter; IQR=interquartile range; KPS = Karnofsky performance scale; GTV=gross tumor volume, PTV=planning target volume; NA= not applicable; GEJ=gastroesophageal junction.
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Footnotes: *0=no dysphagia, 1=dysphagia to normal solids, 2=dysphagia to soft solids, 3=dysphagia to liquids, and 4=aphagia; Analysis method: †t-test, ‡Fisher’s exact test or Fisher-Freeman-Halton test, ¥Wilcoxon-Mann-Whitney, • Chi-squared.
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Table 2. Treatment Characteristics
Intent of RT
Median Range Concurrent Chemotherapy
50.4 32.4-50.4 39 15 7 7 7 75
(52) (20) (9) (9) (9) (100)
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Cisplatin/5FU Cisplatin/Paclitaxel Carboplatin/Paclitaxel Cisplatin/Paclitaxel/Cetuximab Other Total Surgery
8
(29)
7 1 8 18
(88) (13) (100) (64)
11 7 18
(61) (39) (100)
2 2 0 2 28
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(32) (79) (21) (100) (67) (34) (66) (100) (1) (100) (0) (100) (100)
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Salvage Surgery No Yes Total Neoadjuvant Planned Surgery No Yes Total Unknown Surgery No Yes Total Total RT Dose [Gy]
24 19 5 24 50 17 33 50 1 1 0 1 75
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Definitive
18 4 3 3 0 28
Total
(7) (100) (0) (100) (100)
P-value
N
%
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Stented During RT N %
0.33‡
32
(31)
26 6 32 68
(81) (19) (100) (66)
1.00‡
28 40 68
(41) (59) (100)
0.05•
3 3 0 3 103
(3) (100) (0) (100) (100)
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No Stent N %
NA
0.03†
50.4 32.4-50.4
50.4 32.4-50.4 0.48‡
(64) (14) (11) (11) (0) (100)
57 19 10 10 7 103
(55) (18) (10) (10) (7) (100) 0.05•
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13 24 1 38
3DRT IMRT Total
73 2 75
20 8 28
(34) (63) (3) (100)
1 7 0 8
(97) (3) (100)
26 2 28
(71) (29) (100) (13) (88) (0) (100) (93) (7) (100)
55 46 103
(55) (45) (100)
RI PT
Ivor-Lewis Transhiatal Other Total Type of RT
(49) (51) (100)
14 31 1 46
SC
37 38 75
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No Yes Total Type of Surgery
99 4 103
0.51‡
(30) (67) (2) (100)
0.30‡ (96) (4) (100)
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Abbreviations: N=number; RT=radiotherapy; Gy=Gray; RT=radiotherapy; 5FU= fluorouracil; IQR=interquartile range; 3DRT=3D conformal radiotherapy; IMRT=intensity modulated radiotherapy.
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Footnotes: †t-test, ‡ Fisher’s exact test or Fisher-Freeman-Halton, ¥ Wilcoxon-Mann-Whitney, • Chi-squared.
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Table 3. Acute Toxicities (≤90 Days after RT Treatment)
KPS Change Post-RT
No Yes Total ≥ Grade 3 Dehydration
60 15 75
No Yes Total ≥ Grade 3 Anorexia
65 10 75
No Yes Total Weight Loss by End of RT [%] Median IQR
8 20 28
(73) (27) (100) (80) (20) (100) (87) (13) (100)
71 4 75
17 11 28
(95) (5) (100)
(7.6) (5.2 – 10.4)
(4) (21) (61) (14) (100)
N
11 29 56 7 103
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55 20 75
1 6 17 4 28
(29) (71) (100)
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No Yes Total ≥ Grade 3 Esophageal Toxicity*
(13) (31) (52) (4) (100)
(61) (39) (100)
P-value %
63 40 103
0.03¥
(11) (28) (54) (7) (100)
<0.01• (61) (39) (100) 0.05•
77 26 103
(75) (25) (100) 0.07•
20 8 28
(71) (29) (100)
85 18 103
(83) (17) (100)
24 4 28
(86) (14) (100)
95 8 103
(92) (8) (100)
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10 23 39 3 75
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Improvement No Change Decreased ≤ 20 Decreased > 20 Total Any ≥ Grade 3
Total
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Stent During RT N %
SC
No Stent N %
0.13‡
0.45† (9.3) (3.8 – 15.1)
(8.3) (5.1 – 10.9)
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≥ Grade 2 Thromboembolic Event 53 22 75
21 7 28
(71) (29) (100)
(75) (25) (100)
74 29 103
(72) (28) (100)
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No Yes Total
0.66•
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Abbreviations: N=number; RT=radiotherapy; KPS = Karnofsky performance scale; *Esophageal Toxicity includes esophagitis, dysphagia, or hemorrhage. Footnotes: † T-test, ‡ Fisher’s exact test or Fisher-Freeman-Halton test, ¥Wilcoxon-Mann-Whitney , • Chi-squared.
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Table 4. Predictors of ≥ Grade 3 Acute Toxicities
OR
Univariate Logistic Analysis 95% CI P-value
Stent During RT 1.0 6.9
Reference 2.6
18.1
<0.01
Female Male Smoking
1.0 0.4
Reference 0.1
2.5
0.33
No Yes T-Stage
1.0 1.2
Reference 0.5
T1-T2 T3-T4 N-Stage
1.0 2.1
Reference 0.5
N0 N1 N2-N3 Pre-RT KPS, per 10 points decrease (equal to one category on KPS scale)
1.0 2.3 2.8
Reference 0.7 0.8
Adenocarcinoma Squamous Cell Carcinoma Tumor Position Upper Third Middle Third
28.3
<0.01
0.75
1.0 0.8
Reference 0.3
2.7
0.77
0.30
1.0 1.7
Reference 0.3
9.3
0.55
8.4 9.8
0.19 0.11
1.0 1.3 2.0
Reference 0.3 0.4
7.0 10.9
0.74 0.40
3.7
0.02
1.7
0.8
3.4
0.15
5.1
0.72 1.0 1.6
Reference 0.0
57.2
0.81
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Histology
2.1
Reference 2.3
2.9
1.0 1.3
Reference 0.3
1.0 0.3
Reference 0.0
8.2
1.0 8.1
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No Stent Stent During RT Gender
OR
Multivariate Logistic Analysis 95% CI P-value
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Factor
0.50
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0.0
No Yes Age, per 1 year increase
1.0 2.8 1.0
Reference 0.9 1.0
8.5 1.1
0.08 0.51
GTV Length
1.1
0.9
1.2
0.40
GTV Volume
1.0
1.0
1.0
0.66
RT Dose
1.0
1.0
1.0
0.21
Mean Lung Dose
1.0
1.0
1.0
0.80
Lung V10
1.0
1.0
Lung V5
1.0
1.0
Heart V40
1.0
1.0
Plastic Stent Metal Stent Chemotherapy Type
1.0 1.9
Reference 0.4
Cisplatin/5FU Cisplatin/Paclitaxel Carboplatin/Paclitaxel Cisplatin/Paclitaxel/Cetuximab Other
1.0 0.5 0.3 2.1 1.0
Reference 0.2 0.1 0.5 0.2
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0.77
1.7
0.1
39.4
0.75
1.0 2.7
Reference 0.7
9.6
0.14
1.0
1.0
1.0
0.09
Reference 0.1 0.0 0.5 0.2
1.8 1.6 14.3 8.5
0.25 0.14 0.26 0.88
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0.74
1.0
0.78
1.0
0.83
9.8
0.47
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Stent Type*
10.9
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0.7
SC
Lower Third Hospitalization ≤30 Days before RT
1.6 1.8 8.1 5.0
0.23 0.20 0.30 0.97
1.0 0.4 0.2 2.6 1.2
Abbreviations: OR=odds ratio; CI=confidence interval; RT=radiotherapy; KPS = Karnofsky performance scale; GTV=gross tumor volume; PTV=planning target volume; GEJ=gastroesophageal junction; cm=centimeter; 5FU=5-florouracil; V10=volume receiving 10 Gray (Gy); V5=volume receiving 5 Gy; V40=volume receiving 40 Gy. Footnotes: *Not included in MVA modeling because of multicollinearity with esophageal stent placement.
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Table 5. Summary of Neoadjuvant Stent Studies
% Success
% requirin g dilation s
Christie A; 2001[14]
16
CT/CRT
NR
SEMS
NR
NR
Siddiqui A; 2007[26]
6
CRT
NR
SEPS
83
NR
Bower M; 2009[9]
25
CRT
Target 50.4
SEPS
100
56
Adler D; 2009[22]
13
CRT
NR
SEPS
85
54
Martin R; 2009[25]
5
CRT
NR
SEPS
100
Siddiqui A; 2009[13]
12
CRT
NR
SEPS
Lopes T; 2010[15]
11
CRT
NR
Langer F; 2010[11]
38
CT/CRT
Brown R; 2011[12]
32
CT/CRT
Cha nge in weig ht
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Insertion
Change in mean serum albumi n
Complications (%)
Ches t disc omf ort
Ste nt mig rati on
Eros ion or fistu la
SC
RT Dose [Gy]
Stent Type Studie d
EP
% Requiring suppleme ntary tube feeding
% Requiring unplanne d stent revision
% Progressing to surgery
Y
NR
NR
0
0
12
12
12
NR
Y
↑
↑
0
60
0
0
0
100
Y
↑
↔
0
24
0
8
20
56
Y
NR
NR
93
46
0
15
15
23
NR
Y
↔
NR
0
20
0
20
0
NR
92
17
Y
↑
↑
67
36
0
0
0
NR
SEMS
91
82
Y
NR
NR
30
20
10
0
30
20
NR
SEP/M S
97
32
Y
↓
NR
NR
32
16
3
29
53
NR
SEPS
100
88
Y
↓
↓
3
25
0
3
0
63
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N of patient s
Neoadj therap y
Signific ant improv ement in dyspha gia
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16
CT
NR
SEMS
100
NR
Y
↔
↔
0
44
0
0
0
63
Griffiths E; 2012[23]
9
CT
NR
SEBS
96
NR
Y
NR
NR
0
NR
NR
22
66
0
Krokidis M; 2013[24]
11
CT/CRT
NR
SEBS
100
45
Y
NR
NR
0
18
18
9
27
NR
Martin R; 2014[18]
52
CT/CRT
Media n 48.6
SEPS
NR
NR
Y
↔
NR
6
0
2
6
NR
Siddiqui A; 2012[20]
55
CRT
NR
SEMS
100
0
Current Study
18
CRT
Media n 50.4
SEP/M S
100
NR
SC
RI PT
Pellen M; 2012[19]
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↔
Y
NR
↔
15
31
2
0
4
15
Y
↓
↔
39
39
17
50
56
39
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Abbreviations: Gy=Gray; CT=chemotherapy; CRT=chemoradiotherapy; NR=not reported; SEMS=self-expanding metal stent; SEPS=self-expanding
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plastic stent; SEBS=self-expanding biodegradable stents
A
1.00
Overall Survival
0.80
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0.60 0.40
p=0.026
Number at risk No Stent: 75 Stent: 28
6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96
SC
0
Months Post Diagnosis 46 12
25 5
20 3
15 2
13 2
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0.00
RI PT
0.20
No Stent
B
2 0
Stent
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0.80 0.60
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Overall Survival
6 1
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1.00
7 1
0.40 0.20 0.00
p=0.016 0
Number at risk No Stent: 25 Stent: 25
6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 Months Post Diagnosis 18 12
10 5
10 3
9 2
No Stent
8 2
5 1 Stent
4 1
1 0
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Utilization of esophageal stents to relieve dysphagia is increasing in patients with locally advanced esophagus cancer while impacts on toxicity and outcomes are unclear. We retrospectively analyzed our cohort of curatively treated esophageal cancer patients and analyzed toxicities and outcomes comparing stent vs. no-stent patients. We found that patients who received stents had more acute esophageal toxicity, were less likely to undergo esophagectomy, and had worse overall survival than no-stent patients.
S0360-3016(17)33523-X
DOI:
10.1016/j.ijrobp.2017.06.2457
Reference:
ROB 24391
To appear in:
International Journal of Radiation Oncology • Biology • Physics
Received Date: 31 October 2016 Revised Date:
25 May 2017
Accepted Date: 19 June 2017
Please cite this article as: Francis SR, Orton A, Thorpe C, Stoddard G, Lloyd S, Anker CJ, Toxicity and Outcomes in Patients with and without Esophageal Stents in Locally Advanced Esophagus Cancer, International Journal of Radiation Oncology • Biology • Physics (2017), doi: 10.1016/ j.ijrobp.2017.06.2457. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Title: Toxicity and Outcomes in Patients with and without Esophageal Stents in Locally Advanced Esophagus Cancer Short Title: Toxicity of Esophageal Stents in Locally Advanced Esophagus Cancer
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Keywords: esophagus cancer; esophageal cancer; esophageal stent; stents; neoadjuvant therapy; radiotherapy; chemoradiotherapy; acute toxicity Authors: Samual R. Francis1, Andrew Orton1, Cameron Thorpe1, Greg Stoddard2, Shane Lloyd1, Christopher J. Anker3 1
Radiation Oncology, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah
2
Radiation Oncology, University of Vermont Cancer Center, Burlington , Vermont
Corresponding Author:
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Christopher J. Anker, MD, Division of Radiation Oncology University of Vermont Cancer Center 111 Colchester Ave, Burlington, VT 05401 Tel: (802) 847-3506 E-mail: [email protected]
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3
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Department of Medicine, Study Design and Biostatistics Center, University of Utah, Salt Lake City, Utah
Conflict of Interest Statement:
None of the authors have any conflicts of interest or financial disclosures.
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Acknowledgments:
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The authors wish to thank Michelle Denney for her assistance in editing and preparation of the manuscript.
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Title: Toxicity and Outcomes in Patients with and without Esophageal Stents in Locally Advanced Esophagus Cancer
1
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Abstract
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Purpose/Objectives: Esophageal stenting is often considered to relieve dysphagia in patients with locoregionally advanced esophageal cancer. We sought to determine effects of stenting on acute toxicities and oncologic outcomes in patients treated with chemoradiotherapy (CRT).
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Materials/Methods: Patients treated with curative intent RT for locoregionally advanced esophageal cancer at our institution were retrospectively analyzed. Chi-squared or Fisher exact test was used to
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compare demographic and tumor characteristics between patients with or without esophageal stenting before RT. Univariate (UVA) and multivariate (MVA) logistic regression modeling were used to identify predictors for acute toxicities. A propensity score matched analysis with shared frailty Cox hazard regression was performed based on stent status to identify stent effect on survival. Acute toxicities were
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graded using Common Terminology Criteria for Adverse Events version 4.
Results: Between 2005-2013, 103 consecutive patients received CRT. Twenty-eight had a stent during CRT. Median dose was 50.4 Gy (Gray) for all patients. Grade ≥3 acute toxicities were seen in 71% of
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stent versus (vs.) 27% of no-stent patients (p<0.01), including esophagitis (39% vs. 20%, p=0.05), dehydration (29% vs. 13%, p=0.07), and anorexia (14% vs. 5%, p=0.13). Twenty-nine percent of stent and
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51% of no-stent patients underwent esophagectomy (p=0.05). The only significant predictor for acute toxicity on MVA was esophageal stenting (OR 8.1, p<0.01). After propensity score matching, stent patients had worse median overall survival compared to no-stent patients (11.5 vs. 22.0 months, HR 2.3 p=0.016).
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Conclusion: In patients receiving CRT with curative intent, esophageal stenting was associated with significantly increased grade ≥3 acute toxicities, fewer patients proceeding to esophagectomy, and
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worse overall survival.
Introduction
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Patients with esophageal cancer frequently present with weight loss, dysphagia, and poor nutritional status. Whether undergoing neoadjuvant or definitive chemoradiation (CRT), adequate nutritional
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support is essential to ensuring the best surgical and oncologic outcomes [13,16,31,40]. Simple oral dietary supplementation is often insufficient given advanced dysphagia; therefore, different methods have been implemented to assist with maintenance of nutritional status during treatment. Enteral feeding is preferred to parenteral nutrition given reduced costs and fewer infectious complications [41].
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Nasogastric tubes are uncomfortable and have a higher rate of failure than percutaneous tube placement [19], while gastrostomy and jejunostomy tubes have a risk of infection and surgical complications [17,48].
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Esophageal stenting has emerged as an attractive means to relieve malignant dysphagia. While esophageal stenting consistently relieves dysphagia, it is not without risk. Commonly, patients
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experience chest discomfort or pain and frequent stent migration [2,8,10,24,42]. Less common, but serious side effects include esophageal perforation, fistula, abscess, and death [12,24,27]. While initially used in the palliative setting [9,36], esophageal stenting is being increasingly used in the curative setting and as a bridge to surgery [2,8,10,12,24,27,34,39,44]. Chemoradiation, either definitive or neoadjuvant, remains the standard of care for locoregionally advanced esophageal cancer, yet there is insufficient data regarding the safety and benefit of esophageal stenting in this setting. Therefore, we sought to
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determine the effect of esophageal stenting on acute toxicities and oncologic outcomes in patients
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treated with curative intent CRT.
Methods
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Patients
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After approval by the institutional review board, patients treated with chemoradiotherapy (CRT) with curative intent for locally advanced esophageal cancer (T3-T4 or node positive) at XXXX were identified and their charts were retrospectively analyzed. Only patients with either squamous cell carcinoma or adenocarcinoma histologies were included. Patients were not included if they: had metastatic disease at presentation, had ≥1 primary at presentation, received adjuvant radiotherapy after surgery, received
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only single-agent 5-FU chemotherapy, and/or were treated with palliative intent. The primary indication for esophageal stenting at our institution was malignant dysphagia. Dysphagia
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was scored on a 0-4 scale as follows: 0=no dysphagia, 1=dysphagia to normal solids, 2=dysphagia to soft solids, 3=dysphagia to liquids, and 4=aphagia. Performance status was measured using Karnofsky
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performance scale (KPS). Acute toxicities were defined as those occurring within 90 days of completing radiation treatment and prior to surgery for patients undergoing esophagectomy. We included gross tumor volume (GTV) length in the analysis, which we used as a surrogate for esophageal dose since esophageal dosimetry would be dependent on GTV length. Pre-RT weight loss was based on the patient reported pre-symptom weight and weight at the initial consultation. In the patients for which esophagectomy was performed, it was always done after CRT. Types of esophagectomy included IvorLewis, transhiatal, laparoscopic transhiatal, and minimally invasive esophagectomy. Tumor position was 4
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defined based on the American Joint Committee on Cancer (AJCC) version 7 guidelines by proximal tumor edge distance from incisors as follows: cervical 15 centimeter (cm), upper 20 cm, middle 25 cm,
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lower 30 cm, gastroesophageal junction (GEJ) 40 cm [1]. Statistical Analysis
A chi-squared test was used to compare binary patient characteristics of the stent and no-stent groups,
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as long as three expected cell frequencies were at least 5 and the fourth one was at least 1; otherwise, Fisher’s exact test was used. For unordered categorical data with more than two categories, the chi-
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squared test was used if more than 20% of the expected cell frequencies were at least 5 and no expected cell frequency was less than 1; otherwise, the Fisher-Freeman-Halton test was used. Ordered categorical data were compared using Wilcoxon-Mann-Whitney (WMW) test. Student’s t-test was used to analyze continuous variables for two independent groups and Kruskal-Wallis analysis of variance
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(ANOVA) was used to analyze three or more independent groups.
Univariate (UVA) and multivariate (MVA) analyses via logistic regression modeling were used to identify predictors for acute toxicities, reported as odds ratios (ORs). The MVA regression model was created by
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including covariates with a P-value <0.2 on UVA and those felt to be clinically relevant to acute toxicity outcomes. For categorical covariates, if one of the covariate levels in comparison to the reference level
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had a p<0.2, then it was included in the final model [11,28]. Acute toxicities were graded using Common Terminology Criteria for Adverse Events (CTCAE) version 4. The primary oncologic outcome of interest was overall survival (OS), which was defined as time from initiation of radiotherapy to date of death or last follow-up. Propensity scores (PS) predicting for stent placement were generated for each patient using a model including age, gender, clinical stage, T-stage, N-stage, initial KPS, tumor position, tumor grade, histology,
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radiation dose, type of chemotherapy, and hospitalization ≤30 days prior to CRT according to the method previously described by Rosenbaum and Rubin [5,6,26]. One-to-one matching was performed using a nearest-neighbor algorithm assuming independent observations, fixed weights, and the
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assumption that the variance of the outcome does not depend on the PS. Pairing between cases was limited to the region of common support. Caliper width was narrowed in a step-wise fashion until the covariate distributions were balanced after matching [7]. After matching, a UV shared frailty Cox
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proportional hazard regression was used to estimate the effect of esophageal stents on OS. KaplanMeier survival analysis was performed both before and after PS analysis to generate OS curves. All
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analyses were performed using the Stata version 14.2 statistical package (Stata-Corp, College Station, TX).
Patient Characteristics
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Results
One hundred three consecutive patients who received CRT between the years 2005-2013 at XXXX met
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inclusion for analysis (Table 1). Median follow-up was 13.7 months (range 1.9 – 99.9 months).
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Twenty-eight patients had a stent during CRT comprising the stent group. Sixty-one percent of the stent group received a metal stent, and 39% received a plastic stent. Sixty-eight percent of stent patients had complications related to stenting (Supplemental Table A1). There were no significant differences in complications between plastic and metal stents. Most common complications included 39% with pain, 32% stent migration, and 14% reflux. Four patients had stent migration with stent exchange before starting CRT. Four patients had the stent removed during radiation. One of these patients was restented. Reasons for removal include migration in 3 patients and migration and pain in 1 patient. Eight
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patients had stents removed endoscopically after CRT: 5 due to migration, 1 due to stricture, and 2 for unknown reasons. The median time to stent migration after placement was 15.5 days (range 3-88 days). Significant complications included 3 patients with esophageal perforation, 2 of which required emergent
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surgical repair, and 1 patient with hematemesis that was treated conservatively.
The most common prescription dose for all patients was 50.4 Gy (Gray) in 28 fractions. While both groups received the same median dose, the stent group had more patients that received a lower total
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dose than the no-stent group (Table 2). The majority of patients were treated with 3D conformal radiation, and most commonly a 4-field technique was used. All patients received concurrent
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chemotherapy, with the most common regimen being cisplatin and fluorouracil (5FU) (55%) and the second most common regimen used was cisplatin and paclitaxel (18%) (Table 2). Patients listed as receiving “other” chemotherapy include: 3 patients who received cisplatin, paclitaxel, and 5FU; 1 patient who received paclitaxel, carboplatin, and cetuximab; 1 patient who received cisplatin; 1 patient who
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received paclitaxel and 5FU; and 1 patient who received cisplatin and irinotecan. Stent patients had a lower pre-treatment KPS than no-stent patients (Median KPS 80 [range 70-90] stent versus [vs.] 80 [range 70-100] no-stent, p=0.03). For both groups, the most common histology was adenocarcinoma
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(96% stent and 89% no-stent, p=0.26) and the most common location was the lower third of the
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esophagus (93% stent and 89% no-stent, p=0.62). Fourteen percent of no-stent compared to 33% of stent patients had pre-treatment dysphagia scores ≥2 (p=0.10). Before starting CRT stent patients lost a median of 12% (interquartile range [IQR] 7 – 19%) of their body weight and no-stent patients lost a median of 5% (IQR 0 – 11%) (p<0.01). One-hundred percent of stent patients had T3 tumors compared to 83% of no-stent patients (p=0.05). The median GTV was 96.0 cm3 (IQR 60.3 – 136.8 cm3) vs. 55.6 cm3 (IQR 34.6 – 93.5 cm3) in the stent and no-stent
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groups, respectively (p<0.01). Seventy-four percent of patients in the stent group reported a lower dysphagia score one-week post-stent.
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Sixty-four percent of stent patients and 67% of no-stent patients were treated with neoadjuvant CRT with a plan for surgery (Table 2). Of these, 39% of stent patients compared to 66% of no-stent patients underwent esophagectomy (p=0.05). The most common type of surgery was a transhiatal technique (63% of no-stent and 88% of stent patients, respectively). The median time from completion of CRT to
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surgery was 59 days (IQR 49 – 78 days). The most common reasons neoadjuvant intent patients did not receive surgery were due to development of metastatic disease (3 stent vs. 7 no-stent patients), poor
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functional status associated with poor nutritional intake, worsened comorbid conditions, and/or difficulty with activities of daily living (4 stent vs. 3 no-stent patients), unresectable (3 stent vs. 1 nostent patients), or patient declined (1 stent vs. 5 no-stent patients).There was no significant difference in the rate of 30-day post-operative complications between the two groups (55% no-stent vs. 50% stent,
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p=1.00). Three no-stent patients and 1 stent patient died within 30 days after discharge postesophagectomy.
Thirty-two percent of no-stent patients and 29% of stent patients were treated with definitive CRT. Five
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patients in the no-stent group and 1 in the stent group had salvage esophagectomy. The median time to
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salvage surgery after completing definitive CRT was 132 days (range 68 – 706 days). After salvage surgery, 3 patients died within 2 years, and the other 3 were lost to follow-up.
Acute Toxicity Analysis
Grade ≥3 acute toxicities were seen in 71% of the stent group compared to 27% of no-stent patients (p<0.01), including esophageal toxicity (39% vs. 20%, p=0.05), dehydration (29% vs. 13%, p=0.07), and
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anorexia (14% vs. 5%, p=0.13), respectively (Table 3). Overall 28% of patients had an acute thromboembolic event. Additionally, performance status improved after radiation in 13% of no-stent patients compared to 4% of stent patients (p=0.03). Additionally, more stent patients had a decrease in
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KPS of >20 after treatment (14% stent vs. 4% no-stent, p=0.03). On subset analysis, the association between stent and grade ≥3 toxicity remained significant for patients receiving neoadjuvant CRT (72% stent vs. 24% no-stent, p<0.01) but not for those receiving definitive CRT (63% stent vs. 33% no-stent,
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p=0.22). There was no statistical difference between rates of toxicities between metal or plastic stents, but both groups had higher rates of toxicity than the no-stent group (Supplemental Table A2). There was
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a trend towards worse post-CRT KPS for the metal stents compared to plastic stent (p=0.06). From start to finish of radiation, no-stent patients lost a median of 8% (IQR 5 – 10%) of body weight, and stent patients lost 9% (IQR 4 – 15%) of body weight (p=0.45). Prior to radiation, albumin levels were low (<3.4 g/dL) in 7% of no-stent and 6% of stent patients (p=1.00). After radiation, albumin levels were low in
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46% of no-stent and 67% of stent patients (p=0.33). For those patients treated with neoadjuvant intent, 36% of no-stent compared to 75% of stent patients had low albumin after radiation (p=0.18). Feeding tubes were placed before or during RT in 20% of no-stent and 54% of stent patients (p<0.01).
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On UVA logistic regression, we found that esophageal stenting (OR 6.9, p<0.01) and pre-CRT KPS (OR 2.1, p=0.02) were significant predictors for grade ≥3 acute toxicity. We did not find an association
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between acute toxicity and esophageal (i.e. GTV length), heart, or lung dose. On MVA logistic regression, we found that esophageal stenting (OR 8.1, p<0.01) was the only significant factor associated with grade ≥3 acute toxicity (Table 4). Even after excluding from analysis patients with > grade 1 dysphagia prior to starting CRT, stenting remained the sole predictor of toxicity (MVA OR 14.3, p<0.01). Survival Analysis
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The median OS for the entire cohort was 15.7 months (95% Confidence Interval [CI], 11.7 – 19.1 months). On subset analysis, the no-stent group had a longer median OS (16.8 months, 95% CI 12.4 – 23.4 months) compared to the stent group (9.1 months, 95% CI 7.8 – 16.4 months, log-rank p=0.026)
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(Figure 1, A).
After PS matching, a matched cohort of 25 no-stent and 25 stent patients was available for analysis. Patient characteristics were balanced between no-stent and stent groups (Supplemental Table A3). The
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median OS for no-stent patients was 22.0 months(95% CI,12.4 – 66.5 months) vs. 11.5 months (95% CI,7.9 – 16.8 months) for stent patients (Figure 1, B). On shared frailty UV Cox regression, stenting was
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associated with worse overall survival (Hazard Ratio [HR] 2.33; 95% CI, 1.17 – 4.62; p=0.016). Given that esophagectomy was not a baseline characteristic, it was not controlled for in our propensity analysis; however, on independent Cox UVA, esophagectomy was associated with improved survival (HR
Sensitivity Analysis
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0.41, p<0.01).
Strictly speaking, esophagectomy is not a confounder in the stenting-overall survival association, as it
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occurs after stenting. This makes it an intermediate variable and so should not be included in the model. Still, as a type of sensitivity analysis, we added it to our PS matched shared frailty Cox regression
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model as a time-varying covariate (not part of the propensity score but as a predictor variable, along with stenting as a predictor variable). In this model, stenting remained associated with worse overall survival (HR 2.3; 95%CI, 1.1 – 4.5, p=0.019).
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Discussion Our findings suggest that esophageal stent placement prior to neoadjuvant CRT is associated with worse
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acute toxicities and survival. In this retrospective analysis of esophageal cancer patients treated with curative intent, we found that esophageal stents placed prior to radiotherapy were associated with significantly increased ≥3 acute toxicities, particularly esophageal toxicity, as well as decreased overall
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survival.
As has been noted in prior studies [3,8,10,12,20,23,24,27,33,34,39,42-44], we also found that
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esophageal stent placement is effective at rapid improvement of dysphagia. However, stent placement is not without risks, as the majority of patients studied experienced complications, which commonly included significant pain or reflux. Stent migration was experienced by almost one-third of patients, which some may consider an expected outcome secondary to response to treatment and not necessarily a complication. In our series feeding tubes were placed in significantly more patients with stents and
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post-treatment albumin levels were low in more stent patients, though this was not significant. Additionally, even though stents improve dysphagia, the effectiveness of stenting to improve nutritional status remains unclear. In one series of 11 patients who received stents, all were malnourished at
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diagnosis [29]. The group had a mean dysphagia score of 2.6 prior to stenting which improved to 0.5
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after stenting. One patient had a perforation, 4 had stent migration, 3 required nasogastric feeding tube placement, and 1 required total parenteral nutrition (TPN). Only 4 patients had stabilization of weight and nutritional status and went to surgery. Given high complication rates and poor impact on improving nutritional status, further recruitment of patients for stenting was halted [29]. Additionally, a comprehensive review of the literature by Jones et al., did not show any consistency of benefit on nutritional status, serum albumin, or weight following stent placement [22]. They found that chest discomfort and stent migration were common complications among the studies included, which
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required frequent reintervention. Other uncommon, but life threatening complications, included esophageal perforation, mediastinitis, aortic erosion, and trachea-esophageal fistula. An update of their
supported based on current evidence in the neoadjuvant setting [22].
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summary table is provided in Table 5. Ultimately, they concluded that the use of stents could not be
We also found an association between esophageal stents and worse OS. These findings are consistent with recent findings by Mariette et al., who reported that self-expanding metal stents worsen R0
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resection rates, have increased peri-operative morbidity, lead to increased cancer recurrence, and decrease overall survival [32]. We also found that proceeding to esophagectomy was associated with an
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improved OS and that fewer patients with stents received surgery compared to those without stents. Possible mechanisms for increased toxicity from stents include dosimetric studies which have found that metal stents increase backscatter and thereby increase mucosal dose [4,25]. Additionally, stent placement has been found to significantly increase the target volumes for a patient, as well as increase
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dose to the heart, liver, and lungs [18]. However, in our study, we did not find a significant association between stent material, radiation dose, or tumor size and risk of toxicity. While patients who received stents did have larger tumor volumes (GTVs), higher T-stage, and worse pre-treatment KPS, after
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of toxicity.
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controlling for these factors on MVA, we found that esophageal stenting was an independent predictor
Our study contains typical limitations of retrospective data analyses, including incomplete medical records and lack of standardized follow-up. Additionally, it is possible that some unobserved covariate that was not accounted for may be contributing to the worse outcomes and toxicities associated with esophageal stents. Furthermore, our study was limited to analyzing stent effects on acute toxicity as our long-term toxicity data was incomplete and we did not have a cause of death on many patients, and thus assessing cause-specific survival was not possible. In spite of these limitations, with rigorous 12
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statistical analyses, we have demonstrated a clear association between esophageal stent placement prior to radiation and increased risk of significant toxicities as well as worse survival. This is the first study that we are aware of to report the association between toxicity outcomes in a comparative
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fashion for stent and no-stent patients. Our data, in addition to previously cited data [32], raise concerns about the safety and efficacy of esophageal stents used in the non-palliative setting for esophageal cancer patients being treated with curative intent. Esophageal stenting in the curative setting ideally
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should be evaluated in the setting of a randomized clinical trial to definitively determine the impact on patient outcomes.
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For optimal nutritional management we suggest a multidisciplinary approach with individualized nutritional evaluation and dietetic advice prior to initiating CRT. The goal should be to maximize oral nutrition intake, and may require supplementary enrichment of diet and/or modification of consistency and quantities of foods as indicated. For patients unable to intake adequate nutrition orally, enteral
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tube feeding, rather than parenteral nutrition, should be used [15,31,41]. A recent systematic review of 11 randomized controlled studies found that percutaneous endoscopy gastrostomy (PEG) was associated with lower probability of intervention failure compared with nasogastric tubes (NGT) in
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patients with swallowing disturbances [19]. While concerns regarding PEG tubes in the neoadjuvant setting have included compromising the future gastric conduit and limiting surgical options for
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neoesophagus reconstruction [38,45], several studies have shown PEG tubes to be safe and without a statistically increased risk of esophagectomy complications [30,47,48] although power could have been an issue[48]. Due to some persisting concerns for increased operative time, complexity, and complications [48], as supported by the NCCN guidelines we recommend first considering jejunostomy tube (J-tube) placement when surgery is a possibility, especially as J-tube placement is often performed routinely as part of an esophagectomy [37,48], reserving PEG tubes for those patients where surgery is not planned. Diagnostic laparoscopy may be considered for the detection of radiographically occult 13
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disease in select patients with distal (e.g. Siewart II or III) esophageal tumors [35,37], and therefore a Jtube could be considered at the time of laparoscopy to streamline patient care [46,48]. Furthermore, while not an immediate effect, chemotherapy and radiation have both been shown to improve
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malignant dysphagia by reducing tumor burden [14,21]. In the palliative setting, Hanna et al found time to improvement in dysphagia slower with RT as compared to stents (50% vs 85% at 2 weeks), but it was more durable (90% vs 80% at 10 weeks)[21]. Given these effective alternatives for nutritional support,
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and concerns about detrimental effect of stents, we do not recommend routine stent use in the curative
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setting outside of a clinical trial.
Conclusion: Esophageal stenting is associated with significantly increased grade ≥3 acute toxicities and worse OS in patients receiving CRT therapy with curative intent. For those unable to maintain adequate oral nutrition before starting CRT, rather than a stent we instead recommend J-tubes for potentially
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operable patients and PEG tubes for those not planning on surgery.
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This research did not receive any specific grant from funding agencies in the public, commercial, or not-
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for-profit sectors.
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[40]
: official journal of the International Society for Diseases of the Esophagus / I.S.D.E 2012;25:4853. Schiesser M, et al. The correlation of nutrition risk index, nutrition risk score, and bioimpedance analysis with postoperative complications in patients undergoing gastrointestinal surgery. Surgery 2009;145:519-526. Seres DS, Valcarcel M Guillaume A. Advantages of enteral nutrition over parenteral nutrition. Therapeutic advances in gastroenterology 2013;6:157-167. Siddiqui AA, et al. Self-expanding plastic esophageal stents versus jejunostomy tubes for the maintenance of nutrition during neoadjuvant chemoradiation therapy in patients with esophageal cancer: A retrospective study. Diseases of the esophagus : official journal of the International Society for Diseases of the Esophagus / I.S.D.E 2009;22:216-222. Siddiqui AA, et al. Expandable polyester silicon-covered stent for malignant esophageal strictures before neoadjuvant chemoradiation: A pilot study. Dig Dis Sci 2007;52:823-829. Siddiqui AA, et al. Placement of fully covered self-expandable metal stents in patients with locally advanced esophageal cancer before neoadjuvant therapy. Gastrointest Endosc 2012;76:44-51. Singh A Gelrud A. Adverse events associated with percutaneous enteral access. Gastrointest Endosc Clin N Am 2015;25:71-82. Siow SL, et al. Laparoscopic t-tube feeding jejunostomy as an adjunct to staging laparoscopy for upper gastrointestinal malignancies: The technique and review of outcomes. BMC Surg 2017;17:25. Stockeld D, et al. Percutaneous endoscopic gastrostomy for nutrition in patients with oesophageal cancer. Eur J Surg 2001;167:839-844. Wright GP, Foster SM Chung MH. Esophagectomy in patients with prior percutaneous endoscopic gastrostomy tube placement. American journal of surgery 2014;207:361-365; discussion 364-365.
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Figure Legends
AC C
EP
TE D
M AN U
SC
RI PT
Figure 1. Kaplan-Meier curves showing overall survival (OS) based on stent placement. A: Shows OS for the pre-propensity score match cohort. B: Shows OS for the post-propensity score match cohort.
19
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Table 1. Patient Demographics and Clinical Characteristics Stent During RT N %
Total N %
Age [years]
0.77†
63.2 58.0-70.7
2 (3) (27) (40) (20) (11) (100)
AC C
2 20 30 15 8 75
18 8 26
(77) (23) (100)
5 7 62 1 75
0 1 13 13 1 28
(7) (9) (83) (1) (100)
SC
56 17 73 2
(4) (96) (100)
(7) (93) (100)
5 98 103
(5) (95) (100)
M AN U
No Yes Total Unknown Stage
2 26 28
(69) (31) (100)
74 25 99
0.44‡
(75) (25) (100)
4
TE D
3 72 75
T1 T2 T3 T4 Total
63.3 57.0-70.7
0.61‡
Female Male Total Current Tobacco Use
IIA IIB IIIA IIIB IIIC Total T Stage
63.8 55.3-70.1
EP
Median IQR Gender
P-value
RI PT
No Stent N %
(0) (4) (46) (46) (4) (100)
0.02¥ 2 21 43 28 9 103
(2) (20) (42) (27) (9) (100) 0.05¥
0 0 28 0 28
(0) (0) (100) (0) (100)
5 7 90 1 103
(5) (7) (87) (1) (100)
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N Stage (17) (39) (36) (8) (100)
RI PT
18 40 37 8 103
80 70-90
Grade 1 Grade 2 Grade 3 Total Unknown Tumor Volume [cm3]
2 32 33 67 8
Median IQR Tumor Length [cm]
55.6 34.6-93.5
27 1 28
(89) (11) (100) (3) (48) (49) (100)
(96) (4) (100)
0 12 13 25
(0) (43) (46) (100)
AC C
EP
3
6.5 5.5-8.0
18.7 15.5-21.5
80 70-100
SC
80 70-100 67 8 75
Median IQR Tumor Position
(4) (46) (46) (4) (100)
0.03†
Adenocarcinoma Squamous Cell Carcinoma Total Tumor Grade
Median IQR PTV Length [cm]
1 13 13 1 28
(23) (36) (32) (9) (100)
M AN U
Median Range Tumor Histology
17 27 24 7 75
TE D
N0 N1 N2 N3 Total KPS Pre-treatment
0.22¥
96.0 60.3-136.8
94 9 103 2 44 46 92
0.26•
(91) (9) (100) 0.73¥
(2) (43) (45) (100)
11 <0.01† 67.2 40.8 – 110.9 0.20†
7.8 6.0-9.0
7.0 5.5-8.5 0.13†
19.8 17.4 -21.6
19.3 16.8-21.5 0.62¥
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(2) (8) (90) (100)
RI PT
2 8 93 103
NA
(5.4) (0 – 11.2)
Low (<3.4 g/dL) Normal Total Unknown Hospitalization ≤30 Days before RT
2 25 27 48
(25) (61) (7) (7) (0) (100)
(12.2) (7.2-18.7)
(7) (93) (100)
AC C
18 44 5 5 0 72 3
66 9 75
(39) (7) (54) (100)
5 14 7 1 1 28 0
(88) (12) (100)
1 15 16 12
11 2 15 28
(39) (7) (54) (100)
SC
11 2 15 28
NA NA NA NA
0 1 2 3 4 Total Unknown Albumin Level Pre-RT
No Yes Total
(4) (4) (93) (100)
M AN U
Pre-RT Weight Loss [%] Median IQR Pre-RT Dysphagia Score*
1 1 26 28
(1) (9) (89) (100)
(18) (50) (25) (4) (4) (100)
TE D
Plastic Stent Partially Covered Metal Stent Fully Covered Metal Stent Total
1 7 67 75
EP
Upper Third Mid Third Lower Third Total Stent Type
<0.01†
8.3 (1.1-15.6)
23 58 12 6 1 100 3
0.10¥
(23) (58) (12) (6) (1) (100) 1.00‡
(6) (94) (100)
3 40 43 60
(7) (93) (100)
0.23• 22 6 28
(79) (21) (100)
88 15 103
(85) (15) (100)
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RI PT
Abbreviations: N= number; RT=radiotherapy; cm=centimeter; IQR=interquartile range; KPS = Karnofsky performance scale; GTV=gross tumor volume, PTV=planning target volume; NA= not applicable; GEJ=gastroesophageal junction.
AC C
EP
TE D
M AN U
SC
Footnotes: *0=no dysphagia, 1=dysphagia to normal solids, 2=dysphagia to soft solids, 3=dysphagia to liquids, and 4=aphagia; Analysis method: †t-test, ‡Fisher’s exact test or Fisher-Freeman-Halton test, ¥Wilcoxon-Mann-Whitney, • Chi-squared.
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Table 2. Treatment Characteristics
Intent of RT
Median Range Concurrent Chemotherapy
50.4 32.4-50.4 39 15 7 7 7 75
(52) (20) (9) (9) (9) (100)
AC C
Cisplatin/5FU Cisplatin/Paclitaxel Carboplatin/Paclitaxel Cisplatin/Paclitaxel/Cetuximab Other Total Surgery
8
(29)
7 1 8 18
(88) (13) (100) (64)
11 7 18
(61) (39) (100)
2 2 0 2 28
M AN U
(32) (79) (21) (100) (67) (34) (66) (100) (1) (100) (0) (100) (100)
TE D
Salvage Surgery No Yes Total Neoadjuvant Planned Surgery No Yes Total Unknown Surgery No Yes Total Total RT Dose [Gy]
24 19 5 24 50 17 33 50 1 1 0 1 75
EP
Definitive
18 4 3 3 0 28
Total
(7) (100) (0) (100) (100)
P-value
N
%
RI PT
Stented During RT N %
0.33‡
32
(31)
26 6 32 68
(81) (19) (100) (66)
1.00‡
28 40 68
(41) (59) (100)
0.05•
3 3 0 3 103
(3) (100) (0) (100) (100)
SC
No Stent N %
NA
0.03†
50.4 32.4-50.4
50.4 32.4-50.4 0.48‡
(64) (14) (11) (11) (0) (100)
57 19 10 10 7 103
(55) (18) (10) (10) (7) (100) 0.05•
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13 24 1 38
3DRT IMRT Total
73 2 75
20 8 28
(34) (63) (3) (100)
1 7 0 8
(97) (3) (100)
26 2 28
(71) (29) (100) (13) (88) (0) (100) (93) (7) (100)
55 46 103
(55) (45) (100)
RI PT
Ivor-Lewis Transhiatal Other Total Type of RT
(49) (51) (100)
14 31 1 46
SC
37 38 75
M AN U
No Yes Total Type of Surgery
99 4 103
0.51‡
(30) (67) (2) (100)
0.30‡ (96) (4) (100)
TE D
Abbreviations: N=number; RT=radiotherapy; Gy=Gray; RT=radiotherapy; 5FU= fluorouracil; IQR=interquartile range; 3DRT=3D conformal radiotherapy; IMRT=intensity modulated radiotherapy.
AC C
EP
Footnotes: †t-test, ‡ Fisher’s exact test or Fisher-Freeman-Halton, ¥ Wilcoxon-Mann-Whitney, • Chi-squared.
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Table 3. Acute Toxicities (≤90 Days after RT Treatment)
KPS Change Post-RT
No Yes Total ≥ Grade 3 Dehydration
60 15 75
No Yes Total ≥ Grade 3 Anorexia
65 10 75
No Yes Total Weight Loss by End of RT [%] Median IQR
8 20 28
(73) (27) (100) (80) (20) (100) (87) (13) (100)
71 4 75
17 11 28
(95) (5) (100)
(7.6) (5.2 – 10.4)
(4) (21) (61) (14) (100)
N
11 29 56 7 103
M AN U
55 20 75
1 6 17 4 28
(29) (71) (100)
TE D
No Yes Total ≥ Grade 3 Esophageal Toxicity*
(13) (31) (52) (4) (100)
(61) (39) (100)
P-value %
63 40 103
0.03¥
(11) (28) (54) (7) (100)
<0.01• (61) (39) (100) 0.05•
77 26 103
(75) (25) (100) 0.07•
20 8 28
(71) (29) (100)
85 18 103
(83) (17) (100)
24 4 28
(86) (14) (100)
95 8 103
(92) (8) (100)
EP
10 23 39 3 75
AC C
Improvement No Change Decreased ≤ 20 Decreased > 20 Total Any ≥ Grade 3
Total
RI PT
Stent During RT N %
SC
No Stent N %
0.13‡
0.45† (9.3) (3.8 – 15.1)
(8.3) (5.1 – 10.9)
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≥ Grade 2 Thromboembolic Event 53 22 75
21 7 28
(71) (29) (100)
(75) (25) (100)
74 29 103
(72) (28) (100)
RI PT
No Yes Total
0.66•
AC C
EP
TE D
M AN U
SC
Abbreviations: N=number; RT=radiotherapy; KPS = Karnofsky performance scale; *Esophageal Toxicity includes esophagitis, dysphagia, or hemorrhage. Footnotes: † T-test, ‡ Fisher’s exact test or Fisher-Freeman-Halton test, ¥Wilcoxon-Mann-Whitney , • Chi-squared.
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Table 4. Predictors of ≥ Grade 3 Acute Toxicities
OR
Univariate Logistic Analysis 95% CI P-value
Stent During RT 1.0 6.9
Reference 2.6
18.1
<0.01
Female Male Smoking
1.0 0.4
Reference 0.1
2.5
0.33
No Yes T-Stage
1.0 1.2
Reference 0.5
T1-T2 T3-T4 N-Stage
1.0 2.1
Reference 0.5
N0 N1 N2-N3 Pre-RT KPS, per 10 points decrease (equal to one category on KPS scale)
1.0 2.3 2.8
Reference 0.7 0.8
Adenocarcinoma Squamous Cell Carcinoma Tumor Position Upper Third Middle Third
28.3
<0.01
0.75
1.0 0.8
Reference 0.3
2.7
0.77
0.30
1.0 1.7
Reference 0.3
9.3
0.55
8.4 9.8
0.19 0.11
1.0 1.3 2.0
Reference 0.3 0.4
7.0 10.9
0.74 0.40
3.7
0.02
1.7
0.8
3.4
0.15
5.1
0.72 1.0 1.6
Reference 0.0
57.2
0.81
M AN U 8.1
TE D
EP 1.1
AC C
Histology
2.1
Reference 2.3
2.9
1.0 1.3
Reference 0.3
1.0 0.3
Reference 0.0
8.2
1.0 8.1
SC
No Stent Stent During RT Gender
OR
Multivariate Logistic Analysis 95% CI P-value
RI PT
Factor
0.50
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0.0
No Yes Age, per 1 year increase
1.0 2.8 1.0
Reference 0.9 1.0
8.5 1.1
0.08 0.51
GTV Length
1.1
0.9
1.2
0.40
GTV Volume
1.0
1.0
1.0
0.66
RT Dose
1.0
1.0
1.0
0.21
Mean Lung Dose
1.0
1.0
1.0
0.80
Lung V10
1.0
1.0
Lung V5
1.0
1.0
Heart V40
1.0
1.0
Plastic Stent Metal Stent Chemotherapy Type
1.0 1.9
Reference 0.4
Cisplatin/5FU Cisplatin/Paclitaxel Carboplatin/Paclitaxel Cisplatin/Paclitaxel/Cetuximab Other
1.0 0.5 0.3 2.1 1.0
Reference 0.2 0.1 0.5 0.2
EP
AC C
0.77
1.7
0.1
39.4
0.75
1.0 2.7
Reference 0.7
9.6
0.14
1.0
1.0
1.0
0.09
Reference 0.1 0.0 0.5 0.2
1.8 1.6 14.3 8.5
0.25 0.14 0.26 0.88
M AN U 1.0
0.74
1.0
0.78
1.0
0.83
9.8
0.47
TE D
Stent Type*
10.9
RI PT
0.7
SC
Lower Third Hospitalization ≤30 Days before RT
1.6 1.8 8.1 5.0
0.23 0.20 0.30 0.97
1.0 0.4 0.2 2.6 1.2
Abbreviations: OR=odds ratio; CI=confidence interval; RT=radiotherapy; KPS = Karnofsky performance scale; GTV=gross tumor volume; PTV=planning target volume; GEJ=gastroesophageal junction; cm=centimeter; 5FU=5-florouracil; V10=volume receiving 10 Gray (Gy); V5=volume receiving 5 Gy; V40=volume receiving 40 Gy. Footnotes: *Not included in MVA modeling because of multicollinearity with esophageal stent placement.
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Table 5. Summary of Neoadjuvant Stent Studies
% Success
% requirin g dilation s
Christie A; 2001[14]
16
CT/CRT
NR
SEMS
NR
NR
Siddiqui A; 2007[26]
6
CRT
NR
SEPS
83
NR
Bower M; 2009[9]
25
CRT
Target 50.4
SEPS
100
56
Adler D; 2009[22]
13
CRT
NR
SEPS
85
54
Martin R; 2009[25]
5
CRT
NR
SEPS
100
Siddiqui A; 2009[13]
12
CRT
NR
SEPS
Lopes T; 2010[15]
11
CRT
NR
Langer F; 2010[11]
38
CT/CRT
Brown R; 2011[12]
32
CT/CRT
Cha nge in weig ht
RI PT
Insertion
Change in mean serum albumi n
Complications (%)
Ches t disc omf ort
Ste nt mig rati on
Eros ion or fistu la
SC
RT Dose [Gy]
Stent Type Studie d
EP
% Requiring suppleme ntary tube feeding
% Requiring unplanne d stent revision
% Progressing to surgery
Y
NR
NR
0
0
12
12
12
NR
Y
↑
↑
0
60
0
0
0
100
Y
↑
↔
0
24
0
8
20
56
Y
NR
NR
93
46
0
15
15
23
NR
Y
↔
NR
0
20
0
20
0
NR
92
17
Y
↑
↑
67
36
0
0
0
NR
SEMS
91
82
Y
NR
NR
30
20
10
0
30
20
NR
SEP/M S
97
32
Y
↓
NR
NR
32
16
3
29
53
NR
SEPS
100
88
Y
↓
↓
3
25
0
3
0
63
AC C
TE D
M AN U
Study
N of patient s
Neoadj therap y
Signific ant improv ement in dyspha gia
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16
CT
NR
SEMS
100
NR
Y
↔
↔
0
44
0
0
0
63
Griffiths E; 2012[23]
9
CT
NR
SEBS
96
NR
Y
NR
NR
0
NR
NR
22
66
0
Krokidis M; 2013[24]
11
CT/CRT
NR
SEBS
100
45
Y
NR
NR
0
18
18
9
27
NR
Martin R; 2014[18]
52
CT/CRT
Media n 48.6
SEPS
NR
NR
Y
↔
NR
6
0
2
6
NR
Siddiqui A; 2012[20]
55
CRT
NR
SEMS
100
0
Current Study
18
CRT
Media n 50.4
SEP/M S
100
NR
SC
RI PT
Pellen M; 2012[19]
M AN U
↔
Y
NR
↔
15
31
2
0
4
15
Y
↓
↔
39
39
17
50
56
39
TE D
Abbreviations: Gy=Gray; CT=chemotherapy; CRT=chemoradiotherapy; NR=not reported; SEMS=self-expanding metal stent; SEPS=self-expanding
AC C
EP
plastic stent; SEBS=self-expanding biodegradable stents
A
1.00
Overall Survival
0.80
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0.60 0.40
p=0.026
Number at risk No Stent: 75 Stent: 28
6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96
SC
0
Months Post Diagnosis 46 12
25 5
20 3
15 2
13 2
M AN U
0.00
RI PT
0.20
No Stent
B
2 0
Stent
EP
0.80 0.60
AC C
Overall Survival
6 1
TE D
1.00
7 1
0.40 0.20 0.00
p=0.016 0
Number at risk No Stent: 25 Stent: 25
6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 Months Post Diagnosis 18 12
10 5
10 3
9 2
No Stent
8 2
5 1 Stent
4 1
1 0
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AC C
EP
TE D
M AN U
SC
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Utilization of esophageal stents to relieve dysphagia is increasing in patients with locally advanced esophagus cancer while impacts on toxicity and outcomes are unclear. We retrospectively analyzed our cohort of curatively treated esophageal cancer patients and analyzed toxicities and outcomes comparing stent vs. no-stent patients. We found that patients who received stents had more acute esophageal toxicity, were less likely to undergo esophagectomy, and had worse overall survival than no-stent patients.