- Email: [email protected]
Low-Dose Versus High-Dose Radiation Therapy for the Palliation of Dysphagia From Esophageal Cancer: A Multicenter Retrospective Cohort Study
Journal Pre-proof Low dose versus high dose radiotherapy for the palliation of dysphagia from esophageal cancer: a multicenter retrospective cohort study Bram D. Vermeulen, MD, Paul M. Jeene, MD, Jasmijn Sijben, Robin Krol, MD, PhD, Heidi Rütten, MD, Johannes A. Bogers, MD, Pètra M. Braam, MD, PhD, Peter D. Siersema, MD, PhD PII:
S1879-8500(19)30316-9
DOI:
https://doi.org/10.1016/j.prro.2019.10.010
Reference:
PRRO 1145
To appear in:
Practical Radiation Oncology
Received Date: 22 July 2019 Revised Date:
18 September 2019
Accepted Date: 16 October 2019
Please cite this article as: Vermeulen BD, Jeene PM, Sijben J, Krol R, Rütten H, Bogers JA, Braam PM, Siersema PD, Low dose versus high dose radiotherapy for the palliation of dysphagia from esophageal cancer: a multicenter retrospective cohort study, Practical Radiation Oncology (2019), doi: https:// doi.org/10.1016/j.prro.2019.10.010. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. 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. © 2019 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.
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Low dose versus high dose radiotherapy for the palliation of
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dysphagia from esophageal cancer: a multicenter retrospective
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cohort study
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Running title: Low vs High Dose RT in Palliation of Dysphagia
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Bram D. Vermeulen1, MD; Paul M. Jeene2, MD; Jasmijn Sijben1; Robin Krol3, MD, PhD;
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Heidi Rütten4, MD; Johannes A. Bogers5, MD; Pètra M. Braam4, MD, PhD; Peter D.
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Siersema1, MD, PhD
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Corresponding author
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Bram D. Vermeulen, Department of Gastroenterology and Hepatology (route 455), Radboud
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university medical center, Geert Grooteplein-Zuid 8, 6500 HB, Nijmegen, the Netherlands
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Phone: +31611079557. Email: [email protected]
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Institutions:
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1. Department of Gastroenterology and Hepatology, Radboud university medical center, Nijmegen, the Netherlands
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2. Radiotherapy Group, Deventer, the Netherlands
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3. Department of Gastroenterology and Hepatology, Rijnstate Ziekenhuis, Arnhem, the
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Netherlands 4. Department of Radiotherapy, Radboud university medical center, Nijmegen, the Netherlands 5. Radiotherapy Group, Arnhem, the Netherlands
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Conflict of interest statement
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Bram D. Vermeulen declares that he has no conflict of interest
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Paul M. Jeene declares that he has no conflict of interest
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Jasmijn Sijben declares that she has no conflict of interest
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Robin Krol declares that he has no conflict of interest
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Heidi Rütten declares that she has no conflict of interest
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Johannes A. Bogers declares that he has no conflict of interest
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Pètra M. Braam declares that he has no conflict of interest
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Peter D. Siersema received research grants from Boston Scientific, Cook Medical and MI-
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Tech for some of the studies referenced in this review, and is on the advisory board of Ella-
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CS.
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Funding statement
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No funding was acquired for this research and publication
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Acknowledgments
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We acknowledge Margo C. Noordhoek who has contributed in the management of data
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needed for this study
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Author responsible for statistical analyses
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Bram D. Vermeulen
Keywords: esophageal cancer; palliation of dysphagia; external beam radiotherapy; intraluminal brachytherapy.
Abstract Background and purpose: Clinical evidence regarding optimal radiation dose for palliation of dysphagia from esophageal cancer is generally lacking. In an effort to investigate optimal radiation dose, we assessed two different radiation schedules for palliation of dysphagia. Materials and methods: We performed a multicenter, retrospective study comparing low dose radiotherapy (LR: 5x4Gy external beam radiotherapy [EBRT]) with high dose radiotherapy (HR: 10x3Gy EBRT and 12Gy single-dose intra-luminal brachytherapy) for palliation of dysphagia in patients with inoperable or metastasized esophageal cancer. Primary outcome was improvement of dysphagia at 6 weeks after start of radiotherapy. Additional outcomes were persistent/recurrent dysphagia during patients’ remaining life, severe adverse events (SAE) and survival. Results: In total, 292 patients (LR, n=117; HR, n=175) were included in this study. After matching, 144 patients (72 in each group) were compared. Improvement of dysphagia at 6 weeks was achieved in 50% of patients after LR and in 66% after HR (p=0.071). Persistent/recurrent dysphagia occurred in 64% of patients after LR and in 42% after HR (p=0.012). No difference in SAE rate was found (p=0.889). Median survival was 88 days (95%CI 64–112) after LR and 177 days (95%CI 131–223) after HR (p<0.001). Conclusion: This study shows that both LR and HR were well tolerated and effective in short-term relief of dysphagia in patients with inoperable or metastasized esophageal cancer. HR was associated with better long-term relief of dysphagia when compared with LR. Our findings suggest that HR could be considered for patients with a longer life-expectancy but prospective studies are required.
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Introduction Esophageal cancer is the sixth most common cancer leading to death worldwide, with an estimated 572,000 new cases and 508,600 deaths in 2018.1 At the time of diagnosis of esophageal cancer, more than 50% of patients have either inoperable tumors or radiographically visible metastases.2 Dysphagia is the most common symptom of incurable obstructive esophageal cancer and can be managed with several palliative treatment options.3 The European Society of Gastrointestinal Endoscopy (ESGE) guidelines recommend esophageal stent placement or intra-luminal brachytherapy (ILBT) for palliation of dysphagia from advanced esophageal cancer.4 Selection of a palliative option is mainly determined by the patients’ life-expectancy. Patients with a longer life-expectancy are best treated with ILBT because of the increased dysphagia-free survival when compared with stent placement.5 Despite these strong recommendations, ILBT is not frequently considered as treatment option.6, 7 As an alternative to ILBT, external beam radiotherapy (EBRT) has emerged in clinical practice.8, 9 Nonetheless, as comparative clinical studies are lacking, the optimal radiation dose has yet to be determined for palliation of dysphagia from inoperable or metastasized esophageal cancer. Accordingly, a recent study in the Netherlands showed that initial palliative radiotherapy varies widely in clinical daily practice.10 The authors suggested that the absence of therapeutic guidance may explain this finding. Therefore, in an effort to investigate optimal radiation dose, we assessed two different radiation schedules for palliation of dysphagia. In this multicenter, retrospective study, we compared low dose radiotherapy (LR) with high dose radiotherapy (HR) in patients with inoperable or metastasized esophageal cancer and dysphagia.
Materials and Methods 2
Between March 2003 and October 2018, consecutive patients treated with palliative radiotherapy for dysphagia from esophageal cancer were registered in a prospectively maintained database, including 3 radiotherapy centers in the Netherlands. Patients were included in the retrospective analysis when they had a first episode of dysphagia (grade ≥1 according to Ogilvie11) caused by inoperable or metastasized carcinoma of the esophagus or esophagogastric junction (EGJ) and were treated with first-line LR or HR palliative radiotherapy at the discretion of the radiation oncologist. Exclusion criteria were: (1) previous treatment of esophageal carcinoma with curative intent; (2) previous palliative treatment of dysphagia with radiotherapy or stent placement; (3) no completion of allocated radiation dosage; and (4) no electronic medical patient records. Extracted data from the electronic medical record included patient and tumor characteristics, severity of dysphagia, treatment characteristics and outcome during follow-up until death. Follow-up of patients consisted of a scheduled outpatient visit or telephone call at 6 weeks after start of radiotherapy and thereafter at the discretion of the treating physician (e.g., in case of recurrent dysphagia). Follow-up was identical for patients in both treatment groups. Persistent and recurrent dysphagia were assessed and documented at and after 6 weeks of follow-up, respectively. Additional palliation of dysphagia was also documented and registered. Dysphagia was scored according to Ogilvie11 (Table 1) or, when necessary, inferred from the physician’s documentation. American Joint Committee on Cancer (AJCC) stage was calculated using criteria from the seventh edition of the AJCC Cancer Staging Manual.12 The study protocol was approved by the Medical Ethics Committee and Institutional Review Board (IRB) of all participating centers. The study protocol was designed after enrolling patients in the prospective database.
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External beam radiotherapy and planning All patients were treated with three-dimensional conformal radiotherapy or intensity modulated radiotherapy (IMRT) and underwent a planning computed tomography (CT) with or without oral contrast prior to EBRT. Intravenous contrast enhancement and fourdimensional CT were applied when appropriate. Cone beam CT or an electronic portal imaging device was used for treatment position verification. The gross tumor volume (GTV) was planned to include the primary tumor and the esophageal circumference at tumor level. In most cases, the clinical target volume consisted of the GTV plus a 1 cm margin, adapted to anatomical borders. Planning target volume margins were defined as per institutional protocols. Dose to target volume was prescribed as per International Commission on Radiation Units and Measurements (ICRU) 62 recommendations (95-107 isodose coverage) and organ at risk (lung, spinal cord and heart) constraints defined as per institutional protocols.13
Intraluminal brachytherapy Prior to ILBT, endoscopy was performed. Dilation was performed as per indication to a maximum of 11 mm. A guidewire was inserted over which a flexible applicator (BonvoisinGérard esophageal applicator, Nucletron B.V., Veenendaal, the Netherlands) with a diameter of 8-11 mm was placed through the tumor. A 12Gy single-dose was administered with the radioactive source 192Ir. The 100% isodose was defined at 1 cm from the source axis of the applicator. The PLATO (Plato software, Nucletron B.V., Veenendaal, the Netherlands) or Ocentra Brachy (Elekta AB, Stockholm, Sweden) planning systems were used to plan dose administration for each standard active length. All patients were consciously sedated using midazolam during the procedure. Sucralfate was prescribed for a period of up to 4 weeks after ILBT as a prophylactic measure for odynophagia.
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Radiation dose schedules In the LR group, patients were treated with EBRT in 5 fractions of 4Gy. This corresponds with an EQD2 of 23Gy for tumor and acute toxicity (α/β=10) and an EQD2 of 28Gy for late toxicity (α/β=3). In the HR group, patients were treated with EBRT in 10 fractions of 3Gy and ILBT in 1 fraction of 12Gy. For comparison, we assumed a homogeneous single-dose ILBT of 12Gy. Together, this corresponds with a cumulative EQD2 of 55Gy for tumor and acute toxicity (α/β=10) and an EQD2 of 72Gy for late toxicity (α/β=3).
Outcome measures and definitions The primary outcome measure was improvement of dysphagia by at least one grade at 6 weeks after start of radiotherapy. The secondary outcome measure was persistent or recurrent dysphagia during followup after radiotherapy, which represented failure of dysphagia palliation during patients’ remaining life after low dose or high dose radiotherapy. Persistent dysphagia was defined as no improvement of dysphagia score ≥6 weeks after start of radiotherapy. Recurrent dysphagia was defined as the recurrence of dysphagia (grade ≥2) during follow-up of patients with improvement of dysphagia. Other outcome measures included: (1) overall survival after start of radiotherapy; (2) dysphagia-adjusted survival of patients with improved dysphagia, which represented the number of days alive without (grade 0) or with mild (grade 1) dysphagia (Table 1); (3) severe adverse events (SAE); and (4) treatment for persistent or recurrent dysphagia. SAE was defined as an event related to radiotherapy that required endoscopy, hospitalization or prescription of opiates.
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Statistical analysis Improvement of dysphagia rate at 6 weeks after radiotherapy and persistent/recurrent dysphagia was compared between groups with a X2-test. Kaplan-Meier and log-rank tests were used to compare persistent/recurrent dysphagia, treatment for persistent/recurrent dysphagia, SAEs and overall survival between groups, while adjusting for time to occurrence (patients were censored at death or end of follow-up). To estimate the effect of HR on persistent/recurrent dysphagia when compared with LR, univariate Cox regression analysis was performed and expressed as hazard ratio, 95% confidence interval (CI) and significance level. In order to study comparable groups and to minimize the risk of bias, propensity score matching was used to balance baseline patient characteristics between the treatment groups. A propensity score was generated using logistic regression, based on the covariates age, gender, Karnofsky performance score, previous chemotherapy, tumor characteristics (histology, esophageal location and length), cancer stage and metastases (location and number of sites). Subsequently, matching without replacement (1:1) was performed to generate matched pairs of cases in which the within-pair difference was minimized by setting a caliper of 0.1 of the SD of the logit of the propensity score. We compared parametric and non-parametric continuous data with a t-test and MannWhitney U tests, respectively, and categorical data with a X2-test. Results were expressed as frequencies and percentages, means (± standard deviation [SD]) and medians (95%CI), when appropriate. Before and after matching, analysis of study outcome measures was performed with SPSS version 25.0 (SPSS Inc., Chicago, Illinois). Propensity score matching was performed with the FUZZY extension bundle of the SPSS statistical package (v1.4.7; SPSS Inc.,
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Chicago, Illinois) with Python plug-in. We regarded a p-value of <0.05 as statistically significant.
Results Patient characteristics From the prospective registry, we identified 361 consecutive patients who underwent palliative low dose or high dose radiotherapy for inoperable or metastasized esophageal cancer. A total of 69 patients were excluded because no electronic medical patient records were available (n=57), no completion of allocated radiation dosage (n=9) or previous treatment for esophageal cancer with curative intent (n=3). The remaining 292 patients were included in the study, of which 117 were treated with LR and 175 with HR. Figure 1 shows the study flow diagram of patient selection, treatment and outcome before and after matching. Before matching, significant differences at baseline between patients undergoing LR and HR were found for tumor stage and location, Karnofsky performance score, previous chemotherapy and location of metastasis. After matching, 144 patients (72 in each group) without significant differences in baseline characteristics remained to be analyzed. Baseline patient characteristics and differences between groups before and after matching are shown in Table 2.
Primary and secondary outcome measures Results of the unmatched and matched outcome measures are shown in Table 3. For 29 (10%) patients, 6-week dysphagia scores were missing or not well documented. Improvement of dysphagia was achieved in 58 (55%) patients after LR and in 104 (66%) patients after HR (p=0.066). After matching, improvement of dysphagia was achieved in 31 (50%) patients 7
after LR and in 44 (66%) patients after HR (p=0.071). Furthermore, persistent/recurrent dysphagia occurred in 63 (61%) patients after LR and in 70 (45%) patients after HR (p=0.015). Cox regression analysis showed that HR was associated with a 16% decrease in persistent/recurrent dysphagia when compared with LR (hazard ratio=0.6, 95%CI: 0.4–0.9, p=0.010). After matching, persistent/recurrent dysphagia occurred in 39 (64%) patients after LR and in 27 (42%) patients after HR (p=0.012). When compared with the Kaplan-Meier and log-rank tests that corrected for time to occurrence and survival differences, the significant differences between groups were still present (p=0.012).
Other outcome measures Median survival in all patients was 157 days (95%CI 139–175). Median survival was 90 days (95%CI 63–117) after LR and 177 days (95%CI 150–204) after HR (p<0.001; Figure 2). After matching, the difference in survival between treatment groups persisted. Median survival was 88 days (95%CI 64–112) after LR and 177 days (95%CI 131–223) after HR (p<0.001). This observed difference in survival was not significantly different between participating centers (p=0.20). Median dysphagia-adjusted survival of all patients with improved dysphagia (n=162) was 126 days (95%CI 109–143). Median dysphagia-adjusted survival was 73 days (95%CI 19-127) after LR and 133 days (95%CI 95–171) after HR (p=0.001). In these patients, recurrent dysphagia occurred in 16 patients (33%) after LR and in 16 patients (21%) after HR (p=0.002). Table 3 shows SAEs in all patients and for each treatment group. A total of 47 SAEs occurred in 44 (15%) patients. SAEs included severe retrosternal pain (n=25), esophageal hemorrhage (n=13), (aspiration) pneumonia (n=5), esophago-respiratory fistula (n=3) and esophageal perforation (n=1). The number of patients with SAE was not significantly
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different between treatment groups (p=0.750). In total, 16 SAEs occurred in 15 (13%) patients after LR and 31 SAEs in 29 (17%) patients after HR (p=0.750). After matching, no significant difference in number of patients with SAE was found after LR or HR (9 patients [13%] vs. 12 patients [17%], p=0.889). Treatment for persistent or recurrent dysphagia was indicated in 27 (23%) patients after LR and in 30 (17%) patients after HR (p<0.001; Figure 3). In these patients (n=57), repeat endoscopy showed that recurrent dysphagia was caused by tumor recurrence in 37 (65%) patients, benign radiation stricture in 5 (9%) patients and tumor ulceration in 2 (4%) patients. In the other 12 (21%) patients, the cause of recurrent dysphagia remained unknown. Recurrent dysphagia was treated with stent placement in 16 (28%) patients, repeat EBRT in 15 (26%) patients, nasogastric tube feeding in 6 (11%) patients, ILBT in 3 (5%) patients, percutaneous endoscopic gastrostomy in 2 (4%) patients and endoscopic bougie dilation in 1 (2%) patient (Table 4). The other 12 patients (21%) did not undergo further treatment for recurrent dysphagia after repeat endoscopy.
Discussion Our multicenter cohort study compared low dose radiotherapy with high dose radiotherapy for palliation of dysphagia in patients with inoperable or metastasized esophageal cancer. We found no difference in short-term relief of dysphagia between both treatment groups. However, HR showed better relief of dysphagia during patients’ remaining life and was not associated with a higher SAE rate when compared with LR. The observed effect of HR is in line with several other studies investigating palliative HR in patients with inoperable or metastasized esophageal cancer.14-17 In particular, one randomized study demonstrated the additional effect of a stent loaded with high dose 9
irradiation seeds when compared with conventional stent placement.18 Nonetheless, these studies did not compare HR with LR. In contrast, one randomized controlled trial compared LR (i.e., ILBT: 2x8Gy) with HR (i.e., ILBT: 2x8Gy; and EBRT: 10x3Gy) in patients palliated for inoperable esophageal cancer. It was found that HR improved relief of dysphagia when compared with LR. In addition, no difference in adverse events was observed between treatment groups.19 As opposed to our study, this trial included only inoperable esophageal squamous cell carcinoma patients without metastases. Therefore, the current study is the first to compare palliative LR versus HR in a population predominantly consisting of patients with metastasized esophageal adenocarcinoma. Findings from our study may have several implications for clinical practice. First, HR showed sustained relief of dysphagia during patients’ remaining life with an acceptable SAE rate. Therefore, we suggest that clinicians could consider HR for patients with an expected longer life-expectancy. On the other hand, for patients with an expected short life-expectancy, LR should be regarded as first-line palliative treatment as no difference in short-term relief of dysphagia was found when compared with HR. Moreover, patients with a short lifeexpectancy may benefit more from the short 5-day course of LR as opposed to HR which is performed over an extended period of 2-3 weeks. The important question remains how clinicians can predict patients’ survival. Despite the fact that prediction of survival is challenging in patients with advanced stage cancer20, 21, this study shows that accurate prediction of survival in patients with advanced esophageal carcinoma was achieved in the majority of patients. Factors used by clinicians to estimate survival included Karnofsky performance score, previous chemotherapy, cancer stage, location and number of metastases. Accordingly, all of these patient characteristics differed significantly between both treatment groups at baseline. However, after matching patients for these factors, the survival difference persisted (Table 3). Lack of matching on additional
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predictive factors used by clinicians may explain this finding. For example, due to missing data, we could not match on weight loss.22, 23 In support of this, a prediction model was recently developed that can accurately predict survival of patients with metastatic esophageal cancer. In addition to the above mentioned factors, this model also incorporated age, histology, tumor differentiation grade, weight loss and location of lymph node metastases.23 This study may provide another clinical implication for patients with advanced esophageal cancer in whom palliative HR is considered. That is, the high biological effective dose at the tumor site was achieved by adding single-dose ILBT (12Gy) to EBRT. In current daily practice however, despite recommendations of European guidelines4, 24, only very few centers routinely consider ILBT for palliation of dysphagia due to treatment complexity and lack of expertise.6, 7 Moreover, as opposed to the European guidelines, the United States guidelines currently recommend EBRT as first-line palliative modality.25 To anticipate on these findings, we suggest treating patients with an expected longer life-expectancy with an equivalent high dose of EBRT (i.e., EQD2 of 55Gy for tumor and acute toxicity (α/β=10)) without using ILBT, which may achieve improved palliation of dysphagia during patients’ remaining life.26 Accordingly, future studies should further explore optimal palliative radiotherapy dosages for patients with advanced esophageal cancer. One of the strengths of our multicenter study is that it is the first to compare palliative LR versus HR in patients with predominantly metastasized adenocarcinoma. The studied population reflects the Western population of patients with esophageal cancer.27 Furthermore, when compared with previous studies, we assessed a relatively large sample size of patients undergoing first-line palliative radiotherapy.8, 14-17, 28 Another strength of this study is the use of propensity score matching to compare patient groups. This high quality statistical method allows to adjust for established and potential confounders.29 Nonetheless, the retrospective nature and lack of randomization
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should be recognized in the interpretation of our findings. Despite reducing the risk of bias by comparing matched patients, limitations in our data set did not allow for matching on all known and potential confounders. Moreover, observational studies have the inherent risk of residual confounding that cannot be fully corrected for. Above all, the most appropriate study design comparing LR with HR is a randomized controlled trial. In conclusion, this multicenter retrospective study shows that both LR and HR were well tolerated and effective in short-term relief of dysphagia from inoperable or metastasized esophageal cancer. However, HR was associated with better relief of dysphagia during patients’ remaining life when compared with LR. Therefore, our findings suggest that HR could be considered for patients with a longer life-expectancy. Further, well designed studies should focus on optimizing palliative radiotherapy dosages for patients with advanced esophageal cancer.
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Figure legends
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Figure 1. Study flow diagram of patient selection, treatment and outcome, before and after
84
propensity score matching. LR = low dose radiotherapy; HR = high dose radiotherapy; n =
85
number of patients; % = percentage.
86
Figure 2. Survival after palliative radiotherapy among patients with inoperable or
87
metastasized esophageal cancer. Kaplan-Meier plot shows differences in survival between
88
patients treated with LR or HR. LR = low dose radiotherapy; HR = high dose radiotherapy.
89
Figure 3. Freedom from treatment for persistent or recurrent dysphagia after palliation of
90
dysphagia with radiotherapy for inoperable or metastasized esophageal cancer. Kaplan-Meier
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analysis shows differences in treatment for persistent or recurrent dysphagia between patients
92
treated with LR or HR. LR = low dose radiotherapy; HR = high dose radiotherapy.
93
17
1
Table 1. Ogilvie dysphagia score used for outcome evaluation in patients treated with low dose or high dose radiotherapy for palliation of
2
esophageal carcinoma.
3 4 5 6 7 8
Grade
Description
0
Ability to eat a normal diet
1
Ability to eat some solids
2
Ability to swallow semisolids only
3
Ability to swallow liquids only
4
Complete dysphagia for liquids
9 10
Table 2. Comparison of baseline characteristics of 292 patients who underwent low dose or high dose radiotherapy for palliation of esophageal carcinoma, before and after propensity score matching Before matching
After matching
All patients
LR
HR
292
117
175
Age*, mean (±SD)
70 (11)
70 (10)
70 (12)
Gender* (male), n (%)
226 (77)
92 (79)
134 (77)
Histology*, n (%)
p-value
LR
HR
p-value
72
72
0.841
70 (10)
68 (11)
0.327
0.680
57 (79)
55 (76)
0.688 0.734
0.643
AC
193 (68)
77 (66)
116 (70)
..
48 (67)
51 (71)
..
SCC
67 (24)
31 (27)
36 (22)
..
19 (26)
18 (25)
..
Other
23 (8)
9 (8)
14 (8)
..
5 (7)
3 (4)
..
6.1 (3.0)
6.4 (3.5)
6.0 (2.6)
0.249
6.2 (3.6)
6.1 (2.7)
0.834
Tumor length*, cm, mean (±SD)
Location*, n (%)
0.755
<0.001
Esophagus
221 (76)
74 (63)
147 (84)
..
53 (74)
55 (77)
..
EGJ/Cardia
71 (24)
43 (37)
28 (16)
..
19 (26)
17 (23)
..
Indication for palliative therapy*, n (%)
0.538
0.035
Metastasis
218 (75)
92 (79)
126 (72)
..
60 (83)
60 (83)
..
Inoperable
75 (23)
26 (17)
49 (27)
..
12 (17)
12 (17)
..
Liver metastases*, n (%)
94 (34)
49 (47)
45 (26)
0.001
28 (39)
26 (36)
0.731
Peritoneal/bone/brain metastases*, n (%) 53 (19)
32 (29)
21 (12)
<0.001
15 (21)
15 (21)
1.000
Number of metastatic sites (≥2)*, n (%)
51 (49)
49 (29)
0.001
30 (42)
30 (42)
0.886
100 (36)
Cancer staging*, n (%) 1
0.385 9 (3)
3 (3)
6 (4)
..
0.945 2 (3)
2 (3)
..
2
19 (7)
3 (3)
16 (9)
..
3 (4)
4 (6)
..
3
33 (12)
11 (10)
22 (13)
..
7 (10)
8 (9)
..
4
218 (78)
92 (84)
126 (74)
..
60 (83)
60 (83)
..
Ogilvie score before treatment, n (%)
0.270
0.786
1
37 (13)
19 (16)
18 (10)
..
10 (14)
10 (14)
..
2
125 (43)
47 (40)
78 (45)
..
27 (38)
25 (35)
..
3
93 (32)
35 (30)
58 (33)
..
26 (36)
29 (40)
..
4
20 (7)
11 (9)
9 (5)
..
7 (10)
4 (6)
..
65 (24)
17 (16)
48 (29)
0.013
17 (24)
18 (25)
0.846
KPS [90-100], n (%) KPS*, n (%) 90-100
0.502
0.032 65 (24)
17 (16)
48 (29)
..
17 (24)
18 (25)
..
70-80
120 (44)
50 (47)
70 (42)
..
30 (42)
31 (43)
..
50-60
66 (24)
26 (24)
40 (24)
..
16 (22)
21 (29)
..
30-40
19 (7)
12 (11)
7 (4)
..
8 (11)
2 (3)
..
20
2 (1)
2 (2)
0
..
1 (1)
0 (0)
..
Palliative chemotherapy*, n (%)
94 (32)
55 (48)
39 (22)
<0.001
27 (38)
29 (40)
0.732
Treatment interval, days, median [IQR]
34 [25-44]
35 [26-45] 28 [22-42]
0.031
27 [21-39] 35 [26-42]
0.042
LR, low dose radiotherapy; HR, high dose radiotherapy; n, number of patients; , percentage; SD, standard deviation; AC, adenocarcinoma; SCC, squamous cell carcinoma; cm, centimeter; EGJ, esophagogastric junction; IQR, interquartile range; KPS, Karnofsky performance score. * Variables used for propensity score matching.
Table 3. Comparison of clinical outcome and serious adverse events in patients treated with low dose or high dose radiotherapy for palliation of esophageal carcinoma, before and after propensity score matching Before matching
Survival, days (median [95%CI])
After matching
All patients
LR
HR
n = 292
n = 117
n = 175
157 [139-175]
p-value
90 [63-117] 177 [150-204] <0.001
LR
HR
n = 72
n = 72
p-value
74 [47-101] 176 [135-217] <0.001
Improvement of dysphagia, n (%)
162 (62)
58 (55)
104 (66)
0.066
31 (50)
44 (66)
0.071
Persistent/recurrent dysphagia, n (%)
133 (51)
63 (61)
70 (45)
0.015
39 (64)
27 (42)
0.012
Total patients with SAE, n (%)‡
47 (15)
16 (13)
31 (17)
0.750†
9 (13)
12 (17)
0.889†
Severe retrosternal pain
25
9
16
..
6
5
..
Hemorrhage
13
4
9
..
2
5
..
(Aspiration) pneumonia
5
1
4
..
0
2
..
Fistula
3
2
1
..
1
0
..
Perforation
1
0
1
..
0
1
..
† Log-rank test for time to first severe adverse event. ‡ More than one serious adverse event arose in some patients. LR, low dose radiotherapy; HR, high dose radiotherapy; n, number of patients; CI, confidence interval; %, percentage; SAE, serious adverse event.
Table 4. Additional palliation of persistent or recurrent dysphagia in patients treated with low dose or high dose radiotherapy for palliation of esophageal carcinoma. p-value
All patients
LR
HR
n = 292
n = 117
n = 175
43 (15)
23 (20)
20 (11)
0.052
Stent placement
16 (28)
6 (26)
10 (50)
0.105
EBRT
15 (26)
12 (52)
3 (15)
0.011
Nasogastric tube feeding
6 (11)
3 (13)
3 (15)
0.853
ILBT
3 (5)
1 (4)
2 (10)
0.468
Endoscopic gastrostomy
2 (4)
1 (4)
1 (5)
0.919
Endoscopic bougie dilation
1 (2)
0 (0)
1 (5)
0.873
Additional palliation of dysphagia, n (%)
LR, low dose radiotherapy; HR, high dose radiotherapy; n, number of patients; EBRT, external beam radiotherapy; ILBT, intra-luminal brachytherapy.
S1879-8500(19)30316-9
DOI:
https://doi.org/10.1016/j.prro.2019.10.010
Reference:
PRRO 1145
To appear in:
Practical Radiation Oncology
Received Date: 22 July 2019 Revised Date:
18 September 2019
Accepted Date: 16 October 2019
Please cite this article as: Vermeulen BD, Jeene PM, Sijben J, Krol R, Rütten H, Bogers JA, Braam PM, Siersema PD, Low dose versus high dose radiotherapy for the palliation of dysphagia from esophageal cancer: a multicenter retrospective cohort study, Practical Radiation Oncology (2019), doi: https:// doi.org/10.1016/j.prro.2019.10.010. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. 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. © 2019 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.
1
Low dose versus high dose radiotherapy for the palliation of
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dysphagia from esophageal cancer: a multicenter retrospective
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cohort study
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Running title: Low vs High Dose RT in Palliation of Dysphagia
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Bram D. Vermeulen1, MD; Paul M. Jeene2, MD; Jasmijn Sijben1; Robin Krol3, MD, PhD;
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Heidi Rütten4, MD; Johannes A. Bogers5, MD; Pètra M. Braam4, MD, PhD; Peter D.
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Siersema1, MD, PhD
8 9
Corresponding author
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Bram D. Vermeulen, Department of Gastroenterology and Hepatology (route 455), Radboud
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university medical center, Geert Grooteplein-Zuid 8, 6500 HB, Nijmegen, the Netherlands
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Phone: +31611079557. Email: [email protected]
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Institutions:
14 15
1. Department of Gastroenterology and Hepatology, Radboud university medical center, Nijmegen, the Netherlands
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2. Radiotherapy Group, Deventer, the Netherlands
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3. Department of Gastroenterology and Hepatology, Rijnstate Ziekenhuis, Arnhem, the
18 19 20 21 22
Netherlands 4. Department of Radiotherapy, Radboud university medical center, Nijmegen, the Netherlands 5. Radiotherapy Group, Arnhem, the Netherlands
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Conflict of interest statement
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Bram D. Vermeulen declares that he has no conflict of interest
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Paul M. Jeene declares that he has no conflict of interest
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Jasmijn Sijben declares that she has no conflict of interest
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Robin Krol declares that he has no conflict of interest
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Heidi Rütten declares that she has no conflict of interest
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Johannes A. Bogers declares that he has no conflict of interest
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Pètra M. Braam declares that he has no conflict of interest
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Peter D. Siersema received research grants from Boston Scientific, Cook Medical and MI-
32
Tech for some of the studies referenced in this review, and is on the advisory board of Ella-
33
CS.
34 35
Funding statement
36
No funding was acquired for this research and publication
37 38
Acknowledgments
39
We acknowledge Margo C. Noordhoek who has contributed in the management of data
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needed for this study
41 42 43
Author responsible for statistical analyses
44
Bram D. Vermeulen
Keywords: esophageal cancer; palliation of dysphagia; external beam radiotherapy; intraluminal brachytherapy.
Abstract Background and purpose: Clinical evidence regarding optimal radiation dose for palliation of dysphagia from esophageal cancer is generally lacking. In an effort to investigate optimal radiation dose, we assessed two different radiation schedules for palliation of dysphagia. Materials and methods: We performed a multicenter, retrospective study comparing low dose radiotherapy (LR: 5x4Gy external beam radiotherapy [EBRT]) with high dose radiotherapy (HR: 10x3Gy EBRT and 12Gy single-dose intra-luminal brachytherapy) for palliation of dysphagia in patients with inoperable or metastasized esophageal cancer. Primary outcome was improvement of dysphagia at 6 weeks after start of radiotherapy. Additional outcomes were persistent/recurrent dysphagia during patients’ remaining life, severe adverse events (SAE) and survival. Results: In total, 292 patients (LR, n=117; HR, n=175) were included in this study. After matching, 144 patients (72 in each group) were compared. Improvement of dysphagia at 6 weeks was achieved in 50% of patients after LR and in 66% after HR (p=0.071). Persistent/recurrent dysphagia occurred in 64% of patients after LR and in 42% after HR (p=0.012). No difference in SAE rate was found (p=0.889). Median survival was 88 days (95%CI 64–112) after LR and 177 days (95%CI 131–223) after HR (p<0.001). Conclusion: This study shows that both LR and HR were well tolerated and effective in short-term relief of dysphagia in patients with inoperable or metastasized esophageal cancer. HR was associated with better long-term relief of dysphagia when compared with LR. Our findings suggest that HR could be considered for patients with a longer life-expectancy but prospective studies are required.
1
Introduction Esophageal cancer is the sixth most common cancer leading to death worldwide, with an estimated 572,000 new cases and 508,600 deaths in 2018.1 At the time of diagnosis of esophageal cancer, more than 50% of patients have either inoperable tumors or radiographically visible metastases.2 Dysphagia is the most common symptom of incurable obstructive esophageal cancer and can be managed with several palliative treatment options.3 The European Society of Gastrointestinal Endoscopy (ESGE) guidelines recommend esophageal stent placement or intra-luminal brachytherapy (ILBT) for palliation of dysphagia from advanced esophageal cancer.4 Selection of a palliative option is mainly determined by the patients’ life-expectancy. Patients with a longer life-expectancy are best treated with ILBT because of the increased dysphagia-free survival when compared with stent placement.5 Despite these strong recommendations, ILBT is not frequently considered as treatment option.6, 7 As an alternative to ILBT, external beam radiotherapy (EBRT) has emerged in clinical practice.8, 9 Nonetheless, as comparative clinical studies are lacking, the optimal radiation dose has yet to be determined for palliation of dysphagia from inoperable or metastasized esophageal cancer. Accordingly, a recent study in the Netherlands showed that initial palliative radiotherapy varies widely in clinical daily practice.10 The authors suggested that the absence of therapeutic guidance may explain this finding. Therefore, in an effort to investigate optimal radiation dose, we assessed two different radiation schedules for palliation of dysphagia. In this multicenter, retrospective study, we compared low dose radiotherapy (LR) with high dose radiotherapy (HR) in patients with inoperable or metastasized esophageal cancer and dysphagia.
Materials and Methods 2
Between March 2003 and October 2018, consecutive patients treated with palliative radiotherapy for dysphagia from esophageal cancer were registered in a prospectively maintained database, including 3 radiotherapy centers in the Netherlands. Patients were included in the retrospective analysis when they had a first episode of dysphagia (grade ≥1 according to Ogilvie11) caused by inoperable or metastasized carcinoma of the esophagus or esophagogastric junction (EGJ) and were treated with first-line LR or HR palliative radiotherapy at the discretion of the radiation oncologist. Exclusion criteria were: (1) previous treatment of esophageal carcinoma with curative intent; (2) previous palliative treatment of dysphagia with radiotherapy or stent placement; (3) no completion of allocated radiation dosage; and (4) no electronic medical patient records. Extracted data from the electronic medical record included patient and tumor characteristics, severity of dysphagia, treatment characteristics and outcome during follow-up until death. Follow-up of patients consisted of a scheduled outpatient visit or telephone call at 6 weeks after start of radiotherapy and thereafter at the discretion of the treating physician (e.g., in case of recurrent dysphagia). Follow-up was identical for patients in both treatment groups. Persistent and recurrent dysphagia were assessed and documented at and after 6 weeks of follow-up, respectively. Additional palliation of dysphagia was also documented and registered. Dysphagia was scored according to Ogilvie11 (Table 1) or, when necessary, inferred from the physician’s documentation. American Joint Committee on Cancer (AJCC) stage was calculated using criteria from the seventh edition of the AJCC Cancer Staging Manual.12 The study protocol was approved by the Medical Ethics Committee and Institutional Review Board (IRB) of all participating centers. The study protocol was designed after enrolling patients in the prospective database.
3
External beam radiotherapy and planning All patients were treated with three-dimensional conformal radiotherapy or intensity modulated radiotherapy (IMRT) and underwent a planning computed tomography (CT) with or without oral contrast prior to EBRT. Intravenous contrast enhancement and fourdimensional CT were applied when appropriate. Cone beam CT or an electronic portal imaging device was used for treatment position verification. The gross tumor volume (GTV) was planned to include the primary tumor and the esophageal circumference at tumor level. In most cases, the clinical target volume consisted of the GTV plus a 1 cm margin, adapted to anatomical borders. Planning target volume margins were defined as per institutional protocols. Dose to target volume was prescribed as per International Commission on Radiation Units and Measurements (ICRU) 62 recommendations (95-107 isodose coverage) and organ at risk (lung, spinal cord and heart) constraints defined as per institutional protocols.13
Intraluminal brachytherapy Prior to ILBT, endoscopy was performed. Dilation was performed as per indication to a maximum of 11 mm. A guidewire was inserted over which a flexible applicator (BonvoisinGérard esophageal applicator, Nucletron B.V., Veenendaal, the Netherlands) with a diameter of 8-11 mm was placed through the tumor. A 12Gy single-dose was administered with the radioactive source 192Ir. The 100% isodose was defined at 1 cm from the source axis of the applicator. The PLATO (Plato software, Nucletron B.V., Veenendaal, the Netherlands) or Ocentra Brachy (Elekta AB, Stockholm, Sweden) planning systems were used to plan dose administration for each standard active length. All patients were consciously sedated using midazolam during the procedure. Sucralfate was prescribed for a period of up to 4 weeks after ILBT as a prophylactic measure for odynophagia.
4
Radiation dose schedules In the LR group, patients were treated with EBRT in 5 fractions of 4Gy. This corresponds with an EQD2 of 23Gy for tumor and acute toxicity (α/β=10) and an EQD2 of 28Gy for late toxicity (α/β=3). In the HR group, patients were treated with EBRT in 10 fractions of 3Gy and ILBT in 1 fraction of 12Gy. For comparison, we assumed a homogeneous single-dose ILBT of 12Gy. Together, this corresponds with a cumulative EQD2 of 55Gy for tumor and acute toxicity (α/β=10) and an EQD2 of 72Gy for late toxicity (α/β=3).
Outcome measures and definitions The primary outcome measure was improvement of dysphagia by at least one grade at 6 weeks after start of radiotherapy. The secondary outcome measure was persistent or recurrent dysphagia during followup after radiotherapy, which represented failure of dysphagia palliation during patients’ remaining life after low dose or high dose radiotherapy. Persistent dysphagia was defined as no improvement of dysphagia score ≥6 weeks after start of radiotherapy. Recurrent dysphagia was defined as the recurrence of dysphagia (grade ≥2) during follow-up of patients with improvement of dysphagia. Other outcome measures included: (1) overall survival after start of radiotherapy; (2) dysphagia-adjusted survival of patients with improved dysphagia, which represented the number of days alive without (grade 0) or with mild (grade 1) dysphagia (Table 1); (3) severe adverse events (SAE); and (4) treatment for persistent or recurrent dysphagia. SAE was defined as an event related to radiotherapy that required endoscopy, hospitalization or prescription of opiates.
5
Statistical analysis Improvement of dysphagia rate at 6 weeks after radiotherapy and persistent/recurrent dysphagia was compared between groups with a X2-test. Kaplan-Meier and log-rank tests were used to compare persistent/recurrent dysphagia, treatment for persistent/recurrent dysphagia, SAEs and overall survival between groups, while adjusting for time to occurrence (patients were censored at death or end of follow-up). To estimate the effect of HR on persistent/recurrent dysphagia when compared with LR, univariate Cox regression analysis was performed and expressed as hazard ratio, 95% confidence interval (CI) and significance level. In order to study comparable groups and to minimize the risk of bias, propensity score matching was used to balance baseline patient characteristics between the treatment groups. A propensity score was generated using logistic regression, based on the covariates age, gender, Karnofsky performance score, previous chemotherapy, tumor characteristics (histology, esophageal location and length), cancer stage and metastases (location and number of sites). Subsequently, matching without replacement (1:1) was performed to generate matched pairs of cases in which the within-pair difference was minimized by setting a caliper of 0.1 of the SD of the logit of the propensity score. We compared parametric and non-parametric continuous data with a t-test and MannWhitney U tests, respectively, and categorical data with a X2-test. Results were expressed as frequencies and percentages, means (± standard deviation [SD]) and medians (95%CI), when appropriate. Before and after matching, analysis of study outcome measures was performed with SPSS version 25.0 (SPSS Inc., Chicago, Illinois). Propensity score matching was performed with the FUZZY extension bundle of the SPSS statistical package (v1.4.7; SPSS Inc.,
6
Chicago, Illinois) with Python plug-in. We regarded a p-value of <0.05 as statistically significant.
Results Patient characteristics From the prospective registry, we identified 361 consecutive patients who underwent palliative low dose or high dose radiotherapy for inoperable or metastasized esophageal cancer. A total of 69 patients were excluded because no electronic medical patient records were available (n=57), no completion of allocated radiation dosage (n=9) or previous treatment for esophageal cancer with curative intent (n=3). The remaining 292 patients were included in the study, of which 117 were treated with LR and 175 with HR. Figure 1 shows the study flow diagram of patient selection, treatment and outcome before and after matching. Before matching, significant differences at baseline between patients undergoing LR and HR were found for tumor stage and location, Karnofsky performance score, previous chemotherapy and location of metastasis. After matching, 144 patients (72 in each group) without significant differences in baseline characteristics remained to be analyzed. Baseline patient characteristics and differences between groups before and after matching are shown in Table 2.
Primary and secondary outcome measures Results of the unmatched and matched outcome measures are shown in Table 3. For 29 (10%) patients, 6-week dysphagia scores were missing or not well documented. Improvement of dysphagia was achieved in 58 (55%) patients after LR and in 104 (66%) patients after HR (p=0.066). After matching, improvement of dysphagia was achieved in 31 (50%) patients 7
after LR and in 44 (66%) patients after HR (p=0.071). Furthermore, persistent/recurrent dysphagia occurred in 63 (61%) patients after LR and in 70 (45%) patients after HR (p=0.015). Cox regression analysis showed that HR was associated with a 16% decrease in persistent/recurrent dysphagia when compared with LR (hazard ratio=0.6, 95%CI: 0.4–0.9, p=0.010). After matching, persistent/recurrent dysphagia occurred in 39 (64%) patients after LR and in 27 (42%) patients after HR (p=0.012). When compared with the Kaplan-Meier and log-rank tests that corrected for time to occurrence and survival differences, the significant differences between groups were still present (p=0.012).
Other outcome measures Median survival in all patients was 157 days (95%CI 139–175). Median survival was 90 days (95%CI 63–117) after LR and 177 days (95%CI 150–204) after HR (p<0.001; Figure 2). After matching, the difference in survival between treatment groups persisted. Median survival was 88 days (95%CI 64–112) after LR and 177 days (95%CI 131–223) after HR (p<0.001). This observed difference in survival was not significantly different between participating centers (p=0.20). Median dysphagia-adjusted survival of all patients with improved dysphagia (n=162) was 126 days (95%CI 109–143). Median dysphagia-adjusted survival was 73 days (95%CI 19-127) after LR and 133 days (95%CI 95–171) after HR (p=0.001). In these patients, recurrent dysphagia occurred in 16 patients (33%) after LR and in 16 patients (21%) after HR (p=0.002). Table 3 shows SAEs in all patients and for each treatment group. A total of 47 SAEs occurred in 44 (15%) patients. SAEs included severe retrosternal pain (n=25), esophageal hemorrhage (n=13), (aspiration) pneumonia (n=5), esophago-respiratory fistula (n=3) and esophageal perforation (n=1). The number of patients with SAE was not significantly
8
different between treatment groups (p=0.750). In total, 16 SAEs occurred in 15 (13%) patients after LR and 31 SAEs in 29 (17%) patients after HR (p=0.750). After matching, no significant difference in number of patients with SAE was found after LR or HR (9 patients [13%] vs. 12 patients [17%], p=0.889). Treatment for persistent or recurrent dysphagia was indicated in 27 (23%) patients after LR and in 30 (17%) patients after HR (p<0.001; Figure 3). In these patients (n=57), repeat endoscopy showed that recurrent dysphagia was caused by tumor recurrence in 37 (65%) patients, benign radiation stricture in 5 (9%) patients and tumor ulceration in 2 (4%) patients. In the other 12 (21%) patients, the cause of recurrent dysphagia remained unknown. Recurrent dysphagia was treated with stent placement in 16 (28%) patients, repeat EBRT in 15 (26%) patients, nasogastric tube feeding in 6 (11%) patients, ILBT in 3 (5%) patients, percutaneous endoscopic gastrostomy in 2 (4%) patients and endoscopic bougie dilation in 1 (2%) patient (Table 4). The other 12 patients (21%) did not undergo further treatment for recurrent dysphagia after repeat endoscopy.
Discussion Our multicenter cohort study compared low dose radiotherapy with high dose radiotherapy for palliation of dysphagia in patients with inoperable or metastasized esophageal cancer. We found no difference in short-term relief of dysphagia between both treatment groups. However, HR showed better relief of dysphagia during patients’ remaining life and was not associated with a higher SAE rate when compared with LR. The observed effect of HR is in line with several other studies investigating palliative HR in patients with inoperable or metastasized esophageal cancer.14-17 In particular, one randomized study demonstrated the additional effect of a stent loaded with high dose 9
irradiation seeds when compared with conventional stent placement.18 Nonetheless, these studies did not compare HR with LR. In contrast, one randomized controlled trial compared LR (i.e., ILBT: 2x8Gy) with HR (i.e., ILBT: 2x8Gy; and EBRT: 10x3Gy) in patients palliated for inoperable esophageal cancer. It was found that HR improved relief of dysphagia when compared with LR. In addition, no difference in adverse events was observed between treatment groups.19 As opposed to our study, this trial included only inoperable esophageal squamous cell carcinoma patients without metastases. Therefore, the current study is the first to compare palliative LR versus HR in a population predominantly consisting of patients with metastasized esophageal adenocarcinoma. Findings from our study may have several implications for clinical practice. First, HR showed sustained relief of dysphagia during patients’ remaining life with an acceptable SAE rate. Therefore, we suggest that clinicians could consider HR for patients with an expected longer life-expectancy. On the other hand, for patients with an expected short life-expectancy, LR should be regarded as first-line palliative treatment as no difference in short-term relief of dysphagia was found when compared with HR. Moreover, patients with a short lifeexpectancy may benefit more from the short 5-day course of LR as opposed to HR which is performed over an extended period of 2-3 weeks. The important question remains how clinicians can predict patients’ survival. Despite the fact that prediction of survival is challenging in patients with advanced stage cancer20, 21, this study shows that accurate prediction of survival in patients with advanced esophageal carcinoma was achieved in the majority of patients. Factors used by clinicians to estimate survival included Karnofsky performance score, previous chemotherapy, cancer stage, location and number of metastases. Accordingly, all of these patient characteristics differed significantly between both treatment groups at baseline. However, after matching patients for these factors, the survival difference persisted (Table 3). Lack of matching on additional
10
predictive factors used by clinicians may explain this finding. For example, due to missing data, we could not match on weight loss.22, 23 In support of this, a prediction model was recently developed that can accurately predict survival of patients with metastatic esophageal cancer. In addition to the above mentioned factors, this model also incorporated age, histology, tumor differentiation grade, weight loss and location of lymph node metastases.23 This study may provide another clinical implication for patients with advanced esophageal cancer in whom palliative HR is considered. That is, the high biological effective dose at the tumor site was achieved by adding single-dose ILBT (12Gy) to EBRT. In current daily practice however, despite recommendations of European guidelines4, 24, only very few centers routinely consider ILBT for palliation of dysphagia due to treatment complexity and lack of expertise.6, 7 Moreover, as opposed to the European guidelines, the United States guidelines currently recommend EBRT as first-line palliative modality.25 To anticipate on these findings, we suggest treating patients with an expected longer life-expectancy with an equivalent high dose of EBRT (i.e., EQD2 of 55Gy for tumor and acute toxicity (α/β=10)) without using ILBT, which may achieve improved palliation of dysphagia during patients’ remaining life.26 Accordingly, future studies should further explore optimal palliative radiotherapy dosages for patients with advanced esophageal cancer. One of the strengths of our multicenter study is that it is the first to compare palliative LR versus HR in patients with predominantly metastasized adenocarcinoma. The studied population reflects the Western population of patients with esophageal cancer.27 Furthermore, when compared with previous studies, we assessed a relatively large sample size of patients undergoing first-line palliative radiotherapy.8, 14-17, 28 Another strength of this study is the use of propensity score matching to compare patient groups. This high quality statistical method allows to adjust for established and potential confounders.29 Nonetheless, the retrospective nature and lack of randomization
11
should be recognized in the interpretation of our findings. Despite reducing the risk of bias by comparing matched patients, limitations in our data set did not allow for matching on all known and potential confounders. Moreover, observational studies have the inherent risk of residual confounding that cannot be fully corrected for. Above all, the most appropriate study design comparing LR with HR is a randomized controlled trial. In conclusion, this multicenter retrospective study shows that both LR and HR were well tolerated and effective in short-term relief of dysphagia from inoperable or metastasized esophageal cancer. However, HR was associated with better relief of dysphagia during patients’ remaining life when compared with LR. Therefore, our findings suggest that HR could be considered for patients with a longer life-expectancy. Further, well designed studies should focus on optimizing palliative radiotherapy dosages for patients with advanced esophageal cancer.
12
1
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16
82
Figure legends
83
Figure 1. Study flow diagram of patient selection, treatment and outcome, before and after
84
propensity score matching. LR = low dose radiotherapy; HR = high dose radiotherapy; n =
85
number of patients; % = percentage.
86
Figure 2. Survival after palliative radiotherapy among patients with inoperable or
87
metastasized esophageal cancer. Kaplan-Meier plot shows differences in survival between
88
patients treated with LR or HR. LR = low dose radiotherapy; HR = high dose radiotherapy.
89
Figure 3. Freedom from treatment for persistent or recurrent dysphagia after palliation of
90
dysphagia with radiotherapy for inoperable or metastasized esophageal cancer. Kaplan-Meier
91
analysis shows differences in treatment for persistent or recurrent dysphagia between patients
92
treated with LR or HR. LR = low dose radiotherapy; HR = high dose radiotherapy.
93
17
1
Table 1. Ogilvie dysphagia score used for outcome evaluation in patients treated with low dose or high dose radiotherapy for palliation of
2
esophageal carcinoma.
3 4 5 6 7 8
Grade
Description
0
Ability to eat a normal diet
1
Ability to eat some solids
2
Ability to swallow semisolids only
3
Ability to swallow liquids only
4
Complete dysphagia for liquids
9 10
Table 2. Comparison of baseline characteristics of 292 patients who underwent low dose or high dose radiotherapy for palliation of esophageal carcinoma, before and after propensity score matching Before matching
After matching
All patients
LR
HR
292
117
175
Age*, mean (±SD)
70 (11)
70 (10)
70 (12)
Gender* (male), n (%)
226 (77)
92 (79)
134 (77)
Histology*, n (%)
p-value
LR
HR
p-value
72
72
0.841
70 (10)
68 (11)
0.327
0.680
57 (79)
55 (76)
0.688 0.734
0.643
AC
193 (68)
77 (66)
116 (70)
..
48 (67)
51 (71)
..
SCC
67 (24)
31 (27)
36 (22)
..
19 (26)
18 (25)
..
Other
23 (8)
9 (8)
14 (8)
..
5 (7)
3 (4)
..
6.1 (3.0)
6.4 (3.5)
6.0 (2.6)
0.249
6.2 (3.6)
6.1 (2.7)
0.834
Tumor length*, cm, mean (±SD)
Location*, n (%)
0.755
<0.001
Esophagus
221 (76)
74 (63)
147 (84)
..
53 (74)
55 (77)
..
EGJ/Cardia
71 (24)
43 (37)
28 (16)
..
19 (26)
17 (23)
..
Indication for palliative therapy*, n (%)
0.538
0.035
Metastasis
218 (75)
92 (79)
126 (72)
..
60 (83)
60 (83)
..
Inoperable
75 (23)
26 (17)
49 (27)
..
12 (17)
12 (17)
..
Liver metastases*, n (%)
94 (34)
49 (47)
45 (26)
0.001
28 (39)
26 (36)
0.731
Peritoneal/bone/brain metastases*, n (%) 53 (19)
32 (29)
21 (12)
<0.001
15 (21)
15 (21)
1.000
Number of metastatic sites (≥2)*, n (%)
51 (49)
49 (29)
0.001
30 (42)
30 (42)
0.886
100 (36)
Cancer staging*, n (%) 1
0.385 9 (3)
3 (3)
6 (4)
..
0.945 2 (3)
2 (3)
..
2
19 (7)
3 (3)
16 (9)
..
3 (4)
4 (6)
..
3
33 (12)
11 (10)
22 (13)
..
7 (10)
8 (9)
..
4
218 (78)
92 (84)
126 (74)
..
60 (83)
60 (83)
..
Ogilvie score before treatment, n (%)
0.270
0.786
1
37 (13)
19 (16)
18 (10)
..
10 (14)
10 (14)
..
2
125 (43)
47 (40)
78 (45)
..
27 (38)
25 (35)
..
3
93 (32)
35 (30)
58 (33)
..
26 (36)
29 (40)
..
4
20 (7)
11 (9)
9 (5)
..
7 (10)
4 (6)
..
65 (24)
17 (16)
48 (29)
0.013
17 (24)
18 (25)
0.846
KPS [90-100], n (%) KPS*, n (%) 90-100
0.502
0.032 65 (24)
17 (16)
48 (29)
..
17 (24)
18 (25)
..
70-80
120 (44)
50 (47)
70 (42)
..
30 (42)
31 (43)
..
50-60
66 (24)
26 (24)
40 (24)
..
16 (22)
21 (29)
..
30-40
19 (7)
12 (11)
7 (4)
..
8 (11)
2 (3)
..
20
2 (1)
2 (2)
0
..
1 (1)
0 (0)
..
Palliative chemotherapy*, n (%)
94 (32)
55 (48)
39 (22)
<0.001
27 (38)
29 (40)
0.732
Treatment interval, days, median [IQR]
34 [25-44]
35 [26-45] 28 [22-42]
0.031
27 [21-39] 35 [26-42]
0.042
LR, low dose radiotherapy; HR, high dose radiotherapy; n, number of patients; , percentage; SD, standard deviation; AC, adenocarcinoma; SCC, squamous cell carcinoma; cm, centimeter; EGJ, esophagogastric junction; IQR, interquartile range; KPS, Karnofsky performance score. * Variables used for propensity score matching.
Table 3. Comparison of clinical outcome and serious adverse events in patients treated with low dose or high dose radiotherapy for palliation of esophageal carcinoma, before and after propensity score matching Before matching
Survival, days (median [95%CI])
After matching
All patients
LR
HR
n = 292
n = 117
n = 175
157 [139-175]
p-value
90 [63-117] 177 [150-204] <0.001
LR
HR
n = 72
n = 72
p-value
74 [47-101] 176 [135-217] <0.001
Improvement of dysphagia, n (%)
162 (62)
58 (55)
104 (66)
0.066
31 (50)
44 (66)
0.071
Persistent/recurrent dysphagia, n (%)
133 (51)
63 (61)
70 (45)
0.015
39 (64)
27 (42)
0.012
Total patients with SAE, n (%)‡
47 (15)
16 (13)
31 (17)
0.750†
9 (13)
12 (17)
0.889†
Severe retrosternal pain
25
9
16
..
6
5
..
Hemorrhage
13
4
9
..
2
5
..
(Aspiration) pneumonia
5
1
4
..
0
2
..
Fistula
3
2
1
..
1
0
..
Perforation
1
0
1
..
0
1
..
† Log-rank test for time to first severe adverse event. ‡ More than one serious adverse event arose in some patients. LR, low dose radiotherapy; HR, high dose radiotherapy; n, number of patients; CI, confidence interval; %, percentage; SAE, serious adverse event.
Table 4. Additional palliation of persistent or recurrent dysphagia in patients treated with low dose or high dose radiotherapy for palliation of esophageal carcinoma. p-value
All patients
LR
HR
n = 292
n = 117
n = 175
43 (15)
23 (20)
20 (11)
0.052
Stent placement
16 (28)
6 (26)
10 (50)
0.105
EBRT
15 (26)
12 (52)
3 (15)
0.011
Nasogastric tube feeding
6 (11)
3 (13)
3 (15)
0.853
ILBT
3 (5)
1 (4)
2 (10)
0.468
Endoscopic gastrostomy
2 (4)
1 (4)
1 (5)
0.919
Endoscopic bougie dilation
1 (2)
0 (0)
1 (5)
0.873
Additional palliation of dysphagia, n (%)
LR, low dose radiotherapy; HR, high dose radiotherapy; n, number of patients; EBRT, external beam radiotherapy; ILBT, intra-luminal brachytherapy.