Comparative Outcomes After Definitive Chemoradiotherapy Using Proton Beam Therapy Versus Intensity Modulated Radiation Therapy for Esophageal Cancer: A Retrospective, Single-Institutional Analysis

Accepted Manuscript Comparative Outcomes after Definitive Chemoradiotherapy using Proton Beam Therapy versus Intensity-Modulated Radiation Therapy for Esophageal Cancer: A Retrospective Single-Institutional Analysis Mian Xi, MD, Cai Xu, MD, Zhongxing Liao, MD, Joe Y. Chang, MD, PhD, Daniel R. Gomez, MD, Melenda Jeter, MD, MPH, James D. Cox, MD, Ritsuko Komaki, MD, Reza Mehran, MD, Mariela A. Blum, MD, Wayne L. Hofstetter, MD, Dipen M. Maru, MD, Manoop S. Bhutani, MD, Jeffrey H. Lee, MD, Brian Weston, MD, Jaffer A. Ajani, MD, Steven H. Lin, MD, PhD PII:

S0360-3016(17)33516-2

DOI:

10.1016/j.ijrobp.2017.06.2450

Reference:

ROB 24384

To appear in:

International Journal of Radiation Oncology • Biology • Physics

Received Date: 16 February 2017 Revised Date:

4 June 2017

Accepted Date: 19 June 2017

Please cite this article as: Xi M, Xu C, Liao Z, Chang JY, Gomez DR, Jeter M, Cox JD, Komaki R, Mehran R, Blum MA, Hofstetter WL, Maru DM, Bhutani MS, Lee JH, Weston B, Ajani JA, Lin SH, Comparative Outcomes after Definitive Chemoradiotherapy using Proton Beam Therapy versus Intensity-Modulated Radiation Therapy for Esophageal Cancer: A Retrospective Single-Institutional Analysis, International Journal of Radiation Oncology • Biology • Physics (2017), doi: 10.1016/ j.ijrobp.2017.06.2450. 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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ACCEPTED MANUSCRIPT Original Article

Comparative Outcomes after Definitive Chemoradiotherapy using Proton Beam Therapy versus Intensity-Modulated Radiation Therapy

Running title: Definitive Proton versus IMRT in EC

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for Esophageal Cancer: A Retrospective Single-Institutional Analysis

Mian Xi, MD1,2, Cai Xu, MD1,3, Zhongxing Liao, MD1, Joe Y. Chang, MD, PhD1, Daniel

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R. Gomez, MD1, Melenda Jeter, MD, MPH1, James D. Cox, MD1, Ritsuko Komaki, MD1,

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Reza Mehran, MD4, Mariela A. Blum, MD5, Wayne L. Hofstetter, MD4, Dipen M. Maru, MD6, Manoop S. Bhutani, MD7, Jeffrey H. Lee, MD7, Brian Weston, MD7, Jaffer A. Ajani, MD5, Steven H. Lin, MD, PhD1

Department of Radiation Oncology, The University of Texas MD Anderson Cancer

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1

Center, Houston, TX, USA; 2

Department of Radiation Oncology, Cancer Center, Sun Yat-sen University, State Key

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Laboratory of Oncology in South China, Collaborative Innovation Centre for Cancer

3

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Medicine, Guangzhou, Guangdong, China; Department of Radiation Oncology, Cancer Hospital & Institute, Chinese Academy of

Medical Sciences, Peking Union Medical College, Beijing, China; 4

Department of Thoracic and Cardiovascular Surgery, The University of Texas M. D.

Anderson Cancer Center, Houston, Texas, USA; 5

Department of Gastrointestinal Medical Oncology, The University of Texas M. D.

Anderson Cancer Center, Houston, Texas, USA;

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Department of Pathology, The University of Texas M. D. Anderson Cancer Center,

Houston, Texas, USA; 7

Department of Gastroenterology, The University of Texas M. D. Anderson Cancer Center,

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Houston, Texas, USA.

Corresponding Author: Dr. Steven H. Lin, Department of Radiation Oncology, Unit 97,

77030,

USA.

Tel:

[email protected]

713-563-8490,

Fax:

713-563-2366,

Email:

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Texas

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The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston,

Funding: This study was funded in part by The Mabuchi Research Fund and The

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University of Texas MD Anderson Cancer Center and by the National Cancer Institute Cancer Center Support Grant CA016672.

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Conflict of interest: S.H.L. has received research funding from Elekta, STCube

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Pharmaceuticals, Peregrine Pharmaceuticals, Hitachi Chemical, and Roche/Genentech, has served as consultant for AstraZeneca, and received honoraria from US Oncology and ProCure. All other authors have no conflicts of interest to declare.

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ACCEPTED MANUSCRIPT Original Article

Comparative Outcomes after Definitive Chemoradiotherapy using Proton Beam Therapy versus Intensity-Modulated Radiation Therapy

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Running title: Definitive Proton versus IMRT in EC

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for Esophageal Cancer: A Retrospective Single-Institutional Analysis

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ACCEPTED MANUSCRIPT ABSTRACT

Purpose: To compare clinical outcomes between proton beam therapy (PBT) and intensity-modulated radiation therapy (IMRT) in patients with esophageal cancer (EC)

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treated with definitive chemoradiotherapy (CRT). Methods and Materials: From 2007 through 2014, 343 EC patients who received definitive CRT with either PBT (n = 132) or IMRT (n = 211) were retrospectively

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analyzed. Survival, recurrence, and treatment toxicity were compared between groups.

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Cox proportional hazards regression model was performed to test the association between patient/treatment variables and survival.

Results: Patient/treatment variables were overall well balanced except for age and race. Compared to IMRT, PBT had significantly better overall survival (OS; P = 0.011),

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progression-free survival (PFS; P = 0.001), distant metastasis-free survival (DMFS; P = 0.031), as well as marginally better locoregional failure-free survival (LRFFS; P = 0.075). No significant differences in rates of treatment-related toxicities were observed between

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groups. On multivariate analysis, IMRT had worse OS (hazard ratio [HR], 1.454; P =

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0.01), PFS (HR, 1.562; P = 0.001), and LRFFS (HR, 1.461; P = 0.041) than PBT. Subgroup analysis by clinical stage revealed considerably higher 5-year OS (34.6% vs. 25.0%, P = 0.038) and PFS rates (33.5% vs. 13.2%, P = 0.005) in PBT group for patients with stage III. However, no significant intergroup differences in survival were identified for stage I/II patients. Conclusions: Compared with IMRT, PBT might be associated with improved OS, PFS, and LRFFS, especially in EC patients with locally advanced disease. These results need

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Keywords: Esophageal cancer, proton therapy, intensity-modulated radiation therapy,

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definitive chemoradiotherapy, survival.

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ACCEPTED MANUSCRIPT Introduction

Radiation therapy is a critical component of the multidisciplinary management for esophageal cancer (EC). At present, three-dimensional conformal radiotherapy (3DCRT)

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is the most widely used radiation technique in EC (1). However, multiple dosimetric studies have demonstrated the superiority of intensity-modulated radiation therapy (IMRT) over 3DCRT in improving dose conformity and normal tissue sparing (2-4). Moreover,

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retrospectively comparative studies strongly suggested that the dosimetric advantages of

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IMRT could translate into clinical benefits for EC, including an improvement in survival, lower cardiopulmonary mortality as well as the reduction in the risk of postoperative complications compared with 3DCRT (5-8). Therefore, despite a lack of high-quality prospective evidence, IMRT has been increasingly adopted for treating EC over the past

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decade.

Proton beam therapy (PBT) is a technologically advanced radiation modality used for treating EC in recent years. With the distinct physical properties of charged particles, PBT

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can improve target coverage and significantly reduce dose to the surrounding normal

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tissues when compared to photon therapy (9). In addition, the higher relative biological effectiveness (RBE) of protons might have the potential to further improve survival outcomes (10). Dosimetric comparisons have well documented the dosimetric benefits of PBT over IMRT, and several single-institutional clinical studies have indicated the efficacy and safety of concurrent chemoradiotherapy (CRT) with PBT in EC (11-16). Despite theoretical superiority, there were only a few reports comparing toxicity outcomes between PBT and 3DCRT/IMRT in EC patients (7, 17). The long-term clinical

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outcome of PBT over IMRT has never been well addressed, especially for the subset of patients receiving definitive CRT. For the present study, we have evaluated a relatively large cohort patients treated at our institution, in order to examine the clinical outcomes of

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PBT and IMRT for EC patients who received definitive CRT.

Methods and Materials

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Patients

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Between January 2007 and June 2014, consecutive patients with biopsy-confirmed thoracic esophageal adenocarcinoma or squamous cell carcinoma from a prospectively maintained single-institutional database were reviewed (Supplementary Figure 1). All patients underwent definitive CRT delivered with either PBT or IMRT. Patients were

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excluded if they had M1 disease, did not have baseline positron emission tomography/computed tomography (PET/CT), had prior or concomitant malignancy, received adjuvant chemotherapy, received surgery within 6 months after CRT, or had

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incomplete clinical records. The institutional review board approved this study.

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All patients were staged with esophagogastroduodenoscopy (EGD) with endoscopic ultrasound, chest/abdominal CT with contrast, and PET/CT. Tumors were (re)staged according to the 7th edition of the American Joint Committee on Cancer TNM classification (18). In accordance with institutional practice guidelines, each patient was evaluated by a multidisciplinary team before treatment. On the basis of baseline characteristics, individual health insurance, and machine availability, the patient assignment to PBT or IMRT was at the discretion of multidisciplinary team and patients’

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Treatment

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All patients were treated with concurrent CRT and a fraction of them underwent induction chemotherapy before CRT. Patients generally received concurrent platinum- or taxane-based

chemotherapy

with

fluorouracil

during

radiotherapy.

The

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platinum/fluorouracil regimen consisted of weekly cisplatin 30 mg/m2 or carboplatin with

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an area under the curve of 2.0 on day 1 and fluorouracil 300 mg/m2/day as continuous infusion for 96 hours every week for 5-6 cycles. For the taxane/fluorouracil regimen, paclitaxel was administered at a dose of 45-50 mg/m2 or docetaxel at 25-30 mg/m2 on day 1 and fluorouracil 300 mg/m2/day for 96 hours every week. Several patients received

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capecitabine at 800 mg/m2 twice daily on days 1-5 weekly instead of fluorouracil. Gross tumor volume (GTV) was defined as the primary tumor and regional lymph nodes positive on EUS and PET/CT. Clinical target volume (CTV) was defined as the

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GTV plus 3-4 cm proximal and distal margins and a radial margin of 1.0 cm.

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Supraclavicular lymph nodes were included electively for upper EC and celiac axis nodal region were included for distal EC based on the discretion of radiation oncologists. Planning target volume (PTV) was determined by adding a 0.5–1.0 cm margin to the CTV. The standard prescription dose was 50.4 Gy(RBE) delivered in 28 fractions. IMRT plans were generated using the Pinnacle treatment planning system (Philips Healthcare), and the PBT plans were generated using the Eclipse planning system (Varian Medical Systems). There are two types of PBT technique: passive-scattering proton therapy (PSPT) and

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intensity-modulated proton therapy (IMPT). Different from the traditional PSPT using collimators and compensators to conform dose, the IMPT technique is based on pencil beam scanning technology, which can simultaneously optimize the energy and intensity of

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beams. As previously described, 6-18 MV photon beams and 150-250 MeV proton beams were used according to depth of tumor, and optimal beam arrangements were optimized for each patient (13, 19). Briefly, the most common beam arrangements were 5-6 fields

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using the step-and-shoot technique for IMRT and a two-field posterior/left posterior

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oblique for PBT. Standard dose constraints were applied for IMRT and PBT: mean lung dose <20 Gy, total lung volume receiving greater than 20 Gy (V20) of <35%, heart V40 <40%, liver V30 <30%, and maximum spinal cord dose <45 Gy.

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Follow-up

Patients were typically followed every 3 months during the first year after completion of CRT, every 6 months for the next 2 years, and then annually until 5 years, including blood periodic

EGDs

with

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tests,

biopsies,

chest/abdominal

CT,

and/or

PET/CT.

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Treatment-related toxicities were scored according to the Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. The first failure pattern was used to classify locoregional or distant recurrence. Locoregional recurrence (LRR) was defined as the persistence or recurrence within esophagus or regional lymph nodes, and distant recurrence included distant organ metastases and non-regional lymph node metastases (supraclavicular or para-aortic nodes). The data were last updated in August 2016.

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ACCEPTED MANUSCRIPT Statistical Analysis

Categorical variables were compared using the Chi-square test or Fisher’s exact test, whereas continuous data were compared using the Mann-Whitney U test between

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treatment groups. Age, primary tumor length, and radiation dose were grouped by the median value as a cut-off. All survival times were defined from the date of diagnosis. Kaplan-Meier method was used to calculate overall survival (OS), progression-free

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survival (PFS), locoregional failure-free survival (LRFFS), and distant metastasis-free

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survival (DMFS). PFS was determined until any recurrence, death, or last follow-up. Log-rank test was used to analyze intergroup differences, and prognostic factors with univariate significance of P <0.2 were further tested in multivariate analysis using Cox proportional hazards regression model (backward stepwise). Statistical analyses were

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performed using SPSS 22.0 software (SPSS Inc., Chicago, IL). P <0.05 was considered

Results

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statistically significant.

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Patient Characteristics

Patient and treatment characteristics are summarized in Table 1. A total of 343 eligible patients were included in this study: 211 patients (61.5%) who received IMRT and 132 patients (38.5%) who received PBT. PBT use increased from a rate of 37.1% in 2007–2010 to 62.9% in 2011–2014. Selective observation after good response of CRT was the most common reason (54.2%) for patients not receiving surgery. A total of 80 patients (23.3%) underwent definitive CRT because of unresectable or medically

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inoperable disease, and 22.4% of patients developed early distant recurrences before surgery. The median age of the whole cohort was 67 years (range, 20–92 years) and the median length of the primary tumor was 5.0 cm (range, 1.0–19.0 cm).

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Median radiation dose was 50.4 Gy both in IMRT group (range, 41.4–66.0 Gy) and in PBT group (range, 45.0–63.0 Gy). Since the whole cohort of this study included a few patients (6.4%) who intended but failed to undergo subsequent esophagectomy after CRT,

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20 patients in IMRT group and 2 patients in PBT group received a dose of <50.4 Gy. In

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addition, a total of 43 patients (12.5%) were treated with higher dose (>50.4 Gy) mainly based on physician bias, especially for squamous cell carcinoma of the proximal esophagus. The majority of patients (94.7%) in PBT group were treated with PSPT, and only 7 patients (5.3%) received IMPT.

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The comparison of patient characteristics revealed that the majority of baseline and treatment variables were overall comparable between the two treatment groups, including sex, performance status, weight loss, histology, histologic grade, tumor location, tumor

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length, TNM stage, whether receiving induction chemotherapy, radiation dose, concurrent

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chemotherapy regimen, and reasons for no surgery. However, the elderly Caucasian patients were more likely to receive PBT.

Dosimetric Comparison Dosimetric comparisons were performed for the cohort of 308 data-accessible patients (Supplementary Table 1). Compared with IMRT plans, the PBT plans provided significant improvements in PTV dose coverage (93.6% vs. 94.8%, P < 0.001). The average doses to

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the lung and heart were 10.0 Gy and 19.9 Gy for IMRT versus 6.5 Gy and 11.6 Gy for PBT, respectively (P < 0.001). Compared with IMRT group, the PBT group had significantly lower V5 (48.1% vs. 28.4%, P < 0.001), V10 (32.3% vs. 23.2%, P < 0.001),

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and V20 (18.4% vs. 11.3%, P < 0.001) of the lung. The V30 of the heart (18.9% vs. 24.4%, P < 0.001) were also significantly lower for the PBT group than that for the IMRT

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group but no difference was observed for V40 (14.0% vs. 14.3%, P = 0.712).

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Toxicity

As shown in Table 2, no significant differences in rates of treatment-related toxicities were observed between groups. Grade 3 or 4 toxicities occurred in 45.0% of patients in IMRT group and 37.9% in PBT group (P = 0.192). Four patients (1.9%) in IMRT group

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versus 1 patient (0.8%) in PBT group (P = 0.653) had grade 5 toxicities.

Survival and Recurrence

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The median follow-up time for survivors was 65.1 months (range, 19.4–115.3 months) for

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the IMRT group and 44.8 months (range, 11.9–110.3 months) for the PBT group, respectively. At this analysis, 77 patients (22.4%) experienced LRR only, 84 (24.6%) had distant recurrence only, and 55 (16.0%) had concurrent locoregional and distant failure in the whole group. Compared with the IMRT group, the PBT group was associated with a non-significantly lower LRR rate (41.7% vs. 33.3%, P = 0.121) and a significantly lower distant recurrence rate (45.0% vs. 33.3%, P = 0.032). For patients with LRR only (50 patients in the IMRT group and 27 patients in the PBT group), 17 (34.0%) and 9 patients

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(33.3%) received salvage surgery in the IMRT and PBT groups, respectively (P = 0.953). At 5 years, the PBT group had significantly higher OS (41.6% vs. 31.6%, P = 0.011), PFS (34.9% vs. 20.4%, P = 0.001), and DMFS rates (64.9% vs. 49.6%, P = 0.031) than

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did the IMRT group (Figure 1A-C). There was also a trend toward higher 5-year LRFFS rate with the PBT group versus the IMRT group (59.9% vs. 49.9%, P = 0.075; Figure 1D). Although there were no significant differences in reasons for patients not receiving

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surgery between groups, more patients in the IMRT group developed early distant

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recurrences before surgery than those in the PBT group (25.1% vs. 18.2%), which may have resulted in biased survival results. Therefore, survival comparisons between groups in patients without early distant recurrences were also conducted. For these patients (n = 266), the PBT group still showed remarkably better OS (P = 0.019; Supplementary Figure

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2A), PFS (P = 0.002; Supplementary Figure 2B), LRFFS (P = 0.025; Supplementary Figure 2C), and DMFS (P = 0.023; Supplementary Figure 2D) than the IMRT group. Since 28.3% of patients received induction chemotherapy before CRT, we further

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performed survival comparisons between IMRT and PBT groups in patients without

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induction chemotherapy (n = 246). Similarly with the whole cohort, the PBT group demonstrated significantly better OS (P = 0.041), PFS (P = 0.012), and DMFS (P = 0.025) than the IMRT group in these patients (Supplementary Figure 3). As the rates of PBT usage differed between 2007-2010 and 2011-2014, we evaluated

the impact of the time period of diagnosis on clinical outcomes. On univariate analysis, we found no association of time period with OS (HR 1.045; 95% CI 0.794–1.375; P = 0.756), PFS (HR 0.999; 95% CI 0.776–1.287; P = 0.994), LRFFS (HR 0.885; 95% CI

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Prognostic Factors for Survival

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Univariate and multivariate analyses were performed to determine prognostic factors for OS, PFS, LRFFS, and DMFS in the whole group (Table 3). The multivariate analysis identified that the radiotherapy modality of IMRT was associated with significantly worse

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OS (hazard ratio [HR], 1.454; 95% confidence interval [CI], 1.092–1.936; P = 0.01), PFS

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(HR, 1.562; 95% CI, 1.193–2.045; P = 0.001), and LRFFS (HR, 1.461; 95% CI, 1.016–2.102; P = 0.041) compared with PBT, but not related with DMFS. In addition to radiotherapy modality, clinical T stage (T1-2 vs. T3-4) was also an independent prognostic factor for OS (HR, 3.27; 95% CI, 1.768–6.048; P <0.001), PFS (HR, 2.051;

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95% CI, 1.229–3.421; P = 0.006), and LRFFS (HR, 2.464; 95% CI, 1.248–4.865; P = 0.009). On multivariate analysis for DMFS, age, sex, tumor location, primary tumor

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length, and clinical N stage were found to be independent prognostic factors.

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Subgroup Analysis by Clinical Stage On account of the importance of TNM stage on prognosis for EC, subgroup analysis was performed to investigate the survival benefit of PBT. For patients with stage I/II disease (n = 117), no statistically significant differences were identified in OS (P = 0.199), PFS (P = 0.133), LRFFS (P = 0.822), or DMFS (P = 0.08) between IMRT and PBT groups (Figure 2). In contrast, for patients with stage III disease (n = 226), the PBT group demonstrated significantly higher 5-year OS (34.6% vs. 25.0%, P = 0.038; Figure 3A) and PFS rates

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(33.5% vs. 13.2%, P = 0.005; Figure 3B) than the IMRT group. The 5-year LRFFS rate was also higher in the PBT group compared with the IMRT group, with marginally significant difference (62.6% vs. 43.4%, P = 0.051; Figure 3C). However, there was no

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significant difference in DMFS between groups in advanced stage patients (P = 0.191; Figure 3D).

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Discussion

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Similar to other malignancies, radiation techniques for EC have evolved over time. Whether the theoretical advantage of a new technique could translate into clinical benefit is a major concern in clinical practice. However, due to the lack of results from completed prospective trials comparing PBT with IMRT directly, the survival benefit of PBT is

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unclear. Based on this retrospective single-institution comparative study in a patient cohort treated by the same multidisciplinary group over the eight year span of the study period, we identified that the PBT group had significantly better survival outcomes than

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the IMRT group. In addition, the subgroup analysis further revealed that the survival

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benefit of PBT was only evident in the locally advanced stage but not the early stage patients. Considering cost-effectiveness, PBT might be a good option for patients with locally advanced stage EC, which comprises nearly two-thirds of the patients with non-metastatic EC.

Although definitive CRT is the standard of care for patients with unresectable or medically inoperable EC, the survival outcomes remain disappointing, with 3-year OS rates of around 40% to 50% using photon therapy (5, 20-22). Currently, there have been 4

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single-institutional studies reporting the survival of concurrent CRT with PBT in EC (13-16). The available PBT/chemotherapy data showed improved 3-year OS rates of 51.7%–70.4% when compared to historical results from photon therapy (13-16). Our

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study found that OS was significantly more favorable in the PBT group than that in the IMRT group (5-year OS rate, 41.6% vs. 31.6%, P = 0.011), which confirmed the survival benefit of PBT. Our study also demonstrated that radiation modality was an independent

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prognostic factor for OS, PFS, and LRFFS but not for DMFS in multivariate analysis.

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Similar survival outcomes have been suggested in other tumor sites, such as hepatocellular carcinoma and head and neck tumors (23, 24). It is difficult to fully account for all possible reasons why PBT group had more favorable survival, but it might be partially explained by the dosimetric advantages of PBT over IMRT. First, with the

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physical advantage of Bragg peak, the radiation dose of photons can be concentrated within the target, and the dose to adjacent organs could be minimized. Compared with photon therapy, the PBT technique could provide more conformal target coverage than

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IMRT, which has been proved by our dosimetric analysis. Thus, PBT might result in

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better locoregional control than IMRT, particularly for advanced stage EC. On the other hand, it has been demonstrated that the superior normal organ-sparing effect of IMRT over 3DCRT has a significantly clinical impact on reducing cardiac mortality in EC patients (5,6). As expected, the dosimetric comparisons had demonstrated that PBT provided significantly superior sparing of lung and heart over IMRT in the current study. While it is plausible that the better sparing of lung and heart effect of PBT might have contributed to the reduction in cardiopulmonary mortality in the PBT group, but we don’t

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have direct proof that this is in fact true since many of the deaths are due to unknown causes. What is important is that PBT had better disease control as well as overall survival. Second, it is plausible that there could be greater biological efficacy of protons, such as a

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RBE >1.1, which could have led to a more favorable local tumor control benefit. The improved local tumor control may have better systemic tumor control in the long term (25). Third, it has been documented that protons could mediate calreticulin cell-surface

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expression and increase sensitivity of tumor cells to cytotoxic T-lymphocyte killing,

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which might be also beneficial for disease control (26). Lastly, the reduction in low dose bath, which could result in less lymphopenia risk and improved immune surveillance in PBT patients, may have contributed to better tumor control (27). Whether the improved lymphopenia risk directly mediated the better cancer control advantage of PBT is a

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subject of intense future investigation at our institution.

The dosimetric advantages of PBT over IMRT in sparing normal tissues have been consistently verified by several planning studies (11, 12, 28). A dosimetric study in 15

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patients with distal EC showed that the PBT plans significantly reduced lung V5, V10,

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V20, and mean lung dose compared with the IMRT plans (11). Another study of comparing IMRT with IMPT plans in 21 patients with middle EC, conducted by the University of Oxford, identified that IMPT plans could achieve considerable reduction of mean dose to lung (reduced by 51.4%) and heart (reduced by 40.9%) (12). Likewise, a recent study reported by Welsh et al supported the dosimetric benefits of IMPT in sparing lung, heart, spinal cord, and liver (28). In addition to dosimetric studies, several clinical studies have displayed the actual dose to normal tissues. For example, Lin et al reported

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that the mean lung dose and mean heart dose were 6.3 Gy and 13.3 Gy for 54 EC patients receiving PBT, respectively (13). In contrast, another clinical study showed that the actual mean lung dose and mean heart dose were 10.9 Gy and 22.4 Gy for 258 patients treated

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with IMRT at the same institution (8). In our study, the directly actual dosimetric comparison also indicated the superiority of PBT over IMRT in sparing normal tissues. Therefore, PBT patients did have significantly lower dose to lung and heart than IMRT

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patients, which is consistent with the results of planning studies. Nevertheless, whether

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these dosimetric advantages of PBT over IMRT can convert into clinical improvement in reducing toxicities is still inconclusive due to the limited data in the literature. Wang et al compared the incidence of postoperative complications after trimodality therapy for EC among 3DCRT (208 patients), IMRT (164 patients), and PBT (72 patients) (7). PBT

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showed significantly lower risk of pulmonary and gastrointestinal complications than 3DCRT, whereas the differences between PBT and IMRT were not statistically significant. In the current study, the rate of grade 3-4 toxicities was also non-significantly lower in the

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PBT group than that in the IMRT group (37.9% vs. 45.0%, P = 0.192). However, we

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should note that a greater proportion of elderly patients (≥67 years) received PBT than IMRT (70.5% vs. 38.4%, P<0.001) due to insurance coverage. This confounding factor should be considered owing to the relationship between age and treatment tolerability. Prospective randomized trials will be helpful to address this issue. Compared with PSPT, the more advanced technique of IMPT is associated with further dosimetric benefits in dose conformity and sparing lung and heart (19). Up to now, only one study from the University of Washington Medical Center had been published to

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report the preliminary results of IMPT in EC (16). In this study, 13 EC patients received neoadjuvant CRT with IMPT, 12 of them underwent R0 resection, and 25% of patients achieved pathologic complete response. No grade ≥4 acute toxicity or grade ≥2 radiation

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pneumonitis was observed and only 1 patient (7.7%) experienced grade 3 esophagitis. Given the lack of clinical comparison between PSPT and IMPT in literature, whether IMPT can further improve clinical outcomes remains unknown. In the present study, only

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7 patients were treated with IMPT, which did not permit us to do further analysis.

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The concurrent chemotherapy regimen might affect the clinical response to CRT and survival outcomes in EC. However, although there has been multiple studies investigating the efficacy of different combinations of cytotoxic agents in recent years, no regimen has been widely accepted as being superior to the others (29). According to the results of 0113,

the

fluorouracil-based

arm

had

better

survival

than

the

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RTOG

non-fluorouracil-based arm in EC patients treated with definitive CRT (2-year OS rates: 56% vs. 37%). Moreover, the fluorouracil-based arm indicated less grade 4 toxicity and

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less treatment-related mortality compared with the non-fluorouracil-based arm (30).

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Therefore, given the safety and efficacy data, fluorouracil-based regimen has been the most commonly used regimen in the treatment of localized EC at our institution. Additionally, Javeri et al investigated the influence of the type of cytotoxics on survival and found that no difference was noted in survival between patients treated with taxane/fluorouracil or platinum/fluorouracil (31), which is consistent with our results. Despite our positive findings, there are many limitations in this research. With all the caveats of a retrospective review, we cannot fully explain all the reasons why some

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patients were treated with PBT but not IMRT. Patient assignment was typically done by the determination of multidisciplinary team and patients’ intent, however, the selection for the use of PBT or IMRT is usually not based on the disease characteristics but often due to

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economic reasons. The denial of insurance coverage for PBT was the major barrier towards PBT utilization. Moreover, we have noticed that Caucasian patients were more likely to receive PBT, suggesting that the choice of radiotherapy modality might also be

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influenced by socioeconomic status, as some of the more affluent patients could afford

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paying out-of-pocket. In addition, patients with greater tumor burden were appealed to be treated with PBT based on its better normal tissue sparing despite the larger treatment volume. Although it is without statistical significance, PBT patients tend to be more favorable in some clinical characteristics (e.g., less baseline weight loss, lower histologic

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grade, smaller tumors, and earlier N stage). Therefore, we can’t fully exclude the possibility that these slight imbalances might have influenced the final results. In addition, due to the retrospective nature and long-term follow-up, several patients did not have

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accurate documentation of the cause of death, which limited us to report cardiopulmonary

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mortality in this study.

Conclusions

Comparing clinical outcomes between PBT and IMRT demonstrates that PBT were associated with improved OS, PFS, and LRFFS, especially in EC patients with advanced stage. These results from the current study suggest that the theoretical advantage of PBT over IMRT might convert into survival benefit. Prospective controlled studies will better

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establish the role of PBT in EC.

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15. Ishikawa H, Hashimoto T, Moriwaki T, et al. Proton beam therapy combined with concurrent chemotherapy for esophageal cancer. Anticancer Res 2015;35:1757-1762. 16. Zeng YC, Vyas S, Dang Q, et al. Proton therapy posterior beam approach with pencil

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18. Edge SB, Byrd DR, Compton CC, et al (eds). AJCC Cancer Staging Manual (ed 7). New York, NY, Springer, 2010.

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22. Yu WW, Zhu ZF, Fu XL, et al. Simultaneous integrated boost intensity-modulated radiotherapy in esophageal carcinoma: early results of a phase II study. Strahlenther Onkol 2014;190:979-986.

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23. Qi WX, Fu S, Zhang Q, et al. Charged particle therapy versus photon therapy for patients with hepatocellular carcinoma: a systematic review and meta-analysis. Radiother Oncol 2015;114:289-295.

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25. Shapiro J, van Lanschot JJ, Hulshof MC, et al. Neoadjuvant chemoradiotherapy plus

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surgery versus surgery alone for oesophageal or junctional cancer (CROSS): long-term results of a randomised controlled trial. Lancet Oncol 2015;16:1090-1098. 26. Gameiro SR, Malamas AS, Bernstein MB, et al. Tumor Cells Surviving Exposure to Proton or Photon Radiation Share a Common Immunogenic Modulation Signature,

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28. Welsh J, Gomez D, Palmer MB, et al. Intensity-modulated proton therapy further reduces normal tissue exposure during definitive therapy for locally advanced distal esophageal tumors: a dosimetric study. Int J Radiat Oncol Biol Phys 2011;81:1336-1342.

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29. Conroy T, Galais MP, Raoul JL, et al. Definitive chemoradiotherapy with FOLFOX versus

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Oncol 2014;15:305-314. 30. Ajani JA, Winter K, Komaki R, et al. Phase II randomized trial of two nonoperative regimens of induction chemotherapy followed by chemoradiation in patients with

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localized carcinoma of the esophagus: RTOG 0113. J Clin Oncol 2008;26:4551-4556.

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31. Javeri H, Arora R, Correa AM, et al. Influence of induction chemotherapy and class of cytotoxics on pathologic response and survival after preoperative chemoradiation

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in patients with carcinoma of the esophagus. Cancer 2008;113:1302-1308.

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ACCEPTED MANUSCRIPT Figure Legends

Figure 1. Overall survival (A), progression-free survival (B), locoregional failure-free

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survival (C), and distant metastasis-free survival (D) of IMRT group versus PBT group.

Figure 2. Overall survival (A), progression-free survival (B), locoregional failure-free survival (C), and distant metastasis-free survival (D) of IMRT group versus PBT group in

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patients with stage I/II.

Figure 3. Overall survival (A), progression-free survival (B), locoregional failure-free survival (C), and distant metastasis-free survival (D) of IMRT group versus PBT group in

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patients with stage III.

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274 (79.9) 69 (20.1)

130 (61.6) 81 (38.4)

166 (78.7) 45 (21.3)

170 (80.6) 41 (19.4)

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290 (84.5) 53 (15.5)

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169 (49.3) 174 (50.7)

IMRT (n = 211) , %

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248 (72.3) 95 (27.7)

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205 (59.8) 138 (40.2)

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90 (26.2) 253 (73.8)

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Table 1 Patient Characteristics Characteristic Age (years) <67 ≥67 Sex Male Female Race Caucasian Others Smoking history Yes No Alcohol history Yes No ECOG performance status 0 1–2 Weight loss <10% ≥10% Histology Adenocarcinoma SCC Histologic grade

260 (75.8) 83 (24.2)

151 (71.6) 60 (28.4) 125 (59.2) 86 (40.8)

PBT (n = 132), %

P-value <0.001

39 (29.5) 93 (70.5) 0.480 108 (81.8) 24 (18.2) 0.010 120 (90.9) 12 (9.1) 0.699 97 (73.5) 35 (26.5) 0.802 80 (60.6) 52 (39.4) 0.680

57 (27.0) 154 (73.0)

33 (25.0) 99 (75.0) 0.124

154 (73.0) 57 (27.0)

106 (80.3) 26 (19.7) 0.292

245 (71.4) 98 (28.6)

155 (73.5) 56 (26.5)

90 (68.2) 42 (31.8) 0.222

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165 (48.1) 178 (51.9)

96 (45.5) 115 (54.5)

69 (52.3) 63 (47.7)

208 (60.6) 135 (39.4)

121 (57.3) 90 (42.7) 24 (11.4) 187 (88.6)

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38 (11.1) 305 (88.9)

57 (27.0) 154 (73.0)

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95 (27.7) 248 (72.3)

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105 (30.6) 238 (69.4)

61 (28.9) 150 (71.1)

38 (28.8) 94 (71.2) 0.114 87 (65.9) 45 (34.1) 0.825 14 (10.6) 118 (89.4) 0.387 44 (33.3) 88 (66.7) 0.644

70 (33.2) 141 (66.8)

47 (35.6) 85 (64.4)

97 (28.3) 246 (71.7)

59 (28.0) 152 (72.0)

38 (28.8) 94 (71.2)

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117 (34.1) 226 (65.9)

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G1-2 G3 Tumor location Upper/middle Distal/GEJ Primary tumor length ≤5 cm >5 cm Clinical T stage T1-2 T3-4 Clinical N stage N0 N+ Clinical TNM stage I/II III Induction chemotherapy Yes No Radiation dose (Gy) ≤50.4 >50.4 Concurrent chemotherapy regimen Platinum/fluorouracil Taxane/fluorouracil Other regimen*

300 (87.5) 43 (12.5)

0.869

0.604 183 (86.7) 28 (13.3)

117 (88.6) 15 (11.4) 0.125

74 (21.6) 216 (63.0) 53 (15.5)

48 (22.7) 137 (64.9) 26 (12.3)

26 (19.7) 79 (59.8) 27 (20.5)

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Reasons for no surgery 0.258 Unresectable or medically inoperable 80 (23.3) 50 (23.7) 30 (22.7) Selective observation 186 (54.2) 108 (51.2) 78 (59.1) Distant recurrence before surgery 77 (22.4) 53 (25.1) 24 (18.2) Salvage surgery 0.129 Yes 37 (10.8) 27 (12.8) 10 (7.6) No 306 (89.2) 184 (87.2) 122 (92.4) Years of diagnosis <0.001 2007–2010 177 (51.6) 128 (60.7) 49 (37.1) 2011–2014 166 (48.4) 83 (39.3) 83 (62.9) Abbreviations: IMRT, intensity-modulated radiation therapy; PBT, proton beam therapy; ECOG, Eastern Cooperative Oncology Group; SCC, squamous cell carcinoma; GEJ, gastroesophageal junction. *Other regimen: taxane/platinum or irinotecan/fluorouracil or irinotecan/platinum.

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Table 2 Treatment-related Toxicity IMRT Group (n = 211) PBT Group (n = 132) P-value Grade 1 Grade 2 Grade 3 Grade 4 Grade 5 Grade 1 Grade 2 Grade 3 Grade 4 Grade 5 Fatigue 46 (21.8) 67 (31.8) 9 (4.3) 0 (0.0) 0 (0.0) 36 (27.3) 38 (28.8) 5 (3.8) 0 (0.0) 0 (0.0) 0.711 Weight loss 96 (45.5) 22 (10.4) 3 (1.4) 0 (0.0) 0 (0.0) 63 (47.7) 14 (10.6) 1 (0.8) 0 (0.0) 0 (0.0) 0.929 Nausea 30 (14.2) 58 (27.5) 15 (7.1) 0 (0.0) 0 (0.0) 24 (18.2) 21 (15.9) 9 (6.8) 0 (0.0) 0 (0.0) 0.090 Anorexia 27 (12.8) 36 (17.1) 4 (1.9) 0 (0.0) 0 (0.0) 22 (16.7) 24 (18.2) 2 (1.5) 0 (0.0) 0 (0.0) 0.722 Esophagitis 25 (11.8) 66 (31.3) 30 (14.2) 0 (0.0) 1 (0.5) 12 (9.1) 45 (34.1) 15 (11.4) 0 (0.0) 0 (0.0) 0.717 Pneumonitis 17 (8.1) 8 (3.8) 4 (1.9) 1 (0.5) 1 (0.5) 10 (7.6) 3 (2.3) 1 (0.8) 0 (0.0) 1 (0.8) 0.825 Skin reaction 63 (29.9) 12 (5.7) 2 (0.9) 0 (0.0) 0 (0.0) 31 (23.5) 11 (8.3) 2 (1.5) 0 (0.0) 0 (0.0) 0.494 Pulmonary fibrosis 13 (6.2) 3 (1.4) 0 (0.0) 0 (0.0) 0 (0.0) 7 (5.3) 1 (0.8) 0 (0.0) 0 (0.0) 0 (0.0) 0.807 Pleural effusion 50 (23.7) 10 (4.7) 4 (1.9) 0 (0.0) 0 (0.0) 19 (14.4) 6 (4.5) 1 (0.8) 0 (0.0) 0 (0.0) 0.141 Pericardial effusion 23 (10.9) 0 (0.0) 5 (2.4) 0 (0.0) 0 (0.0) 14 (10.6) 0 (0.0) 1 (0.8) 0 (0.0) 0 (0.0) 0.536 Esophageal fistula 0 (0.0) 0 (0.0) 2 (0.9) 0 (0.0) 1 (0.5) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0.388 Esophageal stricture 2 (0.9) 6 (2.8) 16 (7.6) 0 (0.0) 1 (0.5) 2 (1.5) 4 (3.0) 13 (9.8) 0 (0.0) 0 (0.0) 0.842 Abbreviations: IMRT, intensity-modulated radiation therapy; PBT, proton beam therapy.

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Table 3 Multivariate Analysis for Survival End-point Independent factors Hazard ratio 95% CI P-value OS ECOG performance status (0 vs. 1–2) 1.391 1.016–1.905 0.040 Clinical T stage (T1-2 vs. T3-4) 3.270 1.768–6.048 <0.001 Clinical N stage (N0 vs. N+) 1.363 1.004–1.851 0.047 Radiotherapy modality (PBT vs. IMRT) 1.454 1.092–1.936 0.010 PFS Sex (female vs. male) 1.479 1.053–2.079 0.024 Primary tumor length (≤5 vs. >5 cm) 1.571 1.210–-2.041 0.001 Clinical T stage (T1-2 vs. T3-4) 2.051 1.229–3.421 0.006 Radiotherapy modality (PBT vs. IMRT) 1.562 1.193–2.045 0.001 LRFFS Clinical T stage (T1-2 vs. T3-4) 2.464 1.248–4.865 0.009 Radiotherapy modality (PBT vs. IMRT) 1.461 1.016–2.102 0.041 DMFS Age (<67 vs. ≥67) 0.685 0.485–0.969 0.032 Sex (female vs. male) 1.715 1.007–2.920 0.047 Tumor location (upper/middle vs. distal/GEJ) 1.633 1.038–2.568 0.034 Primary tumor length (≤5 vs. >5 cm) 1.838 1.294–2.610 0.001 Clinical N stage (N0 vs. N+) 1.633 1.067–2.501 0.024 Abbreviations: OS, overall survival; PFS, progression-free survival; LRFFS, locoregional failure-free survival; DMFS, distant metastasis-free survival; ECOG, Eastern Cooperative Oncology Group; PBT, proton beam therapy; IMRT, intensity-modulated radiation therapy; GEJ, gastroesophageal junction.

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Summary This study aimed to compare clinical outcomes between proton therapy and intensity-modulated radiation therapy (IMRT) in well-matched patients with esophageal cancer who received

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definitive chemoradiotherapy. The results indicated that proton therapy was associated with significantly improved overall survival, progression-free survival, and locoregional failure-free survival compared with IMRT, especially in patients with locally advanced disease. The results

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from the current study suggest that the dosimetric advantage of proton therapy appeared to

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translate into improved clinical benefit.