Radiotherapy target volumes in esophageal cancer: The twisting kaleidoscope

Gautam Sarma; Jyotiman Nath; Biswajit Sarma

doi:10.4103/jrcr.jrcr_25_22

REVIEW ARTICLE

Year : 2023 | Volume : 14 | Issue : 1 | Page : 1-7

Radiotherapy target volumes in esophageal cancer: The twisting kaleidoscope

Gautam Sarma, Jyotiman Nath, Biswajit Sarma
Department of Radiation Oncology, Dr. B Borooah Cancer Institute, Guwahati, Assam, India

Date of Submission	31-Mar-2022
Date of Acceptance	20-Apr-2022
Date of Web Publication	01-Nov-2022

Correspondence Address:
Dr. Biswajit Sarma
Department of Radiation Oncology, Dr. B Borooah Cancer Institute, Guwahati, Assam
India

Source of Support: None, Conflict of Interest: None

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DOI: 10.4103/jrcr.jrcr_25_22

Abstract

Incidence of carcinoma esophagus accounts for approximately 6% of all gastrointestinal malignancies. According to GLOBOCAN 2020 data, 604,100 cases of carcinoma esophagus were detected (3.1% of total cases), and it was the 8^th most common cancer in the world. The first choice of treatment for resectable esophageal cancer is surgery. Neoadjuvant radio-chemotherapy improved the overall survival (OS) of patients with advanced carcinomas of the esophagus by about 10% in 5 years, as shown by different studies. In unresectable cases, carcinoma esophagus definitive chemoradiation is the treatment of choice. Determination of the target volume of the esophagus has changed with time due to the advancement of technology. Determining the target volumes accurately is essential to achieve precise dose delivery to the targets. Controversies still exist between different regions and societies regarding target volume determination. However, the choice of the treatment volumes, techniques, and dose for optimal use must be individualized. Patients' disease status, preference, and comorbidities should also be considered while making decisions. This article will review the different target volumes, techniques, and doses used in various large trials used in definitive, neoadjuvant, and adjuvant studies.

Keywords: Carcinoma, chemoradiation, esophagus, radiotherapy, target volume

How to cite this article:
Sarma G, Nath J, Sarma B. Radiotherapy target volumes in esophageal cancer: The twisting kaleidoscope. J Radiat Cancer Res 2023;14:1-7

How to cite this URL:
Sarma G, Nath J, Sarma B. Radiotherapy target volumes in esophageal cancer: The twisting kaleidoscope. J Radiat Cancer Res [serial online] 2023 [cited 2023 Jun 7];14:1-7. Available from: https://www.journalrcr.org/text.asp?2023/14/1/1/360283

Introduction

Incidence of carcinoma esophagus accounts for approximately 6% of all gastrointestinal malignancies.^[1] The epidemiology of esophageal cancer is defined by its substantial variability in histologic type, geographic area, gender, race, and ethnic background.^[2] According to geography, the incidence of esophageal carcinoma varies and is highest in Linxian, China, Russia, and the Caspian region of Iran. It is known as the esophageal cancer belt, extending from Iran through the central Asian republics to north-central China. In northern France, Kazakhstan, and South Africa, the incidence of esophageal carcinoma is as high as 50–99/100,000.

According to GLOBOCAN 2020 data, 604,100 cases of carcinoma esophagus were detected (3.1% of total cases), and it was the 8^th most common cancer in the world.^[3]

The first choice of treatment for resectable esophageal cancer is surgery. In early esophageal cancer (T1-2), surgical resection usually results in long-term survival, but surgery alone has a poorer prognosis in the advanced stage (T3-4).^[4] Neoadjuvant radio-chemotherapy improved the OS of patients with advanced carcinomas of the esophagus by about 10% in 5 years, according to current Cochrane analysis, meta-analysis, the actual perspective, randomized Chemo Radiotherapy for Oesophageal cancer followed by Surgery Study (CROSS)-trial, and retrospective studies.^[5] In cases with unresectable carcinoma esophagus, definitive chemoradiation is the treatment of choice.

Determination of the target volume of the esophagus has changed with time due to the advancement of technology. International Commission on Radiation Units and Measurements report 50 and 62 are presently followed worldwide to define target volumes.^[6],[7] Modern conformal radiotherapy (RT) techniques mainly aim to reduce acute and chronic side effects of RT. It is of utmost importance to determine the target volumes accurately to achieve precise dose delivery to the targets. However, controversies still exist between different regions and societies regarding target volume determination.

This article will review the different target volumes, techniques, and doses used in various large trials used in definitive, neoadjuvant, and adjuvant studies.

Radiotherapy techniques and dosage used in definitive chemoradiotherapy trials

Radiation Therapy Oncology Group 85-01 trial

Radiation Therapy Oncology Group 85-01 trial included 129 patients with carcinoma esophagus with squamous cell carcinoma (SCC) (86%) or adenocarcinoma (14%) without gastric involvement or distant metastases. Patients were randomized into two arms. One arm received radiation alone to 64 Gy in 32 fractions, and the other arm received radiation of 50 Gy in 25 fractions with concurrent chemotherapy 5-FU and cisplatin.

At 5 years' follow-up, the OS for the combined chemoradiation arm was found to be 26% and 0% in RT alone arm.

Radiotherapy

The RT field extended from the supraclavicular region to the gastroesophageal junction. Five centimeter proximal and distal margins were added to the gross tumor volume (GTV). Bilateral supraclavicular regions were included for the upper and mid-thoracic esophagus. In the radiation alone arm, a dose of 50 Gy in 25 fractions was delivered in the first phase. It was followed by a boost dose of 14 Gy in 7 fractions with a 5-cm margin proximal and distal to the tumor.

In the chemoradiation arm, a dose of 30 Gy was delivered in 15 fractions. The radiation field extended from the supraclavicular region to the gastroesophageal junction. This was followed by 20 Gy in 10 fractions, including the gross tumor with 5-cm proximal and distal margins.^[8]

Chemotherapy

Concurrent cisplatin 75 mg/m² body surface area (BSA) was given on day 1 of weeks 1, 5, 8, and 11. 5FU was administered as a continuous infusion of 1 g/m² BSA for the first 4 days of weeks 1, 5, 8, and 11.

INT 0123 (Radiation Therapy Oncology Group 94-05) trial

Two hundred and eighteen patients diagnosed with either SCC (85%) or adenocarcinoma (15%) were randomized into two arms. Both arms received combined modality therapy chemoradiation. Both arms received the same concurrent chemotherapy regimen of cisplatin and fluorouracil. One arm received a high dose (HD) of radiation of 6480 cGy (high-dose), and the other arm received radiation to the standard dose of 5040 cGy.

Radiotherapy

Six megavolt (MV) photon energy was used to deliver radiation using multiple-field techniques. Patients were treated 5 days/week at 1.8 Gy/day.

Standard dose (50.4 Gy) target volume: The superior and inferior borders of the radiation field were 5 cm beyond the primary tumor. The anterior, lateral, and posterior borders had a margin of 2 cm from the primary tumor. The endoscopic ultrasound (EUS), barium swallow, or computed tomography (CT) scan defined the target volume. The radiation portal included the primary and the regional lymph nodes. For tumors of the cervical esophagus, the supraclavicular lymph nodes were included. A separate photon or electron boost to the supraclavicular lymph nodes was allowed to bring the total dose to 50.4 Gy.

High-dose (64.8 Gy) target volume: Patients randomized to the high-dose arm received a boost dose of radiation of 14.4 Gy after an initial dose of 50.4 Gy. In the boost volume, the proximal and distal margins of the target volume were kept at 2 cm from both ends of the tumor. The anterior, lateral, and posterior borders were the same as the initial target volume. Regional and primary nodes were not included in the boost volume.

Chemotherapy

Cisplatin 75 mg/m² bolus was given over 30 min with adequate hydration, mannitol, and antiemetic coverage on day 1.

5-FU 1000 mg/m²/24 h was given by continuous infusion on days 1 to 4 of each cycle. The chemotherapy cycles were repeated every 28 days. Patients had a 4-week rest after the completion of radiation and then received an additional two cycles (days 1 and 29) of chemotherapy. Therefore, cycle three of chemotherapy started on week 11 in the high-dose arm and week 9 in the standard-dose arm.

The result of this study shows that there was no significant difference in median survival (13 vs. 18.1 months), 2-year survival (31% vs. 40%), or locoregional failure (56% vs. 52%) between the high-dose and standard-dose arms, respectively. This trial established 5040 cGy as the standard dose for definitive chemoradiation.^[9]

ARTDECO trial

Two hundred sixty patients diagnosed with carcinoma esophagus referred for definitive chemoradiotherapy were randomly assigned between two arms. SCC histology constituted 61% of cases, and adenocarcinoma was 39%. A standard deviation (SD) arm planned to receive a radiation dose of 50.4 Gy in 28 fractions for 5.5 weeks to the tumor and regional lymph nodes, and a HD arm is planned to receive radiation up to a total dose of 61.6 Gy to the primary tumor. Chemotherapy consisted of courses of concurrent carboplatin (area under curve 2) and paclitaxel (50 mg/m²) in both arms once a week for 6 weeks. Both the arms got at least five doses of concurrent chemotherapy.

Radiotherapy

Six MV photons were used to deliver radiation using multiple conformal beams.

The clinical target volume (CTV) of the 50.4 Gy consists of 3-cm margins added to the proximal and distal ends of the GTV. CTV included primary GTV and the regional lymph node area. The regional lymph nodal areas included in the treatment portals were periesophageal fatty tissue, the supraclavicular area on both sides, the aortopulmonary window, and the subcarinal area. The fatty tissue along the left gastric artery in the hepatogastric ligament and regions within the 3-cm proximal and distal extension from the GTV is also included in the portals. All pathologic nodes had to be included in the CTV with at least a 0.5-cm margin. In the case tumor extends into the stomach, the CTV margin was limited to 2 cm in the direction of the cardia. The planning target volume (PTV) consisted of the CTV plus a margin of 1 cm in all directions [Figure 1]. [Table 1] depicts RT details including the CTV margins used in the major trials of definitive chemoradiation.

Figure 1: Radiotherapy target volume as per landmark trials (a) PTV as in CROSS Trial (b) CTV as in RTOG 1010 Trial (c) CTV as in ARTDECO Trial. PTV: Planning target volume, CTV: Clinical target volume. RTOG: Radiation Therapy Oncology Group, CROSS: Chemo Radiotherapy for Oesophageal cancer followed by Surgery Study

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Table 1: Radiotherapy parameters in some of the definitive chemoradiotherapy trials

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The HD arm received a simultaneous integrated boost dose of an additional 0.4 Gy (total of 2.2 Gy per fraction). The PTV of the integrated boost dose consisted of the GTV plus a margin of 1 cm in all directions. Using kilovolt images or cone-beam CT scans, weekly position verifications were carried out.

Chemotherapy

Carboplatin (area under the curve [AUC] of 2) and paclitaxel (50 mg/m²) were administered once weekly starting on day 1 for 6 weeks concurrent with RT in both arms. No adjuvant or neoadjuvant chemotherapy was administered.

This study concluded that radiation dose escalation from 50.4 Gy to 61.6 Gy for 5.5 weeks for esophageal tumors did not improve local tumor control or survival. A dose of 50.4 Gy remains the SD, with acceptable locoregional and survival outcomes.^[10]

Radiotherapy techniques and dosage used in neoadjuvant chemoradiotherapy trials

Neoadjuvant chemoradiotherapy plus surgery versus surgery alone for oesophageal or junctional cancer (CROSS trial)

Radiotherapy

Planning CT scan was taken from the cricoid to the L1 vertebra with a slice thickness of 5 mm. Patients were prescribed a total dose of 41.4 Gy in 23 fractions. All patients were irradiated by external beam radiation using the three-dimensional (3D) conformal radiation technique. The patients were positioned in the supine position. Orthogonal laser beams were used to assess reproducibility. The GTV was defined by the primary tumor and any enlarged regional lymph nodes. The GTV was determined using all available information: physical examination, endoscopy, EUS, and CT of the thorax/abdomen. The PTV was generated using a proximal and distal margin of 4 cm around the GTV [Figure 1]. A 1.5-cm radial margin around the GTV was given to include the areas of subclinical involvement and to compensate for tumor motion and setup variations. In the case of tumor extension into the stomach, a distal margin of 3 cm was chosen.

Chemotherapy regimen

Paclitaxel 50 mg/m² BSA and carboplatin (AUC = 2) were given by intravenous infusion on days 1, 8, 15, 22, and 29.^[11]

Radiation Therapy Oncology Group 1010 trial

This study created CTV using 4-cm superior/inferior and 1.0–1.5-cm radial expansion around the GTV. PTV was generated by giving CTV a uniform 0.5–1-cm expansion. The radiation dose of 4500 cGy was delivered in the first phase. Subsequently, GTV was boosted to a total dose of 5040cGy by giving a uniform 0.5–1.0-cm expansion around the GTV for the last three fractions [Figure 1]. Patients were randomized in two arms. One arm received doublet chemotherapy with paclitaxel and carboplatin, while the other arm received triplet chemotherapy using paclitaxel, carboplatin, and trastuzumab. Patients underwent surgery after 5–8 weeks of completion of neoadjuvant chemoradiation.

This trial concluded that disease-free survival (DFS) was not improved with the addition of Trastuzumab to the trimodality treatment of adenocarcinoma esophagus.^[12]

The CALGB 9781 trial

This trial randomized patients to neoadjuvant chemoradiation using a radiation dose of 50.4 Gy in 28 fractions with concurrent cisplatin and 5-FU followed by surgery versus surgery alone.

The median and 5-year survival rates were 4.5 years and 39% for patients receiving chemoradiation and 1.8 years and 16% for patients undergoing surgery alone.^[13]

NEOCRTEC 5010 trial

The Neoadjuvant Chemoradiotherapy (NCRT) for Esophageal Cancer 5010 (NEOCRTEC5010) randomized clinical trial compared treatment with NCRT (squamous cell ca only) followed by surgery (NCRT group) versus treatment with surgery alone (surgery group).

Radion therapy dose–volume and techniques

The GTV encompassed the primary tumor and enlarged regional lymph nodes. The CTV included the GTV with an additional 3.0-cm proximal and distal margin and 0.5- to 1.0-cm radial margin to cover the area of subclinical involvement. The PTV was created to include an 0.8-cm margin from the CTV for setup variations and respiratory-induced tumor motion. RT was delivered with 6–8 MV photons using the 3D conformal RT technique. The planned dose for the planned target volume was 40.0 Gy in 20 fractions over 4 weeks.

Chemotherapy in neoadjuvant arm: Patients in the NCRT group received either 25 mg/m² of vinorelbine on days 1 and 8 and 75 mg/m² of cisplatin on days 1 or 25 mg/m² of cisplatin on days 1–4 of a 21-day cycle for two cycles.

This trial shows that patients receiving NCRT plus surgery had prolonged OS compared with those receiving surgery alone, with a 5-year survival rate of 59.9% versus 49.1%, respectively. Compared with the surgery group, patients in the NCRT group also had prolonged DFS (hazard ratio, 0.60; 95% confidence interval, 0.45–0.80; P < 0.001), with a 5-year survival rate of 63.6% versus 43.0%, respectively.^[14] [Table 2] depicts RT details including the CTV margins used in the major trials of neoadjuvant chemoradiation.

Table 2: Radiotherapy parameters in some of the neoadjuvant chemoradiotherapy trials

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Radiotherapy techniques and dosage used in adjuvant trials

In the prospective randomized controlled study done by Fok et al., 130 patients of carcinoma esophagus were recruited. Patients were randomized to receive adjuvant postoperative radiation or observation.
The RT field was set up using a craniocaudal margin of 5 cm to the initial tumor as delineated by preoperative barium swallow. A 6–9 mm radial margin was given around the target volume. If the resection margin was positive, the anastomotic junction was included in the target volume. A RT dose of 49 Gy in 14 fractions was delivered. They concluded that the adjuvant RT arm's median OS was worse.^[15]
Xiao et al. conducted a randomized prospective controlled study in 2003 where they included 495 patients with SCC of the esophagus after total esophagectomy. They randomized them into two arms. One arm received postoperative radiation therapy (n = 220) and the other observation (n = 275).
The cranial border of the radiation field was kept at the tip of the cricoid cartilage to include the bilateral supraclavicular region. The caudal border of the field extended to encompass the entire mediastinum, the site of anastomosis, and the left epiploic and paracardiac lymphatics. The dose prescribed was 60 Gy in 30 fractions. The supraclavicular region received a radiation dose of 50 Gy in 25 fractions. This study showed a nonsignificant improvement in survival with the addition of RT from 32% to 41% (P = 0.45). Stage III patients had a distinct, significant OS improvement with the addition of RT from 13% to 35% at 5 years (P = 0.003).^[16]
A phase 2/3 prospective randomized controlled trial on adjuvant RT or concurrent chemo RT after surgery versus surgery alone was conducted by Xiao et al. in China in 2020. CTV was different for different anatomic locations of the primary tumor. CTV corresponds to the site of the tumor bed and lymphatic drainage.

For the tumors of the upper thoracic esophagus, the upper border of CTV started from the cricothyroid membrane. The lower border of CTV was at the level of 3-cm distal to the lower margin of the tumor bed or carina. The lymphatic stations included were lower cervical, bilateral supraclavicular, 1R, 1L, 2R, 2L, 3P, 4R, 4L, and 7.

For tumors located in the mid-thoracic esophagus, the upper margin of the city was at the level of the first thoracic vertebra, and the lower margin was at the level of 3 cm from the distal margin of the tumor bed. The lymphatic stations included here were the same as the upper thoracic esophagus; additionally, part of station eight was included.

For tumors located in the lower thoracic esophagus, the upper margin of the CTV was taken at the first thoracic vertebral body and the lower margin at the celiac axis. The lymph nodal stations included were bilateral supraclavicular stations 1R, 1L, 2R, 2L, 3p, 4R, 4L, 7, 8, 16, 17, 18, 19, and 20.

Anastomotic junction was included in the CTV for patients with upper-thoracic tumors and patients who have an insufficient proximal margin (<3cm). The dose prescribed was 54 Gy in 27 fractions in the adjuvant radiation arm and 50.4 Gy in 28 fractions in the adjuvant chemoradiation arm. Chemotherapy drugs used were paclitaxel (135–150 mg/m²) and cisplatin or nedaplatin (50–75) mg/m² BSA. The result of this study is awaited.^[4]

Recommendation by different guidelines

European Society for Medical Oncology clinical practice guideline recommends a radiation dose of 41.4 Gy in 23 fractions along with concurrent paclitaxel (50 mg/m² BSA) and carboplatin (AUC = 2) as a treatment standard for resectable carcinoma esophagus. For definitive chemoradiation, a radiation dose of 50.4 Gy in 28 fractions and concurrent cisplatin and 5FU is recommended^[17]
National Comprehensive Cancer Network (NCCN) recommends neoadjuvant RT dose 41.4 Gy–50.4 Gy in 23–28 fractions. The radiation dose of 50.4 Gy in 28 fractions is recommended for a definitive setting.

Concurrent chemotherapy with paclitaxel (50 mg/m² BSA) and carboplatin (AUC = 2) weekly is recommended in the definitive and neoadjuvant setting.^[18]

Discussion

The role of RT in managing esophageal cancer has evolved in the last two decades. The techniques of RT, dose, target volume, etc., have been continuously developing with the results of various trials. Historically when radiation therapy alone was used to treat localized cancer, the 2–year OS was below 20%. However, the long-term results of the CROSS trial have shown that the absolute 10-year OS benefit was 13% in the patients of neoadjuvant chemo RT arm (38% vs. 25%) than the surgery only. There is also a reduced risk of death from esophageal cancer. This improvement in OS is well attributed to the more developed RT treatment delivery.

In earlier trials like RTOG8501, the target volume included the whole of the esophagus, including the supraclavicular region and the gastroesophageal junction. The target volume was modified in the Intergroup 0123 trial to cover the 5 cm of the gross disease's proximal and distal. In the more recent ARTEDECO trial, the investigators have used more tailored CTV margins of 3 cm craniocaudally from the gross disease. The improved quality of life among the patients of recent trials may be well attributed to the tailored CTV margins.

There is now sufficient evidence to support the use of neoadjuvant chemoradiation before surgery for oesophageal cancer. The NEOCRTEC5010 and the CROSS trial established the use of neoadjuvant chemoradiation before surgery in both adenocarcinoma and SCC of the esophagus. For the patients who undergo definitive chemoradiation, controversy regarding the radiation dose has existed for decades. Few meta-analyses showed the superiority of higher radiation doses for the definitive treatment of esophageal cancer.^[19],[20] The NCCN recommended a definitive radiation dose of 50 or 50.4 Gy is based on the two-decade-old INT 0123 trial, which showed no benefit in the dose-escalated arm and was prematurely closed to increased toxicity and futility.

Similarly, the recently published Phase III ARTEDECO trial could not show any significant benefit of a higher radiation dose over the standard dose of around 50 Gy in the definitive management of esophageal cancer. Newer RT techniques, such as three-dimensional conformal radiotherapy 3, intensity-modulated radiotherapy (IMRT), or volumetric-modulated arc therapy (VMAT), have improved and replaced traditional techniques. Compliance with RT was more than 90% in the ARTDECO study due to the use of IMRT in all the patients. However, the choice of the treatment volumes, techniques, and dose for optimal use must be individualized. A patient's disease status, preference, and comorbidities should also be considered while making a decision.

Conclusion

RT is imperative in managing esophageal cancer, both as definitive local therapy and as an adjunct to surgical resection. RT target volumes, techniques, and doses for the esophagus have evolved with newer technologies and large randomized trials. 50 Gy or 50.4 Gy with concurrent chemotherapy is standard for definitive therapy. Neoadjuvant RT of 41.4 Gy with concurrent chemotherapy before surgery has shown survival benefits in long-term follow-up over surgery alone. The CTV margins for definitive chemoradiation have changed from 5 cm to a more precise 3-cm craniocaudal margin in the recent ARTDECO trial. However, in the centers practicing 2D RT, 5-cm proximal and distal margin to the GTV is still recommended. Similarly, the more recent trials on neoadjuvant chemoradiation have used smaller craniocaudal CTV of 3 cm with similar oncological outcomes. Advanced radiation techniques such as IMRT, VMAT, and protons result superior outcomes with improved quality of life.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

References

1.	Ott K, Weber W, Siewert JR. The importance of PET in the diagnosis and response evaluation of esophageal cancer. Dis Esophagus 2006;19:433-42.
2.	Brown LM, Devesa SS. Epidemiologic trends in esophageal and gastric cancer in the United States. Surg Oncol Clin N Am 2002;11:235-56.
3.	Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2021;71:209-49.
4.	Bollschweiler E, Hölscher AH, Schmidt M, Warnecke-Eberz U. Neoadjuvant treatment for advanced esophageal cancer: Response assessment before surgery and how to predict response to chemoradiation before starting treatment. Chin J Cancer Res 2015;27:221-30.
5.	Fan N, Wang Z, Zhou C, Bludau M, Contino G, Zhao Y, et al. Comparison of outcomes between neoadjuvant chemoradiotherapy and neoadjuvant chemotherapy in patients with locally advanced esophageal cancer: A network meta-analysis. EClinicalMedicine 2021;42:101183.
6.	International Commission on Radiation Units and Measurements (ICRU). ICRU Report 50: Prescribing, Recording, and Reporting Photon Beam Therapy. Bethesda, MD: ICRU Publications; 1993.
7.	International Commission on Radiation Units and Measurements (ICRU). ICRU Report 62: Prescribing, Recording, and Reporting Photon Beam Therapy (Supplement to ICRU Report 50). Bethesda, MD: ICRU Publications; 1999.
8.	Cooper J, Guo M, Herskovic A, Macdonald J, Martenson, Jr J, Al-Sarraf M et al. Chemoradiotherapy of Locally Advanced Esophageal Cancer. JAMA. 1999;281(17).
9.	Minsky BD, Pajak TF, Ginsberg RJ, Pisansky TM, Martenson J, Komaki R, et al. INT 0123 (Radiation Therapy Oncology Group 94-05) phase III trial of combined-modality therapy for esophageal cancer: High-dose versus standard-dose radiation therapy. J Clin Oncol 2002;20:1167-74.
10.	Hulshof MC, Geijsen ED, Rozema T, Oppedijk V, Buijsen J, Neelis KJ, et al. Randomized study on dose escalation in definitive chemoradiation for patients with locally advanced esophageal cancer (ARTDECO Study). J Clin Oncol 2021;39:2816-24.
11.	van Hagen P, Hulshof MC, van Lanschot JJ, Steyerberg EW, van Berge Henegouwen MI, Wijnhoven BP, et al. Preoperative chemoradiotherapy for esophageal or junctional cancer. N Engl J Med 2012;366:2074-84.
12.	Safran H, Winter K, Wigle D, DiPetrillo T, Haddock M, Hong T, et al. Trastuzumab with trimodality treatment for esophageal adenocarcinoma with HER2 overexpression: NRG Oncology/ RTOG 1010. J Clin Oncol 2020;38(15 Suppl):4500.
13.	Tepper J, Krasna MJ, Niedzwiecki D, Hollis D, Reed CE, Goldberg R, et al. Phase III trial of trimodality therapy with cisplatin, fluorouracil, radiotherapy, and surgery compared with surgery alone for esophageal cancer: CALGB 9781. J Clin Oncol 2008;26:1086-92.
14.	Yang H, Liu H, Chen Y, Zhu C, Fang W, Yu Z, et al. Neoadjuvant chemoradiotherapy followed by surgery versus surgery alone for locally advanced squamous cell carcinoma of the esophagus (NEOCRTEC5010): A Phase III Multicenter, Randomized, Open-Label Clinical Trial. J Clin Oncol 2018;36:2796-803.
15.	Fok M, Sham JS, Choy D, Cheng SW, Wong J. Postoperative radiotherapy for carcinoma of the esophagus: A prospective, randomized controlled study. Surgery 1993;113:138-47.
16.	Xiao ZF, Yang ZY, Liang J, Miao YJ, Wang M, Yin WB, et al. Value of radiotherapy after radical surgery for esophageal carcinoma: A report of 495 patients. Ann Thorac Surg 2003;75:331-6.
17.	Lordick F, Mariette C, Haustermans K, Obermannová R, Arnold D. Oesophageal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2016;27:v50-7.
18.	Available from: https://www.nccn.org/guidelines/guidelines-process/transparency-process-and-recommendations/GetFileFrom.FileManager?fileManagerId=11557. [Last accessed on 2022 Mar 27].
19.	Chow R, Lock M, Lee SL, Lo SS, Simone CB 2^nd. Esophageal cancer radiotherapy dose escalation meta regression commentary: “High vs. low radiation dose of concurrent chemoradiotherapy for esophageal carcinoma with modern radiotherapy techniques: A meta-analysis”. Front Oncol 2021;11:700300.
20.	Xiao L, Czito BG, Pang Q, Hui Z, Jing S, Shan B, et al. Do higher radiation doses with concurrent chemotherapy in the definitive treatment of esophageal cancer improve outcomes? A meta-analysis and systematic review. J Cancer 2020;11:4605-13.