Radiotherapy treatment planning for esophageal cancer: JASTRO guidelines 2024 for radiotherapy treatment planning

Abstract

The Japanese Society for Radiation Oncology (JASTRO) Guidelines for Radiotherapy Treatment Planning have been revised every four years to incorporate the latest findings since the publication of the first edition in 2004. This is a review which presents the 2024 JASTRO Guidelines for radiotherapy treatment planning for esophageal cancer in English. Regarding the treatment of esophageal cancer, various new findings have emerged over the past 4 years, leading to significant updates in the 2020 edition, particularly in the following six areas: (i) additional details on indications for superficial cancer, (ii) inclusion of clinical trial results (JCOG1109) for neoadjuvant chemotherapy and chemoradiotherapy in locally advanced cases in Japan, (iii) updated references on prophylactic lymph node irradiation, (iv) updates on IMRT, (v) revisions in accordance with the 5th edition of the Esophageal Cancer Treatment Guidelines, and (vi) additions of FOLFOX to concurrent chemotherapy regimens.

SIGNIFICANCE AND INDICATIONS OF RADIOTHERAPY

In cases of superficial cancer (T1a, T1b) following endoscopic treatment (EMR/ESD), prophylactic chemoradiotherapy may be considered if pathological findings indicate a possibility of lymph node metastasis. This is generally performed when there is submucosal invasion or positive vascular invasion [1]. Additionally, when endoscopic resection is challenging or residual disease is suspected after EMR/ESD, it becomes a treatment option alongside surgery.

2) For locally or regionally advanced cases, neoadjuvant chemotherapy (DCF) combining Docetaxel, Cisplatin, and Fluorouracil followed by surgery is considered the standard treatment in Japan. For cases in which surgery is not feasible, (chemo)radiotherapy is often chosen as an alternative.

3) As an adjuvant therapy, chemoradiotherapy has been shown in international meta-analyses to improve prognosis when used as neoadjuvant chemoradiotherapy [2]; however, its effectiveness has not been widely recognized in Japan. A three-arm randomized controlled trial (JCOG1109) was conducted in Japan to evaluate this approach. The study demonstrated that neoadjuvant chemotherapy with docetaxel, cisplatin, and fluorouracil (DCF) significantly outperformed neoadjuvant chemotherapy with two agents, cisplatin and fluorouracil (CF). However, while neoadjuvant chemoradiotherapy (CF + RT) showed better outcomes than those of CF chemotherapy alone, the difference was not statistically significant. Although neoadjuvant chemoradiotherapy (CF + RT) achieved a higher local control rate, it was associated with a higher incidence of deaths due to other causes. Based on these findings, the standard treatment for esophageal squamous cell carcinoma in Japan (in patients with resectable locally advanced disease without prior treatment history, cT1N1-3 M0 or cT2-3 N0-3 M0, aged 20–75 years, and ECOG PS of 0–1) is neoadjuvant chemotherapy with DCF followed by surgery [3]. A randomized comparative trial in China focusing on cT3–4aN0-1 M0 esophageal squamous cell carcinoma in which the outcomes of neoadjuvant chemotherapy followed by surgery were compared with the outcomes of neoadjuvant chemoradiotherapy followed by surgery showed no significant difference in 3-year overall survival and recurrence-free survival rates [4].

4) For locoregional recurrence after curative surgery, chemoradiotherapy is often performed if there is no prior history of radiotherapy to the same site [5, 6]. The NCCN guidelines also recommend chemoradiotherapy as the preferred treatment [7].

RADIATION THERAPY

Radiotherapy treatment planning

Three-dimensional treatment planning using CT is standard. Radiation therapy planning that takes respiratory motion into account is necessary, particularly for the lower thoracic region, abdominal esophagus, and associated lymph nodes. For lesions in the lower esophagus, it is recommended to use four-dimensional CT for treatment planning whenever possible or to confirm respiratory motion using an X-ray simulator.

Target volume

① Gross tumor volume (GTV) 

①−1 GTV-primary 

Determination of the tumor’s upper and lower margins is made on the basis of a comprehensive evaluation using endoscopy, fluoroscopy, CT, MRI, and positron emission tomography (PET). In cases of superficial cancer in which the lesion cannot be visualized by CT or fluoroscopy, metallic clips are placed endoscopically at the proximal and distal ends of the lesion. Chromoendoscopy is essential, and careful attention should be paid to multiple lesions. Since clips often become dislodged, it is advisable to perform CT imaging for treatment planning immediately after clip placement or to take plain X-ray images in the treatment position.

①−2 GTV-lymph node 

Lymph node metastasis is comprehensively evaluated by imaging and palpation findings. While it is challenging to accurately assess lymph node metastasis using imaging alone, it has been reported that lymph nodes with a short-axis diameter of 5 mm or larger should be considered as metastatic lesions requiring treatment [8]. Even for lymph nodes smaller than 5 mm, attention should be given to those for which the short-axis diameter and long-axis diameter are of nearly equal lengths [9]. Conversely, even in patients without metastases, right recurrent nerve nodes with a short-axis diameter of 5 mm or larger were found in 24.9% of patients, and subcarinal nodes in 83.5% of patients [10]. If metastasis is suspected on the basis of a comprehensive evaluation, it may be included as a GTV-lymph node (particularly for highly metastatic sites such as #106). In JCOG 0502 (target population: cT1bN0M0), the accuracy rate for clinical staging of lymph nodes was only 27% [11].

The sensitivity and specificity of FDG-PET for detecting metastatic lymph nodes in esophageal cancer are not necessarily high, and it is not appropriate to rely solely on PET findings to determine metastatic lymph nodes and plan treatment [12]. On the other hand, it has been reported that PET improves the positive predictive value for lymph node metastasis compared to that when contrast-enhanced CT is used [13].

② Clinical target volume (CTV) 

②−1 CTV-primary 

Pathological studies have shown that a 30 mm margin covers 94% of microscopic invasion. For the primary lesion [14], a margin of ~2–4 cm along the cranio-caudal direction of the esophagus is added to the entire circumference of the GTV-primary.

②−2 CTV-lymph node 

Metastatic lesions are treated as identical to the GTV-lymph node (0 mm margin). However, if extracapsular invasion is suspected, a margin of ~5 mm is added.

②−3 CTV-lymph elective nodal area 

In cases of T1a, lymph node metastasis is rarely observed, and prophylactic irradiation of lymph node areas is unnecessary. For T1b and more advanced cases, lymph node metastasis increases sharply, and prophylactic irradiation fields are often established as appropriate. However, recent reports suggest that prophylactic lymph node irradiation may not be necessary when combined with chemotherapy [15, 16]. The indications and clinical significance of prophylactic lymph node irradiation have not reached a clear consensus; however, meta-analyses have shown that omitting prophylactic irradiation results in less acute toxicity and better overall survival rates [17]. When setting prophylactic irradiation fields for regional lymph nodes, consideration is primarily given to the N1 and N2 regions defined in the 11th edition of the Japanese Classification of Esophageal Cancer [18], which correspond to the regions typically dissected during surgery. These regions are listed in Table 1. Notably, in the 12th edition of the Japanese Classification of Esophageal Cancer [19], published in 2022, the N classification has been revised to align with the Union for International Cancer Control (UICC) system, categorizing nodes based on the number of metastases. While there is no established consensus on the setting of prophylactic irradiation fields in clinical practice, examples are provided in the atlas of esophageal cancer lymph node regions included in Table 2 and Fig. 2.

Table 1.

Lymph node groups depending on the location of the tumor according to Japanese Classification of Esophageal Cancer, 11th Edition [18]

Primary Site	Group 1 (N1)	Group (N2)
Cervical Esophagus (Ce)	101, 106rec	102, 104, 105
Upper Thoracic Esophagus (Ut)	101, 105, 106rec	104, 106tbL, 107, 108, 109
Middle Thoracic Esophagus (Mt)	108, 106rec, 1, 2, 3a	101, 104, 105, 107, 109, 110, 112aoA, 112pul, 7, 9, 20
Lower Thoracic Esophagus (Lt)	110, 1, 2, 3a, 7, 20	101, 106rec, 107, 108, 109, 112aoA, 112pul, 9
Abdominal Esophagus (Ae)	110, 1, 2, 3a, 7, 20	111, 112aoA, 112pul, 8a, 9, 11p, 19

The lymph node regions to be considered for inclusion in the CTV are shown in Fig. 2.

Table 2.

Atlas for elective lymph node areas of thoracic esophageal cancer

a) Ut (Upper Thoracic Esophageal Cancer)
Number   Japanese Classification of Esophageal Cancer, 11th Edition [18]	Name	Upper Bound	Lower Bound	Right Margin	Left Margin	Anterior Margin	Posterior Margin
101	Cervical Paraesophageal LNs	Cricoid Cartilage	~2 cm below tracheal bifurcation
104R, 104 L	Supraclavicular LNs			Outer margin of the sternocleidomastoid muscle	Outer margin of the sternocleidomastoid muscle
105	Upper Thoracic Paraesophageal LNs			Lateral edge of anterior scalene muscle	Lateral edge of anterior scalene muscle	Thyroid, Bilateral Internal Jugular Veins	Prevertebral muscles and vertebral body
106recR, 106recL	Recurrent Nerve LNs			Right Common Carotid Artery	Left Common Carotid Artery	Brachiocephalic Artery, Left Brachiocephalic Vein	Vertebral body and the nearest descending aorta
106pre (part)	Pretracheal LNs			Right Subclavian Artery, Brachiocephalic Artery	Left Subclavian Artery	Superior Vena Cava, Ascending Aorta
106tbR (part), 106tbL	Tracheobronchial LNs			Right Brachiocephalic Vein, Superior Vena Cava	Aortic Arch, Left Pulmonary Artery	Right Pulmonary Artery
107	Subcarinal LNs			Azygos Vein, Right Main Bronchus	Left Main Bronchus
112Ao (part)	Posterior Thoracic Paraaortic LNs
b) Mt (Middle Thoracic Esophageal Cancer)
Number	Name	Upper Bound	Lower Bound	Right Margin	Left Margin	Anterior Margin	Posterior Margin
101 (part)	Cervical Paraesophageal LNs	Thyroid Sternum Upper Margin	~2 cm below tracheal bifurcation
105	Upper Thoracic Paraesophageal LNs			Right Common Carotid Artery	Left Common Carotid Artery	Thyroid, Bilateral Internal Jugular Veins	Prevertebral muscles and vertebral body
106recR, 106recL	Recurrent Nerve LNs			Right Subclavian Artery	Left Subclavian Artery	Brachiocephalic Artery, Left Brachiocephalic Vein	Vertebral body and the nearest descending aorta
106pre (part)	Pretracheal LNs			Brachiocephalic Artery, Right Brachiocephalic Vein	Aortic Arch	Superior Vena Cava, Ascending Aorta
106tbR (part), 106tbL	Tracheobronchial LNs			Superior Vena Cava, Azygos Vein	Left Pulmonary Artery	Right Pulmonary Artery
107	Subcarinal LNs			Right Main Bronchus	Left Main Bronchus
109 (part)	Main Bronchus LNs
108	Middle Thoracic Paraesophageal LNs	~2 cm below tracheal bifurcation	Esophageal Hiatus of Diaphragm	Fat tissue surrounding esophagus and right lung boundary	Descending Aorta and Pericardium (Heart) Contact Point	Pericardium (Heart)
110	Lower Thoracic Paraesophageal LNs						Vertebral Body, Descending Aorta
111	Supradiaphragmic LNs						Vertebral Body and Nearest Descending Aorta Point
112Ao (part)	Posterior Thoracic Paraaortic LNs
1	Right Paracardial LNs	Esophageal Hiatus of Diaphragm	Origin of Celiac Artery		Stomach, Pancreas, Splenic Vein
2	Left Paracardial LNs			Liver (Left Lobe, Caudate Lobe)		Left Lobe of Liver, Splenic Vein	Dorsal ~1 cm from Cardia of Stomach
3	Lesser Curvature LNs			Inferior Vena Cava		~1 cm ventral from Left Gastric Artery	Splenic Artery, Diaphragm
7	LNs along the Left Gastric Artery						Abdominal Aorta
c) Lt (Lower thoracic esophageal cancer)
Number	Name	Upper Bound	Lower Bound	Right Margin	Left Margin	Anterior Margin	Posterior Margin
101 (part)	Cervical Paraesophageal LNs	Thyroid Sternum Upper Margin	~2 cm below tracheal bifurcation
105	Upper Thoracic Paraesophageal LNs			Right Common Carotid Artery	Left Common Carotid Artery	Thyroid, Bilateral Internal Jugular Veins	Prevertebral muscles and vertebral body
106recR, 106recL	Recurrent Nerve LNs			Right Subclavian Artery	Left Subclavian Artery	Brachiocephalic Artery, Left Brachiocephalic Vein	Vertebral body and the nearest descending aorta
106pre (part)	Pretracheal LNs			Brachiocephalic Artery, Right Brachiocephalic Vein	Aortic Arch	Superior Vena Cava, Ascending Aorta
106tbR (part), 106tbL	Tracheobronchial LNs			Superior Vena Cava, Azygos Vein	Left Pulmonary Artery	Right Pulmonary Artery
107	Subcarinal LNs			Right Main Bronchus	Left Main Bronchus
109 (part)	Main Bronchus LNs
108	Middle Thoracic Paraesophageal LNs	~2 cm below tracheal bifurcation	Esophageal Hiatus of Diaphragm	Fat tissue surrounding esophagus and right lung boundary	Descending Aorta and Pericardium (Heart) Contact Point	Pericardium (Heart)
110	Lower Thoracic Paraesophageal LNs						Vertebral Body, Descending Aorta
111	Supradiaphragmic LNs						Vertebral Body and Nearest Descending Aorta Point
112Ao (part)	Posterior Thoracic Paraaortic LNs
1	Right Paracardial LNs	Esophageal Hiatus of Diaphragm	~5 mm Caudal from Origin of Celiac Artery
2	Left Paracardial LNs			Liver (Left Lobe, Caudate Lobe)	Stomach, Pancreas, Splenic Vein	Liver (Left Lobe), Pancreas, Splenic Vein	~1 cm dorsal from cardia of stomach
3	Lesser curvature LNs			~1 cm Right of Celiac Artery	~1 cm Left of Celiac Artery	~1 cm Ventral from Left Gastric Artery	Splenic artery, diaphragm
7	LNs along the left gastric artery						Abdominal Aorta
9	LNs along the Celiac Artery

Fig. 2.

Atlas for lymph node regions of thoracic esophageal cancer. (a) Atlas for lymph node region in cases of the primary tumor being upper thoracic esophageal cancer. (b) Atlas for lymph node region in cases of the primary tumor being middle thoracic esophageal cancer (orange) or lower thoracic esophageal cancer (orange and blue).

③ Planning target volume (PTV) 

③−1 PTV1(initial PTV) 

CTV-primary + CTV-lymph node ± CTV-lymph elective nodal area is adjusted for respiratory motion to create ITV1. Additionally, appropriate margins are added to account for patient setup reproducibility errors (~0.5–1 cm in the lateral and anteroposterior directions and ~1 cm in the cranial-caudal direction when using current CBCT-based position verification), resulting in PTV1 [20]. It has been reported that an ITV setting of 0.8 cm in the anterior–posterior and lateral directions and 1.8 cm in the cranio-caudal direction can cover the esophagus with 95% probability for lower esophageal motion on four-dimensional CT (4DCT) [21].

③−2 PTV2(PTV during boost phase) 

CTV-primary and CTV-lymph node, identified as metastatic, are adjusted for respiratory motion to define ITV2. An additional margin (~0.5–1 cm in the lateral and anterior–posterior directions and ~1 cm in the cranio-caudal direction) is added to account for patient setup and reproducibility errors, resulting in PTV2.

Organs at risk

The lungs, spinal cord, and heart as well as the thyroid gland, brachial plexus, kidneys, liver, and other organs included in the irradiation field are designated as organs at risk.

Irradiation methods

Radiation is delivered using 6–10 MV X-rays. Examples of dose distributions for 3D-CRT and VMAT are shown in Fig. 1. Even with 3D-CRT, multi-beam irradiation has been increasingly used from the outset for relatively localized CTVs to reduce late cardiac complications. Recently, as mentioned earlier, prophylactic nodal irradiation has often been omitted from the beginning, and IMRT (VMAT) has been increasingly used for treatment. Meta-analyses and large retrospective studies in Asia have shown that survival rates after IMRT are better than those after 3D-CRT [22–24].

Fig. 1.

The left image shows the dose distribution with 10 MV X-rays using a four-field technique, and the right image shows the dose distribution with 10 MV X-rays using VMAT. In this case, a prescription dose of 60 Gy was used, and the areas receiving 20 Gy or more are displayed with a color wash.

Dose fractionation

In present-day Japan, chemoradiotherapy is typically delivered at 50–60 Gy over 25–30 fractions in 5–6 weeks, whileradiotherapy alone is often administered at 60–70 Gy over 30–35 fractions in 6–7 weeks. From the results of a randomized comparative trial [25] conducted in Western countries in which the outcomes of chemoradiotherapy delivered at 50.4 and 64.8 Gy were compared, it was concluded that 50.4 Gy should be the standard radiation dose. Recent SEER analysis results have also demonstrated that dose escalation beyond 50.4 Gy does not improve overall survival outcomes [26]. Reports from Asian countries suggest that doses exceeding 60 Gy are associated with better survival outcomes [27–29]. However, a randomized comparative study conducted in China in which 50.4 versus 59.4 Gy using IMRT was evaluated showed no significant differences, and 50.4 Gy has been established as the standard radiation dose in China [30]. A meta-analysis of four randomized controlled trials published in 2023 also revealed that higher doses of 60–66 Gy were associated with increased adverse events and did not show improvements in local control rates or overall survival compared to those with 50–50.4 Gy [31].

In chemoradiotherapy following endoscopic treatment (EMR/ESD), a dose of ~41.4 Gy in 23 fractions is typically used. For cases with residual disease, an additional dose of 9.0 Gy in 5 fractions is often delivered to the remaining lesion. Prolongation of the treatment period can lead to a decrease in local control rates, so treatment interruptions should be minimized [32]. In conventional fractionation, the spinal cord dose is limited to 44 Gy. To reduce late adverse events in the heart and lungs, it is desirable to keep the lung V20 <30–35% and the V5 below 50%. Additionally, it is desirable to reduce the mean heart dose to <30 Gy and the V45 of the left ventricle to <2% [33, 34]; however, this is often unachievable in cases of advanced mid-to-lower esophageal cancer when including prophylactic fields and prescribing 60 Gy.

^*The effectiveness of proton therapy for reducing doses to the heart and lungs has been demonstrated, but proton therapy is not currently covered by national health insurance in Japan [35].

Combined therapy

Chemotherapy 

In the definitive treatment of esophageal cancer, chemoradiotherapy is superior to radiotherapy alone [25]. In cases of postoperative recurrent esophageal cancer, chemoradiotherapy is often considered superior to radiotherapy alone, although there has been no study in which chemoradiotherapy and radiotherapy were directly compared. On the other hand, radiotherapy alone is frequently used for high-risk cases, such as elderly patients or patients with comorbidities. However, since there is no clear definition of ‘elderly,’ the applicability should be assessed on a case-by-case basis.

In chemoradiotherapy, the combination with CF is considered standard. In JCOG0303, low-dose continuous infusion CF therapy did not show advantages in survival or adverse events compared to those with standard-dose CF therapy [36]. In recent years, favorable treatment outcomes have been reported with the combination of DCF and radiotherapy; however, caution is required due to the high incidence of adverse events [37]. Additionally, for patients intolerant to Cisplatin, the combination of Oxaliplatin, L-Leucovorin, and Fluorouracil (FOLFOX) may be used as an alternative option [38].

Endoscopic resection 

If submucosal invasion (particularly SM2 or deeper) is confirmed following endoscopic treatment, esophagectomy and lymph node dissection have often been performed as additional treatments to prevent lymph node recurrence. However, it has been reported that the use of chemoradiotherapy after endoscopic resection achieves treatment outcomes comparable to those of additional surgery [39], leading to an increasing number of cases in which endoscopic resection combined with chemoradiotherapy is implemented.

STANDARD TREATMENT OUTCOMES

A multicenter clinical study on outcomes in patients who underwent definitive chemoradiotherapy or radiotherapy alone between 2004 and 2008 showed median 5-year survival rates of 73% for stage I, 40% for resectable stage II-III, and 18% for unresectable T4 or M1 lymph node cases [40]. A phase II trial of chemoradiotherapy for resectable stage I esophageal cancer was conducted as JCOG9708, and the 4-year overall survival rate was 80.5% [41]. Based on that, the JCOG0502 trial was conducted for comparing the outcomes of surgery and chemoradiotherapy. Unfortunately, the randomized portion of the trial was terminated prematurely due to insufficient patient enrollment, but the non-randomized portion demonstrated non-inferiority. In the definitive chemoradiotherapy group, the 5-year overall survival rate was 85.5%, with esophageal preservation rates of 88.7% at 3 years and 80.4% at 5 years, showing a high rate of esophageal preservation [42]. The outcomes of prophylactic additional radiotherapy after endoscopic mucosal resection (EMR) in the JCOG0508 study showed a 5-year overall survival rate of 89.7% [1].

In the JCOG0909 trial, a phase II study was conducted on definitive chemoradiotherapy ± salvage surgery for resectable stage II/III esophageal cancer, and the study showed a 3-year overall survival rate of 74.2% and a 3-year esophageal preservation survival rate of 63.6% [43]. The strategy of conversion surgery, in which surgery is performed if cases of T3br or T4 are deemed resectable during mid-treatment evaluation, has garnered attention, and JCOG1510 is currently underway. It has been suggested that achieving R0 resection can lead to long-term survival [44].

ADVERSE EVENTS

Adverse events in the acute phase

Radiation dermatitis, radiation esophagitis, and radiation pneumonitis are representative side effects. In T4 cases, esophageal perforation may occasionally occur, and once perforation occurs, survival is difficult to achieve. When combined with chemotherapy, attention must be paid to anorexia, bone marrow suppression, and impaired renal function.

Adverse events in the late phase

Attention should be paid to pulmonary fibrosis, pleuritis, pericarditis, cardiovascular disorders, myocardial damage, hypothyroidism, and esophageal stenosis. It has been reported that esophageal stenosis frequently occurs following chemoradiotherapy after endoscopic treatment [45]. It has also been reported that combining stent placement with definitive radiotherapy results in a high incidence of severe complications and worsened survival outcomes; therefore, stent insertion should be avoided prior to definitive radiotherapy [46]. However, for patients with a short life expectancy, a meta-analysis has shown that adding palliative radiation therapy after stent placement can extend the median survival time [47]. In esophageal cancer, the use of immunotherapy is associated with immune-related adverse events; however, there has been no report of an increase in severe adverse events even in patients who has history of radiotherapy. However, although it is not currently performed in Japan, it has been reported that simultaneous use of immunotherapy and radiotherapy may lead to a higher incidence of severe adverse events [48].

NOTES

This guideline was formulated with consideration for alignment with the 5th edition of the Clinical Practice Guidelines for Esophageal Cancer [49].

ACKNOWLEDGEMENTS

The authors have obtained permission for publication of English version from Kanehara & Co., Ltd. and the Japanese Society for Radiation Oncology (JASTRO).

CONFLICT OF INTEREST

K.J. received research funding from Elekta K.K, Varian Medical Systems, and received honorarium fundings from AstraZeneca. K.N. received honorarium fundings from AstraZeneca. Y.I. received honorarium fundings from Chugai. NK received research funding from Daiichi Sankyo. T.A. received research funding from Varian Medical Systems. H.M. received honorarium fundings from MSD. K.T. received honorarium fundings from AstraZeneca. H.I. received research funding from Elekta K.K and CICS. The other authors declare that they have no conflict of interest.