Set-up errors of the neck are underestimated using the overall registration frame of head and neck in IMRT for NPC

Abstract

Background:

There is no standardized registration frame of cone beam CT (CBCT) in intensity modulated radiotherapy (IMRT) for nasopharyngeal carcinoma (NPC). The overall registration frame that covers the whole head and neck is the most commonly used CBCT registration frame for NPC patients in IMRT.

Objective:

To compare the set-up errors using different registration frames of CBCT for NPC to assess the set-up errors for different region of the commonly used clinical overall registration frame.

Methods:

294 CBCT images of 59 NPC patients were collected. Four registration frames were used for matching. The set-up errors were obtained using an automatic matching algorithm and then compared. The expansion margin from the clinical target volume (CTV) to the planned target volume (PTV) in the four groups was also calculated.

Results:

The average range of the isocenter translation and rotation errors of four registration frames are 0.89∼2.41 mm and 0.49∼1.53°, respectively, which results in a significant difference in the set-up errors (p < 0.05). The set-up errors obtained from the overall frame are smaller than those obtained from the head, upper neck, and lower neck frames. The margin ranges of the overall, head, upper neck, and lower neck frames in three translation directions are 1.49∼2.39 mm, 1.92∼2.45 mm, 1.86∼3.54 mm and 3.02∼4.78 mm, respectively. The expansion margins calculated from the overall frame are not enough, especially for the lower neck.

Conclusion:

Set-up errors of the neck are underestimated by the overall registration frame. Thus, it is important to improve the position immobilization of the neck, especially the lower neck. The margin of the target volume of the head and neck region should be expanded separately if circumstances permit.

Keywords

Nasopharyngeal carcinoma set-up error registration frame IMRT CBCT

1 Introduction

Radical radiotherapy (RT) or RT combined with chemotherapy is the standard treatment strategy for non-metastatic nasopharyngeal carcinoma (NPC) [1]. With the development of radiotherapy techniques, the more advanced intensity-modulated radiation therapy (IMRT) has become the standard radiotherapy technique for NPC treatment [2]. Compared to two dimensional/ three dimensional (2D/3D)-RT, the dose distribution of IMRT is more conformal to the target volumes and areas at risk, which means IMRT allows precise dose delivery to the tumor and maximum dose reduction in the normal tissues [3]. It has been pointed out that IMRT was associated with better local control rate and overall survival rate for NPC [4]. It should be noticed that the set-up errors have a great impact on the efficacy and toxicity of IMRT. Set-up errors are deviations of the patient position during treatment compared to the reference position at the planning computed tomography (CT) scan (CT_plan). Set-up errors include translation errors (measured in millimeter) and rotation errors (measured in degree) [5]. Translation errors larger than 2 mm or rotation errors larger than 3° would increase the risk of underdosing of target volumes and overdosing of nearby risk organs [6].

To decrease the set-up errors, cone beam computed tomography (CBCT) technique was introduced and became an important technique for image-guided radiation therapy (IGRT) [7]. A registration frame is a region of interest (clip-box) which is used to calculate the set-up errors by an automatic algorithm. In general, the registration frame needs to cover all the radiotherapy target volumes, and in the case of NPC, usually the overall of the head and neck. Most of the methods to evaluate the set-up errors assume that the anatomy of the patients is rigid [8]. However, head and neck region is a non-rigid structure, the set-up errors of different parts, including the head, upper neck,and lower neck regions, are different [9]. Registration frames that only include the head, upper neck, and lower neck alone can more accurately reflect set-up errors of that part than an overall registration frame that includes the overall of the head and neck. In the current study, we aimed to compare the set-up errors obtained from different registration frames (the overall frame, the head frame, the upper neck frame, and the lower neck frame) in CBCT for NPC during IMRT to assess the set-up errors for different region of the commonly used clinical overall registration frame. This study may help to identify the regions with the largest set-up errors using the overall registration frame during head and neck radiotherapy and provide new ideas for improving the immobilization technique in the future.

2 Methods

2.1 Patient cohort

From January 1st 2019 to December 31st 2019, a total of 59 NPC patients in our hospital were included in this cross-sectional study. The inclusion criteria were as follows: (1) patients were diagnosed as NPC pathologically, (2) treated with IMRT using Varian Trilogy system, (3) no distant metastasis. Patients older than 70 years, with serious complications, with poor compliance or pregnancy were excluded.

2.2 Position immobilization, CT localization, planning and design

The patients were in supine position and immobilized with head, neck, and shoulder thermoplastic film + individualized Styrofoam head and neck cushion [10]. No bite block was used. Patients were scanned in the CT (CT_plan) simulator (Philips) in head first supine position. The scan extended from the top of the skull to 5 cm under the clavicular bone, with 3 mm image slice thickness. Then the images were transferred to the treatment planning system (Eclipse v15.5). The radiation oncologists delineated the target volumes and organs at risk according to the previously published guidelines [11, 12] and the physicists designed the IMRT plan. After the treatment plan was confirmed, the CT_plan images, target volumes and the reconstructed images of treatment plan were saved in the computer.

2.3 Calculation of set-up errors

An on-board imager (OBI) system, which is a component of the Varian Trilogy linear accelerator (Varian Medical Systems, USA) was used. It comprises of a retractable kV X-ray tube and a kilo-voltage (kV) amorphous silicon (a-Si) flat-panel detector placed at 90° to the center axis of the treatment beam. The treatment beam isocenter is nominally aligned with the OBI isocenter. Multiple projections are obtained at different gantry positions to generate the CBCT images.

Before the first time of radiotherapy, CBCT images were acquired. Then CBCT scans were performed weekly during radiotherapy. After each CBCT scan, the CBCT images registration with the CT_plan images was performed on a registration frame before radiotherapy of the day using the automatic image registration algorithm of VARIAN OBI system. The automatic image registration method is based on an intensity-based registration method that relies on mutual information optimization. CT_plan images are used as reference. Set-up errors are deviations with respect to the reference CT_plan, which are measured as translation along left-right (mm), superior-inferior (mm), anterior-posterior (mm) axes and rotation around the vertical axes (sagittal plane, coronal plane, and cross section) using automatic image registration method [13].

The following four registration frames were used for automatic image registration by VARIAN OBI system: (1) the overall frame, (2) head frame, (3) upper neck frame, and (4) lower neck frame. The boundaries of the four registration frames were shown in Fig. 1 and Table 1. The division of the four registration frames was based on previous research reports [14]. The set-up errors calculated using the four different registration frames were obtained.

Fig. 1

The four registration frames of CBCT for NPC radiotherapy. (A) The cross section of the overall frame. (B) The sagittal plane of the overall frame. (C) The coronal plane of the overall frame. (D) The cross section of the head frame. (E) The sagittal plane of the head frame. (F) The coronal plane of the head frame. (G) The cross section of the upper neck frame. (H) The sagittal plane of the upper neck frame. (I) The coronal plane of the upper neck frame. (J) The cross section of the lower neck frame. (K) The sagittal plane of the lower neck frame. (L) The coronal plane of the lower neck frame. Red line rectangle: The boundaries of the registration frames. The curve lines in blue and red: radiotherapy target volumes.

Table 1

The boundaries of the four registration frames

Matching frame	Superior boundary	Inferior boundary	Anterior boundary	Posterior boundary	Left boundary	Right boundary
Overall	Skull base	Lower margin of the sixth cervical vertebra	Nose	Posterior margin of occipital bone	Edge of the left ear	Edge of the right ear
Head	Skull base	Lower margin of the second cervical vertebra	Nose	Posterior margin of occipital bone	Edge of the left ear	Edge of the right ear
Upper neck	Upper margin of the first cervical vertebra	Lower margin of the third cervical vertebra	Nose	Posterior margin of occipital bone	Edge of the left ear	Edge of the right ear
Lower neck	Upper margin of the fourth cervical vertebra	Lower margin of the sixth cervical vertebra	Nose	Posterior margin of occipital bone	Edge of the left ear	Edge of the right ear

2.4 Statistics

The statistics were performed using SPSS v23.0 software. The average set-up errors between the four registration frames were compared by analysis of variance (ANOVA) and LSD-t test. In the practice of radiotherapy, the confirmed tumor that is palpable or visible by physical or radiological examination is defined as gross tumor volume (GTV). The GTV plus a margin for subclinical tumor is the clinical target volume (CTV). GTV and CTV are delineated by a physician. The planning target volume (PTV) is the CTV plus a margin to account for geometrical uncertainty and variations in its location relative to the radiation beams caused by organ mobility, organ deformation, and set-up errors [15]. The expansion margin from CTV to PTV is calculated according to the following formula: m(margin) = 2.5∑+0.7δ [16], “∑” is the standard deviation of the distribution of systematic deviations and “δ” is the average standard deviation of the distribution of random deviations. The results were considered as statistically significant if p < 0.05.

3 Results

3.1 Patients characteristics

A total of 59 NPC patients were included in the study. Forty-six cases were male. The age of the patients was range from 19 to 68 years old and the media age was 46 years old. Three patients were diagnosed with stage II disease, 26 with stage III disease, and 30 with stage IV disease (Table 2).

Table 2
Summary of patient characteristics

Characteristics n (%)

Gender Male 46 (78.0)

Female 13 (22.0)

Stage II 3 (5.1)

III 26 (44.1)

IV 30 (50.8)

Total 59 (100)

Characteristics	n (%)
Gender	Male	46 (78.0)
	Female	13 (22.0)
Stage	II	3 (5.1)
	III	26 (44.1)
	IV	30 (50.8)
Total	59 (100)

3.2 Set-up errors of different registration frames

The range of the average translation errors and rotation errors obtained from the four different registration frames were 0.89–2.41 mm and 0.49–1.53°, respectively. The translation errors and rational errors between the four groups in all directions were statistically different (Table 3).

Table 3
The set-up errors of four different registration frames

Overall Head Upper neck Lower neck F value P value ^†

Left-right (mm) 0.92±0.86 1.01±0.94 1.16±1.10 1.75±1.48 32.72 <0.001

Superior-inferior (mm) 1.35±1.19 1.40±1.25 2.05±1.70 1.79±1.40 16.79 <0.001

Anterior-posterior (mm) 0.89±0.79 1.18±1.08 1.48±1.31 2.41±2.15 63.23 <0.001

sagittal plane (°) 0.53±0.46 0.83±0.76 1.53±1.29 1.19±0.96 65.18 <0.001

coronal plane (°) 0.49±0.45 0.68±0.59 0.93±0.84 1.10±0.98 37.95 <0.001

cross section (°) 0.98±0.79 1.07±0.87 1.42±1.17 1.52±1.30 17.69 <0.001

	Overall	Head	Upper neck	Lower neck	F value	P value ^†
Left-right (mm)	0.92±0.86	1.01±0.94	1.16±1.10	1.75±1.48	32.72	<0.001
Superior-inferior (mm)	1.35±1.19	1.40±1.25	2.05±1.70	1.79±1.40	16.79	<0.001
Anterior-posterior (mm)	0.89±0.79	1.18±1.08	1.48±1.31	2.41±2.15	63.23	<0.001
sagittal plane (°)	0.53±0.46	0.83±0.76	1.53±1.29	1.19±0.96	65.18	<0.001
coronal plane (°)	0.49±0.45	0.68±0.59	0.93±0.84	1.10±0.98	37.95	<0.001
cross section (°)	0.98±0.79	1.07±0.87	1.42±1.17	1.52±1.30	17.69	<0.001

^†The average positioning errors between the four matching frames were compared by analysis of variance (ANOVA) and LSD-t test.

We further analyzed the number of cases with translation error greater than 3 mm or with rotation error greater than 3°. Among the four registration frames, cases with translation errors > 3 mm or with rotation errors > 3° occurred most often in the lower neck registration frame and least often in the overall frame (Table 3). It should be noticed that there were more cases with translation error > 3 mm in the superior-inferior direction and more cases with rotation error > 3° in sagittal plane in the upper neck registration frame than that in the lower neck registration frame (Table 4).

Table 4

The number of cases with translation direction errors > 3 mm or rotation errors > 3° in different matching frames (n [% ])

	Overall	Head	Upper neck	Lower neck
Left-right	4 (1.4)	5 (1.7)	11 (3.7)	38 (12.9)
Superior-inferior	19 (6.5)	21 (7.1)	53 (18)	40 (13.6)
Anterior-posterior	2 (0.7)	11 (3.7)	18 (6.1)	68 (23.1)
sagittal plane	1 (0.3)	9 (1.4)	40 (13.6)	10 (3.4)
coronal plane	0 (0)	0 (0)	11 (3.7)	16 (5.4)
cross section	5 (1.7)	13 (4.4)	28 (9.5)	35 (11.9)

Pairwise comparison was further performed to compare the set-up errors between different registration frames. Between the overall and the head registration frame, translation errors in the anterior-posterior direction, rotation errors in the sagittal plane and coronal plane were significantly different (p < 0.05). Translation errors and rotation errors in all direction between the overall and the upper neck registration frame, and between the overall and the lower neck registration frame were statistically different (p < 0.05) (Table 5). The results indicated that the set-up errors of the neck, especially the lower neck, were underestimated by the overall registration frame.

Table 5

Pairwise comparison between different registration frames.

	Left-		Superior-		Anterior-		sagittal		coronal		cross
	right		inferior		posterior		plane		plane		section
	(mm)		(mm)		(mm)		(°)		(°)		(°)
	t	P	t	P	t	P	t	P	t	P	t	P
Overall vs. head	–0.92	>0.05	–0.44	>0.05	–2.45	<0.05	–4.01	<0.05	–2.96	<0.05	–1.03	>0.05
Overall vs. upper neck	–2.55	<0.05	–6.10	<0.05	–5.05	<0.05	–13.18	<0.05	–7.07	<0.05	–5.03	<0.05
Overall vs. lower neck	–8.97	<0.05	–3.83	<0.05	–12.96	<0.05	–8.67	<0.05	–9.84	<0.05	–6.09	<0.05
Head vs. upper neck	–1.62	>0.05	–5.66	<0.05	–2.60	<0.05	–9.17	<0.05	–4.12	<0.05	–4.00	<0.05
Head vs. lower neck	–8.04	<0.05	–3.39	<0.05	–10.51	<0.05	–4.66	<0.05	–6.89	<0.05	–5.06	<0.05
Upper neck vs. lower neck	–6.42	<0.05	2.27	<0.05	–7.91	<0.05	4.51	<0.05	–2.77	<0.05	–1.06	>0.05

3.3 Expansion margin of the four different registration frames

To analyze the registration frame’s impact on the expansion margin from CTV to PTV, we calculated the expansion margin of the four registration frames according to Van-Herk formular [16]. The expansion margins of the different registration frames were shown in Table 6. As shown in the results, the expansion margin calculated from the head, upper neck, and lower neck registration were larger than that from the overall registration frame. The results suggest that the expansion margins calculated from the overall frame were not enough, especially for the lower neck.

Table 6
The extension boundaries (mm) of four different matching frames

∑ δ MPTV

Left-right Superior-inferior Anterior-posterior Left-right Superior-inferior Anterior-posterior Left-right Superior-inferior Anterior-posterior

Overall 0.61 0.84 0.51 0.3 0.4 0.29 1.73 2.39 1.49

Head 0.67 0.87 0.75 0.35 0.38 0.38 1.92 2.45 2.14

Upper neck 0.82 1.26 1.03 0.36 0.56 0.41 2.86 3.54 1.86

Lower neck 1.08 0.98 1.7 0.48 0.46 0.77 3.02 2.78 4.78

	∑	δ	MPTV
Overall	0.61	0.84	0.51	0.3	0.4	0.29	1.73	2.39	1.49
Head	0.67	0.87	0.75	0.35	0.38	0.38	1.92	2.45	2.14
Upper neck	0.82	1.26	1.03	0.36	0.56	0.41	2.86	3.54	1.86
Lower neck	1.08	0.98	1.7	0.48	0.46	0.77	3.02	2.78	4.78

∑, standard deviation of the distribution of systematic deviations. δ, average standard deviation of the distribution of random deviations.

4 Discussion

Although the application of IMRT has improved the local control rate and decreased toxicity for NPC patients [17], there are still about 10% patients suffering local and regional recurrence [17, 18]. A study retrospectively analyzed 645 NPC patients who received radiotherapy. It was found that recurrence occurred in 60 cases. 33.3% of these recurrent cases were reginal node recurrence [19]. Two other studies showed that the incidence of nodal failure after definitive radiotherapy in NPC patients was 13–32% [20, 21]. The dose distribution of the target volume was affected by PTV. Inaccurate PTV may increase the risk of underdosing of target volumes, and thus increase the risk of recurrence. PTV was expanded from CTV with an expansion margin calculated based on the set-up errors. The high recurrence rate of the regional nodes may be related to the set-up errors in the neck area [22, 23].

To reduce the set-up errors, the technique of CBCT has been widely used to realize IGRT nowadays [5 , 25]. The registration frame should be defined before CBCT registration. At present, the experts’ consensus suggests that the registration frame of the head and neck cancer should include the overall target volume, organs at risk and structures adjacent to the target volume [11]. However, because the head-and-neck area is a non-rigid structure, this overall registration frame may have some defects and cannot accurately reflect the set-up errors of different areas of the head and neck. Thus, there is great controversy about this registration frame.

In the current study, we defined four different registration frames: the overall frame, the head frame, the upper neck frame, and the lower neck frame. The overall frame was defined as the experts’ consensus [11]. The definition of the other three registration frame was shown in Table 2. The set-up errors of the head frames, upper neck frame and lower neck frame reflect the set-up errors of the head area, upper neck area and lower neck area more accurately than the overall frame. The set-up errors obtained from the four registration frames were compared.

We found that the translation errors in the anterior-posterior direction and rotation errors in the sagittal plane and coronal plane were statistically different (p < 0.05) between the overall and the head registration frames. Between the overall and the upper neck/lower neck registration frame, the translation errors and rotation errors also showed significant difference (p < 0.05). The set-up errors in all directions between the head and the lower neck registration frame were statistically different too (p < 0.05). The above results were consistent with previous studies [26, 27].

The difference of set-up errors between different registration frames is associated with the characteristics of the head and neck structures. The head has more rigid structures and the position set-up is immobilized better. But the neck has more muscles, which are easy to distort during position immobilization. In addition, in the middle and late stages of radiotherapy, the tumor in the neck shrinks after treatment. And the treatment toxicity leads to weight loss, resulting in the loosening of the thermoplastic mask and the increasing of the set-up errors [28]. What’s more, forced extension or flexion of the neck could lead to poor fit between the patient’s contour and the mask and increased the set-up errors [29]. Studies have shown that the average value of rotation error > 1 ° can affect volume receiving 95% of the prescribed dose [30, 31]. Our current study indicated that the average rotation error of the upper neck and lower neck registration frames were greater than 1°, though the rotation error of the overall frame was less than 1°, which may lead to inaccurate target dose, decreased efficacy and increased toxicity [6]. The rotation error of the upper neck and lower neck maybe underestimated by the overall frame. Rotation error should be minimized during radiotherapy, especially when the overall frame was used for registration.

A certain expansion margin should be expanded from CTV to PTV to ensure the coverage of the target volume. The expansion margins calculated in our current study was 1.5–4.8 mm, which was consistent with the results of other studies [32 –34]. However, we found out that the margins were different between the four registration frames. The margin of the overall, head, upper neck and lower neck were 1.49∼2.39 mm, 1.92∼2.45 mm, 1.86∼3.54 mm, 3.02∼4.78 mm, respectively. The PTV expanded with the margins calculated based on the overall frame may not be sufficient to cover the neck target area. The expansion margin of the neck area should be greater than that of the head. In clinical practice, it should be a better choice to expand the margin of head area and the neck area separately. What’s more, the immobilization technique of the neck should be improved to decrease the set-up errors of the neck area.

Base on this study, we propose two methods for improving immobilization. The first one is to use a mouthpiece to reduce the gap between the face mask and the patient to achieve better fixation. The second method is to extend the length of the Styrofoam to cover the buttocks. That means we may use a head, neck, and shoulder thermoplastic film + individualized Styrofoam cushion that cover from head to buttocks to immobilized the patients (In the current study, the Styrofoam only cover from the head to the shoulder). We are currently conducting clinical trials to validate both of these approaches.

The limits of the current study should also be noticed. First, the sample included in the study was small and it was hard to discover and validate the independent influencing factors. Second, all the patients were from a single treatment center. Third, the set-up errors included inter-fractionated error and intra-fractionated error. In the current study, only the inter-fractionated error was considered. However, intra-fractionated error was very small in the head and neck radiotherapy and had very small impact on the set-up error.

5 Conclusion

To sum up, the set-up errors obtained from the four registration frames were significantly different. The set-up error obtained by the automatic matching of the overall frame cannot accurately reflect the set-up error in IMRT for NPC. The actual set-up error of the neck was larger than the one calculated by the overall registration frame. We should improve the position immobilization of the neck, especially the lower neck. The margin of the target volume of the head and the neck areas should be expanded separately, if circumstances permit.

Ethics approval and consent to participate

The study was approved by the ethics committee of the Sun Yat-sen University Cancer Center.

List of abbreviations

radiotherapy

NPC

nasopharyngeal carcinoma

IMRT

intensity-modulated radiation therapy

2D/3D

two dimensional/ three dimensional

computed tomography

CBCT

cone beam computed tomography

IGRT

image-guided radiation therapy

ANOVA

analysis of variance

CTV

clinical target volume

PTV

planning target volume

margin

volume receiving 95% of the prescribed dose

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Competing interests

The authors declare that they have no competing interests.

Funding

No funding was received for the current study.

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Set-up errors of the neck are underestimated using the overall registration frame of head and neck in IMRT for NPC

Abstract

Background:

Objective:

Methods:

Results:

Conclusion:

Keywords

1 Introduction

2 Methods

2.1 Patient cohort

2.2 Position immobilization, CT localization, planning and design

2.3 Calculation of set-up errors

3 Results

3.1 Patients characteristics

Table 2 Summary of patient characteristics Characteristics n (%) Gender Male 46 (78.0) Female 13 (22.0) Stage II 3 (5.1) III 26 (44.1) IV 30 (50.8) Total 59 (100)

5 Conclusion

List of abbreviations

Availability of data and materials

Competing interests

Funding

References

Table 2
Summary of patient characteristics

Characteristics n (%)

Gender Male 46 (78.0)

Female 13 (22.0)

Stage II 3 (5.1)

III 26 (44.1)

IV 30 (50.8)

Total 59 (100)