Esophageal cancer: Determination of internal target volume for conformal radiotherapy

Radiotherapy and Oncology 80 (2006) 327–332 www.thegreenjournal.com

Target volume definition

Esophageal cancer: Determination of internal target volume for conformal radiotherapy F. Lorchela,b,c,*, J.L. Dumasa, A. Noe ¨lb,c, D. Wolfc, J.F. Bosseta, P. Alettib,c a

´rapie, CHU Besanc¸on, Bd Fleming, Besanc¸on cedex, France, bService de Radiothe ´rapie and, cC.R.A.N–C.N.R.S Service de Radiothe `s-Nancy, France UMR 7039, Vandoeuvre-le

Abstract Background and purpose: To evaluate esophageal tumor and OAR movement during the respiratory cycle in order to obtain optimal values for ITV and PRV. To correlate tumor motion with chest wall displacement – information of value in the free-breathing gating system. Material and method: Inclusion criteria were: histologically proven squamous-cell carcinoma (SCC) or adenocarcinoma at stage T3–T4 NX or TX N1 M0 according to the UICC 1997 classification. Two spiral scans were performed with breathhold respiration under spirometric control: one at end expiration (EBH) and the other at end inspiration (IBH). Displacements between exhalation and inhalation were calculated according to ICRU report 42 recommendations. For the correlation study, CT-scan acquisition was performed at the isocenter over a 20–40 s period. After Fourier Transform, frequency spectra for amplitude and phase of tumor and chest wall motions were performed for each patient. Results: Cumulative distribution of CTV motion in absolute values showed that 95% of data ranged from 0 to 1 cm. Cumulative distribution of GTV motion in absolute values showed that 95% of data ranged from 0 to 0.8 cm. The correlation study demonstrated no specific relationship between respiratory and esophageal motions. Conclusion: The ITV margin for 3D conformal radiotherapy in esophageal cancer was 1 cm when 95% of motions were taken into account in this clinical study involving eight patients. Before using a free-breathing gating system, the correlation between external markers and target displacement during irradiation must be established for each patient. c 2006 Elsevier Ireland Ltd. All rights reserved. Radiotherapy and Oncology 80 (2006) 327–332.



Keywords: Esophageal cancer; Radiotherapy; Gating; Internal target volume; Correlation study

The current standard treatment for locally advanced or inoperable esophageal cancer is chemo-radiotherapy (CT-RT) [7], principally involving conformal radiotherapy (3D-CRT). Parameters of interest include the gross tumor volume (GTV) and clinical target volume (CTV), both of which are established by CT scan in the treatment position, and the planning target volume (PTV), defined by the ICRU as the internal target volume (ITV) plus the set-up margin (SM) [9]. The ITV takes into account physiologic organ movements, particularly those due to respiration, and ensures adequate coverage of the CTV throughout the respiratory cycle. A margin is also added to organ at risk (OAR) volumes to give planning organ at risk volumes (PRV). Physiologic motion of thoracic tumors, particularly in the breast and lung, has been studied [3,4,6,14,16, 19,22].To the present authors’ knowledge, however, there are no reports concerning movement of esophageal tumors, or even the healthy esophagus, during the respi-



ratory cycle. In the authors’ radiotherapy department, an arbitrary ITV value of 0.5 cm has been adopted for intrathoracic esophageal tumors. The PTV margin is therefore 1 cm after the addition of SM (0.5 cm). Respiratory-gated radiotherapy (gating) reduces tumor motion by synchronising the treatment beam and the respiratory cycle. Some approaches involve voluntary breath holding (Active Breathing Control – Elekta or SpiroDyn – Dyn’R) [2,12,23]. In others, the patient breathes freely but movement is monitored via tracking of an infra-red light reflecting marker on the chest wall (Real-Time Position Management – Varian Medical Systems) [4,10]. This requires correlation of tumor motion and chest wall motion. The aim of the present study was to evaluate esophageal tumor and OAR movement in order to define optimal ITV and PRV. An attempt was also made to correlate tumor motion and chest wall displacement.

0167-8140/$ - see front matter c 2006 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.radonc.2006.08.003

328

ITV in esophageal cancer

Patients and methods Selection criteria Inclusion criteria were histologically proven squamouscell carcinoma (SCC) or adenocarcinoma at stage T3–T4 NX or TX N1 M0 according to the UICC 1997 classification. Patients provided informed consent before beginning the study. Tumor and patient characteristics are listed in Table 1.

Spirometric control All CT scans were performed with spirometric control (SPIRODYN – Dyn’R – Muret; France) and using software specific for lung function measurement. The spirometer was positioned at the patient’s head. Nose-clips were used to prevent nasal air leak, and respiratory volumes were collected via a mouthpiece. Before CT-scan acquisition, patients participated in an individual respiratory training session in the treatment position. Video glasses (Cy-Visor – DAEYANG E&C – Seoul – Korea) enabled them to follow variations in the respiratory cycle. Three distinct breathing levels were defined: • Sustained breath-hold after normal expiration (EBH – level 1). • Sustained breath-hold after normal inspiration (IBH – level 2). • Free breathing level (FB – level 3) in tidal volume (TV) for quality assurance. Each breath-hold level was discussed with the patient to ensure good reproducibility in the CT-scanner facility.

CT-scanning A POSIFIX 2 (MCP France-Paris) immobilisation device was used for thoracic and shoulder support. Scans were acquired

Table 1 Clinical and tumor characteristics in the eight patients Variable

Stratification

n

%

OMS

0 1 2

4 2 2

50 25 25

Age (years)

Median (range)

69.9 (46.3–78)

Dysphagia

2 3 4

2 5 1

25 62.5 12.5

Histology

Adenocarcinoma Squamous cell carcinoma

2 6

25 75

Localisation

Cervical Upper third Mid third Lower third

1 1 4 2

12.5 12.5 50 25

T

2 3

1 7

12.5 87.5

N

0 1

5 3

62.5 37.5

with a slice thickness of 0.5 cm from the C2–C3 junction to the L3–L4 junction. Three spiral scans were performed at each level defined during the respiratory training session: one acquisition in free breathing (FB), one at end expiration (EBH), and one at end inspiration (IBH). All scans lasted for approximately 25 s, and were performed in one session without a break. Results of all scans were transferred with a DICOM Store to the THERAPLAN Plus (MDS Nordion) treatment planning system. All spirometric procedures (training and CT-scan acquisitions) were carried out correctly with high compliance, even among patients with poor performance status (OMS 2). This indicates that the technique has good reproducibility.

Volume delineation Anatomical structures were delineated using the OTP treatment planning system (THERAPLAN-MDS Nordion) on all scans by a single physician (FL) in order to minimise delineation bias [17]. GTV included the tumor and pathological lymph nodes on CT scan, and was assessed with the help of esophagoscopy. Nodes were defined as positive if the diameter was 1 cm or more on at least one CT-scan slice. CTV was not assessed as a geometrical expansion from the GTV, but included tumor and pathological lymph nodes, with a 50-mm margin in the cephalad axis to cover potential microscopic extension. It also included lymph groups of drainage and was drawn up to anatomical interfaces (pleura, heart, vertebral body, etc.). Lung volumes were determined using an automatic contouring function. Cardiac volume was measured manually, and spinal cord volume was delineated every 4 cm-slice and completed with an interpolation function.

Organ motion study Displacements were calculated between exhalation and inhalation, and evaluated from one reference point – the ICRU point, corresponding to the isocenter of the FB planning scan. Displacements were calculated in cm for each respiratory level. In accord with ICRU report 42, displacements were standardised as follows: • Transverse displacement: +x left displacement (L); x right displacement (R). • Longitudinal displacement: +y superior displacement (SUP); y inferior displacement (INF). • Sagittal displacement: +z anterior displacement (ANT); z posterior displacement (POST).

GTV, CTV Displacements were analysed at four points (anterior, posterior, right lateral and left lateral) and three levels (upper level of target volume, lower level of target volume and isocenter).

Organs at risk With regard to the spinal cord, sagittal displacements were calculated at three levels (isocenter, upper slice of

F. Lorchel et al. / Radiotherapy and Oncology 80 (2006) 327–332 25

100

95%

80

15

60 Nbe Cumulative

10

40

5

20

0

Cumulative (%)

20

Number

CTV, lower slice of CTV) from the most anterior point of the volume. Kidney displacements were calculated longitudinally from the vascular hilum. Longitudinal movements of diaphragm and lung apex were calculated from the isocenter by determining the slice level of the hepatic dome for the right diaphragm and the splenic dome for the left diaphragm, and the slice level of each apex in the lung window. Mean displacements were expressed in cm with standard deviation (SD) and 95% confidence interval (CI). ITV results were expressed in terms of probability, with a margin dependent on the risk of accepted error (5%) for conformal radiotherapy.

329

0 0 0,1 0,2 0,3 0,4 0,5 0,6 0,7 0,8 0,9

1 1,1 1,2 1,3 1,4

Displacements (cm)

Correlation study CT-scan images were acquired at isocenter, without table displacement, at 0.8 s intervals from 20 to 40 s. Displacements of the chest wall point of reference (corresponding to the cutaneous lead marker on the sagittal axis) and the esophageal point of reference (corresponding to the ANT point of the GTV as described above) were determined in the ANT-POST direction. Data were gathered using Interpft function (via Fourier) from MATLAB software to increase the number of analysable points. They were then subjected to the Fourier Transform using the FFT (Fast Fourier Transform) function of MATLAB software to obtain frequency spectra for the amplitude and phase of tumor and thoracic motion. The frequencies used ranged from 0.05 to 0.625 Hz for a 20-s CT scan-acquisition, and from 0.025 to 0.625 Hz for a 40-s acquisition. Typical breathing in this data set had a frequency of 0.15–0.25 Hz and was analysable, unlike heart beat frequency that set over the detection threshold.

Results Organ motion study

Fig. 1. Cumulative distribution of CTV displacements (cm) in three directions (SUP-INF; ANT-SUP; R LAT-L LAT).

to 1 cm Fig. 1 . Therefore, a 1-cm margin is proposed for ITV in esophageal cancer. For GTV, mean displacements of 0.03 cm ±0.37 (CI = 0.07) in real value and 0.26 cm ±0.27 (CI = 0.05) in absolute value were obtained. Cumulative distribution of GTV motion in absolute terms showed that 95% of the data ranged from 0 to 0.8 cm. A PRV margin of 0.8 cm is therefore proposed for the healthy esophagus.

Organs at risk Data for spinal cord, kidneys, lung apex and diaphragm are shown in Table 3. Spinal cord the mean displacement between EBH and IBH was very small: about 0.1 cm. A 0.1-cm PRV for spinal cord is therefore proposed. Kidneys a mean inferior displacement of 0.7 cm was observed, and this value is proposed for right and left kidney PRV. Diaphragm mean movement ranged from 1.31 to 1.56 cm in the inferior direction, with very little difference between right and left.

GTV and CTV Mean 3D movements of GTV and CTV are shown in Table 2. Considering all CTV displacements in the three directions, mean displacements of 0.00 cm ±0.45 (CI = 0.08) in real value and 0.33 cm ±0.31 (CI = 0.06) in absolute value were observed. Cumulative distribution of CTV motion in absolute terms showed that 95% of the data ranged from 0

Correlation study Data from six patients could be analysed for a correlation between chest wall and tumor motion. Fig. 2 shows two examples: patient 2 with an irregular breathing cycle, and patient 7 with a regular breathing cycle.

Table 2 Mean 3D movements in cm (±SD) of GTV and CTV at the top, at the isocenter and at the bottom of the target volume, between exhale and inhale Motions

GTV Sup

ANT POST LAT R LAT L SUP INF

0.15 ± 0.63 0.09 ± 0.3 0.00 ± 0.19 0.13 ± 0.22 0.38 ± 0.41

CTV Isocenter 0.19 ± 0.17 0.14 ± 0.13 0.15 ± 0.17 0.24 ± 0.27

Inf 0.25 ± 0.34 0.18 ± 0.33 0.14±0.31 0.2 ± 0.48 0.13 ± 0.22

Sup 0.16 ± 0.24 0.1 ± 0.41 0.01 ± 0.45 0.08 ± 0.23 0.44 ± 0.39

Isocenter 0.18 ± 0.51 0.15 ± 0.19 0.05 ± 0.34 0.09 ± 0.59

Inf 0.05 ± 0.5 0.35 ± 0.44 0.06 ± 0.42 0.08 ± 0.54 0.06 ± 0.3

330

ITV in esophageal cancer

Table 3 Sagittal displacements (cm) of the spinal cord at three levels of CTV (upper, isocenter and lower level) and longitudinal displacements (cm) of kidneys, lung apex and diaphragms during the respiratory cycle EBH

IBH

FB

Mean

SD

Mean

Spinal cord Sup level Isocenter Inf level

0 0 0

0 0 0

0.10 0.10 0.09

0.32 0.13 0.21

0.01 0.04 0.05

0.51 0.13 0.15

R kidney L kidney R apex L apex R diaphragm L diaphragm

0 0 0 0 0 0

0 0 0 0 0 0

0.70 0.70 0.31 0.19 1.56 1.31

0.87 0.51 0.35 0.24 0.95 0.50

0.83 0.50 0.25 0.13 1.00 1.31

0.62 0.58 0.25 0.22 1.46 1.03

Amplitude (cm)

Position (cm) Patient 2

SD

35 30

0.6

25

0.5

Tumour Chest RF: 0.08 Hz

11.5

10.5 0

5

10

15

20

0.4

20

0.3

15

0.2

10

0.1

5

25

0

0

0.1

0.3

0.5

Time (sec) Position (cm) Patient 7

0.7

Amplitude (cm)

0

5 10

15 20 25 30 35

Time (sec)

0.3

0.5

0.7

30

0.6

12.5

0.1

35

0.7

13.5

0

Phase (degres)

25

0.5

Tumour Chest RF: 0.225 Hz

0

Frequency (Hz)

15.5

14.5

SD

Phase (degres)

0.7

12.5

Mean

0.4

20

0.3

15

0.2

10

0.1

5

0

0

0.2

0.4

0.6

0

0.2

0.4

0.6

Frequency (Hz)

Fig. 2. Correlation study. The first graph represents temporal data, the second and the third show the Fourier spectra for amplitude and phase respectively. Examples: patient 2 has an irregular breathing cycle, and patient 7 has a regular breathing cycle. RF, respiratory frequency.

Patient 2 exhibited a good correlation between chest wall and tumor motion; respiratory frequency (RF) correlated with the highest amplitude of the tumor cycle, and phases were identical at RF for both chest wall and tumor motions. In patient 7, the main tumor movement frequencies did not correspond with the RF or with the phase spectra. It was therefore concluded that tumor motion did not correlate with chest wall displacement. Of the six patients included in the investigation, only two showed a correlation between respiratory chest wall displacement and tumor motion.

Discussion This study showed that a margin of 1 cm covered 95% of CTV motions of esophageal cancer between exhale and inhale. The statistical method of determining ITV was adopted in accord with ICRU specifications for quality assurance, but there is as yet no standardised technique with which to determine the internal margin. Antolak and Rosen suggested adding a CTV to PTV margin of 1.65 times the standard deviation of the margin errors so as to have any point on the surface of the CTV within the PTV 95% of the time [1]. They assumed that mobility of the CTV could be described by three orthogonal indepen-

F. Lorchel et al. / Radiotherapy and Oncology 80 (2006) 327–332

dent Gaussian (normal) distributions. In the present authors’ experience, cumulative distribution of the data is not really Gaussian (data not shown) but centers on 0, 0.5 and 1 cm values. Adopting the Antolak and Rosen definition, the ITV here would be 0.75 cm in real terms and 0.5 cm in absolute terms – quite different from the reported results. The discrepancy could induce some geographic misses. Van So ¨rnsen de Koste et al. [18] suggested performing one complete rapid scan of the entire thorax and a limited slow scan of the tumor. In their study of seven patients with lung cancer, the addition of a 5-mm 3D margin to the PTV derived from the slow scan ensured 99% coverage of optimal PTV generated from six fast scans. Shih et al. [15] fused a fast helical scan at shallow free breathing with two breath-hold scans at the end of tidal volume expiration and inspiration among 14 patients with lung tumors. ITV was defined as the composite volume of each GTV from all three scans. The study showed that the internal margin varied significantly depending on the method of CT scanning used to determine the GTV. An additional internal margin of 0.5 cm was necessary for combined breath-hold scans (mean 0.11 cm, SD = 0.19 cm). Thus, the combination of two breath-hold scans at the end of tidal expiration and inspiration could underestimate ITV. Determination of ITV for esophageal tumor is different from that for lung tumors because of the former’s mediastinal situation. Van So ¨rnsen de Koste et al. [19] studied the mobility of mediastinal lymph nodes on multiple planning CT-scans in eight patients with NSCLC. The encompassing nodal volume (ENV) of all contours of a particular node was manually contoured. The addition of a margin of 5 mm to individual nodes was found to result in a mean ENV coverage of P95% at all sites. This margin could therefore be considered adequate to account for variations in both contouring and mobility. In the present study, a 5mm margin ensured only 78% coverage of CTV displacements. Finally, there is no accurate means of accounting for the internal motion of intra-thoracic tumor. Additional studies using 4D CT scan should help. The methodology used here involved CT scanning with a slice thickness of 0.5 cm, but this technique may be less accurate than fluoroscopic analysis in the anterior or lateral view. In order to determine whether or not the 0.5 cm slice influences the overall data on displacement, the analysis described above was performed excluding all SUP-INF movements. Absolute ITV values of 0.33 cm ±0.3 (IC = 0.06) for CTV and 0.27 cm ±0.25 (IC = 0.05) for GTV were obtained – similar to those for ITV with INF-SUP movements. Gating systems adapted to breathing motion use external markers that must predict the moving tumor’s position, and a spatial and temporal relationship between them must be verified. Hoisak et al. [8] studied the correlation between lung tumor motion and abdominal external surrogate indicators of respiration. Spirometric measurement of respiratory volumes showed that the correlation between tumor displacement and respiratory volume was greater and more reproducible than that between tumor displacement and abdominal displacement.

331

Ozhasoglu and Murphy [13] observed patterns of breathing motion that are complex, variable and individual. No temporal or spatial correlation was clearly demonstrated in their study between five tumors (lung or pancreatic) and abdominal or chest wall displacements, other than in one patient with a pancreatic tumor. Vedam et al. [20] developed a method of accounting for any difference in phase between internal tumor motion and external marker motion. The periodic motion of the marker was synchronised with the fluoroscopy signal from the simulator. Those data provided the information necessary to set the CTV to PTV margins to be applied for a gated treatment plan with the RPM System, but the method is applicable only to tumors that move with the same magnitude and in the same phase as the diaphragm; these include liver tumors, breast tumors and lung tumors in the vicinity of the diaphragm [21]. Mageras et al. [11] also found a high degree of correlation between external marker movement and diaphragm motion in four of six patients with lung cancer (mean R = 0.97, range 0.95–0.99) using the RPM system. Gierga et al. [5] studied the correlation between internal clips and external markers placed on the abdominal skin surface of four patients with liver tumors using a lateral fluoroscopic view recorded for about 30 s. When they applied Fourier analysis to transform the data from the time domain to the frequency domain, the frequency spectra for both the tumors and the external markers were similar to the respiratory frequency. Thus, correlation between external marker displacement and the movement of tumors in the vicinity of the diaphragm (lung and liver) has been clearly demonstrated, and the RPM system can be used in such situations. With regard to the example patients in the present correlation study, despite the appearance of the graphs showing well-matched cycles for patient 7, the best correlation between tumor and chest wall motion was in patient 2 after frequency spectrum analysis by Fourier Transform. Considerable caution must be used in attempting to correlate tumor and chest wall motion if a free-breathing gating system is adopted. For each patient, a preliminary correlation study must be performed using a Fourier Transform analysis.

Conclusion The ITV for 3D conformal radiotherapy of esophageal cancer was 1 cm when 95% of movements were included in this clinical study of eight patients. Before using a free breathing gating system, the correlation between external markers and target displacement during irradiation must be verified for each patient. A simple clinical study using Fourier Transform can be implemented as a pre-treatment procedure.

Acknowledgements The authors thank Camille Gaffard, Caroline Poirot and Lambert Maı¨er (I.S.I.F.C, UFR Sciences et Techniques, 16 route de Gray, 25030 Besanc ¸on cedex) for their help and advice concerning the correlation study.

332

ITV in esophageal cancer

This study was supported by grants from PHRC 2003 and la Ligue contre le Cancer – Comite ´s du Doubs, Jura, Haute-Sao ˆne et Montbe ´liard. Thanks are also due to Varian Medical System for their help in supporting the study. * Corresponding author. Dr. Fabrice Lorchel, Radiotherapy Department, University Hospital Jean Minjoz, 25030 Besanc ¸on, France. E-mail address: [email protected] Received 6 September 2005; received in revised form 1 August 2006; accepted 3 August 2006

[11]

[12]

[13]

[14]

References [1] Antolak JA, Rosen II. Planning target volumes for radiotherapy: how much margin is needed? Int J Radiat Oncol Biol Phys 1999;44:1165–70. [2] Barnes EA, Murray BR, Robinson DM, et al. Dosimetric evaluation of lung tumor immobilization using breath hold at deep inspiration. Int J Radiat Oncol Biol Phys 2001;50:1091–8. [3] Chen QS, Weinhous MS, Deibel FC, et al. Fluoroscopic study of tumor motion due to breathing: facilitating precise radiation therapy for lung cancer patients. Med Phys 2001;28:1850–6. [4] Ford EC, Mageras GS, Yorke E, et al. Evaluation of respiratory movement during gated radiotherapy using film and electronic portal imaging. Int J Radiat Oncol Biol Phys 2002;52:522–31. [5] Gierga DP, Brewer J, Sharp GC, et al. The correlation between internal and external markers for abdominal tumors: implications for respiratory gating. Int J Radiat Oncol Biol Phys 2005;61:1551–8. [6] Giraud P, De Rycke Y, Dubray B, et al. Conformal radiotherapy (CRT) planning for lung cancer: analysis of intrathoracic organ motion during extreme phases of breathing. Int J Radiat Oncol Biol Phys 2001;51:1081–92. [7] Herskovic A, Martz K, al-Sarraf M, et al. Combined chemotherapy and radiotherapy compared with radiotherapy alone in patients with cancer of the esophagus. N Engl J Med 1992;326:1593–8. [8] Hoisak JD, Sixel KE, Tirona R, et al. Correlation of lung tumor motion with external surrogate indicators of respiration. Int J Radiat Oncol Biol Phys 2004;60:1298–306. [9] ICRU. ICRU Report 62: Prescribing,recording and reporting photon beam therapy (supplement to ICRU Report 50). In: ICRU eds. Bethesda, MD, 1999. [10] Kubo HD, Len PM, Minohara S, Mostafavi H. Breathingsynchronized radiotherapy program at the University of

[15]

[16]

[17]

[18]

[19]

[20]

[21]

[22]

[23]

California Davis Cancer Center. Med Phys 2000;27:346–53. Mageras GS, Yorke E, Rosenzweig K, et al. Fluoroscopic evaluation of diaphragmatic motion reduction with a respiratory gated radiotherapy system. J Appl Clin Med Phys 2001;2:191–200. Mah D, Hanley J, Rosenzweig KE, et al. Technical aspects of the deep inspiration breath-hold technique in the treatment of thoracic cancer. Int J Radiat Oncol Biol Phys 2000;48:1175–85. Ozhasoglu C, Murphy MJ. Issues in respiratory motion compensation during external-beam radiotherapy. Int J Radiat Oncol Biol Phys 2002;52:1389–99. Pedersen AN, Korreman S, Nystrom H, Specht L. Breathing adapted radiotherapy of breast cancer: reduction of cardiac and pulmonary doses using voluntary inspiration breath-hold. Radiother Oncol 2004;72:53–60. Shih HA, Jiang SB, Aljarrah KM, et al. Internal target volume determined with expansion margins beyond composite gross tumor volume in three-dimensional conformal radiotherapy for lung cancer. Int J Radiat Oncol Biol Phys 2004;60:613–22. Sixel KE, Ruschin M, Tirona R, Cheung PC. Digital fluoroscopy to quantify lung tumor motion: potential for patient-specific planning target volumes. Int J Radiat Oncol Biol Phys 2003;57:717–23. Tai P, Van Dyk J, Battista J, et al. Improving the consistency in cervical esophageal target volume definition by special training. Int J Radiat Oncol Biol Phys 2002;53:766–74. van Sornsen de Koste JR, Lagerwaard FJ, Nijssen-Visser MR, et al. Tumor location cannot predict the mobility of lung tumors: a 3D analysis of data generated from multiple CT scans. Int J Radiat Oncol Biol Phys 2003;56:348–54. van Sornsen de Koste JR, Lagerwaard FJ, Nijssen-Visser MR, et al. What margins are necessary for incorporating mediastinal nodal mobility into involved-field radiotherapy for lung cancer? Int J Radiat Oncol Biol Phys 2002;53:1211–5. Vedam SS, Keall PJ, Kini VR, Mohan R. Determining parameters for respiration-gated radiotherapy. Med Phys 2001;28:2139–46. Vedam SS, Kini VR, Keall PJ, et al. Quantifying the predictability of diaphragm motion during respiration with a noninvasive external marker. Med Phys 2003;30:505–13. Wagman R, Yorke E, Ford E, et al. Respiratory gating for liver tumors: use in dose escalation. Int J Radiat Oncol Biol Phys 2003;55:659–68. Wong JW, Sharpe MB, Jaffray DA, et al. The use of active breathing control (ABC) to reduce margin for breathing motion. Int J Radiat Oncol Biol Phys 1999;44:911–9.