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doi   10.1700/989.10719
Tumori 2011;97(5):603-608


Multiphase-computed tomography-based target volume definition in conventional fractionated radiotherapy of lung tumors: dosimetric and reliable comparison with the technique using addition of generic margins
Zheng Wang1,2, Xueguan Lu1, Gang Zhou1, Liming Yan1, Liyuan Zhang1, Yaqun Zhu1, and Ye Tian1
1Department of Radiation Oncology, Second Affiliated Hospital of Soochow University, Suzhou; 2Department of Radiation Oncology, Changshu Affiliated Hospital of Soochow University, Suzhou, China

Key words: conventional radiotherapy, internal target volume, lung neoplasm, tumor motion.

Acknowledgments: This work was supported by grants from the Jiangsu Province Nature Science Fund of China (BK2009126).

Correspondence to: Dr Xueguan Lu, Department of Radiation Oncology, Second Affiliated Hospital of Soochow University, 1055 Sanxiang Road, Suzhou 215004, Jiangsu Province, China.
Tel 86-512-67784823;
fax 86-512-68284303;
e-mail luxueguanok@yahoo.com.cn

Received November 25, 2010;
accepted March 16, 2011.

abstract

Aims and background. The aim of the present study was to compare radiotherapeutic plans based on internal target volume determined by between multiphase computed tomography and addition of a generic margin in lung tumors and to evaluate the reliability of ITV determined by multiphase computed tomography during conventional fractionated radiotherapy.
Methods and study design. The radiotherapeutic plans based on internal target volume determined by between multiphase computed tomography and addition of a generic margin in 10 patients with lung tumors were applied. The difference of two planning target volumes (PTV) and irradiated dose and volume of normal lung tissue were compared. Weekly new targets were delineated on repeated computed tomography scans, and weekly dose coverage of clinical target volume under two different treatment plans was evaluated.
Results. For all patients, PTV3CT volume based on multiphase computed tomography was significantly smaller than that of PTVcon based on addition of a generic margin (t = 6.831, P <0.001). The volume receiving more than 20 Gy in Plan3CT and Plancon was 16.7 ± 5.2% and 20.0 ± 5.2% (t = 7.565, P <0.001), the volume receiving more than 5 Gy was 36.6 ± 7.2% and 42.7 ± 6.4% (t = 7.459, P <0.001), and mean lung dose was 1037.5 ± 275.0 cGy and 1246.8 ± 271.0 cGy (t = 8.078, P <0.001), respectively. Both Plan3CT and Plancon provided a satisfactory clinical target volume coverage weekly during conventional fractionated radiotherapy for 6-7 weeks, and the ratio of the volume receiving the prescription dose was 1.03 ± 0.02 and 1.04 ± 0.02, respectively.
Conclusions. The radiotherapeutic plan based on internal target volume determined by multiphase computed tomography can ensure weekly target coverage during conventional fractionated radiotherapy in lung tumors, and it is better than the plan based on the addition of generic internal target volume, which can effectively reduce normal lung tissue irradiation.
Introduction
It is well known that thoracic tumors exhibit significant intra-fractional motion due to respiration1-4. More than 2.5 cm tumor movement has been reported for lung cancer patients during a respiration cycle5-7. Tumor motion can lead to a geometric miss and consequent tumor under-dosage if it has not been properly managed during radiotherapy8,9. To address tumor motion, the International Commission on Radiation Units Report 62 introduced the concept of internal target volume (ITV)8. The traditional way to account for tumor motion is to add a safety generic margin (on the order of 1-2 cm for lung tumors) to the clinical target volume (CTV) to get the planning target volume (PTV)10,11. However, many investigators have suggested that an individualized margin should be generated based on patient-specific tumor motion, which helps to improve the target dose coverage during radiotherapy12-14.
Recent advances in imaging technology using four-dimensional (4D) computed tomography (CT) have made it possible to determine a reliable patient-specific tumor motion3,14,15. However, there has been some limited availability for clinical use in many radiotherapeutic centers14. Some investigators use multiphase CT scans taken during free breathing, end inspiration and end expiration to account for patient-specific tumor motion. The scans are fused for treatment planning11,14,16. Some research results have suggested that the simpler technique using multiphase CT scans may provide an acceptable alternative to 4D CT to determine patient-specific tumor motion3,14.
Wang et al.3 found that compared to the conventional approach using helical images for target definition, 4D CT and multiphase CT both had the advantage of providing patient-specific tumor motion, based on which the designed PTV could ensure daily target coverage in hypofractionated stereotactic body radiotherapy (SBRT) of lung cancer. However, the reliability of patient-specific ITV determined by multiphase CT is inconclusive during conventional fractionated radiotherapy for 6-7 weeks in lung tumors.
In the present study, we compared radiotherapeutic plans based on ITV determined by between multiphase CT and addition of a generic margin in lung tumors and evaluated the reliability of ITV determined by multiphase CT during conventional fractionated radiotherapy for 6-7 weeks.
Material and methods
Patients
Approval for the current project was obtained from the local ethics committee together with written informed consent from each patient. Ten patients with lung tumors were recruited for the study between August 2009 and June 2010. The patients who had pleural effusion, pleural adhesion, atelectasis and obstructive pneumonia were excluded from the study. Patient characteristics are summarized in Table 1. 
All patients went on to receive either radical radiotherapy or high-dose palliative radiotherapy. Radiotherapy was administered five times a week at 2 Gy/day. The prescribed total dose for non-small cell lung cancer and pulmonary metastases was 70 Gy. The prescribed total dose was 60 Gy to small cell lung cancer. Four patients received chemotherapy concurrently.



CT scanning protocol, target volume generation and treatment planning before radiotherapy
Before undergoing the CT scanning protocol, each patient underwent an individual coaching session with a radiation oncologist according to the description by Hughes et al.14 Briefly, it consisted of: 1) explaining the rationale behind the protocol with the aid of diagrams; 2) explaining the instructions for normal breathing and end-tidal breath holds (inspiration and expiration); 3) assessing how long the patient could comfortably hold their breath to help to determine the time for the breath-hold CT; 4) a practice run with the patient lying on a couch in the CT scanning position; 5) the patients were also instructed to try to breathe regularly throughout their treatment, i.e. avoiding deep-breath holding, and atypically large tidal volumes. After receiving the coaching session, the patient would be able to fulfill the protocol satisfactorily.
All patients were positioned supine and immobilized in a body cushion with their arms raised above their heads. For each patient, a helical CT scan was acquired under normal free breathing followed by two breath-hold helical CT scans taken at end-inspiration and expiration. The slice thickness of CT scans was 5 mm for all patients.
For each patient, the gross tumor volume (GTV) was delineated in all three scans by an experienced radiation oncologist. Treatment plans were performed using two different methods: 1) One is the Plan3CT. The GTV from all three scans were superimposed to form GTV3CT. A clinical target volume (CTV3CT) was defined by GTV3CT plus an isotropic margin for each direction of 8 mm to account for microscopic spread. Furthermore, a planning target volume (PTV3CT) was performed by CTV3CT plus an isotropic margin of 5 mm to account for repositioning inaccuracies in all directions; 2) another is the Plancon. The GTV under normal free breathing was defined by GTVcon. A CTVcon was defined by GTVcon plus an isotropic margin for each direction of 8 mm, and a PTVcon was performed by CTVcon plus a generic margin for longitudinal direction of 15 mm and axial direction of 10 mm according to the experience from St. Thomas’ Hospital3. Two treatment plans dedicated to Plan3CT and Plancon were generated for each patient by a three-dimensional conformal radiotherapy technique. Planning parameters including beam numbers and angles were kept constant to allow for accurate comparison. In the study, we recommended comparison of parameters GTV and PTV for the radiation target and V20 (volume receiving more than 20 Gy), V5 (volume receiving more than 5 Gy) and mean lung dose (MLD) for normal lung tissue between Plan3CT and Plancon. The difference was tested by the paired t-test.
Weekly CT scanning protocol, target delineation and dose coverage during conventional fractionated radiotherapy
Each patient received CT scanning every week randomly. The weekly helical CT scan was acquired under normal free breathing, and the weekly GTV was delineated. The weekly CTV was generated by the weekly GTV plus an isotropic margin for each direction of 8 mm. Furthermore, we superimposed Plan3CT and Plancon onto the weekly CT images to investigate dose coverage for each weekly CTV. The ratios of Vp of the weekly CTV was recommended to evaluate the reliability of Plan3CT and Plancon during conventional fractionated radiotherapy in lung tumors.
Results
Comparison between Plan3CT and Plancon before radiotherapy
We first compared GTV between Plan3CT and Plancon. As seen in Figure 1, the GTV3CT for each patient is larger than the GTVcon. The percentage of the mean GTV3ct was 151.2% (range, 116.6-228.9%) compared to that of GTVcon in all patients. However, the PTV3CT for each patient is smaller than the PTVcon (Figure 2). PTV3CT and PTVcon was 262.3 ± 170.5 and 374.2 ± 212.0 cm3, respectively. A paired t-test confirmed that the difference was statistically significant (t = 6.831, P <0.001).
The V20, V5, and MLD of normal lung tissue in Plan3ct and Plancon for all patients are summarized in Table 2. As seen in the Table, the V20 in Plan3CT and Plancon was 16.7 ± 5.2% and 20.0 ± 5.2%, respectively (t = 7.565, P <0.001; Figure 3). The V5 in Plan3CT and Plancon was 36.6 ± 7.2% and 42.7 ± 6.4%, respectively (t = 7.459, P <0.001; Figure 3). The MLD in Plan3CT and Plancon was 1037.5 ± 275.0 and 1246.8 ± 271.0 cGy (t = 8.078, P <0.001; Figure 4).
Weekly target coverage of Plan3CT and Plancon
The weekly GTV for each patient was delineated in the weekly helical CT images acquired under normal free breathing. As seen in Figure 5A, the weekly GTV of each patient changed during conventional fractionated radiotherapy. The statistic results showed that the weekly GTV of all patients decreased gradually. The mean GTV in the last week was 48.9% (range, 31.6-73.9) compared to that of GTVcon before radiotherapy in all patients (Figure 5B). Moreover, Plan3CT and Plancon were superimposed onto the weekly CT images to investigate dose coverage for each CTV, respectively. Vp was 1.03 ± 0.02 and 1.04 ± 0.02 for Plan3CT and Plancon, respectively (Figure 6). It was suggested that both Plan3CT and Plancon had good weekly CTV coverage.









Discussion
Thoracic tumors exhibit significant intra-fractional motion due to respiration1-4. Ekberg et al.17 found that the average GTV movement with quiet respiration was about 2.4 mm in the medio-lateral and dorso-ventral directions, and movement in the cranio-caudal direction was on average 3.9 mm with a range of 0-12 mm. In the present study, we found that the percentage of mean GTVcon was 151.2% (range, 116.6-228.9) compared to that of GTV3CT in all patients. This result further confirms that significant tumor motion exists during radiotherapy for lung cancer.
How to manage a mobile tumor during radiotherapy is an interesting issue for radiation oncologist. The most commonly adopted technique is to apply an internal margin to the segmented tumor that incorporates its motion14. The traditional way to account for tumor motion is to add a safety generic margin (on the order of 1-2 cm for lung tumors) to the CTV to get the PTV10,11. However, if a large generic ITV is defined, it may increases the amount of normal tissue in the field, which could lead to an increased toxicity. Conversely, if a small ITV is defined, potentially insufficient irradiation doses are delivered to the tumor, as tumor mobility may extend beyond the previously targeted region18-20. Many investigators have therefore suggested that individualized margins should be generated based on patient-specific ITV, which helps to improve the target dose coverage during radiotherapy12-14.
In the present study, we used a straightforward technique of three multiphase CT scans for generating a patient-specific ITV. The results showed that the PTV3CT based on multiphase CT was significantly smaller than the PTVcon based on addition of a generic margin (P <0.001). Hughes et al.14 also found that the patient-specific ITV based on multiphase CT was markedly smaller than the ITV based on addition of a generic margin, with a mean volume that was almost half of the ITV based on addition of a generic margin. At the same time, our study also revealed that V20 and V5 of Plan3CT were both significantly lower than those of Plancon (P <0.001), and the MLD of Plan3CT was lower than that of Plancon (P <0.001). Wang et al.3 found that 4D CT and three multiphase CT can reduce the amount of normal lung being irradiated compared to the conventional approach using addition of a generic margin. These research results suggested that the patient-specific definition of ITV was more reasonable than that of generic experience.
We further studied the reliability of ITV determined by multiphase CT during conventional fractionated radiotherapy for 6-7 weeks. Wang et al.3 found that the designed PTV based on 4D CT and multiphase 3D CT could ensure daily target coverage in SBRT for lung cancer. However, tumor shape and size did not need to be considered because the period of SBRT is too short (only four fractions). Conversely, lung tumor shape and size may change significantly during conventional fractionated radiotherapy for 6-7 weeks. Kupelian et al.21 found that tumor regression of non-small-cell lung cancer decreased by 1.2% (range, 0.6%-2.3%) everyday during treatment. In our study, we found that the weekly GTV of all patients decreased gradually during conventional radiotherapy. The mean GTV in the last week of radiotherapy was 48.9% (range, 31.6-73.9) compared to the GTV before radiotherapy. Furthermore, PTV based on multiphase CT and addition of a generic margin could ensure weekly target coverage in conventional radiotherapy for 6-7 weeks.
In conclusions, the radiotherapeutic plan based on ITV determined by multiphase CT can ensure weekly target coverage during conventional fractionated radiotherapy of lung cancer, and it is better than the plan based on addition of generic ITV, which can effectively reduce normal lung tissue irradiation.
References
 1. Shimizu S, Shirato H, Kagei K, Nishioka T, Bo X, Dosaka-Akita H, Hashimoto S, Aoyama H, Tsuchiya K, Miyasaka K: Impact of respiratory movement on the computed tomographic images of small lung cancer tumors in three-dimensional (3D) radiotherapy. Int J Radiat Oncol Biol Phys, 46: 1127-1133, 2000.
 2. Harada T, Shirato H, Ogura S, Oizumi S, Yamazaki K, Shimizu S, Onimaru R, Miyasaka K, Nishimura M, Dosaka-Akita H: Real-time tumor-tracking radiation therapy for lung cancinoma by the aid of insertion of a gold marker using bronchofiberscopy. Cancer, 95: 1720-1727, 2002.
 3. Wang L, Hayes S, Paskalev K, Jin L, Buyyounouski MK, Ma CC, Feigenberg S: Dosimetric comparison of stereotactic body radiotherapy using 4D CT and multiphase CT images for treatment planning of lung cancer: evaluation of the impact on daily coverage. Radiother Oncol, 91: 314-324, 2009.
 4. Burnett SS, Sixel KE, Cheung PC, Hoisak JD: A study of tumor motion management in the conformal radiotherapy of lung cancer. Radiother Oncol, 86: 77-85, 2008.
 5. Seppenwoolde Y, Shirato H, Kitamura K, Shimizu S, van Herk M, Lebesque JV, Miyasaka K: Precise and real-time measurement of 3D tumor motion in lung due to breathing and heartbeat, measured during radiotherapy. Int J Radiat Oncol Biol Phys, 53: 822-834, 2002.
 6. Mageras GS, Pevsner A, Yorke ED, Rosenzweig KE, Ford EC, Hertanto A, Larson SM, Lovelock DM, Erdi YE, Nehmeh SA, Humm JL, Ling CC: Measurement of lung tumor motion using respiration-correlated CT. Int J Radiat Oncol Biol Phys, 60: 933-941, 2004.
 7. Plathow C, Fink C, Ley S, Puderbach M, Eichinger M, Zuna I, Schmähl A, Kauczor HU: Measurement of tumor diameter-dependent mobility of lung tumors by dynamic MRI. Radiother Oncol, 73: 349-354, 2004.
 8. ICRU Report 62: Prescribing, recording, and reporting photon beam therapy (Supplement to ICRU Report 50). Bethesda, MD: International Commission on Radiation Units and Measurements, 1999.
 9. Ozhasoglu C, Murphy MJ: Issues in respiratory motion compensation during external beam radiotherapy. Int J Radiat Biol Phys, 52: 1389-1399, 2002.
10. Jiang SB: Radiotherapy of mobile tumors. Semin Radiat Oncol, 16: 239-248, 2006.
11. Fukumoto S, Shirato H, Shimzu S, Ogura S, Onimaru R, Kitamura K, Yamazaki K, Miyasaka K, Nishimura M, Dosaka-Akita H: Small-volume image-guided radiotherapy using hypofractionated, coplanar, and noncoplanar multiple fields for patients with inoperable stage I non-small cell lung carcinomas. Cancer, 95: 1546-1553, 2002.
12. Rietzel E, Liu AK, Doppke KP, Wolfgang JA, Chen AB, Chen GT, Choi NC: Design of 4D treatment planning target volumes. Int J Radiat Oncol Biol Phys, 66: 287-295, 2006.
13. Plathow C, Ley S, Fink C, Puderbach M, Hosch W, Schmähl A, Debus J, Kauczor HU: Analysis of intrathoracic tumor mobility during whole breathing cycle by dynamic MRI. Int J Radiat Oncol Biol Phys, 59: 952-959, 2004.
14. Hughes S, McClelland J, Chandler A, Adams M, Boutland J, Withers D, Ahmad S, Blackall J, Tarte S, Hawkes D, Landau D: A comparison of internal target volume definition by limited four-dimensional computed tomography, the addition of patient-specific margins, or the addition of generic margins when planning radical radiotherapy for lymph node-positive non-small cell lung cancer. Clin Oncol, 20: 293-300, 2008.
15. McClelland JR, Blackall JM, Tarte S, Chandler AC, Hughes S, Ahmad S, Landau DB, Hawkes DJ: A continuous 4D motion model from multiple respiratory cycles for using in lung radiotherapy. Med Phys, 33: 3348-3358, 2006.
16. Wang L, Feigenberg S, Chen L, Pasklev K, Ma CC: Benefit of three-dimensional image-guided stereotactic localization in the hypofractionated treatment of lung cancer. Int J Radiat Oncol Biol Phys, 66: 738-747, 2006.
17. Ekberg L, Holmberg O, Wittgren L, Bjelkengren G, Landberg T: What margins should be added to the clinical target volume in radiotherapy treatment planning for lung cancer? Radiother Oncol, 48: 71-77, 1998.
18. Hof H, Herfarth KK, Münter M, Hoess A, Motsch J, Wannenmacher M, Debus JJ: Stereotactic single-dose radiotherapy of stage I non-small-cell lung cancer (NSCLC). Int J Radiat Oncol Biol Phys, 56: 335-341, 2003.
19. Seki S, Kunieda E, Takeda A, Nagaoka T, Deloar HM, Kawase T, Fukada J, Kawaguchi O, Uematsu M, Kubo A: Differences in the definition of internal target volumes using slow CT alone or in combination with thin-slice CT under breath-holding conditions during the planning of stereotactic radiotherapy for lung cancer. Radiother Oncol, 85: 443-449, 2007.
20. van Sörnsen de Koste JR, Lagerwaard FJ, Nijssen-Visser MR, Graveland WJ, Senan S: 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, 56: 348-354, 2003.
21. Kupelian PA, Ramsey C, Meeks SL, Willoughby TR, Forbes A, Wagner TH, Langen KM: Serial megavoltage CT imaging during external beam radiotherapy for non-small-cell lung cancer: observations on tumor regression during treatment. Int J Radiat Oncol Biol Phys, 63: 1024-1028, 2005.