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Dosimetric Selection for Helical Tomotherapy Based Stereotactic Ablative Radiotherapy for Early-Stage Non-Small Cell Lung Cancer or Lung Metastases

  • Alexander Chi ,

    achiaz2010@gmail.com

    Affiliation Department of Radiation Oncology, West Virginia University, Morgantown, West Virginia, United States of America

  • Zhongxing Liao,

    Affiliation Department of Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America

  • Nam P. Nguyen,

    Affiliation Department of Radiation Oncology, West Virginia University, Morgantown, West Virginia, United States of America

  • Jiahong Xu,

    Affiliation Westat-an Employee-Owned Research Corporation, Rockville, Maryland, United States of America

  • James S. Welsh,

    Affiliation Department of Radiation Oncology, Louisiana State University, Shreveport, Louisiana, United States of America

  • Si Young Jang,

    Affiliation Department of Radiation Oncology, West Virginia University, Morgantown, West Virginia, United States of America

  • Carol Howe,

    Affiliation Medical Library, University of Arizona, Tucson, Arizona, United States of America

  • Ritsuko Komaki

    Affiliation Department of Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America

Dosimetric Selection for Helical Tomotherapy Based Stereotactic Ablative Radiotherapy for Early-Stage Non-Small Cell Lung Cancer or Lung Metastases

  • Alexander Chi, 
  • Zhongxing Liao, 
  • Nam P. Nguyen, 
  • Jiahong Xu, 
  • James S. Welsh, 
  • Si Young Jang, 
  • Carol Howe, 
  • Ritsuko Komaki
PLOS
x

Abstract

Background

No selection criteria for helical tomotherapy (HT) based stereotactic ablative radiotherapy (SABR) to treat early stage non-small cell lung cancer (NSCLC) or solitary lung metastases has been established. In this study, we investigate the dosimetric selection criteria for HT based SABR delivering 70 Gy in 10 fractions to avoid severe toxicity in the treatment of centrally located lesions when adequate target dose coverage is desired.

Materials and Methods

78 HT-SABR plans for solitary lung lesions were created to prescribe 70 Gy in 10 fractions to the planning target volume (PTV). The PTV was set to have ≥95% PTV receiving 70 Gy in each case. The cases for which dose constraints for ≥1 OAR could not be met without compromising the target dose coverage were compared with cases for which all target and OAR dose constraints were met.

Results

There were 23 central lesions for which OAR dose constraints could not be met without compromising PTV dose coverage. Comparing to cases for which optimal HT-based SABR plans were generated, they were associated with larger tumor size (5.72±1.96 cm vs. 3.74±1.49 cm, p<0.0001), higher lung dose, increased number of immediately adjacent OARs ( 3.45±1.34 vs. 1.66±0.81, p<0.0001), and shorter distance to the closest OARs (GTV: 0.26±0.22 cm vs. 0.88±0.54 cm, p<0.0001; PTV 0.19±0.18 cm vs. 0.48±0.36 cm, p = 0.0001).

Conclusion

Delivery of 70 Gy in 10 fractions with HT to meet all the given OAR and PTV dose constraints are most likely when the following parameters are met: lung lesions ≤3.78 cm (11.98 cc), ≤2 immediately adjacent OARs which are ≥0.45 cm from the gross lesion and ≥0.21 cm from the PTV.

Introduction

Helical Tomotherapy (HT) is a technology that delivers fan-beam intensity-modulated radiotherapy (IMRT) under megavoltage computed tomography (MVCT) guidance with continuous and synchronous gantry rotation and couch movement during radiation delivery [1]. Image guided IMRT delivered through HT has been shown to be able to generate highly conformal dose distribution at various anatomical sites since its clinical adaptation [2]. When compared with other techniques of radiation delivery, such as three dimensional conformal radiotherapy (3D-CRT) and conventional linac based IMRT, it may generate superior normal tissue sparing and target dose homogeneity as shown in some studies [3][5]. Therefore, it may provide a dosimetric advantage in the sparing of critical organs at risk (OARs) in complex cases, such as the delivery of stereotactic ablative radiotherapy (SABR) in the treatment of centrally located early stage non-small cell lung cancer (NSCLC) or solitary lung metastases from other primaries because of their ability to generate highly conformal dose avoidance of the OARs. This is of key clinical importance in the avoidance of severe toxicities associated with SABR (also called stereotactic body radiation therapy, SBRT), because such toxicities are mostly associated with central location and close proximity to critical structures in the thorax [6][10].

We have previously demonstrated the feasibility of HT-based SABR for the treatment of centrally located lung lesions [11]. However, no guidelines for the selection of optimal candidates for this procedure was found after a systematic, and extensive search of the literature on SABR through the PubMed, and Google scholar search engines. This prompted us to investigate the dosimetric selection criteria for HT-based SABR in patients with solitary early-stage NSCLC or metastatic lung tumors using the most common dose fractionation schedule used in our institution, 7 Gy×10 fractions, which we chose due to the previously reported excellent local control (>90%) and minimal toxicity associated with this regimen even for large tumors [12]. A minimal biologically effective dose of 100 Gy10 or higher is required for optimal local control [13]. The BED corresponding to this fractionation schedule is 119 Gy10. This study will provide preliminary guidelines in the selection of centrally located early stage NSCLC and solitary lung metastases for designing future prospective clinical studies on HT-based SABR in the thorax.

Materials and Methods

Patient and tumor characteristics

This study has been approved by the institutional review borad (IRB) at the University of Arizona. Since no actual human subjects was involved, no informed consent was needed per IRB. A total of seventy eight patients who underwent radiation therapy for stage I-II NSCLC, isolated recurrences from a lung primary, or metastases to the lung from other primaries in the department of Radiation Oncology at the University of Arizona from 2005 to 2011 have been included in this study. We retrieved the previous planning CT's for each patient to outline the gross tumor. Among them, 58 centrally located lesions were identified. Central location is defined as the area within 2 cm of the proximal bronchial tree, which includes the lower trachea, carina, mainstem bronchi, and the lobar bronchi. The critical structures are the esophagus, the heart, the spinal cord, major blood vessels, the distal trachea, and the proximal bronchial tree in the majority of the cases. Rarely, the brachial plexus, and the stomach were also in the vicinity of the gross disease.

Target volume delineation and SBRT treatment planning

All the target delineation was performed in the Pinnacle treatment planning system (Philips Medical Systems, Bothell, WA). Afterwards, each patient's planning CT scan and the contours were transferred into the Helical Tomotherapy planning system (Tomotherapy Inc.) for treatment planning. The planning target volume (PTV) was the clinical target volume (CTV) with a 5 mm expansion to account for set up errors and residual tumor motion. The CTV equals to the gross tumor volume (GTV) and its immediately adjacent areas which are felt to be at high risk for microscopic disease extension. The lungs, esophagus, spinal cord, and the heart were contoured for each patient. The major vessels, major airway and other additional structures were contoured only when they were adjacent to the GTV.

Treatment plans were generated in the Tomotherapy Hi-Art planning system using 6 MV photons delivered without a flattening filter. A binary multi-leaf collimator (MLC) with a leaf width that projects to a 6.25 mm width at the isocenter which is 85 cm away from the X-ray photon source. In the plans, longitudinal aperture sizes of 1.05 cm or 2.5 cm, and pitch of 0.3 were used. The nominal dose rate at the isocenter was 870 cGy/min (SAD). A modulation factor of 3 was set at the beginning of the optimization process. All SBRT plans prescribed 70 Gy delivered in 10 daily fractions to the PTV with heterogeneity corrections using the superposition-convolution algorithm.

All plans were optimized to have at least 95% of the PTV receiving 100% of the prescription dose, which is in accordance with the American society of therapeutic radiation oncology (ASTRO)'s white paper [14]. The dose volume constraints used at our institution are shown in Table 1, which are described in more detail in our previous publication [11]. These parameters (10 fractions) approximate those used in the RTOG 0236 (3 fractions) [15] in their biologically equivalent isodose effect, which were calculated with the linear quadratic formulism using an α/β ratio of 3. An α/β ratio of 2 and the likelihood for intrafractional patient motion was also taken into consideration while deriving a reasonable dose constraint for the spinal cord. Maximum point dose constraints were used as in line with those used in the RTOG 0236, because the majority of the thoracic OARs other than the lungs were serial structures, severe damage to even a small point could be catastrophic as that reported by Onimaru et al [9], [16]. Target volume coverage took priority over the dose constraints for the OARs in each case because of the concern for significant decrease in tumor control probability (TCP) when there are significant subvolumes of cold spots [17].

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Table 1. Dose constraints for the prescription dose of 70 Gy delivered in 10 fractions.

https://doi.org/10.1371/journal.pone.0035809.t001

Data analysis

The size and location of the GTV (and PTV); the number of adjacent critical structures within 2 cm from the edge of the GTV; and the distances of the GTV and PTV to each of these adjacent structures, respectively, were recorded for each patient. These parameters, and the doses to the PTV & the OARs for patients whose treatment plans met the given dose constraints were compared to those from patients whose treatment plans did not met these constraints using the t-test.

Results

The PTV coverage criteria of ≥95% of the PTV receiving 70 Gy (%PTV70 Gy) was met by all 78 treatment plans. Among them, dose constraints for the OARs could not be all satisfied in order to maintain adequate PTV coverage for 23 centrally located lesions (Centralno). The dose covering 95% of the PTV (D95), %PTV70 Gy, and the maximum dose to the PTV (PTVmax) for this group of lesions were compared with those for 35 central (Central) and 20 peripheral lesions (Peripheral) for which the HT SABR plans met all the PTV and OAR dose parameters. The findings are summarized in Table 2. The PTVmax was significantly higher, while the D95 and %PTV70 Gy were significantly lower in the Centralno group.

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Table 2. Dose Coverage of the PTV for the three groups of lung lesions.

https://doi.org/10.1371/journal.pone.0035809.t002

Dose to the lungs

The dose to the lungs is mainly evaluated by the dose to the total lung (volumeleft lung+volumeright lung−GTV). There was no statistically significant difference in the volumes of the total lung, the ipsilateral lung, and the contralateral lung among the three groups of lesions (p>0.05). The commonly used parameters of the mean lung dose (MLD), and the volume of the total lung receiving 5 Gy, 10 Gy, and 20 Gy (V5, V10, and V20) are listed in Table 3. The V20 was kept to below 20% for all three types of lesions. The MLD for the total lung appears to be higher in the Centralno group. However, it was below the MLD constraint for most cases in this group.

The MLD, V5, V10, and V20 for the ipsilateral and the contralateral lungs are also shown in Table 3 to explore the degree of contralateral lung sparing in HT-based SABR. All three types of lesions were found to have significantly lower doses to the contralateral lung comparing to that to the ipsilateral lung (p<0.0001). Worth mentioning is that the MLD and V20 for the ipsilateral lung are significantly higher for all the central lesions, and the contralateral lung's MLD and V5 are found to be higher in the Centralno group when compared to the other two groups.

Dose to the other OARs

The maximum dose received by the spinal cord, the esophagus, the heart, the major airways, and the major vessels is summarized in Table 4. The Centralno group was found to have significantly higher doses for all OARs when compared to other two groups of lung lesions.

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Table 4. Maximum dose to the organs at risk (including organs immediately adjacent to the tumor).

https://doi.org/10.1371/journal.pone.0035809.t004

Factors influencing the feasibility of HT-based SBRT

A set of tumor factors were investigated to characterize the lesions in the Centralno group when compared with the other two groups of lesions. The findings are summarized in Table 5. The tumor size for the Centralno group was significantly larger. These central lesions, for which HT-based SABR is not feasible, had more than 2 critical structures immediately adjacent to the GTV. In addition, they were significantly closer to the critical structures with an average OAR to GTV, and PTV distances of 0.26 cm, and 0.19 cm, respectively. The median distribution of our data suggests the most ideal candidates for HT-based SABR should have GTV≤3. 78 cm, or 11.98 cc; PTV≤4.90 cm, or 34.43 cc; ≤2 separate adjacent structures immediately adjacent to the GTV, the minimum GTV to OAR distance of ≥0.45 cm, and the minimum PTV to OAR distance of ≥0.21 cm.

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Table 5. Comparison of the tumor characteristics of the Centralno group of lesions with the Central and Peripheral groups of lesions.

https://doi.org/10.1371/journal.pone.0035809.t005

The majority of the lesions was in the left or right upper lobes of the lungs for the centrally located lesions and the peripheral lesions. They were consisted of 68.42%, 47.82%, and 65% of the Central, Centralno, and Peripheral groups of lesions (p>0.05).

Discussion

SABR or SBRT has emerged to become a major treatment approach for early-stage NSCLC or lung metastases with excellent local control in recent years [18], [19]. However, severe toxicities following SABR have been associated with centrally located lesions, which are in close proximity to critical organs [7][10]. The reported fatal complications, mostly grade 5 hemoptysis, are usually associated with a high dose delivered per fraction. This is presumably due to excessive radiation dose to the normal structures (Table 6) [7], [8], [10], [20][23]. Thus, the clinician is faced with a dilemma in this situation: Lowering radiation dose or compromising target coverage may be associated with a high risk of local recurrence and death from tumor progression; or delivering a high dose of radiation which may lead to potentially fatal treatment related toxicities. This prompted us to search for an optimal dose fractionation schedule that may reliably deliver a high dose to the tumor while respecting the constraints to the surrounding normal tissues. In a previous study, we demonstrated that helical tomotherapy, by virtue of its unique radiation delivery approach, may be the ideal IMRT delivery system when treating central lesions with SABR because of the sharp dose gradient it generates, especially for the 7 Gy×10 fractions schedule [11].

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Table 6. Grade 5 toxicity reported in the literature following stereotactic body radiotherapy for centrally located lung cancer.

https://doi.org/10.1371/journal.pone.0035809.t006

In the current study, we further characterize the physical and geometric parameters of solitary lung lesions (central & peripheral) from patients for whom adequate target and OAR dose parameters can be satisfied for HT-based SABR. The OAR dose constraints are in line with those used in the RTOG phase II trial (0236) on SBRT for peripheral T1-2N0M0 NSCLC in terms of the isodose effect through the linear quadratic formalism. In RTOG 0236, only 3.6% grade 4 SBRT related toxicity and no grade 5 toxicity were reported [15]. The spinal cord dose was kept lower due to the concern of increased risk for intrafractional motion when delivering SABR in complicated cases, which often takes a long time. However, low dose to the spinal cord is easily achieved in our experience. In challenging cases, we are willing to accept a maximum spinal cord dose of 30 Gy, which are still acceptable based on accepted practice of treating metastases causing spinal cord compression; and QUNTEC recommendations suggesting that 21 Gy delivered in 3 fractions will translated to <1% risk of myelopathy [24]. In addition, SABR/SBRT treatments delivering a mean linear quadratic 2 Gy equivalent dose (EQD2) of 36.4 Gy (α/β of 2) as maximum point dose was found to be safe with no occurrence of myelopathy, which also supports our practice of keeping our maximum point dose to slightly <30 Gy when it can be easily achieved [25]. In our limited experience, no toxicity has been encountered in patients who were treated with the current set of dose constraints used (Table 1).

To our best knowledge, this is the first study to establish a set of preliminary, yet clinically applicable dosimetric guidelines to aid the selection of centrally located lesions for HT-based SABR. The 7 Gy×10 fraction schedule was chosen mainly because concerns of significant normal tissue toxicity associated with fractionations schedules of shorter duration when centrally located lesions were treated [7][10], [20][23]. In addition, the treatment time for delivering a high dose is usually fairly long for helical tomotherapy. As a result, most institutions usually divide fractional doses ≥10 Gy into two consecutive treatments of equal dose with pre-treatment MVCT set up verification before each treatment on a daily basis. This treatment approach appears to be inconvenient and time consuming in a busy clinic. On the contrary, the 10 fraction schedule is not only found to be associated with an excellent toxicity profile with only 1 case of grade 3 pneumonitis out of 43 patients when fairly large tumors were treated, but also delivers a fractional dose that can be delivered in 1 treatment with helical tomotherapy [12]. Thus, this schedule appears to be a very good choice among many well tested treatment schedules when it comes to treating central lesions with helical tomotherapy. The results indicate that large, centrally located lesions that are in close proximity to multiple OARs are difficult to treat without overdosing the OARs if optimal target dose coverage is desired. These lesions tend to be associated with significantly more heterogeneous dose distribution in the PTV, and more dose scatter to the contralateral lung (Tables 2 and 3). Larger central lesions usually are closer to the immediately adjacent critical thoracic structures than central lesions of a smaller size. Thus, demanding a sharper dose gradient to be generated between the PTV's edge and the immediately adjacent OARs. However, they are often surrounded by an increased number of OARs, which greatly limits the entry angle for free entering beams, thus making adequately covering the PTV without depositing a high dose in the immediately adjacent structures impossible.

Because of the limitation on intensity modulation imposed by the increased number of OARs associated with large central lesions, HT-based SABR may not be the most optimal treatment technique if optimal target coverage is desired, even if other dose fractionation schedules are considered. This is evidenced in a study by Baisden et al using mostly 3 fraction schedules of various doses, which had to accept less optimal target dose coverage when an OAR is very close to the tumor [26]. In such situations, a high dose delivered through a more protracted course while accounting for tumor shrinkage may be a good alternative to SABR. However, this will need to be further investigated in the future.

The normal lung dose does not seem to be a decisive factor in the feasibility of HT-based SABR. V20 is well below 20% for all cases. V20 below 20% was previously shown to be associated with only 1 case of maximally grade 3 pneumonitis (2.3%) in a cohort of patients treated with 7 Gy×10 fractions to the GTV [12]. Also, the MLD for the total lung are well below 14 Gy3 on average in all cases, which puts them at a low risk for severe radiation pneumonitis as shown in many studies [19], [27]. On the contrary, the increased number of OARs immediately adjacent to the tumor target seems to be the key reason for suboptimal critical structure sparing if adequate PTV dose coverage is to be maintained. As a result, we propose to use tumor size (both tumor diameter and volume), the number of separate critical structures immediately adjacent to the tumor, and the distances of the closest structures to the GTV and PTV as a starting point in selecting patients for HT-based SABR.

There are limitations to our study which need to further investigated. One of them is tumor motion management. HT has been previously demonstrated to be adequate for treating moving targets with a hypofractionated course of radiotherapy [28]. Tumor motion can be addressed with four-dimensional (4D) CT to account for internal tumor motion throughout the entire respiratory cycle; while set up errors can be further reduced with HT compatible immobilization devices [29]. 4-D CT has been adopted in our institution since 2009. However, this is not the most essential issue in our study, which only needs hypothetical targets to carry out the investigation. In addition, the prolonged treatment delivery time of a complex treatment plan associated with HT may be partially resolved with newer technology, such as dynamic jaws and dynamic couch which come with the next generation of HT systems [30]. We recognize that there are other dose fractionation schedules, which may be used when treating centrally located lesions. However, as Table 6 illustrates, fatal complications are more likely to occur with high fractional doses, which prompted us to take a conservative approach in dose fractionation selection which is only limited to schedules for which clinical outcome and toxicity profile were previously reported. This may help clinicians in designing prospective SABR trials treating centrally located tumors in the future.

In conclusion, meeting the OAR dose constraints with adequate PTV target dose coverage criteria is most likely to be accomplished for lung lesions with the following characteristics: GTV≤3.78 cm, or 11.98 cc; PTV≤4.90 cm, or 34.43 cc; ≤2 separate adjacent structures immediately adjacent to the GTV, and the distances of GTV and PTV to the OARs of ≥0.45 cm, and ≥0.21 cm, respectively, when the 7 Gy×10 fractions schedule is delivered with HT. As these are only preliminary findings, they will need to be further validated in a phase I prospective trial evaluating SABR for early stages NSCLC and/or solitary lung metastases.

Author Contributions

Conceived and designed the experiments: AC ZL NPN JX RK. Performed the experiments: AC JX SJ. Analyzed the data: JX SJ. Contributed reagents/materials/analysis tools: SJ. Wrote the paper: AC ZL NPN JX SJ JW CH RK. Performed an extensive literature search on the topic of helical tomotherapy: CH.

References

  1. 1. Fenwick JD, Tomé WA, Soisson ET, Mehta MP, Rock Mackie T (2006) Tomotherapy and other innovative IMRT delivery systems. Semin Radiat Oncol 16: 199–208.JD FenwickWA ToméET SoissonMP MehtaT. Rock Mackie2006Tomotherapy and other innovative IMRT delivery systems.Semin Radiat Oncol16199208
  2. 2. Sterzing F, Schubert K, Sroka-Perez G, Kalz J, Debus J, et al. (2008) Helical tomotherapy. Experiences of the first 150 patients in Heidelberg. Strahlenther Onkol 184: 8–14.F. SterzingK. SchubertG. Sroka-PerezJ. KalzJ. Debus2008Helical tomotherapy. Experiences of the first 150 patients in Heidelberg.Strahlenther Onkol184814
  3. 3. Cattaneo GM, Dell'Oca I, Broggi S, Fiorino C, Perna L, et al. (2008) Treatment planning comparison between conformal radiotherapy and helical tomotherapy in the case of locally advanced-stage NSCLC. Radiother Oncol 88: 310–318.GM CattaneoI. Dell'OcaS. BroggiC. FiorinoL. Perna2008Treatment planning comparison between conformal radiotherapy and helical tomotherapy in the case of locally advanced-stage NSCLC.Radiother Oncol88310318
  4. 4. Sheng K, Molloy JA, Read PW (2006) Intensity-modulated radiation therapy (IMRT) dosimetry of the head and neck: a comparison of treatment plans using linear accelerator-based IMRT and helical tomotherapy. Int J Radiat Oncol Biol Phys 65: 917–923.K. ShengJA MolloyPW Read2006Intensity-modulated radiation therapy (IMRT) dosimetry of the head and neck: a comparison of treatment plans using linear accelerator-based IMRT and helical tomotherapy.Int J Radiat Oncol Biol Phys65917923
  5. 5. Rodrigues G, Yartsev S, Chen J, Wong E, D'Souza D, et al. (2006) A comparison of prostate IMRT and helical tomotherapy class solutions. Radiother Oncol 80: 374–377.G. RodriguesS. YartsevJ. ChenE. WongD. D'Souza2006A comparison of prostate IMRT and helical tomotherapy class solutions.Radiother Oncol80374377
  6. 6. Nagata Y, Wulf J, Lax I, Timmerman R, Zimmermann F, et al. (2011) Stereotactic radiotherapy of primary lung cancer and other targets: Results of consultant meeting of the International Atomic Energy Agency. Int J Radiat Oncol Biol Phys 79: 660–669.Y. NagataJ. WulfI. LaxR. TimmermanF. Zimmermann2011Stereotactic radiotherapy of primary lung cancer and other targets: Results of consultant meeting of the International Atomic Energy Agency.Int J Radiat Oncol Biol Phys79660669
  7. 7. Timmerman R, McGarry R, Yiannoutsos C, Papiez L, Tudor K, et al. (2006) Excessive toxicity when treating central tumors in a phase II study of stereotactic body radiation therapy for medically inoperable early-stage lung cancer. J Clin Oncol 24: 4833–4839.R. TimmermanR. McGarryC. YiannoutsosL. PapiezK. Tudor2006Excessive toxicity when treating central tumors in a phase II study of stereotactic body radiation therapy for medically inoperable early-stage lung cancer.J Clin Oncol2448334839
  8. 8. Fakiris AJ, McGarry RC, Yiannoutsos CT, Papiez L, Williams M, et al. (2009) Stereotactic body radiation therapy for early-stage non-small-cell lung carcinoma: four-year results of a prospective phase II study. Int J Radiat Oncol Biol Phys 75: 677–682.AJ FakirisRC McGarryCT YiannoutsosL. PapiezM. Williams2009Stereotactic body radiation therapy for early-stage non-small-cell lung carcinoma: four-year results of a prospective phase II study.Int J Radiat Oncol Biol Phys75677682
  9. 9. Onimaru R, Shirato H, Shimizu S, Kitamura K, Xu B, et al. (2003) Tolerance of organs at risk in small volume, hypofractionated, image-guided radiotherapy for primary and metastatic lung cancers. Int J Radiat Oncol Biol Phys 56: 126–35.R. OnimaruH. ShiratoS. ShimizuK. KitamuraB. Xu2003Tolerance of organs at risk in small volume, hypofractionated, image-guided radiotherapy for primary and metastatic lung cancers.Int J Radiat Oncol Biol Phys5612635
  10. 10. Song SY, Choi W, Shin SS, Lee SW, Ahn SD, et al. (2009) Fractionated stereotactic body radiation therapy for medically inoperable stage I lung cancer adjacent to central large bronchus. Lung Cancer 66: 89–93.SY SongW. ChoiSS ShinSW LeeSD Ahn2009Fractionated stereotactic body radiation therapy for medically inoperable stage I lung cancer adjacent to central large bronchus.Lung Cancer668993
  11. 11. Chi A, Jang SY, Welsh JS, Nguyen NP, Ong E, et al. (2011) Feasibility of helical tomotherapy in stereotactic body radiation therapy for centrally located early stage non-small-cell lung cancer or lung metastases. Int J Radiat Oncol Biol Phys 81: 856–862.A. ChiSY JangJS WelshNP NguyenE. Ong2011Feasibility of helical tomotherapy in stereotactic body radiation therapy for centrally located early stage non-small-cell lung cancer or lung metastases.Int J Radiat Oncol Biol Phys81856862
  12. 12. Xia T, Li H, Sun Q, Wang Y, Fan N, et al. (2006) Promising clinical outcome of stereotactic body radiation therapy for patients with inoperable Stage I/II non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 66: 117–125.T. XiaH. LiQ. SunY. WangN. Fan2006Promising clinical outcome of stereotactic body radiation therapy for patients with inoperable Stage I/II non-small-cell lung cancer.Int J Radiat Oncol Biol Phys66117125
  13. 13. Onishi H, Shirato H, Nagata Y, Hiraoka M, Fujino M, et al. (2007) Hypofractionated stereotactic radiotherapy (HypoFXSRT) for stage I non-small cell lung cancer: updated results of 257 patients in a Japanese multi-institutional study. J Thorac Oncol 2: S94–S100.H. OnishiH. ShiratoY. NagataM. HiraokaM. Fujino2007Hypofractionated stereotactic radiotherapy (HypoFXSRT) for stage I non-small cell lung cancer: updated results of 257 patients in a Japanese multi-institutional study.J Thorac Oncol2S94S100
  14. 14. Solberg TD, Balter JM, Benedict SH, Fraass BA, Kavanagh B, et al. (2012) Quality and safety considerations in stereotactic radiosurgery and stereotactic body radiation therapy: executive summary. Practical Radiat Oncol 2: 2–9.TD SolbergJM BalterSH BenedictBA FraassB. Kavanagh2012Quality and safety considerations in stereotactic radiosurgery and stereotactic body radiation therapy: executive summary.Practical Radiat Oncol229
  15. 15. Timmerman R, Paulus R, Galvin J, Michalski J, Straube W, et al. (2010) Stereotactic body radiation therapy for inoperable early stage lung cancer. JAMA 303: 1070–1076.R. TimmermanR. PaulusJ. GalvinJ. MichalskiW. Straube2010Stereotactic body radiation therapy for inoperable early stage lung cancer.JAMA30310701076
  16. 16. Timmerman R, Heinzerling J, Abdulrahman R, Choy H, Meyer JL (2011) Stereotactic body radiation therapy for thoracic cancers: recommendations for patient selection, setup and therapy. Front Radiat Ther Oncol 43: 395–411.R. TimmermanJ. HeinzerlingR. AbdulrahmanH. ChoyJL Meyer2011Stereotactic body radiation therapy for thoracic cancers: recommendations for patient selection, setup and therapy.Front Radiat Ther Oncol43395411
  17. 17. Tomé WA, Fowler JF (2002) On cold spots in tumor subvolumes. Med Phys 29: 1590–1598.WA ToméJF Fowler2002On cold spots in tumor subvolumes.Med Phys2915901598
  18. 18. Chi A, Liao Z, Nguyen NP, Xu J, Stea B, et al. (2010) Systemic review of the patterns of failure following stereotactic body radiation therapy in early-stage non-small-cell lung cancer: Clinical implication. Radiother Oncol 94: 1–11.A. ChiZ. LiaoNP NguyenJ. XuB. Stea2010Systemic review of the patterns of failure following stereotactic body radiation therapy in early-stage non-small-cell lung cancer: Clinical implication.Radiother Oncol94111
  19. 19. Ricardi U, Filippi AR, Guarneri A, Ragona R, Mantovani C, et al. (2011) Stereotactic body radiation therapy for lung metastases. Lung Cancer 75: 77–81.U. RicardiAR FilippiA. GuarneriR. RagonaC. Mantovani2011Stereotactic body radiation therapy for lung metastases.Lung Cancer757781
  20. 20. Oshiro Y, Aruga T, Tsuboi K, Marino K, Hara R, et al. (2010) Stereotactic body radiotherapy for lung tumors at the pulmonary hilum. Strahlenther Onkol 186: 274–279.Y. OshiroT. ArugaK. TsuboiK. MarinoR. Hara2010Stereotactic body radiotherapy for lung tumors at the pulmonary hilum.Strahlenther Onkol186274279
  21. 21. Peulen H, Karlsson K, Lindberg K, Tullgren O, Baumann P, et al. (2011) Toxicity after reirradiation of pulmonary tumors with stereotactic body radiotherapy. Radiother Oncol 101: 260–266.H. PeulenK. KarlssonK. LindbergO. TullgrenP. Baumann2011Toxicity after reirradiation of pulmonary tumors with stereotactic body radiotherapy.Radiother Oncol101260266
  22. 22. Milano MT, Chen Y, Katz AW, Philip A, Schell MC, et al. (2009) Central thoracic lesions treated with hypofractionated stereotactic body radiotherapy. Radiother Oncol 91: 301–306.MT MilanoY. ChenAW KatzA. PhilipMC Schell2009Central thoracic lesions treated with hypofractionated stereotactic body radiotherapy.Radiother Oncol91301306
  23. 23. Stauder MC, Macdonald OK, Olivier KR, Call JA, Lafata K, et al. (2011) Early pulmonary toxicity following lung stereotactic body radiation therapy delivered in consecutive daily fractions. Radiother Oncol 99: 166–171.MC StauderOK MacdonaldKR OlivierJA CallK. Lafata2011Early pulmonary toxicity following lung stereotactic body radiation therapy delivered in consecutive daily fractions.Radiother Oncol99166171
  24. 24. Kirkpatrick JP, Van der Kogel AJ, Schultheiss TE (2010) Radiation dose-volume effects in the spinal cord. Int J Radiat Oncol Biol Phys 76: S42–S49.JP KirkpatrickAJ Van der KogelTE Schultheiss2010Radiation dose-volume effects in the spinal cord.Int J Radiat Oncol Biol Phys76S42S49
  25. 25. Sahgal A, Ma L, Gibbs I, Gerszten PC, Ryu S, et al. (2010) Spinal cord tolerance for stereotactic body radiotherapy. Int J Radiat Oncol Biol Phys 77: 548–553.A. SahgalL. MaI. GibbsPC GersztenS. Ryu2010Spinal cord tolerance for stereotactic body radiotherapy.Int J Radiat Oncol Biol Phys77548553
  26. 26. Baisden JM, Romney DA, Reish AG, Cai J, Sheng K, et al. (2007) Dose as a function of lung volume and planned treatment volume in helical tomotherapy intensity-modulated radiation therapy-based stereotactic body radiation therapy for small lung tumors. Int J Radiat Oncol Biol Phys 68: 1229–1237.JM BaisdenDA RomneyAG ReishJ. CaiK. Sheng2007Dose as a function of lung volume and planned treatment volume in helical tomotherapy intensity-modulated radiation therapy-based stereotactic body radiation therapy for small lung tumors.Int J Radiat Oncol Biol Phys6812291237
  27. 27. Chi A, Tomé WA, Fowler J, Komaki R, Nguyen NP, et al. (2010) Stereotactic body radiation therapy in non-small-cell lung cancer: linking radiobiological modeling and clinical outcome. Am J Clin Oncol 34: 432–441.A. ChiWA ToméJ. FowlerR. KomakiNP Nguyen2010Stereotactic body radiation therapy in non-small-cell lung cancer: linking radiobiological modeling and clinical outcome.Am J Clin Oncol34432441
  28. 28. Kanagaki B, Read PW, Molloy JA, Larner JM, Sheng K (2007) A motion phantom study on helical tomotherapy: the dosimetric impacts of delivery technique and motion. Phys Med Biol 52: 243–255.B. KanagakiPW ReadJA MolloyJM LarnerK. Sheng2007A motion phantom study on helical tomotherapy: the dosimetric impacts of delivery technique and motion.Phys Med Biol52243255
  29. 29. Gutiérrez AN, Stathakis S, Crownover R, Esquivel C, Shi C, et al. (2011) Clinical evaluation of an immobilization system for stereotactic body radiotherapy using helical tomotherapy. Med Dosim 36: 126–129.AN GutiérrezS. StathakisR. CrownoverC. EsquivelC. Shi2011Clinical evaluation of an immobilization system for stereotactic body radiotherapy using helical tomotherapy.Med Dosim36126129
  30. 30. Sterzing F, Uhl M, Hauswald H, Schubert K, Schubert K, et al. (2010) Dynamic jaws and dynamic couch in helical tomotherapy. Int J Radiat Oncol Biol Phys 76: 1266–1273.F. SterzingM. UhlH. HauswaldK. SchubertK. Schubert2010Dynamic jaws and dynamic couch in helical tomotherapy.Int J Radiat Oncol Biol Phys7612661273