Practical Essentials of Intensity Modulated Radiation Therapy, 3 Ed.

13. Lung Cancer

Simon K. Cheng • Bhupesh Parashar • Ritsuko Komaki • Hasan Murshed

Lung Cancer – Highlights

Key Recent Studies and Guidelines

Jiang et al. (IJROBP 2012) reported that the use of IMRT gave improved overall survival and similar locoregional progression-free and distant metastasis-free survival compared with 3DCRT treatment with low rates of pulmonary and esophageal toxicity. (PMID 22079735)

Timmerman et al. (JAMA 2010) reported the results of RTOG 0236 and showed that inoperable T1-2N0 NSCLC patients treated with SBRT had 3-year primary tumor control rate of 98%, 3-year locoregional control rate of 87%, and 3-year distant metastases rate of 22%. (PMID 20233825)

The RTOG, EORTC, and SWOG (IJROBP 2011) presented an atlas for the contouring of organs at risk for thoracic radiotherapy. (PMID 20934273)

New Target Delineation Contours

FIGURE 13-12. Stereotactic body radiotherapy treatment (SBRT) planning for centrally located tumors. With 4D CT scans, a uniform 0.5 cm expansion in all directions to the ITV (yellow) will define the PTV (red).


1.1. Gross Anatomy

• The right lung has three lobes as a result of a second fissure, the horizontal fissure, which separates the middle lobe from the upper lobe and extends from the anterior margin into the oblique fissure.1

• The left lung is composed of two lobes: an upper and lower lobe. The lingular portion of the left upper lobe corresponds to the middle lobe on the right.

• The trachea enters the superior mediastinum and bifurcates at the carina approximately at the level of the fifth thoracic vertebra (Fig. 13-1A).2

• The hila contain the bronchi, pulmonary arteries and veins, various branches from the pulmonary plexus, bronchial arteries and veins, and lymphatics.

• The proximal bronchial tree consist of the carina, right and left main bronchi, right and left upper lobe bronchi, intermedius bronchus, right middle lobe bronchus, lingular bronchus, right and left lower lobe bronchi (Fig. 13-1B). The zone of the proximal bronchial tree is defined as a volume of 2 cm in all directions around these structures.

1.2. Lung Lymph Node Stations

• Figures 13-2 and 13-3 show the 2009 International Association for the Study of Lung Cancer (IASLC) lymph node map corresponding to the 7th edition of the American Joint Committee on Cancer (AJCC) TNM staging manual.3Anatomical boundaries of each nodal station are detailed below.

• Supraclavicular Zone

º 1. Low cervical, supraclavicular and sternal notch nodes. Upper border: lower margin of cricoid cartilage. Lower border: clavicles bilaterally and, in the midline, the upper border of the manubrium. For lymph node station 1, the midline of the trachea serves as the border between 1R and 1L.

FIGURE 13-1. (A) Segmental anatomy of the lungs. (From Moore KL, Dalley AF. Clinically Oriented Anatomy, 4th ed. Baltimore, MD: Lippincott Williams & Wilkins, 1999.)

• Superior Mediastinal Nodes

º 2R. Upper paratracheal nodes. Upper border: apex of the right lung and in the midline, the upper border of the manubrium. Lower border: intersection of caudal margin of innominate vein with the trachea. As with lymph node station 4R, 2R includes nodes extending to the left lateral border of the trachea.

º 2L. Upper border: apex of the left lung, and in the midline, the upper border of the manubrium. Lower border: superior border of the aortic arch.

º 3a. Prevascular nodes. On the right: Upper border: apex of chest. Lower border: level of carina. Anterior border: posterior aspect of sternum. Posterior border: anterior border of superior vena cava. On the left: Upper border: apex of chest. Lower border: level of carina. Anterior border: posterior aspect of sternum. Posterior border: left carotid artery.

º 3p. Retrotracheal nodes. Located posterior to trachea. Upper border: apex of chest

Lower border: carina.

º 4R. Lower paratracheal nodes. Includes right paratracheal nodes, and pretracheal nodes extending to the left lateral border of trachea. Upper border: intersection of caudal margin of innominate vein with the trachea. Lower border: lower border of azygos vein.

º 4L. Includes nodes to the left of the left lateral border of the trachea, medial to the ligamentum arteriosum. Upper border: upper margin of the aortic arch. Lower border: upper rim of the left main pulmonary artery.

• Aortic Nodes

º 5. Subaortic nodes. Lateral to the ligamentum arteriosum. Upper border: the lower border of the aortic arch. Lower border: upper rim of the left main pulmonary artery.

º 6. Para-aortic nodes. Anterior and lateral to the ascending aorta and aortic arch. Upper border: a line tangential to the upper border of the aortic arch. Lower border: the lower border of the aortic arch.

• Inferior Mediastinal Nodes

º 7. Subcarinal nodes. Upper border: the carina of the trachea. Lower border: the upper border of the lower lobe bronchus on the left; the lower border of the bronchus intermedius on the right.

º 8. Paraesophageal nodes (below carina). Nodes lying adjacent to the wall of the esophagus and to the right or left of the midline, excluding subcarinal nodes. Upper border: the upper border of the lower lobe bronchus on the left; the lower border of the bronchus intermedius on the right. Lower border: the diaphragm.

º 9. Pulmonary ligament nodes. Nodes lying within the pulmonary ligament. Upper border: the inferior pulmonary vein. Lower border: the diaphragm.

FIGURE 13-2. Regional nodal stations for lung cancer. The International Association for the Study of Lung Cancer (IASLC) lymph node map includes the proposed grouping of lymph node stations into “zones” for the purposes of prognostic analyses. (Reprinted from: Goldstraw P (ed.) IASLC Staging Manual in Thoracic Oncology. Orange Park, FL: Editorial Rx Press, 2009, with permission. This figure is also reprinted in the Journal of Thoracic Oncology; see reference 68.)

FIGURE 13-3. Nodal station boundaries for lung cancer. A–F: Illustrations of how the IASLC lymph node map can be applied to clinical staging by computed tomography (CT) scan in axial (A–C), coronal (D), and sagittal (E, F) views. The border between the right and left paratracheal region is shown in (A) and (B). Ao, aorta; AV, azygos vein; Br, bronchus; IA, innominate artery; IV, innominate vein; LA, ligamentum arteriosum; LIV, left innominate vein; LSA, left subclavian artery; PA, pulmonary artery; PV, pulmonary vein; RIV, right innominate vein; SVC, superior vena cava. (Reprinted from: Goldstraw P (ed.) IASLC Staging Manual in Thoracic Oncology. Orange Park, FL: Editorial Rx Press, 2009, with permission. This figure is also reprinted in the Journal of Thoracic Oncology; see reference 68.)

• N1 Nodes

º 10. Hilar nodes. Include nodes immediately adjacent to the mainstem bronchus and hilar vessels including the proximal portions of the pulmonary veins and main pulmonary artery. Upper border: the lower rim of the azygos vein on the right; upper rim of the pulmonary artery on the left. Lower border: interlobar region bilaterally.

º 11. Interlobar nodes. Between the origin of the lobar bronchi.

º 12. Lobar nodes. Adjacent to the lobar bronchi.

º 13. Segmental nodes. Adjacent to the segmental bronchi.

º 14. Subsegmental nodes. Adjacent to the subsegmental bronchi.

1.3. Lymphatic Drainage

• The drainage for each pulmonary lobe is shown in Figure 13-4.4

• Upper lobes drainage: Right upper lobe lymphatics drain to the right paratracheal lymph nodes (4R, 2R). Left upper lobe lymphatics drain more frequently into the para-aortic and subaortic lymph nodes (5, 6, and 4L), but also to the venous angle of the opposite superior mediastinum.

• Middle and lower lobes drainage: The right and left lower lobe lymphatics drain into the hilar and the subcarinal nodes (7) and from there to the right paratracheal nodes (4R, 2R). The left lower lobe also may drain into the left paratracheal nodes (4L, 2L).

• Skip metastases: Direct tumor drainage to the mediastinal lymph nodes bypassing the hilar and interlobar nodes can be seen clinically in 7% to 26% of resected lung cancer specimens. They are more common in upper lobe lesions.

• In the case of chest wall involvement, there is a risk of spread to the intercostal nodes located close to the intercostal vessels and nerves. Paravertebral nodes situated either lateral to or in front of the vertebral bodies may be located along the pathway of the intercostal lymph collector.


• Lung cancer is the leading cause of cancer death in the United States and the rest of the world.58 Unfortunately, most patients already have locally advanced lung cancer at the time of diagnosis.

• Small-cell lung cancers (SCLC) have a higher incidence of distant metastases than non-small-cell lung cancers (NSCLC); of the latter, adenocarcinoma has the highest potential for distant metastases.

FIGURE 13-4. Standard pattern of lymphatic drainage based on 192 lymphoscintigraphies carried out in 179 patients without known nodal dissemination. For the right lobes, most of the lymph flowed into the right supraclavicular nodes through the subcarinal or right tracheobronchial (hilar and paratracheal) nodes. In contrast, the lymphatic drainage from the left lung was more variable: the lymph can reach both the left and right supraclavicular lymph nodes, especially in the case of the lower lobe. (Redrawn from Hata E, Hayakawa K, Miyamoto H, et al. Rationale for extended lymphadenectomy for lung cancer. Theor Surg 1990;5:19–27, with permission.)

• Squamous cell carcinoma tends to spread more locally or intrathoracically rather than hematogenously.

• Tables 13-1 and 13-2 present lymph node involvement by tumor diameter and histologic type, respectively.


3.1. Signs and Symptoms

• The majority of patients present with symptomatic disease.

• Cough (75%), hemoptysis (57%), dyspnea, and recurrent pneumonia are common major symptoms resulting from airway obstruction by central bronchogenic lesions.

• Patients with peripheral tumors are frequently asymptomatic unless there is involvement of the chest wall or intercostal nerves. Dyspnea and chest pain is also common when tumors invade the pleura, chest wall, or mediastinal structures.

• Hoarseness may result from recurrent laryngeal nerve involvement by mediastinal metastasis (more common with left lung tumors and with aorticopulmonary window lymphadenopathy).

• Dysphagia may be caused by compression of the esophagus by tumor.

• Superior vena cava syndrome can arise with right lung tumors or right mediastinal nodal metastasis.

• Tumors at the lung apex may involve the cervical or thoracic nerves, resulting in Pancoast syndrome or superior sulcus tumor syndrome (Horner syndrome, brachial plexopathy, and shoulder pain). Sympathetic nerve involvement results in Horner syndrome (enophthalmos, ptosis, meiosis, and ipsilateral loss of sweating).

• Involvement of the phrenic nerve can result in dyspnea and paralysis of the hemidiaphragm.

• CNS symptoms are seen with brain metastasis or paraneoplastic disease, such as hyponatremia or hypercalcemia (SCLC).

3.2. Physical Examination

• Signs of partial or complete bronchial obstruction, pleural effusion, pneumonia, or atelectasis may be detected by chest examination.

• Inspection of the head and neck may reveal regional lymphatic (N3) spread.

• Metastatic disease can be found by examination of the abdomen (liver metastasis: hepatomegaly) and neuroaxis (cerebral and/or spinal cord metastasis).

3.3. Imaging

3.3.1. Computed Tomography

• Routine chest x-ray is the most common radiologic examination.

• Computed tomography (CT) has been the principal diagnostic tool for diagnosing primary lesions, and the radiological detection of lymph node metastases is based on nodal enlargement, but it cannot differentiate inflammatory disease from neoplasia.

• Mediastinal nodes less than 1 cm in diameter are considered unlikely to contain metastatic disease. Nodes 1 to 2 cm are intermediate, and those larger than 2 cm in a patient with bronchogenic carcinoma almost certainly are metastatic.9

• A convenient and reasonably easy approach is to use a cutoff of 1 cm in the short-axis diameter.10 In a study by McLoud et al.,11 the rate of positive mediastinal lymph node involvement increased from 13% when the node measured less than 1 cm to 62% for nodes of 2 to 2.9 cm.

• CT specificity according to mediastinal nodal site varied from 72% for station 10R (right hilar) to 94% for station 10L (left hilar) when the criteria for positivity were 1 cm or more.11

• In the presence of obstructive pneumonitis, the rate of false positive lymph node involvement increased to 45%.

• If nodes in the draining territory of the tumor are enlarged (more than 1 cm in the short axis) and at least 0.5 cm larger than the nodes in the nondraining territories, CT specificity improves with a positive predictive value of 95%.12

3.3.2. Positron Emission Tomography/Computed Tomography

• Positron emission tomography (PET) scanning with 18F-fluorodeoxyglucose (18F-FDG) is routinely used to determine the malignant nature of suspicious lesions, to more accurately define tumor extent, including lymph node involvement,1316 and to aid in treatment planning.17 In one study, PET influenced radiation delivery in 65% patients receiving definitive radiotherapy (RT).18

• Sensitivity and specificity for staging of individual patients range from approximately 60% to more than 90%, particularly if the PET scans were read in conjunction with the CT scans.19

• A high negative predictive value (~95%) of PET for mediastinal lymph node metastasis implies that invasive procedures are probably not necessary in patients with negative findings of PET in the mediastinum.

• However, 74% positive predictive value means that patients will need pathologic confirmation when a mediastinal hot spot is found on PET.20

3.4. Staging

• The current staging system is the 7th edition of AJCC.3 There are a number of changes in the T classifications, such as (a) division of T1 into T1a (<2 cm) and T1b (2 to 3 cm); (b) division of T2 into T2a (3 to 5 cm) and T2b (5 to 7 cm); and (c) reclassification of T2 tumors >7 cm as T3. Readers are strongly urged to consult the new AJCC staging manual.

• The location of the lymph nodes has been described according to the 2009 IASLC international lymph node map, which defines the nodal stations in relation to fixed anatomic structures, allowing a correlation between imaging studies and at endoscopy and surgery (Fig. 13-3; see also Fig. 13-4).

• Classically, SCLCs are generally staged more simply as limited (confined to one hemithorax/encompassed by a single radiation portal) or extensive. As of 7th edition of AJCC, the TMN classification is also recommended for SCLCs and carcinoid tumors of the lung.

3.5. Detection of Nodal Metastasis

• Cervical mediastinoscopy (through a supra-sternal approach) can biopsy mediastinal lymph node involvement in the left and right upper paratracheal nodes (stations 2L and 2R), left and right lower paratracheal nodes (stations 4L and 4R), and the anterior portion of the subcarinal nodes (station 7).

• Anterior mediastinotomy/Chamberlain procedure is used to biopsy the subaortic and para-aortic nodes (stations 5 and 6), which may be involved with left upper lobe lesions.

• Bronchoscopic ultrasound with fine-needle aspiration can biopsy nodes accessed from the tracheobronchial tree and can readily sample nodal stations 1, 2, 3, 4, 7, 10, and 11.

• Endoscopic ultrasound (EUS) with fine-needle aspiration can be performed on all the mediastinal nodes that can be accessed from the esophagus. EUS particularly provides access to nodes in the lower mediastinum (stations 7, 8, and 9).

• Asamura et al.21 analyzed involvement of the lymph nodes in 337 patients according to tumor size, histologic type, and location (Tables 13-1 to 13-4). Eighty-eight patients (26.1%) had lymph node involvement: 32 (9.5%) at N1, 55 (16.3%) at N2, and 1 patient at N3.

• According to this study, complete hilar and mediastinal lymph node dissection should be done routinely at resection because of the relatively high prevalence of the lymph node involvement, especially with adenocarcinoma lesions of diameter 2 cm or larger. However, for squamous cell carcinomas, the rate of mediastinal lymph node involvement is very low if the tumor is less than 2 cm in diameter.


4.1. Resectable Tumors

• If the disease is not initially surgically resectable, patients can be given combined modality treatment, such as neoadjuvant chemotherapy or chemoradiotherapy (CRT) followed by surgery with or without postoperative thoracic RT.

4.1.1. Preoperative Radiation, Chemotherapy, or Chemoradiation

• Several collaborative studies failed to show significant improvement in survival with use of preoperative radiation.22

• Preoperative chemotherapy has been associated with improved survival versus surgery alone for patients with N2-positive disease.23,24

• Trimodality preoperative CRT for N2-positive patients proved to be an encouraging approach in the SWOG 8805 trial.25

• INT 0139/Radiation Therapy Oncology Group (RTOG) 9309 trial demonstrated that preoperative chemoradiation to 45 Gy followed by surgery is associated with improved progression-free survival versus definitive chemoradiation to 61 Gy (5-year: 22% vs 11%) and better 5-year overall survival; pN0 disease was associated with improved survival, indicating the prognostic importance of mediastinal sterilization by preoperative chemoradiation; trimodality therapy may not be appropriate if pneumonectomy is required, due to a high rate of treatment-related deaths.26

• High-dose thoracic RT (approximately 60 Gy or higher) as a component of preoperative chemoradiation can be delivered safely and offers favorable outcomes.2729

4.1.2. Postoperative Radiation Therapy

• Postoperative irradiation has been advocated for patients with pathologically N2-positive disease (approximately 50 Gy), positive surgical margins (approximately 54 to 60 Gy), or nodal extracapsular extension (approximately 54 to 60 Gy).

• The PORT meta-analysis demonstrated lower survival in patients receiving postoperative radiation; this was related to greater radiation sequelae due likely in part to poor radiation technique in many included studies (e.g., high doses, large fraction sizes, use of lateral fields, use of spinal cord blocks, use of 60Co, lack of CT-based planning). Although there was an absolute reduction in 2-year overall survival from 55% to 48%, subgroup analyses indicated that this adverse effect was greatest for patients with stage I or II, N0 to N1 disease, whereas for those with stage III, N2 disease there was no evidence of an adverse effect.30,31

• Subsequent studies have confirmed a survival benefit of postoperative radiation for pathological N2-positive patients.3234

4.2. Unresectable Tumors

• Definitive radiation therapy (±chemotherapy) is indicated for NSCLC patients who are technically operable but medically inoperable, with 5-year overall survival of approximately 15%.35

• The standard of care was established by the RTOG 73-01 dose-escalation trial.36 The incidence of local failure, evaluated clinically, was lower in patients treated with 60 Gy (33%) versus 50 Gy (39%) versus 40 Gy (44% to 49%). Accordingly, patients receiving definitive RT are generally treated with doses of 60 Gy or higher.

• Combined chemotherapy and irradiation is the treatment of choice for locally advanced, inoperable NSCLC patients with good performance status and absence of significant weight loss or those without other medical contraindications to chemotherapy.37

• Chemotherapy regimens used with radiation include cisplatin/vinblastine, cisplatin/etoposide, paclitaxel/carboplatin, cisplatin/gemcitabine, and cisplatin/pemetrexed (for nonsquamous histology).

• A number of trials have demonstrated superior overall survival for concurrent chemoradiation versus sequential chemoradiation.38,39 RTOG 94-10 demonstrated improved median overall survival with concurrent chemoradiation (cisplatin/vinblastine/60 Gy thoracic RT) versus sequential chemoirradiation (cisplatin/vinblastine/60 Gy): 17.0 versus 14.6 months.38


5.1. Target Volume Determination

• The volume to be treated is determined by the size and location of the primary tumor, involved lymph nodes (either radiologically or pathologically positive), and areas of lymphatic drainage (if elective nodal irradiation [ENI] is delivered).

• Classic RT portals incorporated ENI. However, the merit of ENI (±supraclavicular) nodal irradiation is highly questionable given an elective nodal failure rate of only 5% to 10% in a number of NSCLC series omitting ENI in both early-stage inoperable and locally advanced patients.40,41 Indeed, involved-field RT may facilitate dose escalation to gross disease without unacceptable toxicity. Accordingly, the trend has been to move away from ENI.

• For postoperative RT, the target volume is generally the mediastinum and ipsilateral hilum, with boost fields to areas of extracapsular nodal extension or positive margins.

5.2. Target Volume Delineation

5.2.1. Primary Lesion Volume

• Parenchymal lesions (GTVp) are better defined in the lung window of a CT image for its lung borders, and under the mediastinal or chest/abdomen window for the tumor border adjacent to the mediastinum (Fig. 13-5).

• However, in cases in which atelectasis is present PET helps to delineate the GTVp better than CT does alone (Fig. 13-6).

• Several PET-based delineation methods have been proposed including visual threshold of 40% of maximal SUV (standard uptake value), SUV of 2.5, and a tumor-to-background algorithm.

FIGURE 13-5. A 74-year-old male diagnosed with T2N2M0 lung adenocarcinoma. GTV is green; CTV is red; and spinal canal is orange. (A-C) axial view and (D) coronal view.

FIGURE 13-6. Impact of PET on determination of lung target volumes. (A) GTV is outlined in green on the CT, which included atelectasis and a small amount of pleural effusion without delineation of the mediastinal node. (B) PET showed increased FDG uptake in the mediastinal node outlined in red, which was not delineated on CT. GTV was reduced in the parenchyma excluding atelectasis and post-atelectatic pleural effusion on the PET scan.

FIGURE 13-7. An MRI scan of superior sulcus tumor (SST). (A) Sagittal view of the SST involving the brachial plexus and vertebral bodies and abutting onto the posterior wall of the subclavian artery and aortic arch. (B) Coronal view of left SST extending to the vertebral bodies (T1–T4) and aortic arch.

• RTOG 11-06 uses a tumor-to-background ratio for PET-based delineation and defines the metabolic tumor volume as outlined by the SUV threshold of 1.5 times the mean SUV activity of 1 cm3 sphere in the middle of ascending aorta.

• Superior sulcus tumors, which are located at the apex of the lung, can be delineated with magnetic resonance imaging (MRI) to define invasion into the neural foramen, brachial plexus, subclavian artery, or vertebral body (Fig. 13-7).

• Addressing the extension of subclinical disease (clinical target volume [CTV]), Giraud and colleagues42 analyzed microscopic extensions of resected adenocarcinoma and squamous NSCLC. Margins of 0.8 cm for adenocarcinoma and 0.6 cm for squamous carcinoma encompassed 95% of microscopic extensions.

• The CTV is defined as the GTVp plus 0.5 to 1 cm margin. We use 0.6 cm margin for squamous cell carcinoma or a 0.8 cm margin for adenocarcinoma.

• The planning target volume (PTV) is defined as the CTV plus tumor motion internal margin (IM) and setup uncertainty margin, and can range from 0.5 to 1.5 cm margin.

• Tumors can move up to 0.8 to 1 cm with respiratory motion. As Figure 13-8 shows, the tumor moves when the patient breathes. To account for tumor motion, a four-dimensional CT (4D CT) simulation may be used to generate an internal target volume (ITV). This can be either with the acquisition of 2 CT data sets at end-inhalation and end-exhalation, or up to 10 CT data sets corresponding to various levels of the respiration cycle determined by a respiratory patient monitor.

FIGURE 13-8. Tumor motion and respiratory gating. (A) Anterior and posterior tumor (GTV) motion caused by respiration. (B) Superior and inferior tumor motion with oblique shift caused by respiration. (C) Elimination of GTV motion with respiratory gating.

• If a 4D CT simulation is not available, a free breathing CT can be used with an internal tumor motion margin of 1 cm in superior–inferior direction and 0.5 cm in axial directions.

• Typical setup margin is 0.5 cm uniform expansion but is dependent on institutional guidelines and patient immobilization. Daily image-guided radiation therapy (IGRT) either with 2D films or cone-beam CT can reduce the setup margin to 0.2 to 0.3 cm uniform expansion.

5.2.2. Nodal Volume

• Nodal diseases (GTVn) are better defined in the mediastinal or chest/abdomen window.

• GTVn should include

º Any nodes >1 cm in the short axis

º Any nodes with pathological findings detected on biopsy

º Any nodes with FDG activity above mediastinum blood pool

º Any visible nodes that are growing

º Two or more nodes clustered in the high-risk draining lymphatics stations most proximal to the primary tumor (Fig. 13-3)

• The CTV will consist of 0.5 cm margin around GTVn.

• The PTV will consist of CTV plus a minimal 0.5 cm margin for setup error plus an individual margin for target motion if the IM was not accounted for the planning CT.

5.3. Suggested Target and Normal Tissue Doses

• Target coverage: The prescription isodose surface should encompass at least 95% of PTV or the lowest dose limit of organs at risk if any of them is lower than the prescription dose. The maximum dose should not exceed a value that is 110% of the prescribed dose and the hot spot must be located within the PTV.

• Spinal cord: Maximum dose of the planning spinal cord must not exceed 50.5 Gy to any contiguous volume that is ≥0.03 cm3. No point dose greater than 52 Gy. The QUANTEC recommendations43 are similar, noting that doses above 60 Gy are associated with >6% myelopathy.

• Lung: Total lung volume (total both lung volume minus CTV) receiving 20 Gy (V20) should be less than 37% for patients receiving chemoradiation alone, or mean lung dose less than 20 Gy. Limit the V20ideally to less than 30% when chemoradiation followed by surgery is planned. Patients receiving concurrent chemotherapy and radiation therapy followed by surgery had a significantly higher pulmonary complication rate when the total lung volume receiving 10 Gy (V10) exceeded 40%.44 These dosages are similar to those given in the QUANTEC review45 the latter give the mean lung dose as <20 to 23 Gy with conventional fractionation to keep radiation pneumonitis under 20%.

• Many treatment plans are limited by the tolerance dose to the normal lung. If the lung constraints are exceeded, try reducing the CTV margin to the minimal range and reducing the PTV margin using respiratory gated treatment or IGRT.

• Esophagus: Limit the length of esophagus to less than 33% receiving 60 Gy. The mean dose to the esophagus should be less than 34 Gy. This is the same mean suggested by RTOG 0617 and the QUANTEC review paper.46

• Brachial plexus: The maximum dose of the brachial plexus should be less than 63 to 66 Gy.

• Heart: Limit the volume of the planning heart receiving 50 Gy (V50) to less than 50%. Gagliardi et al.47 discussed cardiac damage in relation to breast cancer patients treated with radiation. They report normal tissue complication probability (NTCP) model estimates whereby V25 Gy < 10% should keep cardiac mortality to <1% at 15 years.

5.4. IMRT Results

• When RT is given to the primary tumor and nodal metastasis, toxicities to the surrounding normal tissues including the alveoli, esophagus, heart, and spinal cord need to be considered.

• The application of IMRT for lung cancer has been delayed because of the uncertainty with larger lung volumes that may be irradiated at lower doses (<v20) and accounting for tumor motion during respiration. Recent studies have addressed these issues.</v

• Studies have shown that IMRT has improved normal tissue and tumor dosimetry, reducing normal tissue toxicities and improved outcomes compared with three-dimensional conformal radiation therapy (3DCRT).48-50 (See Table 13-5 and Table 13-6.)

• Compared to 3DCRT, using IMRT caused the median absolute reduction in the percentage of lung volume irradiated above 10 and 20 Gy to 7% and 10%, respectively. This corresponded with a decrease of >2 Gy in the mean total lung dose (Fig. 13-9).

• Significant improvement in the conformity was observed with IMRT. Both the median value and range of the conformity index decreased with IMRT, indicating a greater ability to warp high-dose volumes around tumors by introducing intensity modulation within the beams (Table 13-5 and Fig. 13-10).

• To comprehend the effect of lung irradiation using IMRT, different NTCP models were used to estimate the risk of radiation pneumonitis (Table 13-6). The reduction in the risk of pneumonitis ranged from 3% with Kwa model51 to 6% using Hayman52 and Yorke53 models, and 12% using Graham model.54

• The esophagus and heart volumes above 55 Gy did not increase with the use of IMRT. Because acute esophagitis and long-term cardiac toxicity are limiting factors in the treatment of lung cancer, dose reduction for these structures should benefit this treatment as well (Table 13-7; see Figs. 13-12 and 13-13).

• As far as all thoracic tissues are concerned, the V20 and higher dose volumes were all reduced with IMRT. However, the V5 of the thorax increased, possibly due to increased number of field arrangement and the multileaf collimator (MLC) leakage with the increased monitor units of the IMRT (Fig. 13-10 and Table 13-8).

FIGURE 13-9. Summary of the total lung V5, V10, and V20 with the 3DCRT and IMRT plans. (From Murshed H, Liu HH, Liao Z, et al. Dose and volume reduction for normal lung using intensity-modulated radiotherapy for advanced-stage non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 2004;58:1258–1267.)

FIGURE 13-10. Comparison of the isodose distribution between 3DCRT (left panel A, B) and IMRT (right panel C, D) in a single case. (A, C) Axial view. (B, D) Coronal view. (From Murshed H, Liu HH, Liao Z, et al. Dose and volume reduction for normal lung using intensity-modulated radiotherapy for advanced-stage non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 2004;58:1258–1267.)

• Step-and-shoot leaf sequence reduced the monitor units by half compared with the sliding window technique and may help to reduce the lung and normal tissue volumes at very low doses.

• Komaki and colleagues retrospectively analyzed 151 locally advanced lung cancer cases treated with concurrent chemotherapy and IMRT and found that with IMRT the rate of high-grade treatment-related pneumonitis was 8%, significantly less compared with 32% for 3DCRT.48

• For patients treated with IMRT, rates of high-grade pneumonitis correlated with lung V5 exceeding 70%. The 12-month incidence for the patients with V5 < 70% was 2%, but for those with V5 > 70%, the rate was 21%.

• Later, Cox and colleagues also retrospectively showed that the use of IMRT represented an important therapeutic gain with significantly decreased high-grade pneumonitis, improved overall survival, and similar locoregional progression-free survival and distant metastasis-free survival rates as compared with 3DCRT treatment.49 In further follow-up at 18 months of a similar cohort of IMRT treated patients, the rate of grade 2 pulmonary fibrosis was 7%.50

• A second concern regarding IMRT is the impact of tumor motion. The interplay between leaf motion and respiration-induced tumor motion could produce dose inhomogeneities. However, such effects tend to wash out because of the larger number of fields in IMRT over the course of few fractions. Planning studies examining the difference in dose between static points and moving target points during step-and-shoot IMRT delivery found that intrafractional variation in target coverage was <5%.5557

• The National Cancer Institute Advanced Technology Consortium (NCI ATC) guidelines in 2006 allowed the use of IMRT for intrathoracic tumors with appropriate patient immobilization, target motion correction, and tissue heterogeneity correction.49


6.1. General Management

• Surgical resection of stage I (T1-2, N0) NSCLC, specifically a lobectomy or pneumonectomy, results in 5-year survival rates of approximately 65% to 90% and is the standard of care for this stage of lung cancer. However, some patients with early-stage NSCLC are not suitable surgical candidates. In some cases, less extensive surgical resection, including wedge or segmental resection with or without mesh brachytherapy, can be performed, however this is associated with increased locoregional failure.58,59

• Conventional fractionated radiation therapy has shown inferior results with 5-year survival rates from 10% to 30%, with local failures within the irradiated area represented in up to 70% of all failures.60,61

• Stereotactic body radiation therapy (SBRT) is a novel technique that allows delivery of very high doses of radiation, usually in several large fractions (hypofractionated), by many coplanar and non-coplanar beams to an immobilized patient. Treatment is guided sterotactically by a set of coordinates obtained with daily image guidance to locate precisely the tumor. With management of internal tumor motion, a much narrow PTV margin may be used.

• Lesion location influences the safety profile of this ablative therapy. Central tumors defined within 2 cm of the proximal bronchial tree (Fig. 13-1B) have significantly higher incidence of pulmonary toxicity with SBRT.62

6.2. Target Volume Determination

6.2.1. Primary Lesion Volume

• Patients should be positioned in stereotactic frames that surround the patient on three sides with large rigid pillows, and a technique to inhibit internal respiratory motion such as abdominal compression should be used.

• Both helical and 4D CT scans can be used. A 4D CT simulation would account for tumor motion and generate an ITV, thereby reducing the PTV margin.

• There is no prophylactic treatment including no margin for presumed microscopic extension and no ENI. With helical scans, additional 0.5 cm in the axial plane and 1.0 cm in the craniocaudal plane will be added to the GTV to constitute the PTV. With 4D CT scans, an uniform 0.5 cm expansion in all directions to the ITV will define the PTV (Fig. 13-11).

6.2.2. Organs at Risk Volumes

• Due to the increased risk of toxicity with this ablative treatment, accurate contouring of normal structures is essential (Fig. 13-11).

• Spinal cord: Contour the bony limits of the spinal canal.

• Lung: Contour both right and left lung with all inflated and collapsed lung included, while subtracting out the GTV or ITV.

• Esophagus: Contour the mucosa, submucosa, and all muscular layers out to the fatty adventitia.

• Brachial plexus: Contour the spinal nerves exiting the neuroforamine from around C5 to T2, and using the subclavian and axillary vessels as a surrogate marker for the major branches of branchial plexus.

• Heart: Contour along with the pericardial sac.

• Proximal bronchial tree: Contour the mucosa, submucosa, and cartilage rings and airway channels.

• Skin: Contour the outer 0.5 cm of the body surface.

6.3. Suggested Target and Normal Tissue Doses

• Different dose regimens for SBRT have been used for peripheral and central lesions, and it is unclear which schedules are the most optimal.6366 Commonly used dose regimens and associated normal tissue constraints are described in Tables 13-9 and 13-10.

• Target coverage will be chosen such that 95% of PTV volume is covered by the prescription dose and 99% of the PTV volume receives a minimum of 90% of the prescription dose.

FIGURE 13-11. Target lesion and normal tissue contouring for SBRT, shown in (A, B) axial, and (C) coronal view. Contours are GTV (green); PTV (red); aorta (pink); proximal bronchial tree (dark blue); proximal bronchial tree plus 2 cm margin (yellow); pulmonary artery (light blue); spinal cord (orange); and vena cava (purple). (D) Isodose lines for SBRT: 60 Gy (green); 50 Gy (purple); 40 Gy (dark blue); 30 Gy (orange); 10 Gy (yellow).

FIGURE 13-12. Comparison of dose–volume histograms (DVHs) of the PTV, total lung, and esophagus between 3DCRT (solid lines) and IMRT (dashed lines). (From Murshed H, Liu HH, Liao Z, et al. Dose and volume reduction for normal lung using intensity-modulated radiotherapy for advanced-stage non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 2004;58:1258–1267.)

FIGURE 13-13. Comparison of DVHs of the spinal cord and heart between 3DCRT (solid lines) and IMRT (dashed lines). (From Murshed H, Liu HH, Liao Z, et al. Dose and volume reduction for normal lung using intensity-modulated radiotherapy for advanced-stage non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 2004;58:1258–1267.)

• Prescription isodose lines covering the PTV will typically lie between 60% and 90% line.

• Tight conformality of PTV coverage is crucial. The maximum dose hot spot should be within the tumor volume. The high-dose spillage should be confined to the PTV such that cumulative volume of all tissue outside the PTV receiving a dose >105% of prescription dose should be no more than 15% of the PTV volume. The low-dose spillage should have a rapid falloff gradient beyond the PTV extending into normal tissue structures in all directions.

6.4. SBRT Results

• Studies have shown that BED10 >100 Gy results in superior local control and overall survival.64 All treatment regimens in Table 13-9 have BED10 >100 Gy.

• For peripheral lesions, RTOG 0236 treated inoperable T1-T2N0 NSCLC patients with SBRT with a total dose of 54 Gy treated in three fractions over 1.5 to 2 weeks. The 3-year primary tumor control rate was 98%; 3-year locoregional control rate was 87%; 3-year distant metastases rate was 22%.63

• For central lesions, an adequate and safe dose- fractionation regimen is still under investigation. Haasbeek and colleagues67 have shown that 60 Gy in eight fractions for central lesions had excellent local control and was well tolerated. Chang and colleagues66 also performed a dose escalation study on central tumors and showed that 50 Gy in four fractions was effective and well tolerated. RTOG 0813 is the current dose-escalation protocol for central lesions starting at 10 Gy × 5 fractions going to 12 Gy × 5 fractions.


1. Boyden EA. In: McGraw-Hill, ed. Segmental Anatomy of the Lungs: A Study of the Patterns of the Segmental Bronchi and Related Pulmonary Vessels. New York: McGraw-Hill, 1955.

2. Gray H. In: Livingstone C, ed. Gray’s Anatomy: The Anatomical Basis of the Medicine and Surgery, 38th ed. New York: Churchill Livingstone 1995.

3. Edge SB, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A. AJCC Cancer Staging Manual, 7th ed. New York: Springer Verlag, 2010.

4. Nagaishi C. Functional Anatomy and Histology of the Lung. Baltimore: University Park Press, 1972.

5. Jemal A, Tiwari RC, Murray T, et al. Cancer statistics, 2004. CA Cancer J Clin 2004;54(1):8–29.

6. Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin 2010;60(5):277–300.

7. GLOBOCAN. Fast Stats, 2008.

8. ACS. Cancer Facts and Figures 2012. Atlanta, GA: American Cancer Society.

9. Grenier P, Dubray B, Carette M. Preoperative thoracic staging of lung cancer: CT and MR evaluation. Diagnost Int Radiol 1989;1:23–28.

10. Glazer GM, Gross BH, Quint LE, Francis IR, Bookstein FL, Orringer MB. Normal mediastinal lymph nodes: number and size according to American Thoracic Society mapping. AJR Am J Roentgenol 1985;144(2):261–265.

11. McLoud TC, Bourgouin PM, Greenberg RW, et al. Bronchogenic carcinoma: analysis of staging in the mediastinum with CT by correlative lymph node mapping and sampling. Radiology 1992;182(2):319–323.

12. Buy JN, Ghossain MA, Poirson F, et al. Computed tomography of mediastinal lymph nodes in nonsmall cell lung cancer. A new approach based on the lymphatic pathway of tumor spread. J Comput Assist Tomogr 1988;12(4):545–552.

13. Farrell MA, McAdams HP, Herndon JE, Patz EF, Jr. Non-small cell lung cancer: FDG PET for nodal staging in patients with stage I disease. Radiology 2000;215(3):886–890.

14. Lowe VJ, Naunheim KS. Positron emission tomography in lung cancer. Ann Thorac Surg 1998;65(6):1821–1829.

15. Marom EM, McAdams HP, Erasmus JJ, et al. Staging non-small cell lung cancer with whole-body PET. Radiology 1999;212(3):803–809.

16. Vanuytsel LJ, Vansteenkiste JF, Stroobants SG, et al. The impact of (18)F-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) lymph node staging on the radiation treatment volumes in patients with non-small cell lung cancer. Radiother Oncol 2000;55(3):317–324.

17. Munley MT, Marks LB, Scarfone C, et al. Multimodality nuclear medicine imaging in three-dimensional radiation treatment planning for lung cancer: challenges and prospects. Lung Cancer 1999;23(2):105–114.

18. Kalff V, Hicks RJ, MacManus MP, et al. Clinical impact of (18)F fluorodeoxyglucose positron emission tomography in patients with non-small-cell lung cancer: a prospective study. J Clin Oncol 2001;19(1):111–118.

19. Vansteenkiste JF, Stroobants SG, De Leyn PR, Dupont PJ, Verbeken EK. Potential use of FDG-PET scan after induction chemotherapy in surgically staged IIIa-N2 non-small-cell lung cancer: a prospective pilot study. The Leuven Lung Cancer Group. Ann Oncol 1998;9(11):1193–1198.

20. Lewis PJ, Salama A. Uptake of fluorine-18-fluorodeoxyglucose in sarcoidosis. J Nucl Med 1994;35(10):1647–1649.

21. Asamura H, Nakayama H, Kondo H, Tsuchiya R, Shimosato Y, Naruke T. Lymph node involvement, recurrence, and prognosis in resected small, peripheral, non-small-cell lung carcinomas: are these carcinomas candidates for video-assisted lobectomy? J Thorac Cardiovasc Surg 1996;111(6):1125–1134.

22. Trakhtenberg A, Kiseleva ES, Pitskhelauri VG, et al. Preoperative radiotherapy in the combined treatment of lung cancer patients. Neoplasma 1988;35(4):459–465.

23. Rosell R, Gomez-Codina J, Camps C, et al. Preresectional chemotherapy in stage IIIA non-small-cell lung cancer: a 7-year assessment of a randomized controlled trial. Lung Cancer 1999;26(1):7–14.

24. Roth JA, Atkinson EN, Fossella F, et al. Long-term follow-up of patients enrolled in a randomized trial comparing perioperative chemotherapy and surgery with surgery alone in resectable stage IIIA non-small-cell lung cancer. Lung Cancer 1998;21(1):1–6.

25. Albain KS, Rusch VW, Crowley JJ, et al. Concurrent cisplatin/etoposide plus chest radiotherapy followed by surgery for stages IIIA (N2) and IIIB non-small-cell lung cancer: mature results of Southwest Oncology Group phase II study 8805. J Clin Oncol 1995;13(8):1880–1892.

26. Albain KS, Swann RS, Rusch VW, et al. Radiotherapy plus chemotherapy with or without surgical resection for stage III non-small-cell lung cancer: a phase III randomised controlled trial. Lancet 2009;374(9687):379–386.

27. Cerfolio RJ, Bryant AS, Spencer SA, Bartolucci AA. Pulmonary resection after high-dose and low-dose chest irradiation. Ann Thorac Surg 2005;80(4):1224–1230; discussion 30.

28. Sonett JR, Suntharalingam M, Edelman MJ, et al. Pulmonary resection after curative intent radiotherapy (>59 Gy) and concurrent chemotherapy in non-small-cell lung cancer. Ann Thorac Surg 2004;78(4):1200–1205; discussion 06.

29. Vora SA, Daly BD, Blaszkowsky L, et al. High dose radiation therapy and chemotherapy as induction treatment for stage III nonsmall cell lung carcinoma. Cancer 2000;89(9):1946–1952.

30. METAGROUP. Meta-Analysis Group. Postoperative radiotherapy for non-small cell lung cancer: PORT Meta-Analysis Trialists Group. Cochrane Database Syst Rev 2000;2:CD002142.

31. POST. Postoperative radiotherapy in non-small-cell lung cancer: systematic review and meta-analysis of individual patient data from nine randomised controlled trials. PORT Meta-analysis Trialists Group. Lancet 1998;352(9124):257–263.

32. Douillard JY, Rosell R, De Lena M, Riggi M, Hurteloup P, Mahe MA. Impact of postoperative radiation therapy on survival in patients with complete resection and stage I, II, or IIIA non-small-cell lung cancer treated with adjuvant chemotherapy: the adjuvant Navelbine International Trialist Association (ANITA) Randomized Trial. Int J Radiat Oncol Biol Phys2008;72(3):695–701.

33. Lally BE, Zelterman D, Colasanto JM, Haffty BG, Detterbeck FC, Wilson LD. Postoperative radiotherapy for stage II or III non-small-cell lung cancer using the surveillance, epidemiology, and end results database. J Clin Oncol 2006;24(19):2998–3006.

34. Sawyer TE, Bonner JA, Gould PM, et al. Effectiveness of postoperative irradiation in stage IIIA non-small cell lung cancer according to regression tree analyses of recurrence risks. Ann Thorac Surg 1997;64(5):1402–1407; discussion 07–08.

35. Sibley GS. Radiotherapy for patients with medically inoperable Stage I nonsmall cell lung carcinoma: smaller volumes and higher doses--a review. Cancer 1998;82(3):433–438.

36. Perez CA, Stanley K, Rubin P, et al. A prospective randomized study of various irradiation doses and fractionation schedules in the treatment of inoperable non-oat-cell carcinoma of the lung. Preliminary report by the Radiation Therapy Oncology Group. Cancer 1980;45(11):2744–2753.

37. Johnson DH. Locally advanced, unresectable non-small cell lung cancer: new treatment strategies. Chest 2000; 117(4 Suppl 1):123S–126S.

38. Curran WJ Jr., Paulus R, Langer CJ, et al. Sequential vs. concurrent chemoradiation for stage III non-small cell lung cancer: randomized phase III trial RTOG 9410. J Natl Cancer Inst 2011;103(19):1452–1460.

39. Furuse K, Fukuoka M, Kawahara M, et al. Phase III study of concurrent versus sequential thoracic radiotherapy in combination with mitomycin, vindesine, and cisplatin in unresectable stage III non-small-cell lung cancer. J Clin Oncol 1999;17(9):2692–2699.

40. Rosenzweig KE, Sura S, Jackson A, Yorke E. Involved-field radiation therapy for inoperable non small-cell lung cancer. J Clin Oncol 2007;25(35):5557–5561.

41. Slotman B, Faivre-Finn C, Kramer G, et al. Prophylactic cranial irradiation in extensive small-cell lung cancer. N Engl J Med 2007;357(7):664–672.

42. Giraud P, Antoine M, Larrouy A, et al. Evaluation of microscopic tumor extension in non-small-cell lung cancer for three-dimensional conformal radiotherapy planning. Int J Radiat Oncol Biol Phys 2000;48(4):1015–1024.

43. Kirkpatrick JP, van der Kogel AJ, Schultheiss TE. Radiation dose-volume effects in the spinal cord. Int J Radiat Oncol Biol Phys 2010;76(3):S42–S49.

44. Lee HK, Vaporciyan AA, Cox JD, et al. Postoperative pulmonary complications after preoperative chemoradiation for esophageal carcinoma: correlation with pulmonary dose-volume histogram parameters. Int J Radiat Oncol Biol Phys 2003;57(5):1317–1322.

45. Marks LB, Bentzen SM, Deasy JO, et al. Radiation dose-volume effects in the lung. Int J Radiat Oncol Biol Phys 2010;76(3 Suppl):S70–S76.

46. Werner-Wasik M, Yorke E, Deasy J, Nam J, Marks LB. Radiation dose-volume effects in the esophagus. Int J Radiat Oncol Biol Phys 2010;76(3 Suppl):S86–S93.

47. Gagliardi G, Constine LS, Moiseenko V, et al. Radiation dose-volume effects in the heart. Int J Radiat Oncol Biol Phys 2010;76(3 Suppl):S77–S85.

48. Yom SS, Liao Z, Liu HH, et al. Initial evaluation of treatment-related pneumonitis in advanced-stage non-small-cell lung cancer patients treated with concurrent chemotherapy and intensity-modulated radiotherapy. Int J Radiat Oncol Biol Phys 2007;68(1):94–102.

49. Liao ZX, Komaki RR, Thames HD, Jr, et al. Influence of technologic advances on outcomes in patients with unresectable, locally advanced non-small-cell lung cancer receiving concomitant chemoradiotherapy. Int J Radiat Oncol Biol Phys 2010;76(3):775–781.

50. Jiang ZQ, Yang K, Komaki R, et al. Long-term clinical outcome of intensity-modulated radiotherapy for inoperable non-small-cell lung cancer: the MD Anderson experience. Int J Radiat Oncol Biol Phys 2012;83(1):332–339.

51. Kwa SL, Lebesque JV, Theuws JC, et al. Radiation pneumonitis as a function of mean lung dose: an analysis of pooled data of 540 patients. Int J Radiat Oncol Biol Phys 1998;42(1):1–9.

52. Hayman JA, Martel MK, Ten Haken RK, et al. Dose escalation in non-small-cell lung cancer using three-dimensional conformal radiation therapy: update of a phase I trial. J Clin Oncol 2001;19(1):127–136.

53. Yorke ED, Jackson A, Rosenzweig KE, et al. Dose-volume factors contributing to the incidence of radiation pneumonitis in non-small-cell lung cancer patients treated with three-dimensional conformal radiation therapy. Int J Radiat Oncol Biol Phys 2002;54(2):329–339.

54. Graham MV, Purdy JA, Emami B, et al. Clinical dose-volume histogram analysis for pneumonitis after 3D treatment for non-small cell lung cancer (NSCLC). Int J Radiat Oncol Biol Phys 1999;45(2):323–329.

55. Bortfeld T, Jokivarsi K, Goitein M, Kung J, Jiang SB. Effects of intra-fraction motion on IMRT dose delivery: statistical analysis and simulation. Phys Med Biol 2002;47(13): 2203–2220.

56. Chui CS, Yorke E, Hong L. The effects of intra-fraction organ motion on the delivery of intensity-modulated field with a multileaf collimator. Med Phys 2003;30(7):1736–1746.

57. Jiang SB, Pope C, Al Jarrah KM, Kung JH, Bortfeld T, Chen GT. An experimental investigation on intra-fractional organ motion effects in lung IMRT treatments. Phys Med Biol 2003;48(12):1773–1784.

58. Chamogeorgakis T, Ieromonachos C, Georgiannakis E, Mallios D. Does lobectomy achieve better survival and recurrence rates than limited pulmonary resection for T1N0M0 non-small cell lung cancer patients? Interact Cardiovasc Thorac Surg 2009;8(3):364–372.

59. Ginsberg RJ, Rubinstein LV. Randomized trial of lobectomy versus limited resection for T1 N0 non-small cell lung cancer. Lung Cancer Study Group. Ann Thorac Surg 1995;60(3): 615–622; discussion 22–23.

60. Dosoretz DE, Katin MJ, Blitzer PH, et al. Medically inoperable lung carcinoma: the role of radiation therapy. Semin Radiat Oncol 1996;6(2):98–104.

61. Qiao X, Tullgren O, Lax I, Sirzen F, Lewensohn R. The role of radiotherapy in treatment of stage I non-small cell lung cancer. Lung Cancer 2003;41(1):1–11.

62. Timmerman R, McGarry R, Yiannoutsos C, et al. 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 2006;24(30): 4833–4839.

63. Timmerman R, Paulus R, Galvin J, et al. Stereotactic body radiation therapy for inoperable early stage lung cancer. JAMA 2010;303(11):1070–1076.

64. Onishi H, Shirato H, Nagata Y, et al. 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 2007;2(7 Suppl 3): S94–S100.

65. Hara R, Itami J, Kondo T, et al. Clinical outcomes of single-fraction stereotactic radiation therapy of lung tumors. Cancer 2006;106(6):1347–1352.

66. Chang JY, Balter PA, Dong L, et al. Stereotactic body radiation therapy in centrally and superiorly located stage I or isolated recurrent non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 2008;72(4):967–971.

67. Haasbeek CJ, Lagerwaard FJ, Slotman BJ, Senan S. Outcomes of stereotactic ablative radiotherapy for centrally located early-stage lung cancer. J Thorac Oncol 2011;6(12):2036–2043.

68. Rusch VW, Asamura H, Watanabe H, et al. Proposal for a new international lymph node map in the forthcoming seventh edition of the TNM classification for lung cancer. J Thorac Oncol 2009;4(5):568–577.

69  Burman C, Kutcher GJ, Emami B, Goitein M. Fitting of normal tissue tolerance data to an analytic function. Int J Radiat Oncol Biol Phys 1991;21(1):123–135.

70. Emami B, Lyman J, Brown A, et al. Tolerance of normal tissue to therapeutic irradiation. Int J Radiat Oncol Biol Phys 1991;21(1):119–122.