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European Organization for Research and Treatment of Cancer (EORTC) recommendations for planning and delivery of high-dose, high precision radiotherapy for lung cancer

      Abstract

      Purpose

      To update literature-based recommendations for techniques used in high-precision thoracic radiotherapy for lung cancer, in both routine practice and clinical trials.

      Methods

      A literature search was performed to identify published articles that were considered clinically relevant and practical to use. Recommendations were categorised under the following headings: patient positioning and immobilisation, Tumour and nodal changes, CT and FDG-PET imaging, target volumes definition, radiotherapy treatment planning and treatment delivery. An adapted grading of evidence from the Infectious Disease Society of America, and for models the TRIPOD criteria, were used.

      Results

      Recommendations were identified for each of the above categories.

      Conclusion

      Recommendations for the clinical implementation of high-precision conformal radiotherapy and stereotactic body radiotherapy for lung tumours were identified from the literature. Techniques that were considered investigational at present are highlighted.

      Keywords

      Considerable advances in thoracic radiotherapy have been made since the last recommendations of the European Organisation for Research and Treatment of Cancer (EORTC) were published in 2010 [
      • De Ruysscher D.
      • Faivre-Finn C.
      • Nestle U.
      • et al.
      European Organisation for Research and Treatment of Cancer recommendations for planning and delivery of high-dose, high-precision radiotherapy for lung cancer.
      ]. These include the routine integration of 4D-CT and Positron Emission Tomography (PET) imaging in treatment planning, accurate dose calculation algorithms, and improved imaging for treatment verification on the treatment machine. A large body of evidence supports the use of stereotactic body radiotherapy (SBRT) in early stage non-small cell lung cancer (NSCLC), where local tumour control rates of around 90% have been reported, with survival rates that match those of surgery in similar patient groups [
      • Zheng X.
      • Schipper M.
      • Kidwell K.
      • et al.
      Survival outcome after stereotactic body radiation therapy and surgery for stage I non-small cell lung cancer: a meta-analysis.
      ,
      • Chang J.Y.
      • Senan S.
      • Paul M.A.
      • et al.
      Stereotactic ablative radiotherapy versus lobectomy for operable stage I non-small-cell lung cancer: a pooled analysis of two randomised trials.
      ]. SBRT is currently under investigation for the treatment of oligometastatic disease [
      • Gomez D.R.
      • Blumenschein Jr., G.R.
      • Lee J.J.
      • et al.
      Local consolidative therapy versus maintenance therapy or observation for patients with oligometastatic non-small-cell lung cancer without progression after first-line systemic therapy: a multicentre, randomised, controlled, phase 2 study.
      ], and its use to activate the immune system is a promising area of research [
      • Reynders K.
      • Illidge T.
      • Siva S.
      • et al.
      The abscopal effect of local radiotherapy: using immunotherapy to make a rare event clinically relevant.
      ]. In locally advanced NSCLC and small cell lung cancer (SCLC), concurrent chemo-radiation remains the standard treatment for most patients, but more insight has been gained with regards to patient selection, such as the elderly [
      • Vansteenkiste J.
      • De Ruysscher D.
      • Eberhardt W.E.
      • et al.
      ESMO Guidelines Working Group. Early and locally advanced non-small-cell lung cancer (NSCLC): ESMO clinical practice guidelines for diagnosis, treatment and follow-up.
      ].
      The rapid pace of advances in technology and clinical practice led the EORTC Radiation Oncology and Lung Cancer Groups to update previous recommendations, in order to assist departments in implementing high-precision radiotherapy for thoracic tumours. Our working party focused on procedures and techniques that are relevant to the daily practice of clinicians, physicists and radiotherapy technologists. By their very nature, such recommendations have an element of subjectivity. As they are based upon current knowledge, they are neither static, nor necessarily applicable to every single individual patient.

      Methods

      MEDLINE and EMBASE were searched with different key words and their permutations including radiotherapy, radiation, 3-D, 4-D, conformal, lung, bronchus, bronchogenic, cancer, carcinoma, tumour, treatment planning, imaging, functional imaging, PET scans, FDG, positioning, mobility, delivery, control, quality assurance, intensity-modulated radiotherapy (IMRT), volumetric modulated arc therapy (VMAT), adaptive radiotherapy, SBRT, SABR, stereotactic, side effects, toxicity, organs at risk, image-guided radiotherapy, dose-guided radiotherapy, gross tumour volume, clinical target volume, planning target volume, from January 2001 to March 2017. Studies that were included in the 2010 version [
      • De Ruysscher D.
      • Faivre-Finn C.
      • Nestle U.
      • et al.
      European Organisation for Research and Treatment of Cancer recommendations for planning and delivery of high-dose, high-precision radiotherapy for lung cancer.
      ] were reinterpreted again to re-evaluate their usefulness. The references identified in individual articles were manually searched. Articles referring to outdated techniques for example from the pre-CT scan and pre-3D era and investigational studies were excluded. Several multi-disciplinary task groups identified and analysed appropriate studies according to their topic: Patient positioning (JB, CWH), tumour and nodal motion (UN, MG, CWH, DM), definition of target volumes (UN, JB, UN, CLP, DDR), generating target volumes (CWH, SS, UN, DM), treatment planning (CWH, SS, DM), dose specification and reporting (CWH, CLP), radiotherapy techniques (CWH, SS, MG, DM), dose–volume constraints (JB, CF, MG, DDR) and treatment delivery (JB, CWH, DM). Thereafter, all evidence was discussed with the whole group.
      The adapted scheme for grading recommendations from the Infectious Disease Society of America [
      • Khan A.R.
      • Khan S.
      • Zimmerman V.
      • et al.
      Quality and strength of evidence of the Infectious Diseases Society of America clinical practice guidelines.
      ] (Table 1) was used.
      Table 1Adapted grading recommendations from the Infectious Disease Society of America
      • Khan A.R.
      • Khan S.
      • Zimmerman V.
      • et al.
      Quality and strength of evidence of the Infectious Diseases Society of America clinical practice guidelines.
      .
      Levels of evidence
      IEvidence of at least one large randomized, controlled trial of good methodological quality (low potential for bias) or meta-analysis of well-conducted randomized trials without heterogeneity
      IISmall randomized trials or large randomized trials with suspicion of bias (low methodological quality) or meta-analyses of such trials or of trials with demonstrated heterogeneity
      IIIProspective cohort studies
      IVRetrospective cohort studies of case–control studies
      VStudies without control group, case reports, experts opinions
      Grades of recommendation
      AStrong evidence for efficacy with a substantial clinical benefit, strongly recommended
      BStrong or moderate evidence for efficacy but with a limited clinical benefit, generally recommended
      CInsufficient evidence for efficacy or benefit does not outweigh the risk of the disadvantages (adverse events, costs, …) optional
      DModerate evidence against efficacy or for adverse outcome, generally not recommended
      EStrong evidence against efficacy or for adverse outcome, never recommended

      Results

      Patient positioning and immobilisation

      We did not identify new studies that would change the 2010 recommendations [
      • De Ruysscher D.
      • Faivre-Finn C.
      • Nestle U.
      • et al.
      European Organisation for Research and Treatment of Cancer recommendations for planning and delivery of high-dose, high-precision radiotherapy for lung cancer.
      ]. Stable and reproducible patient positioning is essential. If possible, patients should be positioned with both arms above the head as this position permits a greater choice of beam positions. However, this position may be unsuitable for individual patients. Reproducible setup can be achieved using a stable arm support, in combination with knee support to improve patient comfort. Several studies have shown that SBRT can be safely delivered without the use of immobilization casts [
      • Timmerman R.
      • Galvin J.
      • Michalski J.
      • et al.
      Accreditation and quality assurance for Radiation Therapy Oncology Group: multicenter clinical trials using Stereotactic Body Radiation Therapy in lung cancer.
      ].

      Tumour and nodal changes

      Inter-fractional tumour shifts

      Inter-fractional changes in anatomy of the target region are frequent, and can be of clinical relevance for both early-stage [
      • Guckenberger M.
      • Meyer J.
      • Wilbert J.
      • et al.
      Cone-beam CT based image-guidance for extracranial stereotactic radiotherapy of intrapulmonary tumors.
      ,
      • Worm E.S.
      • Hansen A.T.
      • Petersen J.B.
      • et al.
      Inter- and intrafractional localisation errors in cone-beam CT guided stereotactic radiation therapy of tumours in the liver and lung.
      ,
      • Sonke J.J.
      • Rossi M.
      • Wolthaus J.
      • et al.
      Frameless stereotactic body radiotherapy for lung cancer using four-dimensional cone beam CT guidance.
      ] and locally advanced disease [
      • Schaake E.E.
      • Rossi M.M.G.
      • Buikhuisen W.A.
      • et al.
      Differential motion between mediastinal lymph nodes and primary tumor in radically irradiated lung cancer patients.
      ,
      • Hoffmann L.
      • Holt M.I.
      • Knap M.M.
      • et al.
      Anatomical landmarks accurately determine interfractional lymph node shifts during radiotherapy of lung cancer patients.
      ]. Inter-fractional shifts between primary tumour and vertebra positions range from 5 to 7 mm on average (3D vector), but may be as high as 3 cm [
      • Guckenberger M.
      • Meyer J.
      • Wilbert J.
      • et al.
      Cone-beam CT based image-guidance for extracranial stereotactic radiotherapy of intrapulmonary tumors.
      ,
      • van Elmpt W.
      • Ollers M.
      • van Herwijnen H.
      • et al.
      Volume or position changes of primary lung tumor during (chemo-)radiotherapy cannot be used as a surrogate for mediastinal lymph node changes: the case for optimal mediastinal lymph node imaging during radiotherapy.
      ]. The use of only an external reference system, such as a stereotactic body frame (SBF), cannot account for such deviations, and consequently, image guidance and patient setup corrections are essential [
      • Guckenberger M.
      • Meyer J.
      • Wilbert J.
      • et al.
      Cone-beam CT based image-guidance for extracranial stereotactic radiotherapy of intrapulmonary tumors.
      ,
      • Worm E.S.
      • Hansen A.T.
      • Petersen J.B.
      • et al.
      Inter- and intrafractional localisation errors in cone-beam CT guided stereotactic radiation therapy of tumours in the liver and lung.
      ].
      The treatment volume in locally advanced lung cancer often consists of several spatially separated targets (tumour(s), nodes) which will exhibit differential motion and shifts [
      • Schaake E.E.
      • Rossi M.M.G.
      • Buikhuisen W.A.
      • et al.
      Differential motion between mediastinal lymph nodes and primary tumor in radically irradiated lung cancer patients.
      ]. These non-rigid uncertainties cannot completely be compensated by image-guidance based on couch corrections. Adaptive radiotherapy has been shown to reduce this source of error [
      • Hoffmann L.
      • Holt M.I.
      • Knap M.M.
      • et al.
      Anatomical landmarks accurately determine interfractional lymph node shifts during radiotherapy of lung cancer patients.
      ].

      Intra-fractional tumour shifts

      The intra-fractional target shifts are usually of small magnitude, ranging from 0.15 to 0.21 cm [
      • Schaake E.E.
      • Rossi M.M.G.
      • Buikhuisen W.A.
      • et al.
      Differential motion between mediastinal lymph nodes and primary tumor in radically irradiated lung cancer patients.
      ]. Small, but systematic, intra-fractional drifts in the cranial and posterior direction were reported [
      • Schaake E.E.
      • Rossi M.M.G.
      • Buikhuisen W.A.
      • et al.
      Differential motion between mediastinal lymph nodes and primary tumor in radically irradiated lung cancer patients.
      ]. Intra-fractional drifts increase when treatment times exceed 34 min [
      • Purdie T.G.
      • Bissonnette J.P.
      • Franks K.
      • et al.
      Cone-beam computed tomography for on-line image guidance of lung stereotactic radiotherapy: localization, verification, and intrafraction tumor position.
      ].

      Intra-fractional respiratory and cardiac motion

      Respiratory tumour motion is frequently observed in primary lung tumours and lymph nodes, with the magnitude varying substantially between patients [
      • Seppenwoolde Y.
      • Shirato H.
      • Kitamura K.
      • et al.
      Precise and real-time measurement of 3D tumor motion in lung due to breathing and heartbeat, measured during radiotherapy.
      ,
      • Pantarotto J.R.
      • Piet A.H.
      • Vincent A.
      • et al.
      Motion analysis of 100 mediastinal lymph nodes: potential pitfalls in treatment planning and adaptive strategies.
      ]. Increased motion has been observed in lower-lobe tumours [
      • Seppenwoolde Y.
      • Shirato H.
      • Kitamura K.
      • et al.
      Precise and real-time measurement of 3D tumor motion in lung due to breathing and heartbeat, measured during radiotherapy.
      ], for smaller primary tumours [
      • Liu H.H.
      • Balter P.
      • Tutt T.
      • et al.
      Assessing respiration-induced tumor motion and internal target volume using four-dimensional computed tomography for radiotherapy of lung cancer.
      ] and for infra-carinal lymph nodes [
      • Donnelly E.D.
      • Parikh P.J.
      • Lu W.
      • et al.
      Assessment of intrafraction mediastinal and hilar lymph node movement and comparison to lung tumor motion using four-dimensional CT.
      ]. However, due to large inter-patient variability, patient-specific motion assessment should be performed [
      • Richter A.
      • Wilbert J.
      • Baier K.
      • et al.
      Feasibility study for markerless tracking of lung tumors in stereotactic body radiotherapy.
      ]. The respiratory motion of a lymph node typically differs from respiratory tumour motion, both in terms of amplitude and phase [
      • Schaake E.E.
      • Rossi M.M.G.
      • Buikhuisen W.A.
      • et al.
      Differential motion between mediastinal lymph nodes and primary tumor in radically irradiated lung cancer patients.
      ,
      • Pantarotto J.R.
      • Piet A.H.
      • Vincent A.
      • et al.
      Motion analysis of 100 mediastinal lymph nodes: potential pitfalls in treatment planning and adaptive strategies.
      ,
      • Donnelly E.D.
      • Parikh P.J.
      • Lu W.
      • et al.
      Assessment of intrafraction mediastinal and hilar lymph node movement and comparison to lung tumor motion using four-dimensional CT.
      ]. For tumours close to heart or aorta, cardiac-induced motion can exceed respiratory motion [
      • Seppenwoolde Y.
      • Shirato H.
      • Kitamura K.
      • et al.
      Precise and real-time measurement of 3D tumor motion in lung due to breathing and heartbeat, measured during radiotherapy.
      ].

      Anatomical changes during fractionated radiotherapy

      Changes in normal anatomy can be observed during a course of radiotherapy, due to pleural effusion, onset or resolution of atelectasis, tumour progression or shrinkage, and changes in body weight [
      • Møller D.S.
      • Khalil A.A.
      • Knap M.M.
      • et al.
      Adaptive radiotherapy of lung cancer patients with pleural effusion or atelectasis.
      ]. Transient anatomical changes were reported in 72% of patients during conventionally fractionated RT for lung cancer [
      • Kwint M.
      • Conijn S.
      • Schaake E.
      • et al.
      Intra thoracic anatomical changes in lung cancer patients during the course of radiotherapy.
      ]. Persistent changes such as atelectasis, pleural effusion or pneumonia were reported in 23% of patients [
      • Møller D.S.
      • Khalil A.A.
      • Knap M.M.
      • et al.
      Adaptive radiotherapy of lung cancer patients with pleural effusion or atelectasis.
      ], and significant disease shrinkage observed in 30% of patients [
      • Kwint M.
      • Conijn S.
      • Schaake E.
      • et al.
      Intra thoracic anatomical changes in lung cancer patients during the course of radiotherapy.
      ,
      • Knap M.M.
      • Hoffmann L.
      • Nordsmark M.
      • et al.
      Daily cone-beam computed tomography used to determine tumour shrinkage and localisation in lung cancer patients.
      ]. Changes observed indicated an average 1–2% volume reduction per treatment day [
      • Kupelian P.A.
      • Ramsey C.
      • Meeks S.L.
      • et al.
      Serial megavoltage CT imaging during external beam radiotherapy for non-small-cell lung cancer: observations on tumor regression during treatment.
      ]. Tumour progression has been reported in up to 10% of patients [
      • Kwint M.
      • Conijn S.
      • Schaake E.
      • et al.
      Intra thoracic anatomical changes in lung cancer patients during the course of radiotherapy.
      ]. As these changes in anatomy may lead to either over- or under-dosage of the PTV and/or OARs, adaptation of the radiation plan may be required, making imaging during treatment mandatory.

      Definition of target volumes

      CT scanning

      We did not identify new studies that would change the 2010 recommendations [
      • De Ruysscher D.
      • Faivre-Finn C.
      • Nestle U.
      • et al.
      European Organisation for Research and Treatment of Cancer recommendations for planning and delivery of high-dose, high-precision radiotherapy for lung cancer.
      ]. Planning CT scans should be acquired in treatment position, and incorporate techniques for evaluating motion compensation.
      A planning CT scan should include the entire lung volume, and typically extends from the level of the cricoid cartilage to the second lumbar vertebra. Acquiring CT scans with a slice thickness of 2–3 mm is recommended [
      • Hurkmans C.W.
      • Cuijpers J.P.
      • Lagerwaard F.J.
      • et al.
      Recommendations for implementing stereotactic radiotherapy in peripheral stage IA non-small cell lung cancer: report from the Quality Assurance Working Party of the randomised phase III ROSEL study.
      ]. Use of intravenous (IV) contrast for CT scanning enables improved delineation of centrally located primary tumours and lymph nodes. In order to be able to account for motion, a 3D-CT is insufficient and a 4D-CT is recommended.

      PET scanning

      Multiple studies have evaluated the potential role for Positron Emission Tomography (PET) with 18F-deoxyglucose (FDG) for radiotherapy treatment planning. FDG-PET has a higher diagnostic accuracy in detecting lymph node metastases, when compared to CT alone [
      • Schmidt-Hansen M.
      • Baldwin D.R.
      • Hasler E.
      • et al.
      PET-CT for assessing mediastinal lymph node involvement in patients with suspected resectable non-small cell lung cancer.
      ]. However, standardisation of the acquisition protocol is necessary, with PET data co-registered with anatomical imaging for radiotherapy planning process [
      • Thorwarth D.
      • Beyer T.
      • Boellaard R.
      • et al.
      Integration of FDG-PET/CT into external beam radiation therapy planning: technical aspects and recommendations on methodological approaches.
      ]. The equipment used for patient immobilisation during PET scans should be identical to that used for CT scanning and treatment, the quality of image co-registration should be verified prior to contouring, as patient movements may lead to incorrect hardware fusion, even when using a PET-CT machine. Caution is advised in using non-rigid registration algorithms, as they have not been evaluated in the context of RT-planning [
      • Thorwarth D.
      • Beyer T.
      • Boellaard R.
      • et al.
      Integration of FDG-PET/CT into external beam radiation therapy planning: technical aspects and recommendations on methodological approaches.
      ]. As chemotherapy can lead to a decrease in FDG-uptake [
      • Weber W.A.
      • Petersen V.
      • Schmidt B.
      • et al.
      Positron emission tomography in non-small-cell lung cancer: prediction of response to chemotherapy by quantitative assessment of glucose use.
      ], post-chemotherapy FDG-accumulations should not be used for the delineation of the gross tumour volume.

      MRI scanning

      MRI may give additional information to CT or PET-imaging, particularly for tumours invading the thoracic wall [
      • Wielpütz M.
      • Kauczor H.U.
      MRI of the lung: state of the art.
      ]. However, the choice of 4D MRI sequences remains investigational, and careful consideration of movement artefacts is needed.

      Role of EBUS and mediastinoscopy

      Although FDG-PET-CT scanning has the highest accuracy of all imaging modalities for the mediastinum, both false positive and false negative lymph nodes are observed [
      • Schmidt-Hansen M.
      • Baldwin D.R.
      • Hasler E.
      • et al.
      PET-CT for assessing mediastinal lymph node involvement in patients with suspected resectable non-small cell lung cancer.
      ]. Endobronchial ultrasound (EBUS) and/or oesophageal ultrasound (EUS) with needle aspiration (E(B)US-NA) have become standard practice for mediastinal staging in patients with positive nodes on FDG-PET or CT staging [
      • Vilmann P.
      • Clementsen P.F.
      • Colella S.
      • et al.
      Combined endobronchial and oesophageal endosonography for the diagnosis and staging of lung cancer. European Society of Gastrointestinal Endoscopy (ESGE) guideline, in cooperation with the European Respiratory Society (ERS) and the European Society of Thoracic Surgeons (ESTS).
      ]. With a sensitivity of over 90%, and a specificity of 100%, mediastinoscopy is only added, in case of a negative EBUS/EUS findings when the FDG-PET-CT scan is positive, or in cN1, or in a central tumour with a diameter exceeding 3 cm [
      • Vilmann P.
      • Clementsen P.F.
      • Colella S.
      • et al.
      Combined endobronchial and oesophageal endosonography for the diagnosis and staging of lung cancer. European Society of Gastrointestinal Endoscopy (ESGE) guideline, in cooperation with the European Respiratory Society (ERS) and the European Society of Thoracic Surgeons (ESTS).
      ,
      • Dooms C.
      • Tournoy K.G.
      • Schuurbiers O.
      • et al.
      Endosonography for mediastinal nodal staging of clinical N1 non-small cell lung cancer: a prospective multicenter study.
      ]. The addition of EBUS/ EUS to FDG-PET-CT can decrease geographical miss by 4–5% [
      • Peeters S.T.
      • Dooms C.
      • Van Baardwijk A.
      • et al.
      Selective mediastinal node irradiation in non-small cell lung cancer in the IMRT/VMAT era: how to use E(B)US-NA information in addition to PET-CT for delineation?.
      ]. In general, lymph nodes that are FDG-PET-positive and EBUS/EUS-negative should be included in the GTV, as the false negative rates of EBUS/EUS are high [
      • Peeters S.T.
      • Dooms C.
      • Van Baardwijk A.
      • et al.
      Selective mediastinal node irradiation in non-small cell lung cancer in the IMRT/VMAT era: how to use E(B)US-NA information in addition to PET-CT for delineation?.
      ].

      Target volumes definition

      Gross tumour volume (GTV)

      We did not identify new studies that would change the 2010 recommendations [
      • De Ruysscher D.
      • Faivre-Finn C.
      • Nestle U.
      • et al.
      European Organisation for Research and Treatment of Cancer recommendations for planning and delivery of high-dose, high-precision radiotherapy for lung cancer.
      ]. The measured diameter of tumours in lung parenchyma or mediastinum is dependent on the window width and level chosen to analyse CT slices [
      • Harris K.M.
      • Adams H.
      • Lloyd D.C.
      • et al.
      The effect on apparent size of simulated pulmonary nodules of using three standard CT window settings.
      ]. CT-based delineation with standardized window settings is recommended. The best concordance between measured and actual diameters and volumes for CT was obtained with the settings: W = 1600 and L = −600 for parenchyma, and W = 400 and L = 20 for mediastinum. However, for larger tumours, the tumour volume on CT can be overestimated [
      • van Loon J.
      • Siedschlag C.
      • Stroom J.
      • et al.
      Microscopic disease extension in three dimensions for non-small-cell lung cancer: development of a prediction model using pathology-validated positron emission tomography and computed tomography features.
      ]. Accurate delineation of the lymph nodes regions, and identification of blood vessels, requires the use of a CT scan with intravenous contrast. Respiratory movements have also to be addressed (see Section “Target volumes definition”).
      The identification of pathological lymph nodes has been discussed in Section “Target volumes definition”.
      The easiest, and most widely used approach for FDG based target volume definition, is visual GTV-contouring, which uses a clinical protocol that integrates all relevant clinical information, the reports of the nuclear medicine physician and radiologist at standardized window setting [
      • Thorwarth D.
      • Beyer T.
      • Boellaard R.
      • et al.
      Integration of FDG-PET/CT into external beam radiation therapy planning: technical aspects and recommendations on methodological approaches.
      ]. Even when PET is co-registered with CT, approaches other than those using visual contouring tools should be used with caution, and only in experienced centres that have calibrated and validated such methods appropriately. The use of FDG-PET scans to differentiate tumour from atelectasis has never been subjected to pathological or clinical studies. Elective nodal irradiation is not indicated in any patient group that receives curative or radical doses of radiotherapy for inoperable NSCLC [
      • De Ruysscher D.
      • Wanders S.
      • van Haren E.
      • et al.
      Selective mediastinal node irradiation based on FDG-PET scan data in patients with non-small-cell lung cancer: a prospective clinical study.
      ,
      • Belderbos J.S.
      • Heemsbergen W.D.
      • De Jaeger K.
      • et al.
      Final results of a Phase I/II dose escalation trial in non-small-cell lung cancer using three-dimensional conformal radiotherapy.
      ], as well as for “limited disease” (i.e., stage I–III) SCLC [
      • van Loon J.
      • De Ruysscher D.
      • Wanders R.
      • et al.
      Selective nodal irradiation on basis of (18)FDG-PET scans in limited-disease small-cell lung cancer: a prospective study.
      ], the latter when based on FDG-PET-CT scans for the supra- and infra-clavicular region.
      Following prior induction chemotherapy, it is unclear if the volume of the primary tumour to receive full-dose radiotherapy can be limited to only the post-chemotherapy volume. For hilar or the mediastinal lymph nodes, pre-chemotherapy nodal CTV should be treated, even when a partial or a complete remission was achieved with chemotherapy [
      • De Ruysscher D.
      • Wanders S.
      • van Haren E.
      • et al.
      Selective mediastinal node irradiation based on FDG-PET scan data in patients with non-small-cell lung cancer: a prospective clinical study.
      ,
      • van Loon J.
      • De Ruysscher D.
      • Wanders R.
      • et al.
      Selective nodal irradiation on basis of (18)FDG-PET scans in limited-disease small-cell lung cancer: a prospective study.
      ]. The use of co-registered pre-treatment and planning CT and/or PET-CT scans can enable a more accurate reconstruction of pre-chemotherapy target volumes [
      • Lagerwaard F.J.
      • van de Vaart P.J.M.
      • Voet P.W.J.
      • et al.
      Can errors in reconstructing pre-chemotherapy target volumes contribute to the inferiority of sequential chemoradiation in stage III non-small cell lung cancer?.
      ].

      Clinical target volume (CTV)

      Most studies in locally advanced lung cancer have used a GTV to CTV extension of approximately 5 mm, both for the primary tumour and for the lymph nodes. A CTV margin around the primary tumour and lymph nodes is recommended [
      • ICRU Report 50
      Prescribing, recording, and reporting photon beam therapy.
      ,
      • ICRU Report 62
      Prescribing, recording, and reporting photon beam therapy (Supplement to ICRU report 50).
      ,
      • ICRU Report 83
      Prescribing, recording, and reporting intensity-modulated photon-beam therapy (IMRT).
      ], which may be tailored according to the histology of the primary tumour [
      • 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.
      ], size of lymph node [
      • Yuan S.
      • Meng X.
      • Yu J.
      • et al.
      Determining optimal clinical target volume margins on the basis of microscopic extracapsular extension of metastatic nodes in patients with non-small-cell lung cancer.
      ] and possibly, imaging characteristics of the tumour [
      • Berthelot K.
      • Thureau S.
      • Giraud P.
      Margin determination from clinical to planning target volume for lung cancer treated with conformal or intensity-modulated irradiation.
      ]. In the absence of prospective trials that have compared disease recurrence patterns with CTV margins adjusted for histology or size, the clinical relevance of the abovementioned factors remains uncertain. The CTV should be manually adjusted, for example when there is no evidence for invasion into a vertebral body or other neighbouring organs. In SBRT treatments, no CTV margins are generally used [
      • Jin J.Y.
      • Ajlouni M.
      • Chen Q.
      • et al.
      Quantification of incidental dose to potential clinical target volume (CTV) under different stereotactic body radiation therapy (SBRT) techniques for non-small cell lung cancer - tumor motion and using internal target volume (ITV) could improve dose distribution in CTV.
      ].
      When post-operative radiotherapy is indicated in locally-advanced NSCLC, the CTV consists of the resected involved mediastinal lymph node regions, the bronchial stump, the ipsilateral hilar and station 4 node region, station 7 and the contra-lateral lymph nodes at risk [
      • Le Péchoux C.
      Role of postoperative radiotherapy in resected non-small cell lung cancer: a reassessment based on new data.
      ,
      • Billiet C.
      • De Ruysscher D.
      • Peeters S.
      • et al.
      Patterns of locoregional relapses in patients with contemporarily staged stage III-N2 NSCLC treated with induction chemotherapy and resection: implications for postoperative radiotherapy target volumes.
      ].

      Planning target volume (PTV)

      The margins used from CTV to PTV depend on all uncertainties related to planning and delivery of radiotherapy (International Commission on Radiation Units and Measurements (ICRU) 83): mechanical, dosimetric, tumour deformation or growth, inter-and intra-fractional setup errors and baseline shifts, respiratory and cardiac motion [
      • ICRU Report 83
      Prescribing, recording, and reporting intensity-modulated photon-beam therapy (IMRT).
      ,
      • Hoffmann L.
      • Holt M.I.
      • Knap M.M.
      • et al.
      Anatomical landmarks accurately determine interfractional lymph node shifts during radiotherapy of lung cancer patients.
      ,
      • Jan N.
      • Balik S.
      • Hugo G.D.
      • et al.
      Interfraction displacement of primary tumour and involved lymph nodes relative to anatomic landmarks in image guided radiation therapy of locally advanced lung cancer.
      ,
      • Higgins J.
      • Bezjak A.
      • Franks K.
      • et al.
      Comparison of spine, carina and tumour as registration landmarks for volumetric image-guided lung radiotherapy.
      ].
      While other factors determining the choice of planning margins are derived from specific clinical settings and populations, respiratory motion is a patient-specific factor which should be determined before treatment, typically using a pre-treatment 4D-CT or 4D PET/CT scan. Applying the same respiratory margin for all patients is discouraged since variations in respiratory motion amplitude are large [
      • Heinzerling J.H.
      • Anderson J.F.
      • Papiez L.
      • et al.
      Four-dimensional computed tomography scan analysis of tumor and organ motion at varying levels of abdominal compression during stereotactic treatment of lung and liver.
      ].
      In general, one can differentiate between passive motion compensation strategies (abdominal compression, internal target volume (ITV) concept, mid-ventilation concept, jet-ventilation) and active motion compensation strategies (gating, breath hold, tracking). Abdominal compression can modestly decrease the respiratory amplitude [
      • Bouilhol G.
      • Ayadi M.
      • Rit S.
      • et al.
      Is abdominal compression useful in lung stereotactic body radiation therapy? A 4DCT and dosimetric lobe-dependent study.
      ], but the dosimetric gain is limited [
      • Underberg R.W.
      • Lagerwaard F.J.
      • Slotman B.J.
      • et al.
      Benefit of respiration-gated stereotactic radiotherapy for stage I lung cancer: an analysis of 4DCT datasets.
      ]. Different gating strategies, where radiation is only delivered during specific phases of the respiratory cycle can be employed to reduce the margin accounting for respiratory motion [
      • Keall P.G.
      • Mageras G.S.
      • Balter J.M.
      • et al.
      The management of respiratory motion in radiation oncology: report of AAPM Radiation Therapy Committee Task Group No. 76.
      ]. Deep inspiration breath hold (DIBH) reduces tumour motion while increasing the lung volume, resulting in decreased doses to lung, and often also to the heart [
      • Giraud P.
      • Morvan E.
      • Claude L.
      • et al.
      STIC Study Centers. Respiratory gating techniques for optimization of lung cancer radiotherapy.
      ,
      • Nuyttens J.J.
      • Prévost J.B.
      • Praag J.
      • et al.
      Lung tumor tracking during stereotactic radiotherapy treatment with the CyberKnife: marker placement and early results.
      ]. Real time tumour tracking is commercially available using robotic radiotherapy [
      • Ottosson W.
      • Rahma F.
      • Sjöström D.
      • et al.
      The advantage of deep-inspiration breath-hold and cone-beam CT based soft-tissue registration for locally advanced lung cancer radiotherapy.
      ] for SBRT treatment, but requires generally implanted markers. Application of one (either active or passive) 4D motion compensation strategy is highly recommended; however, current physical and especially clinical data do not support the superiority of one particular strategy. If respiratory motion management strategies are used, the inter- and intra-fractional shifts may differ from those observed in free breathing (FB). For DIBH, larger inter- and intra-fractional shifts are seen compared to FB [
      • Wolthaus J.W.
      • Sonke J.J.
      • van Herk M.
      • et al.
      Comparison of different strategies to use fourdimensional computed tomography in treatment planning for lung cancer patients.
      ] and the margins applied must account for this.
      The two most common passive methods used to take the respiratory motion into account in a patient specific way are:
      • 1.
        Internal target volume concept (ITV): Delineating all phases of the 4D-CT scan and combining them [
        • Lagerwaard F.J.
        • Haasbeek C.J.
        • Smit E.F.
        • et al.
        Outcomes of risk-adapted fractionated stereotactic radiotherapy for stage I non-small-cell lung cancer.
        ] or delineation guided by a Maximum Intensity projection (MIP) [
        • Underberg R.W.
        • Lagerwaard F.J.
        • Slotman B.J.
        • et al.
        Use of maximum intensity projections (MIP) for target volume generation in 4DCT scans for lung cancer.
        ]. The ITV method takes into account all respiratory motion, including tumour deformations during breathing.
      • 2.
        Mid-ventilation/mid-position concept: Delineating on a 4DCT image reconstruction technique such as the Mid-ventilation scan [
        • Heinzerling J.H.
        • Anderson J.F.
        • Papiez L.
        • et al.
        Four-dimensional computed tomography scan analysis of tumor and organ motion at varying levels of abdominal compression during stereotactic treatment of lung and liver.
        ] which displays the frame whereby the tumour is closest to its mean time weighted tumour position, or the Mid Position scan which displays every voxel in its average position. The respiratory uncertainty is then taken into account as a random error in the CTV to PTV margin calculation [
        • Heinzerling J.H.
        • Anderson J.F.
        • Papiez L.
        • et al.
        Four-dimensional computed tomography scan analysis of tumor and organ motion at varying levels of abdominal compression during stereotactic treatment of lung and liver.
        ,
        • van Herk M.
        Errors and margins in radiotherapy.
        ,
        • Peulen H.
        • Belderbos J.
        • Rossi M.
        • et al.
        Mid-ventilation based PTV margins in Stereotactic Body Radiotherapy (SBRT): a clinical evaluation.
        ,
        • Sonke J.J.
        • Rossi M.
        • Wolthaus J.
        • et al.
        Frameless stereotactic body radiotherapy for lung cancer using four-dimensional cone beam CT guidance.
        ].
      No clinical studies have directly compared the above two methods, but both approaches have shown high local control rates over 90% in patients treated with SBRT [
      • Peulen H.
      • Belderbos J.
      • Rossi M.
      • et al.
      Mid-ventilation based PTV margins in Stereotactic Body Radiotherapy (SBRT): a clinical evaluation.
      ,
      • Verstegen N.E.
      • Lagerwaard F.J.
      • Hashemi S.M.
      • et al.
      Patterns of disease recurrence after SABR for early stage non-small-cell lung cancer: optimizing follow-up schedules for salvage therapy.
      ] thereby indicating their safety.
      Respiratory motion can also be managed by irradiating the tumour at a fixed part of the trajectory (gating) or irradiating the tumour by following the tumour (tracking) [
      • Ottosson W.
      • Rahma F.
      • Sjöström D.
      • et al.
      The advantage of deep-inspiration breath-hold and cone-beam CT based soft-tissue registration for locally advanced lung cancer radiotherapy.
      ,
      • Falk M.
      • Pommer T.
      • Keall P.
      • et al.
      Motion management during IMAT treatment of mobile lung tumors—a comparison of MLC tracking and gated delivery.
      ,
      • Colvill E.
      • Booth J.
      • Nill S.
      • et al.
      A dosimetric comparison of real-time adaptive and non-adaptive radiotherapy: a multi-institutional study encompassing robotic, gimbaled, multileaf collimator and couch tracking.
      ,
      • Cole A.J.
      • Hanna G.G.
      • Jain S.
      • et al.
      Motion management for radical radiotherapy in non-small cell lung cancer.
      ]. However, one has to take into consideration the increased complexity of these techniques.
      Changes arising during the course of irradiation, that cannot be corrected for by on-line image guidance, may require adaptive radiotherapy, where a new treatment plan is made based on the new anatomy [
      • Sonke J.J.
      • Belderbos J.
      Adaptive radiotherapy for lung cancer.
      ,
      • Møller D.S.
      • Holt M.I.
      • Alber M.
      • et al.
      Adaptive radiotherapy for advanced lung cancer ensures target coverage and decreases lung dose.
      ].

      Planning organ at risk volume (PRV)

      The planning organ at risk volume (PRV) concept [
      • McKenzie A.
      • van Herk M.
      • Mijnheer B.
      Margins for geometric uncertainty around organs at risk in radiotherapy.
      ] can be relevant when treating lung cancer, especially in case where a maximum dose constraint is used. For serial organs, including the spinal cord, the main bronchi, the brachial plexus, the oesophagus and large blood vessels, the use of a PRV might be helpful, since it reduces the probability of over dosage [
      • Stroom J.C.
      • Heijmen B.J.
      Limitations of the planning organ at risk volume (PRV) concept.
      ]. The PRV concept is not relevant for the lung because it is a parallel structured organ [
      • Stroom J.C.
      • Heijmen B.J.
      Limitations of the planning organ at risk volume (PRV) concept.
      ]. It should nevertheless be stressed that all published OAR constraints are not based on the PRV concept.

      Treatment planning

      Dose calculations

      Dose calculation algorithms currently used for lung radiotherapy generally take into account changes in electron transport due to density variations, and are referred to as so-called type B or Monte Carlo based algorithms [
      • Knöös T.
      • Wieslander E.
      • Cozzi L.
      • et al.
      Comparison of dose calculation algorithms for treatment planning in external photon beam therapy for clinical situations.
      ,
      • Latifi K.
      • Oliver J.
      • Baker R.
      • et al.
      Study of 201 non-small cell lung cancer patients given stereotactic ablative radiation therapy shows local control dependence on dose calculation algorithm.
      ,
      • Elmpt W.
      • Ollers M.
      • Velders M.
      • et al.
      Transition from a simple to a more advanced dose calculation algorithm for radiotherapy of non-small cell lung cancer (NSCLC): implications for clinical implementation in an individualized dose-escalation protocol.
      ,
      • Xiao Y.
      • Papiez L.
      • Paulus R.
      • et al.
      Dosimetric evaluation of heterogeneity corrections for RTOG 0236: stereotactic body radiotherapy of inoperable stage I-II non-small-cell lung cancer.
      ,
      • Admiraal M.A.
      • Schuring D.
      • Hurkmans C.W.
      Dose calculations accounting for breathing motion in stereotactic lung radiotherapy based on 4D-CT and the internal target volume.
      ,
      • Guckenberger M.
      • Wilbert J.
      • Krieger T.
      • et al.
      Four-dimensional treatment planning for stereotactic body radiotherapy.
      ]. Use of older algorithms are not recommended as they have been associated with more local recurrences [
      • Latifi K.
      • Oliver J.
      • Baker R.
      • et al.
      Study of 201 non-small cell lung cancer patients given stereotactic ablative radiation therapy shows local control dependence on dose calculation algorithm.
      ]. Differences between more advanced algorithms still exist [
      • Mampuya W.A.
      • Matsuo Y.
      • Nakamura A.
      • et al.
      Differences in dose-volumetric data between the analytical anisotropic algorithm and the x-ray voxel Monte Carlo algorithm in stereotactic body radiation therapy for lung cancer.
      ,
      • Tsuruta Y.
      • Nakata M.
      • Nakamura M.
      • et al.
      Dosimetric comparison of Acuros XB, AAA, and XVMC in stereotactic body radiotherapy for lung cancer.
      ,
      • Kry S.F.
      • Alvarez P.
      • Molineu A.
      • et al.
      Algorithms used in heterogeneous dose calculations show systematic differences as measured with the Radiological Physics Center's anthropomorphic thorax phantom used for RTOG credentialing.
      ,
      • Dunn L.
      • Lehmann J.
      • Lye J.
      • et al.
      National dosimetric audit network finds discrepancies in AAA lung inhomogeneity corrections.
      ], with Monte Carlo algorithms possibly more accurate for estimating dose at the tumour periphery [
      • Taylor M.
      • Dunn L.
      • Kron T.
      • et al.
      Determination of peripheral underdosage at the lung-tumor interface using Monte Carlo radiation transport calculations.
      ]. There is no consensus yet about the clinical acceptability and relevance of reported differences [
      • Mampuya W.A.
      • Nakamura M.
      • Hirose Y.
      • et al.
      Difference in dose-volumetric data between the analytical anisotropic algorithm, the dose-to-medium, and the dose-to-water reporting modes of the Acuros XB for lung stereotactic body radiation therapy.
      ,
      • Mampuya W.A.
      • Matsuo Y.
      • Nakamura A.
      • et al.
      Differences in dose-volumetric data between the analytical anisotropic algorithm and the x-ray voxel Monte Carlo algorithm in stereotactic body radiation therapy for lung cancer.
      ,
      • Liu H.
      • Zhuang T.
      • Stephans K.
      • et al.
      Dose differences in intensity-modulated radiotherapy plans calculated with pencil beam and Monte Carlo for lung SBRT.
      ]. Comparisons between 3D dose calculations using the ‘average CT’ dataset and full 4D calculations show small differences of a few per cent [
      • Mitsuyoshi T.
      • Nakamura M.
      • Matsuo Y.
      • et al.
      Dosimetric comparison of lung stereotactic body radiotherapy treatment plans using averaged computed tomography and end-exhalation computed tomography images: evaluation of the effect of different dose-calculation algorithms and prescription methods.
      ,
      • Oechsner M.
      • Odersky L.
      • Berndt J.
      • et al.
      Dosimetric impact of different CT datasets for stereotactic treatment planning using 3D conformal radiotherapy or volumetric modulated arc therapy.
      ].

      Dose specification and reporting

      Dose prescriptions and reporting should comply with international standards [
      • ICRU Report 50
      Prescribing, recording, and reporting photon beam therapy.
      ,
      • ICRU Report 62
      Prescribing, recording, and reporting photon beam therapy (Supplement to ICRU report 50).
      ,
      • ICRU Report 83
      Prescribing, recording, and reporting intensity-modulated photon-beam therapy (IMRT).
      ]. Additionally, the type of dose calculation algorithm and CT dataset on which the calculations are based, should also be reported [
      • ICRU Report 83
      Prescribing, recording, and reporting intensity-modulated photon-beam therapy (IMRT).
      ].

      Beam arrangements

      In principle, all radiotherapy delivery techniques can be used, as long as established dose distribution criteria are met. As intra-fraction motion increases with time, it is advisable to limit treatment times. This can be achieved using co-planar techniques or volumetric arc therapy and flattening filter-free beams [
      • Holt A.
      • van Vliet-Vroegindeweij C.
      • Mans A.
      • et al.
      Volumetric-modulated arc therapy for stereotactic body radiotherapy of lung tumors: a comparison with intensity-modulated radiotherapy techniques.
      ,
      • Ong C.L.
      • Verbakel W.F.
      • Dahele M.
      • et al.
      Fast arc delivery for stereotactic body radiotherapy of vertebral and lung tumors.
      ,
      • Nakagawa K.
      • Haga A.
      • Sakumi A.
      • et al.
      Impact of flattening-filter-free techniques on delivery time for lung stereotactic volumetric modulated arc therapy and image quality of concurrent kilovoltage cone-beam computed tomography: a preliminary phantom study.
      ].

      Dose–volume constraints (Table 2, Table 3)

      To predict the probability of radiation-induced damage, many studies have analysed the relationship with dose–volume histogram (DVH) parameters, either with or without patient characteristics. However, many DVH parameters, strongly correlated with each other, have not been validated in independent data sets [
      • Bentzen S.M.
      • Constine L.S.
      • Deasy J.O.
      • et al.
      Quantitative Analyses of Normal Tissue Effects in the Clinic (QUANTEC): an introduction to the scientific issues.
      ]. Furthermore, studies correlating DVH parameters to clinical outcomes have generally included few patients. As normal tissues may be displaced during radiotherapy, a single imaging study performed before therapy may not accurately reflect the actual delivered dose [
      • Jackson A.
      • Marks L.B.
      • Bentzen S.M.
      • et al.
      The lessons of QUANTEC: recommendations for reporting and gathering data on dose-volume dependencies of treatment outcome.
      ]. There is a need for improved biomarkers or imaging features in radiotherapy prediction models, but these are considered experimental now.
      Table 2EORTC recommendations for planning and delivery of high-dose, high precision radiotherapy for lung cancer.
      Fractionation for stereotactic body radiotherapy (SBRT)
      • SBRT using high doses per fraction should not be given to “ultra-centrally” located tumours (Recommendation grade II, E)
      • SBRT with lower doses per fraction that are adapted to critical organs (“risk adapted”) should be used carefully for centrally located tumours (Recommendation grade IV, C)
      Reproducibility of patient positioning and tumour position
      • A stable and reproducible patient position during all imaging procedures and treatment is essential (Recommendation grade IV, A)
      • SBRT can be safely delivered without rigid immobilization devices (Recommendation grade IV, A)
      • Interventions to reduce tumour motion may be useful in selected patients (Recommendation grade IV, C)
      • Gating and tracking may be of value in a small subgroup of patients with large tumour motion (Recommendation grade IV, B)
      CT scanning
      • A planning CT scan should include the entire lung volume, and typically extends from the level of the cricoid cartilage to the second lumbar vertebra (Recommendation grade IV, A)
      • A 4D-CT scan is recommended as it allows to take into account tumour movements and reduced systematic errors and geographical miss (Recommendation grade IV, A)
      • The use of CT slice thickness of 2–3 mm is recommended as it permits generation of high-resolution digitally reconstructed radiographs (DRR) and facilitates accurate tumour delineation (Recommendation grade IV, A)
      • The use of intravenous contrast can improve the delineation of centrally located primary tumours and lymph nodes (Recommendation grade III, A)
      PET scanning
      • FDG-PET is recommended in the process of target volume definition (Recommendation grade III, A)
      • Strictly standardised protocols, preferentially in cooperation with a department of nuclear medicine, are preferred when FDG-PET scans are used for radiotherapy treatment planning (Recommendation grade IV, A)
      • FDG-PET scans for radiotherapy treatment planning should be acquired in radiotherapy position, and co-registered with a planning CT using rigid methods if the acquisitions are not simultaneously (Recommendation grade IV, A)
      Generating target volumes
      Gross Tumour Volume (GTV)
      • Recommended CT settings for tumour delineation are: for lung: W = 1600 and L = -600, and W = 400 and L = 20 for mediastinum (Recommendation grade III, A)
      • Elective irradiation of mediastinal lymph nodes is not recommended for NSCLC and for limited disease SCLC (Recommendation grade III, A)
      • For NSCLC, selective nodal irradiation based on information from CT, FDG-PET and bronchoscopy, ultrasound-guided fine needle aspiration, mediastinoscopy (if available) is the recommended standard. (Recommendation grade III, A)
      Clinical Target Volume (CTV)
      • A fixed 5 mm CTV margin may be used (Recommendation grade III, B)
      • Manual adjustment of the CTV according to normal tissues (e.g. the bones) may be appropriate (Recommendation grade III, B)
      Planning Target Volume (PTV)
      • Generation of CTV to PTV margin should be calculated from uncertainties based on the patient population, patient positioning, treatment technique, treatment unit used and imaging and setup strategies applied. If any of the above are changed the margins should be changed accordingly. The uncertainties should preferably be determined in each institution. (Recommendation grade III, A)
      • The respiratory induced tumor motion is non-uniform and patient dependent. The applied margins should reflect this (Recommendation grade III, A)
      Planning organ at risk volume (PRV)
      • The use of a PRV margin around critical serial organs should be encouraged to avoid overdosing organs at risk (Recommendation grade IV, C)
      Treatment planning
      Dose calculation
      • Advanced dose calculation algorithms (type B or Monte Carlo based) are strongly recommended for thoracic radiotherapy as they allow for more accurate computation of dose distributions (Recommendation grade III, A)
      • Absolute doses and dose distributions calculated with type A vs. type B or Monte Carlo based algorithms cannot be compared (Recommendation grade III, A)
      • Full 4D dose calculations do not appear to be essential when type B or Monte Carlo based algorithms are used (Recommendation grade III, C)
      Dose specification and reporting
      • Dose prescriptions and reporting should follow the appropriate international ICRU standards (Recommendation grade III, B)
      Beam arrangements
      • Beams directions should be chosen to minimise dose to OARs while maintaining target coverage. If co-planar techniques can be applied with no compromise in terms of dose to OARs compared to non-co-planar techniques they should be used to limit treatment time (Recommendation grade III, A)
      Dose-volume constraints
      • If possible, the V20 or the mean lung dose should be kept than 35–37% and 20 Gy, respectively (Recommendation grade III, A)
      • Patients with idiopathic pulmonary fibrosis (IPF) are at high risk for developing severe and even lethal radiation pneumonitis; radiotherapy should therefore be avoided if possible (Recommendation grade III, A)
      • With conventional concurrent chemo-radiotherapy, doses to the central bronchi in excess of 80 Gy increase the risk of bronchial stenosis and fistula (Recommendation grade III, A)
      • Grade 3 acute esophagitis is associated with higher mean oesophageal dose, V60 and neutropenia, but usually heals within 6 weeks. Dose reductions are in general not recommended (Recommendation grade III, A)
      • Late oesophageal toxicity (stenosis) is only associated with the maximal dose; doses over 76 Gy are not recommended (Recommendation grade III, A)
      • In conventionally fractionated radiotherapy, the dose to 2 cm3 of the brachial plexus should not exceed 76 Gy (Recommendation grade IV, A)
      • In stereotactic radiotherapy, the dose to the brachial plexus should not exceed 26 Gy in 3–4 fractions, the maximal dose should not be over 35 Gy in 3–4 fractions and the V30 not more than 0.2 cm3 (Recommendation grade IV, A)
      • In stereotactic radiotherapy, to keep the incidence of chest wall pain below 5%, the D70cc of the chest wall should not exceed 16 Gy in 4 fractions and the D2cc should not be over 43 Gy in 4 fractions (Recommendation grade III, A)
      • In stereotactic radiotherapy, to keep the incidence of symptomatic rib fractures below 5%, the Dmax should not exceed 225 Gy BED (α/β = 3 Gy) (Recommendation grade III, A)
      • Vertebral fractures occur at doses over 20–30 Gy and are associated with the V30. Avoidance of the vertebra should be attempted (Recommendation grade IV, A)
      • The mean heart dose should be kept as low as possible; no clear safe threshold can be defined (Recommendation grade III, A)
      • Concurrent administration of established carboplatin or cisplatin-based regimen with chest radiotherapy is safe (Recommendation grade I, A)
      • As for most targeted agents no safety data are available for their combination with thoracic radiotherapy, their concomitant administration should be avoided (Recommendation grade III, A)
      • Angiogenesis inhibitors combined with radiotherapy to the mediastinum may lead to lethal haemorrhages and should therefore be avoided (Recommendation grade III, A)
      Treatment delivery
      • Daily online imaging and soft tissue setup is recommended for all patients and should be mandatory for SBRT treatments (Recommendation grade III, A)
      • Adaptive radiotherapy is recommended for patients with large anatomical changes (Recommendation grade IV, A)
      Table 3Summary of Organs at Risk constraints.
      OrganOrgan at riskEndpointDosimetric parameterMaximum value
      Conventionally fractionated radiotherapy
      LungLungs minus GTVSymptomatic radiation induced pneumonitisV2035–37%
      LungLungs minus GTVSymptomatic radiation induced pneumonitisMLD20 Gy
      Central bronchiProximal bronchial treeStenosis and fistulaMaximum dose80 Gy
      OesophagusOesophagusAcute grade 3 oesophagitisMean oesophageal dose, V60ALARA
      OesophagusOesophagusStenosisMaximum dose76 Gy
      Brachial plexusBrachial plexusPlexopathyD2cm376 Gy
      HeartHeartCardiac toxicityMean heart doseALARA
      Stereotactic Body Radiotherapy
      Brachial plexusBrachial plexusPlexopathyMaximum dose35 Gy in 3–4 fractions
      Brachial plexusBrachial plexusPlexopathyV300.2cm3
      Chest wallChest wallChest wall painD70cm316 Gy in 4 fractions
      Chest wallChest wallChest wall painD2cm343 Gy in 4 fractions
      RibsChest wallFractureMaximum dose225 Gy BED (α/β = 3 Gy)
      Any application of DVH parameters or Normal Tissue Complication Probability (NTCP) models in clinical practice should consider only those based on published data, and with a clear knowledge of their limitations [
      • Bentzen S.M.
      • Constine L.S.
      • Deasy J.O.
      • et al.
      Quantitative Analyses of Normal Tissue Effects in the Clinic (QUANTEC): an introduction to the scientific issues.
      ,
      • Jackson A.
      • Marks L.B.
      • Bentzen S.M.
      • et al.
      The lessons of QUANTEC: recommendations for reporting and gathering data on dose-volume dependencies of treatment outcome.
      ]. The LQ model accurately describes the biological effects of different fraction doses for both modelling of tumour control probability and normal tissue complication probability [
      • Kirkpatrick J.P.
      • Brenner D.J.
      • Orton C.G.
      Point/Counterpoint. The linear-quadratic model is inappropriate to model high dose per fraction effects in radiosurgery.
      ,
      • Borst G.R.
      • Ishikawa M.
      • Nijkamp J.
      • et al.
      Radiation pneumonitis after hypofractionated radiotherapy: evaluation of the LQ(L) model and different dose parameters.
      ,
      • Guckenberger M.
      • Klement R.J.
      • Allgäuer M.
      • et al.
      Applicability of the linear-quadratic formalism for modeling local tumor control probability in high dose per fraction stereotactic body radiotherapy for early stage non-small cell lung cancer.
      ,
      • Shuryak I.
      • Carlson D.J.
      • Brown J.M.
      • et al.
      High-dose and fractionation effects in stereotactic radiation therapy: analysis of tumor control data from 2965 patients.
      ]. In the following paragraphs, physical doses are described in the context of conventionally fractionated radiotherapy.
      Both the lung V20 (which is in the original definition the percentage volume of both lungs minus the PTV receiving 20 Gy, although in some studies the GTV has been used) and the mean lung dose (MLD, being the volumes of both lungs minus the GTV), correlate with the risk for radiation pneumonitis [
      • Appelt A.L.
      • Vogelius I.R.
      • Farr K.P.
      • et al.
      Towards individualized dose constraints: adjusting the QUANTEC radiation pneumonitis model for clinical risk factors.
      ]. Although a V20 of 35–37% or an MLD value of 20 Gy (both calculated with a more advanced RT planning algorithm) have been considered “safe”, 10–15% of the patients who meet these constraints may still develop significant (grade 2 or more) radiation-induced toxicity after receiving much lower doses. Conversely, higher V20 or MLD levels may be delivered safely. Lower dose parameters such as lung V5 have in some studies been correlated with higher risk of lung toxicity with either conventional RT or SBRT [
      • Chun S.G.
      • Hu C.
      • Choy H.
      • et al.
      Impact of intensity-modulated radiation therapy technique for locally advanced non-small-cell lung cancer: a secondary analysis of the nrg oncology RTOG 0617 randomized clinical trial.
      ,
      • Stanic S.
      • Paulus R.
      • Timmerman R.D.
      • et al.
      No clinically significant changes in pulmonary function following stereotactic body radiation therapy for early-stage peripheral non-small cell lung cancer: an analysis of RTOG 0236.
      ]. A systematic review showed that cisplatin or carboplatin-based chemotherapy can be used safely with concurrent chest radiotherapy [
      • Vansteenkiste J.
      • De Ruysscher D.
      • Eberhardt W.E.
      • et al.
      ESMO Guidelines Working Group. Early and locally advanced non-small-cell lung cancer (NSCLC): ESMO clinical practice guidelines for diagnosis, treatment and follow-up.
      ,
      • Steuer C.E.
      • Behera M.
      • Ernani V.
      • et al.
      Comparison of Concurrent Use of Thoracic Radiation With Either Carboplatin-Paclitaxel or Cisplatin-Etoposide for Patients With Stage III Non-Small-Cell Lung Cancer: A Systematic Review.
      ]. Predictors of grade 5 pneumonitis were daily dose >2 Gy, V20 and lower-lobe tumour location. Patient features such as lung function, age and gender fail to identify patients at high risk of radiation pneumonitis. However, interstitial lung disease and more particularly idiopathic pulmonary fibrosis, should be highlighted as risk factors for severe pneumonitis [
      • Yamaguchi S.
      • Ohguri T.
      • Matsuki Y.
      • et al.
      Radiotherapy for thoracic tumors: association between subclinical interstitial lung disease and fatal radiation pneumonitis.
      ,
      • Yamaguchi S.
      • Ohguri T.
      • Ide S.
      • et al.
      Stereotactic body radiotherapy for lung tumors in patients with subclinical interstitial lung disease: the potential risk of extensive radiation pneumonitis.
      ,
      • Yamashita H.
      • Nakagawa K.
      • Nakamura N.
      • et al.
      Exceptionally high incidence of symptomatic grade 2–5 radiation pneumonitis after stereotactic radiation therapy for lung tumors.
      ,
      • Takeda A.
      • Enomoto T.
      • Sanuki N.
      • et al.
      Acute exacerbation of subclinical idiopathic pulmonary fibrosis triggered by hypofractionated stereotactic body radiotherapy in a patient with primary lung cancer and slightly focal honeycombing.
      ,
      • Ueki N.
      • Matsuo Y.
      • Togashi Y.
      • et al.
      Impact of pretreatment interstitial lung disease on radiation pneumonitis and survival after stereotactic body radiation therapy for lung cancer.
      ,
      • Yoshitake T.
      • Shioyama Y.
      • Asai K.
      • et al.
      Impact of interstitial changes on radiation pneumonitis after stereotactic body radiation therapy for lung cancer.
      ,
      • Bahig H.
      • Filion E.
      • Vu T.
      • et al.
      Severe radiation pneumonitis after lung stereotactic ablative radiation therapy in patients with interstitial lung disease.
      ,
      • Hara Y.
      • Takeda A.
      • Eriguchi T.
      • et al.
      Stereotactic body radiotherapy for chronic obstructive pulmonary disease patients undergoing or eligible for long-term domiciliary oxygen therapy.
      ]. Such patients should be assessed by an expert pulmonary physician, and patients counselled and informed about high risk of radiation-related side-effects.
      Although a meta-analysis comparing concurrent to sequential chemo-radiotherapy did not observe use of concurrent chemotherapy to be associated with increased lung toxicity [
      • Aupérin A.
      • Le Péchoux C.
      • Rolland E.
      • et al.
      Meta-analysis of concomitant versus sequential radiochemotherapy in locally advanced non-small-cell lung cancer.
      ], drugs such as gemcitabine are not recommended for routine use with concurrent radiotherapy in standard practice [
      • Vansteenkiste J.
      • De Ruysscher D.
      • Eberhardt W.E.
      • et al.
      ESMO Guidelines Working Group. Early and locally advanced non-small-cell lung cancer (NSCLC): ESMO clinical practice guidelines for diagnosis, treatment and follow-up.
      ,
      • van Putten J.W.
      • Price A.
      • van der Leest A.H.
      • et al.
      A Phase I study of gemcitabine with concurrent radiotherapy in stage III, locally advanced non-small cell lung cancer.
      ,
      • Arrieta O.
      • Gallardo-Rincón D.
      • Villarreal-Garza C.
      • et al.
      High frequency of radiation pneumonitis in patients with locally advanced non-small cell lung cancer treated with concurrent radiotherapy and gemcitabine after induction with gemcitabine and carboplatin.
      ]. At present, no targeted agents have shown proven benefit when combined with radiotherapy, and experience with concurrent radiotherapy and EGFR tyrosine kinase inhibitors and bevacizumab has shown increased toxicity [
      • Koh P.K.
      • Faivre-Finn C.
      • Blackhall F.H.
      • et al.
      Targeted agents in non-small cell lung cancer (NSCLC): clinical developments and rationale for the combination with thoracic radiotherapy.
      ].
      Severe bronchial stenosis and fistula may manifest 2 years or more after the main bronchi have received over 80 Gy, which emphasises the need to limit doses to central structures to 80 Gy, and also to follow patients for more than 2 years in order to observe late side effects [
      • Koh P.K.
      • Faivre-Finn C.
      • Blackhall F.H.
      • et al.
      Targeted agents in non-small cell lung cancer (NSCLC): clinical developments and rationale for the combination with thoracic radiotherapy.
      ]. Late proximal bronchial tree complications have been reported following both hypofractionated RT and SBRT, and safe dose constraints remain to be refined [
      • Miller K.L.
      • Shafman T.D.
      • Anscher M.S.
      • et al.
      Bronchial stenosis: an underreported complication of high-dose external beam radiotherapy for lung cancer?.
      ,
      • Cannon D.M.
      • Mehta M.P.
      • Adkison J.B.
      • et al.
      Dose-limiting toxicity after hypofractionated dose-escalated radiotherapy in non-small-cell lung cancer.
      ,
      • 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.
      ,
      • Tekatli H.
      • Senan S.
      • Dahele M.
      • et al.
      Stereotactic ablative radiotherapy (SABR) for central lung tumors: plan quality and long-term clinical outcomes.
      ,
      • Tekatli H.
      • Haasbeek N.
      • Dahele M.
      • et al.
      Outcomes of hypofractionated high-dose radiotherapy in poor-risk patients with “ultracentral” non-small cell lung cancer.
      ,
      • Adebahr S.
      • Collette S.
      • Shash E.
      • et al.
      LungTech, an EORTC phase II trial of stereotactic body radiotherapy for centrally located lung tumours: a clinical perspective.
      ].
      The incidence of transient grade 3–4 acute oesophagitis is low (<5%) when radiotherapy alone or sequential chemo-radiation is used, but may be as high as 30% with concurrent chemo-radiation [
      • Aupérin A.
      • Le Péchoux C.
      • Rolland E.
      • et al.
      Meta-analysis of concomitant versus sequential radiochemotherapy in locally advanced non-small-cell lung cancer.
      ]. Dosimetric factors predictive of grade 3 or higher toxicity, include the mean oesophageal dose (MED) and V60 [
      • Palma D.A.
      • Senan S.
      • Oberije C.
      • et al.
      Predicting esophagitis after chemoradiation therapy for non-small cell lung cancer: an individual patient data meta-analysis.
      ,
      • De Ruysscher D.
      • Dehing C.
      • Bremer R.H.
      • et al.
      Maximal neutropenia during chemotherapy and radiotherapy is significantly associated with the development of acute radiation-induced dysphagia in lung cancer patients.
      ]. As grade 3 oesophagitis generally heals within 3–6 weeks post-treatment, with late side effects such as strictures occurring in less than 1% of patients, the survival benefits of concurrent chemo-radiation generally outweighs the risk of high-grade acute oesophagitis in good performance status patients. For severe late oesophageal toxicity, the maximum oesophageal dose is predictive, and not the mean dose [
      • Chen C.
      • Uyterlinde W.
      • Sonke J.J.
      • et al.
      Severe late esophagus toxicity in NSCLC patients treated with IMRT and concurrent chemotherapy.
      ].
      Retrospective studies suggest that as long as the maximal dose to the brachial plexus (2 cm3) is kept below 76 Gy, the risk of radiation plexopathy is low [
      • Amini A.
      • Yang J.
      • Williamson R.
      • et al.
      Dose constraints to prevent radiation-induced brachial plexopathy in patients treated for lung cancer.
      ,
      • Eblan M.J.
      • Corradetti M.N.
      • Lukens J.N.
      • et al.
      Brachial plexopathy in apical non-small cell lung cancer treated with definitive radiation: dosimetric analysis and clinical implications.
      ]. In patients treated with SABR, delivery of absolute brachial plexus doses over 26 Gy in three to four fractions, and brachial plexus maximal dose over 35 Gy, and V30 of more than 0.2 cm3, all increased the risk of brachial plexopathy [
      • Forquer J.A.
      • Fakiris A.J.
      • Timmerman R.D.
      • et al.
      Brachial plexopathy from stereotactic body radiotherapy in early-stage NSCLC: dose-limiting toxicity in apical tumor sites.
      ].
      In SBRT, the chest wall, ribs and vertebral bodies have become organs at risk, despite the fact that the majority of patients are asymptomatic or complain of mild toxicity. For chest wall pain, the risk increases when the D70cc is over 16 Gy in 4 fractions, and the D2cc above 43 Gy in 4 fractions [
      • Kimsey F.
      • McKay J.
      • Gefter J.
      • et al.
      Dose-response model for chest wall tolerance of stereotactic body radiation therapy.
      ,
      • Murray L.
      • Karakaya E.
      • Hinsley S.
      • et al.
      Lung stereotactic ablative radiotherapy (SABR): dosimetric considerations for chest wall toxicity.
      ]. The risk of symptomatic rib fractures after SBRT was significantly correlated to dose, and was <5% at 26 months when Dmax < 225 Gy (biological equivalent dose (BED), α/β = 3 Gy) [
      • Taremi M.
      • Hope A.
      • Lindsay P.
      • et al.
      Predictors of radiotherapy induced bone injury (RIBI) after stereotactic lung radiotherapy.
      ,
      • Stam B.
      • van der Bijl E.
      • Peulen H.
      • et al.
      Dose-effect analysis of radiation induced rib fractures after thoracic SBRT.
      ]. However, target coverage should generally not be compromised for chest wall sparing, and more fractionated SBRT regimens should be considered in such cases [
      • Coroller T.P.
      • Mak R.H.
      • Lewis J.H.
      • et al.
      Low incidence of chest wall pain with a risk-adapted lung stereotactic body radiation therapy approach using three or five fractions based on chest wall dosimetry.
      ].
      In locally advanced NSCLC, thoracic vertebral fractures were reported in 8% of patients after a 12 month median follow up time [
      • Rodríguez-Ruiz M.E.
      • San Miguel I.
      • Gil-Bazo I.
      • et al.
      Pathological vertebral fracture after stereotactic body radiation therapy for lung metastases. Case report and literature review.
      ,
      • Uyterlinde W.
      • Chen C.
      • Belderbos J.
      • et al.
      Fractures of thoracic vertebrae in patients with locally advanced non-small cell lung carcinoma treated with intensity modulated radiotherapy.
      ]. Significant dosimetric factors associated with vertebral fractures were the V30 and mean vertebral dose, with doses of 20–30 Gy being associated with bone injury [
      • Uyterlinde W.
      • Chen C.
      • Belderbos J.
      • et al.
      Fractures of thoracic vertebrae in patients with locally advanced non-small cell lung carcinoma treated with intensity modulated radiotherapy.
      ]. Although vertebral SBRT is associated with a risk of vertebral fracture, there is limited data available on the risk of such fracture after lung SBRT [
      • Coroller T.P.
      • Mak R.H.
      • Lewis J.H.
      • et al.
      Low incidence of chest wall pain with a risk-adapted lung stereotactic body radiation therapy approach using three or five fractions based on chest wall dosimetry.
      ].
      Historically, heart toxicity was not considered to be of relevance for most lung cancer patients. However, it has become increasingly clear that radiotherapy-related cardiac events may occur within months after radiotherapy [
      • Wang K.
      • Eblan M.J.
      • Deal A.M.
      • et al.
      Cardiac toxicity after radiotherapy for stage iii non-small-cell lung cancer: pooled analysis of dose-escalation trials delivering 70 to 90 Gy.
      ]. Both dose to the heart and patient’s cardiac risk factors determine the incidence of cardiac events. The mean heart doses associated with cardiac events were <10 Gy, 10–20 Gy, or ≥20 Gy and 4%, 7%, and 21%, respectively. It is unclear which regions of the heart are most susceptible for radiation injury. The contribution of heart doses to mortality has not been consistently demonstrated [
      • Wang K.
      • Eblan M.J.
      • Deal A.M.
      • et al.
      Cardiac toxicity after radiotherapy for stage iii non-small-cell lung cancer: pooled analysis of dose-escalation trials delivering 70 to 90 Gy.
      ,
      • Tucker S.L.
      • Liu A.
      • Gomez D.
      • et al.
      Impact of heart and lung dose on early survival in patients with non-small cell lung cancer treated with chemoradiation.
      ,
      • Guberina M.
      • Eberhardt W.
      • Stuschke M.
      • et al.
      Heart dose exposure as prognostic marker after radiotherapy for resectable stage IIIA/B non-small-cell lung cancer: secondary analysis of a randomised trial.
      ], but it is preferred that heart doses be limited as much as possible.
      The tolerance of the spinal cord, like other organs, is a sliding scale, with estimated risks of myelopathy to the full-thickness cord using conventional fractionation of 1.8–2 Gy/fraction of <1% and <10% at 54 Gy and 61 Gy, respectively, with a strong dependency on the dose per fraction (α/β = 0.87 Gy) [
      • Kirkpatrick J.P.
      • van der Kogel A.J.
      • Schultheiss T.E.
      Radiation dose-volume effects in the spinal cord.
      ,
      • Grimm J.
      • Sahgal A.
      • Soltys S.G.
      • et al.
      Estimated risk level of unified stereotactic body radiation therapy dose tolerance limits for spinal cord.
      ].

      Treatment delivery including imaging and dose guidance during treatment

      Image guidance

      Daily online pre-treatment imaging, and setup corrections to reduce the inter-fractional systematic and random errors, allow for use of a smaller CTV to PTV margin [
      • van Elmpt W.
      • Ollers M.
      • van Herwijnen H.
      • et al.
      Volume or position changes of primary lung tumor during (chemo-)radiotherapy cannot be used as a surrogate for mediastinal lymph node changes: the case for optimal mediastinal lymph node imaging during radiotherapy.
      ,
      • Purdie T.G.
      • Bissonnette J.P.
      • Franks K.
      • et al.
      Cone-beam computed tomography for on-line image guidance of lung stereotactic radiotherapy: localization, verification, and intrafraction tumor position.
      ]. The use of cone beam CT (CBCT) scans has been shown to allow a more accurate setup than portal imaging [
      • Borst G.R.
      • Sonke J.J.
      • Betgen A.
      • et al.
      Kilo-voltage cone-beam computed tomography setup measurements for lung cancer patients; first clinical results and comparison with electronic portal-imaging device.
      ]. For SBRT, 4D-CBCT is preferable over 3D-CBCT [
      • Sweeney R.A.
      • Seubert B.
      • Stark S.
      • et al.
      Accuracy and inter-observer variability of 3D versus 4D cone-beam CT based image-guidance in SBRT for lung tumors.
      ]. The highest accuracy is achieved with soft-tissue match on either anatomical landmarks or primary tumour, compared with bones and this accuracy is reported to translate into smaller margins, lower lung dose and less pneumonitis [
      • McKenzie A.
      • van Herk M.
      • Mijnheer B.
      Margins for geometric uncertainty around organs at risk in radiotherapy.
      ,
      • Stroom J.C.
      • Heijmen B.J.
      Limitations of the planning organ at risk volume (PRV) concept.
      ]. The differential motion of tumour and lymph nodes implies that a setup strategy prioritizing one target will result in greater uncertainty in the position of the others, and margin calculations should reflect this uncertainty. Primary tumours are often visible on a CBCT scan but mediastinal lymph-nodes are more difficult to visualise; their position however can be derived from anatomical landmarks [
      • Schaake E.E.
      • Rossi M.M.G.
      • Buikhuisen W.A.
      • et al.
      Differential motion between mediastinal lymph nodes and primary tumor in radically irradiated lung cancer patients.
      ,
      • Hoffmann L.
      • Holt M.I.
      • Knap M.M.
      • et al.
      Anatomical landmarks accurately determine interfractional lymph node shifts during radiotherapy of lung cancer patients.
      ]. The carina is frequently used as a surrogate for nodal position [
      • Schaake E.E.
      • Rossi M.M.G.
      • Buikhuisen W.A.
      • et al.
      Differential motion between mediastinal lymph nodes and primary tumor in radically irradiated lung cancer patients.
      ,
      • Wolthaus J.W.
      • Sonke J.J.
      • van Herk M.
      • et al.
      Comparison of different strategies to use fourdimensional computed tomography in treatment planning for lung cancer patients.
      ], which is most accurate for node stations 4, 5, 7, while other anatomical landmarks may be more suitable for stations 1, 2, 6, 10, 11 [
      • Hoffmann L.
      • Holt M.I.
      • Knap M.M.
      • et al.
      Anatomical landmarks accurately determine interfractional lymph node shifts during radiotherapy of lung cancer patients.
      ]. Daily image guidance with soft-tissue setup is recommended for all fractionation schemes because of frequent intra thoracic anatomical changes [
      • Wielpütz M.
      • Kauczor H.U.
      MRI of the lung: state of the art.
      ,
      • Vilmann P.
      • Clementsen P.F.
      • Colella S.
      • et al.
      Combined endobronchial and oesophageal endosonography for the diagnosis and staging of lung cancer. European Society of Gastrointestinal Endoscopy (ESGE) guideline, in cooperation with the European Respiratory Society (ERS) and the European Society of Thoracic Surgeons (ESTS).
      ,
      • Sonke J.J.
      • Belderbos J.
      Adaptive radiotherapy for lung cancer.
      ]. In SBRT delivery, image guidance based on tumour setup is mandatory, but tumour baseline shifts which could impact on doses to organs at risk should be evaluated [
      • Grimm J.
      • Sahgal A.
      • Soltys S.G.
      • et al.
      Estimated risk level of unified stereotactic body radiation therapy dose tolerance limits for spinal cord.
      ].

      Adaptive radiotherapy

      Soft-tissue setup combined with corresponding margins ensures target coverage in the majority of patients, but this approach may be insufficient for selected patients with either large differential shifts of tumour and nodes, or anatomical changes occurring during treatment [
      • Wielpütz M.
      • Kauczor H.U.
      MRI of the lung: state of the art.
      ,
      • Vilmann P.
      • Clementsen P.F.
      • Colella S.
      • et al.
      Combined endobronchial and oesophageal endosonography for the diagnosis and staging of lung cancer. European Society of Gastrointestinal Endoscopy (ESGE) guideline, in cooperation with the European Respiratory Society (ERS) and the European Society of Thoracic Surgeons (ESTS).
      ,
      • Sonke J.J.
      • Belderbos J.
      Adaptive radiotherapy for lung cancer.
      ]. In deciding when to adapt treatment plans, it is important to keep in mind that only the inter-fractional changes are observed on the pre-treatment CBCT. Since the CTV to PTV margin includes all planning and delivery uncertainties, maintaining the planned dose is therefore not sufficient to keep the target within the PTV. The use of 3D portal dosimetry for detecting dosimetric consequences of anatomical changes has the potential to automate the evaluation, but this represents work in progress [
      • Galerani A.P.
      • Grills I.
      • Hugo G.
      • et al.
      Dosimetric impact of online correction via cone-beam CT-based image guidance for stereotactic lung radiotherapy.
      ,
      • de Smet M.
      • Schuring D.
      • Nijsten S.
      • et al.
      Accuracy of dose calculations on kV cone beam CT images of lung cancer patients.
      ].

      Developing technologies

      New technologies are likely to change the way lung cancer patients will be treated with radiotherapy, with or without emerging targeted drugs and immune therapy.
      Proton therapy has the potential to limit the radiation dose to organs at risk, especially the low dose volumes, or when maximal advantage can be taken from the Bragg peak and the virtual absence of radiation dose distal to it [
      • Chang J.Y.
      • Jabbour S.K.
      • De Ruysscher D.
      • et al.
      International particle therapy co-operative group thoracic subcommittee. Consensus statement on proton therapy in early-stage and locally advanced non-small cell lung cancer.
      ]. The sensitivity of proton beams for anatomical changes are larger than for photons, and the technical requirements are more challenging.
      The MRI-linac combines regular linear accelerator technology with MRI guidance on the machine [
      • Sanderson B.
      • McWilliam A.
      • Faivre-Finn C.
      • et al.
      Using the Malthus programme to predict the recruitment of patients to MR-linac research trials in prostate and lung cancer.
      ]. This could theoretically result in margin reduction and improved adaptation processes. The first machines are being installed, and no clinical data or randomized trials are yet available.

      Discussion

      As many departments are currently equipped with modern radiotherapy tools discussed in this review, it is increasingly feasible to implement high-precision thoracic radiotherapy and SBRT. However, centres must be familiar with the application of these tools for the treatment of lung cancer. The main aim of this review was to formulate practical recommendations for use in departments wishing to introduce such techniques, and these are summarised in Table 2.
      It should be emphasised that nearly all data have been derived from patients treated for NSCLC.
      As the precision in radiotherapy delivery is rapidly evolving, any conclusion or statement in these recommendations may need to be updated as required. This document will be used within the EORTC for the development of study protocols, and to evaluate the technical capabilities of participating centres.

      Conflict of interest

      None of the authors have a conflict of interest to declare.

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