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Intensity-Modulated Radiotherapy for Lung Cancer: Current Status and Future Developments

      Radiotherapy plays an important role in the management of lung cancer, with over 50% of patients receiving this modality at some point during their treatment. Intensity-modulated radiotherapy (IMRT) is a technique that adds fluence modulation to beam shaping, which improves radiotherapy dose conformity around the tumor and spares surrounding normal structures. Treatment with IMRT is becoming more widely available for the treatment of lung cancer, despite the paucity of high level evidence supporting the routine use of this more resource intense and complex technique. In this review article, we have summarized data from planning and clinical studies, discussed challenges in implementing IMRT, and made recommendations on the minimum requirements for safe delivery of IMRT.

      Key Words

      Radiotherapy plays an important role in the management of lung cancer, with over 50% of all lung cancer patients receiving this modality at some point during their treatment. In the radical setting, the ultimate aim of radiotherapy is to achieve local tumor control while limiting damage to the surrounding normal tissue. The impact of local control in non–small-cell lung cancer (NSCLC) has been highlighted by studies demonstrating that it correlates to a survival benefit.
      • Aupérin A
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      • et al.
      Meta-analysis of concomitant versus sequential radiochemotherapy in locally advanced non-small-cell lung cancer.
      ,
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      • Paulus R
      • Moughan J
      • et al.
      Defining local-regional control and its importance in locally advanced non-small cell lung carcinoma.
      In the 1980s, the advent of computed tomography (CT) and the multileaf collimator (MLC) enabled radiation oncologists to shape fields around a target volume with three-dimensional conformal radiotherapy (3DCRT) and this remains the standard procedure in lung radiotherapy.
      • 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.
      However, despite advances in planning and verification, local progression-free survival and overall survival (OS) rates in locally advanced NSCLC remain low (30% and 10–15% at 5 years, respectively).
      • Aupérin A
      • Le Péchoux C
      • Rolland E
      • et al.
      Meta-analysis of concomitant versus sequential radiochemotherapy in locally advanced non-small-cell lung cancer.
      ,
      • Machtay M
      • Paulus R
      • Moughan J
      • et al.
      Defining local-regional control and its importance in locally advanced non-small cell lung carcinoma.
      ,
      • Le Chevalier T
      • Arriagada R
      • Quoix E
      • et al.
      Radiotherapy alone versus combined chemotherapy and radiotherapy in nonresectable non-small-cell lung cancer: first analysis of a randomized trial in 353 patients.
      Currently, the standard dose/fractionation for patients with stage III NSCLC is 60 Gy equivalent dose in 2 Gy/fraction (EQD2). One potential reason for low progression-free survival and OS rates in this group may be that this radiotherapy dose is perhaps too low to achieve local control. Martel et al.
      • Martel MK
      • Ten Haken RK
      • Hazuka MB
      • et al.
      Estimation of tumor control probability model parameters from 3-D dose distributions of non-small cell lung cancer patients.
      estimated that doses of 84 Gy in EQD2 are required for 50% probability of tumor control at 3 years, and biologically effective doses in excess of 100 Gy were needed to achieve greater than 90% local control in stereotactic ablative radiotherapy (SABR) studies.
      • Palma D
      • Senan S
      Stereotactic radiation therapy: changing treatment paradigms for stage I nonsmall cell lung cancer.
      These data suggest that higher biologically effective doses may be required to achieve better local control, but evidence to support dose escalation using conventional fractionation is lacking in the current literature.
      • Bradley JD
      • Paulus R
      • Komaki R
      • Masters GA
      • et al.
      A randomized phase III comparison of standard-dose (60 Gy) versus high-dose (74 Gy) conformal chemoradiotherapy with or without cetuximab for stage III non-small cell lung cancer: Results on radiation dose in RTOG 0617.
      Despite this, many still believe that dose escalation in NSCLC could be of benefit, if facilitated by an improvement in radiotherapy-delivery techniques.
      Intensity-modulated radiotherapy (IMRT) is an advanced form of 3DCRT that modifies the intensity of the radiation across each beam in complex ways, sculpting the high-dose volume around the site of disease and thereby sparing adjacent organs at risk. The superior dose conformity that can be achieved allows avoidance of the surrounding normal tissues.
      • Bree Id
      • van Hinsberg MG
      • van Veelen LR
      High-dose radiotherapy in inoperable nonsmall cell lung cancer: comparison of volumetric modulated arc therapy, dynamic IMRT and 3D conformal radiotherapy.
      • Cattaneo GM
      • Dell'oca I
      • Broggi S
      • et al.
      Treatment planning comparison between conformal radiotherapy and helical tomotherapy in the case of locally advanced-stage NSCLC.
      • Chan OS
      • Lee MC
      • Hung AW
      • Chang AT
      • Yeung RM
      • Lee AW
      The superiority of hybrid-volumetric arc therapy (VMAT) technique over double arcs VMAT and 3D-conformal technique in the treatment of locally advanced non-small cell lung cancer–a planning study.
      • Liu HH
      • Wang X
      • Dong L
      • et al.
      Feasibility of sparing lung and other thoracic structures with intensity-modulated radiotherapy for non-small-cell lung cancer.
      • 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.
      • Ong CL
      • Verbakel WF
      • Cuijpers JP
      • Slotman BJ
      • Lagerwaard FJ
      • Senan S
      Stereotactic radiotherapy for peripheral lung tumors: a comparison of volumetric modulated arc therapy with 3 other delivery techniques.
      • Simeonova A
      • Abo-Madyan Y
      • El-Haddad M
      • et al.
      Comparison of anisotropic aperture based intensity modulated radiotherapy with 3D-conformal radiotherapy for the treatment of large lung tumors.
      This technique allows the treatment of radiotherapy volumes previously considered too large for a radical dose and permits safer dose escalation to the tumor (potentially improving local control).
      IMRT is currently being used routinely for the treatment of both early stage and locally advanced NSCLC in many international academic centers. However, there are no published randomized trials comparing 3DCRT to IMRT in NSCLC
      • Bezjak A
      • Rumble RB
      • Rodrigues G
      • Hope A
      • Warde P
      Members of the IMRT Indications Expert Panel. . Intensity-modulated radiotherapy in the treatment of lung cancer.
      and such studies are unlikely to be forthcoming. In the wider community, uptake of IMRT for lung cancer has been slow, which may in part be due to the relative lack of evidence in this field compared to head and neck and prostate cancer.
      • Lee NY
      • de Arruda FF
      • Puri DR
      • et al.
      A comparison of intensity-modulated radiation therapy and concomitant boost radiotherapy in the setting of concurrent chemotherapy for locally advanced oropharyngeal carcinoma.
      • Lee SW
      • Back GM
      • Yi BY
      • et al.
      Preliminary results of a phase I/II study of simultaneous modulated accelerated radiotherapy for nondisseminated nasopharyngeal carcinoma.
      • Nutting CM
      • Morden JP
      • Harrington KJ
      • PARSPORT Trial Management Group
      • et al.
      Parotid-sparing intensity modulated versus conventional radiotherapy in head and neck cancer (PARSPORT): a phase 3 multicentre randomised controlled trial.
      • Sharma NK
      • Li T
      • Chen DY
      • Pollack A
      • Horwitz EM
      • Buyyounouski MK
      Intensity-modulated radiotherapy reduces gastrointestinal toxicity in patients treated with androgen deprivation therapy for prostate cancer.
      Routine use of this technology also impacts on planning and treatment delivery times, and creates a need for equipment capable of facilitating image-guided treatment. Other considerations include how the “low-dose bath” created by the increased number of beam angles affect acute and late toxicity to the lung
      • Allen AM
      • Czerminska M
      • Jänne PA
      • et al.
      Fatal pneumonitis associated with intensity-modulated radiation therapy for mesothelioma.
      and second malignancy risk,
      • Hall EJ
      Intensity-modulated radiation therapy, protons, and the risk of second cancers.
      and whether improved conformality to the target volume may in fact under-treat micrometastatic disease and lymph node stations previously incidentally treated to a therapeutic dose with 3DCRT.
      • Kepka L
      • Maciejewski B
      • Withers RH
      Does incidental irradiation with doses below 50 gy effectively reduce isolated nodal failures in non-small-cell lung cancer: dose–response relationship.
      In this article, we aim to give an overview of the rationale for IMRT in lung cancer, to present current evidence supporting the use of this technique and finally to highlight future directions.

      MATERIALS AND METHODS

      This article is a review of the literature rather than a systematic review.
      PubMed (1950–2014), EMBASE (1974–2014), and the Cochrane library were searched for phase I–III clinical trials, case-series studies, cohort studies, meta-analysis, and reviews in the English language using the following keywords: lung cancer, NSCLC, radiotherapy, radiation therapy, IMRT, and dose escalation.
      Out of initial 118 articles identified by the search terms, 46 were deemed eligible after screening by title and abstract review. In addition, relevant publications and conference abstracts known to the authors were also included.

      What is IMRT?

      IMRT adds fluence modulation to beam shaping,
      • Intensity Modulated Radiation Therapy Collaborative Working Group
      Intensity-modulated radiotherapy: current status and issues of interest.
      • Sternick E
      • Bortfeld T
      • Bürkelbach J
      • Boesecke R
      • Schlegel W
      Methods of image reconstruction from projections applied to conformation radiotherapy.
      which improves dose conformity around the tumor and spares surrounding normal structures.
      • Intensity Modulated Radiation Therapy Collaborative Working Group
      Intensity-modulated radiotherapy: current status and issues of interest.
      ,
      • Pirzkall A
      • Carol M
      • Lohr F
      • Höss A
      • Wannenmacher M
      • Debus J
      Comparison of intensity-modulated radiotherapy with conventional conformal radiotherapy for complex-shaped tumors.
      There are two main approaches to static IMRT and both deliver radiation from a number of fixed gantry angles and achieve fluence modulation with different MLC arrangements. In its simplest form each IMRT field is segmented into a number of shaped subfields (step and shoot approach). More complex sliding window techniques move the MLCs during “beam on” time. A further development is rotational IMRT or so-called volumetric-modulated arc therapy (VMAT), whereby the linear accelerator rotates around the patient, continually delivering radiation. As the MLCs change during this rotation, hundreds of fields are generated to create a more conformal dose distribution.
      • Otto K
      Volumetric modulated arc therapy: IMRT in a single gantry arc.
      Tomotherapy represents another IMRT delivery technique,
      • Mackie TR
      • Holmes T
      • Swerdloff S
      • et al.
      Tomotherapy: a new concept for the delivery of dynamic conformal radiotherapy.
      where dose is delivered using a technology similar to CT (slice-by-slice of helical dose delivery) combined with a binary MLC for fluency modulation.
      3DCRT planning typically involves trialing different combinations of beam shapes, weights, and gantry angles until a satisfactory dose distribution is achieved (forward planning). This method is impractical for IMRT, due to the large numbers of fields requiring several MLC arrangements. Therefore, IMRT planning utilizes computerized inverse planning, whereby the desired dose distribution is described by a series of instructions to a computer system, which then uses a cost function to optimize beam shapes, beam fluences, and beam weights to achieve the desired outcome. Advantages and disadvantages of using IMRT for lung cancer are presented in Table 1.
      Table 1Advantages and Disadvantages of IMRT for Lung Cancer
       AdvantagesDisadvantages
       Ability to spare organs at riskIncreased contouring, planning, and quality assurance time
       Better coverage of irregular shaped targetsIncreased need to accurately delineate clinical target volumes and involved nodes requiring treatment
       Ability to dose escalateNeed for image guidance
       Able to treat synchronous primary tumors and multiple targets simultaneouslySharp dose gradient—may lead to under-treatment of micrometastatic disease
       Enables treatment of larger radiotherapy volumes to radical dosePotential interplay effects depending on fractionation and complexity of IMRT technique used
      Need for rigorous quality assurance programme Low-dose radiotherapy bath
      IMRT, intensity-modulated radiotherapy.

      Dose Distributions with IMRT Compared to Conventional 3DCRT

      A number of planning studies comparing dosimetric plan quality of 3DCRT and different IMRT techniques have been published in the field of lung cancer. These are summarized in Table 2. All authors except McGrath et al.
      • McGrath SD
      • Matuszak MM
      • Yan D
      • Kestin LL
      • Martinez AA
      • Grills IS
      Volumetric modulated arc therapy for delivery of hypofractionated stereotactic lung radiotherapy: A dosimetric and treatment efficiency analysis.
      demonstrate improved planning target volume (PTV) coverage with IMRT.
      • Bree Id
      • van Hinsberg MG
      • van Veelen LR
      High-dose radiotherapy in inoperable nonsmall cell lung cancer: comparison of volumetric modulated arc therapy, dynamic IMRT and 3D conformal radiotherapy.
      • Cattaneo GM
      • Dell'oca I
      • Broggi S
      • et al.
      Treatment planning comparison between conformal radiotherapy and helical tomotherapy in the case of locally advanced-stage NSCLC.
      • Chan OS
      • Lee MC
      • Hung AW
      • Chang AT
      • Yeung RM
      • Lee AW
      The superiority of hybrid-volumetric arc therapy (VMAT) technique over double arcs VMAT and 3D-conformal technique in the treatment of locally advanced non-small cell lung cancer–a planning study.
      • Liu HH
      • Wang X
      • Dong L
      • et al.
      Feasibility of sparing lung and other thoracic structures with intensity-modulated radiotherapy for non-small-cell lung cancer.
      • 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.
      • Ong CL
      • Verbakel WF
      • Cuijpers JP
      • Slotman BJ
      • Lagerwaard FJ
      • Senan S
      Stereotactic radiotherapy for peripheral lung tumors: a comparison of volumetric modulated arc therapy with 3 other delivery techniques.
      • Simeonova A
      • Abo-Madyan Y
      • El-Haddad M
      • et al.
      Comparison of anisotropic aperture based intensity modulated radiotherapy with 3D-conformal radiotherapy for the treatment of large lung tumors.
      ,
      • Christian JA
      • Bedford JL
      • Webb S
      • Brada M
      Comparison of inverse-planned three-dimensional conformal radiotherapy and intensity-modulated radiotherapy for non-small-cell lung cancer.
      ,31 Conversely, the literature reports mixed results with regards to doses to organs at risk. In general, IMRT reduces the volume of whole lung receiving more than 20 Gy (V20),
      • Cattaneo GM
      • Dell'oca I
      • Broggi S
      • et al.
      Treatment planning comparison between conformal radiotherapy and helical tomotherapy in the case of locally advanced-stage NSCLC.
      • Chan OS
      • Lee MC
      • Hung AW
      • Chang AT
      • Yeung RM
      • Lee AW
      The superiority of hybrid-volumetric arc therapy (VMAT) technique over double arcs VMAT and 3D-conformal technique in the treatment of locally advanced non-small cell lung cancer–a planning study.
      • Liu HH
      • Wang X
      • Dong L
      • et al.
      Feasibility of sparing lung and other thoracic structures with intensity-modulated radiotherapy for non-small-cell lung cancer.
      • 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.
      ,
      • McGrath SD
      • Matuszak MM
      • Yan D
      • Kestin LL
      • Martinez AA
      • Grills IS
      Volumetric modulated arc therapy for delivery of hypofractionated stereotactic lung radiotherapy: A dosimetric and treatment efficiency analysis.
      –31 but the effect of IMRT on lower doses to the lung are not as clear; two groups report a reduction of V5
      • McGrath SD
      • Matuszak MM
      • Yan D
      • Kestin LL
      • Martinez AA
      • Grills IS
      Volumetric modulated arc therapy for delivery of hypofractionated stereotactic lung radiotherapy: A dosimetric and treatment efficiency analysis.
      ,
      • Zhang GG
      • Ku L
      • Dilling TJ
      • et al.
      Volumetric modulated arc planning for lung stereotactic body radiotherapy using conventional and unflattened photon beams: a dosimetric comparison with 3D technique.
      , while another three groups report an increase.
      • Bree Id
      • van Hinsberg MG
      • van Veelen LR
      High-dose radiotherapy in inoperable nonsmall cell lung cancer: comparison of volumetric modulated arc therapy, dynamic IMRT and 3D conformal radiotherapy.
      ,
      • Chan OS
      • Lee MC
      • Hung AW
      • Chang AT
      • Yeung RM
      • Lee AW
      The superiority of hybrid-volumetric arc therapy (VMAT) technique over double arcs VMAT and 3D-conformal technique in the treatment of locally advanced non-small cell lung cancer–a planning study.
      ,
      • Liu HH
      • Wang X
      • Dong L
      • et al.
      Feasibility of sparing lung and other thoracic structures with intensity-modulated radiotherapy for non-small-cell lung cancer.
      Of the groups who investigated the dose to the heart, four demonstrated an advantage with IMRT
      • Bree Id
      • van Hinsberg MG
      • van Veelen LR
      High-dose radiotherapy in inoperable nonsmall cell lung cancer: comparison of volumetric modulated arc therapy, dynamic IMRT and 3D conformal radiotherapy.
      • Cattaneo GM
      • Dell'oca I
      • Broggi S
      • et al.
      Treatment planning comparison between conformal radiotherapy and helical tomotherapy in the case of locally advanced-stage NSCLC.
      • Chan OS
      • Lee MC
      • Hung AW
      • Chang AT
      • Yeung RM
      • Lee AW
      The superiority of hybrid-volumetric arc therapy (VMAT) technique over double arcs VMAT and 3D-conformal technique in the treatment of locally advanced non-small cell lung cancer–a planning study.
      ,
      • 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.
      and two did not find any benefit. When spinal cord dose was examined, five out of six groups found a significant advantage with IMRT.
      • Bree Id
      • van Hinsberg MG
      • van Veelen LR
      High-dose radiotherapy in inoperable nonsmall cell lung cancer: comparison of volumetric modulated arc therapy, dynamic IMRT and 3D conformal radiotherapy.
      ,
      • Chan OS
      • Lee MC
      • Hung AW
      • Chang AT
      • Yeung RM
      • Lee AW
      The superiority of hybrid-volumetric arc therapy (VMAT) technique over double arcs VMAT and 3D-conformal technique in the treatment of locally advanced non-small cell lung cancer–a planning study.
      ,
      • Ong CL
      • Verbakel WF
      • Cuijpers JP
      • Slotman BJ
      • Lagerwaard FJ
      • Senan S
      Stereotactic radiotherapy for peripheral lung tumors: a comparison of volumetric modulated arc therapy with 3 other delivery techniques.
      ,
      • Simeonova A
      • Abo-Madyan Y
      • El-Haddad M
      • et al.
      Comparison of anisotropic aperture based intensity modulated radiotherapy with 3D-conformal radiotherapy for the treatment of large lung tumors.
      ,
      • Christian JA
      • Bedford JL
      • Webb S
      • Brada M
      Comparison of inverse-planned three-dimensional conformal radiotherapy and intensity-modulated radiotherapy for non-small-cell lung cancer.
      Table 2Planning Studies Comparing IMRT to 3DCRT
       PublicationNo. PatientsDiagnosesPTV Size (ccm)Prescription3DCRT TechniqueIMRT TechniquePTVBoth LungsContralateral LungIpsilateral LungHeartSpinal Cord
      13Stage III NSCLC394 (215–745)34–39×1.8 Gy3–5 fieldsTomotherapy, 2.5 cm jaw width, modulation factor <3IMRT (V95%)IMRT (mean, V15, V20, V30, V40)IMRT (mean, V45, V50, V60)NS
       Chan, 2011
      • Chan OS
      • Lee MC
      • Hung AW
      • Chang AT
      • Yeung RM
      • Lee AW
      The superiority of hybrid-volumetric arc therapy (VMAT) technique over double arcs VMAT and 3D-conformal technique in the treatment of locally advanced non-small cell lung cancer–a planning study.
      24Stage III NSCLC–30×2 Gy5–7 coplanar fieldsVMAT: 2 204° arcs. Hybrid-VMAT: 2 204° arcs and 2 static fieldsIMRT (CI, (D5%–D95%))IMRT (mean, V20, V10)3DCRT (V5)IMRT (V40)
      • IMRT
      • (max)
      10Stages IB–IIB NSCLC197 (103–272)32 × 2 Gy6 noncoplanar fields3–9 coplanar fields6 noncoplanar fieldsIMRT (PTV90/V20lung)IMRT (PTV90/V20lung)
      • IMRT
      • (max)
       De Bree, 2012
      • Bree Id
      • van Hinsberg MG
      • van Veelen LR
      High-dose radiotherapy in inoperable nonsmall cell lung cancer: comparison of volumetric modulated arc therapy, dynamic IMRT and 3D conformal radiotherapy.
      20Inoperable NSCLC838 (407–1574)30–33×2 Gy5 fieldsVMAT, 2 arcsStatic field IMRT, 7 coplanar fieldsIMRT (CI)
      • IMRT
      • (mean)3DCRT (V5, V20)
      IMRT (V40)
      • IMRT
      • (max)
      10Stages I–IIIB NSCLC403 (65–762)35×1.8 Gy4 fields: AP/PA fields and oblique off-cord fieldsSW-IMRT plans, 3–9 coplanar fieldsIMRT (CI)IMRT (V20, V30, mean)3DCRT (V5)
      • McGrath,
      • 2010
        • McGrath SD
        • Matuszak MM
        • Yan D
        • Kestin LL
        • Martinez AA
        • Grills IS
        Volumetric modulated arc therapy for delivery of hypofractionated stereotactic lung radiotherapy: A dosimetric and treatment efficiency analysis.
      21Stage IA NSCLC57 (22–125)4×12 Gy
      • 7–10
      • nonopposing
      • noncoplanar
      • fields
      1 partial arc of 180°NS
      • IMRT (20 Gy, 12.5
      • Gy, 10 Gy, 5 Gy)
      NSNS
      41Advanced stage NSCLC—9 equidistant coplanar 6 MV fieldsSW-IMRT, 9 equidistant, coplanar fieldsIMRT (CI), 3DCRT (HI)IMRT (V10, V20)NSNSIMRT (V40)3D (max)
      18Stage INSCLC34 (3–67)8×7.5 Gy −3 × 18 Gy10 noncoplanar fieldsVMAT, 2 arcsIMRT (CI)3DCRT (V20)3DCRT (V5)
      • IMRT
      • (max)
      20Stages I–IV NSCLC515 (CTV)–3–6 18 MV fields13 coplanar fields 17 noncoplanarIMRT (min)
      • IMRT
      • (mean, D30%)
      • IMRT
      • (D30%, V20)
      NS
      • IMRT
      • (max)
       Zhang, 2011
      • Zhang GG
      • Ku L
      • Dilling TJ
      • et al.
      Volumetric modulated arc planning for lung stereotactic body radiotherapy using conventional and unflattened photon beams: a dosimetric comparison with 3D technique.
      15Early stage LC6 (17–161)5×10 Gy
      • 9–11
      • noncoplanar
      • fields
      Coplanar VMAT Noncoplanar VMATFFF VMATIMRT (CI, GI)IMRT (mean, V5, V20)
      3DCRT, three-dimensional conformal radiotherapy; IMRT, intensity-modulated radiotherapy; PTV, planning target volume; VMAT, volumetric modulated arc therapy; CI, conformity index; GI, gradient index; HI, homogeneity index; Vx, volume receiving x Gy; max, maximum dose; Dx%, dose to x% of the organ; –, no information in the publication; NS, no significant difference.
      Table 3 compares different IMRT planning techniques. Apart from treatment time, there is no clear benefit for one technique above the others. All groups comparing standard IMRT techniques with VMAT found a treatment time advantage in favor of VMAT.
      • Chan OS
      • Lee MC
      • Hung AW
      • Chang AT
      • Yeung RM
      • Lee AW
      The superiority of hybrid-volumetric arc therapy (VMAT) technique over double arcs VMAT and 3D-conformal technique in the treatment of locally advanced non-small cell lung cancer–a planning study.
      ,
      • Simeonova A
      • Abo-Madyan Y
      • El-Haddad M
      • et al.
      Comparison of anisotropic aperture based intensity modulated radiotherapy with 3D-conformal radiotherapy for the treatment of large lung tumors.
      ,
      • Bertelsen A
      • Hansen O
      • Brink C
      Does VMAT for treatment of NSCLC patients increase the risk of pneumonitis compared to IMRT ? - a planning study.
      • Holt A
      • van Vliet-Vroegindeweij C
      • Mans A
      • Belderbos JS
      • Damen EM
      Volumetric-modulated arc therapy for stereotactic body radiotherapy of lung tumors: a comparison with intensity-modulated radiotherapy techniques.
      • 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.
      • Weyh A
      • Konski A
      • Nalichowski A
      • Maier J
      • Lack D
      Lung SBRT: dosimetric and delivery comparison of RapidArc, TomoTherapy, and IMR.
      For example, Ong et al.
      • Ong CL
      • Verbakel WF
      • Cuijpers JP
      • Slotman BJ
      • Lagerwaard FJ
      • Senan S
      Stereotactic radiotherapy for peripheral lung tumors: a comparison of volumetric modulated arc therapy with 3 other delivery techniques.
      showed an 8-minute time reduction if VMAT was used compared to IMRT. Weyh et al.
      • Weyh A
      • Konski A
      • Nalichowski A
      • Maier J
      • Lack D
      Lung SBRT: dosimetric and delivery comparison of RapidArc, TomoTherapy, and IMR.
      compared tomotherapy, IMRT, and VMAT and reported a significant treatment time benefit using VMAT (6.5 minutes) compared to the other two techniques (IMRT: 11.1 minutes, tomotherapy: 15.9 minutes). The clinical relevance of this, especially for SABR patients, is that treatment slots can be reduced from 30–40 minutes to significantly shorter times.
      • Boda-Heggemann J
      • Mai S
      • Fleckenstein J
      • et al.
      Flattening-filter-free intensity modulated breath-hold image-guided SABR (Stereotactic ABlative Radiotherapy) can be applied in a 15-min treatment slot.
      ,
      • Verbakel WF
      • Senan S
      • Cuijpers JP
      • Slotman BJ
      • Lagerwaard FJ
      Rapid delivery of stereotactic radiotherapy for peripheral lung tumors using volumetric intensity-modulated arcs.
      This shorter treatment time reduces the risk of intrafractional movement and maximizes on linear accelerator capacity.
      Table 3Planning Studies Comparing Different Types of IMRT Technique
       PublicationNo. PatientsDiagnosisPTV Size (ccm)PrescriptionIMRT TechniquePTVBoth LungsContralateral LungIpsilateral LungHeartSpinal CordTreatment Time
      • Bertelsen,
      • 2012
        • Bertelsen A
        • Hansen O
        • Brink C
        Does VMAT for treatment of NSCLC patients increase the risk of pneumonitis compared to IMRT ? - a planning study.
      15NSCLC252 (77–509) 33 × 2GySS-IMRT 7–9 fields Single arc VMATNSVMAT (V20)VMAT
       Chan, 2011
      • Chan OS
      • Lee MC
      • Hung AW
      • Chang AT
      • Yeung RM
      • Lee AW
      The superiority of hybrid-volumetric arc therapy (VMAT) technique over double arcs VMAT and 3D-conformal technique in the treatment of locally advanced non-small cell lung cancer–a planning study.
      24
      • Stage III
      • NSCLC-30×2 Gy
      VMAT: 2 204° arcs. Hybrid-VMAT: 2 204° arcs and 2 static fieldsHybrid-VMAT (D5%–D95%)Hybrid-VMAT (mean, V20, V10, V5)
      • VMAT
      • (V40)
      NSVMAT
      • Holt,
      • 2011
        • Holt A
        • van Vliet-Vroegindeweij C
        • Mans A
        • Belderbos JS
        • Damen EM
        Volumetric-modulated arc therapy for stereotactic body radiotherapy of lung tumors: a comparison with intensity-modulated radiotherapy techniques.
      27Early-stage LC45 (14–102)3×18GyNoncoplanar IMRT (NC-IMRT) Coplanar VMATNC-IMRTVMAT & NC-IMRT (mean, V5, V20)
      • VMAT
      • (max)
      • NCP-IMRT
      • (max)
      VMAT
      • Jiang,
      • 2011
        • 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.
      12Locally advanced NSCLC34×2GySS-IMRT: 5–7 beams VMAT (1 full arc) P-VMAT (200° partial arc)VMAT (CI, HI)IMRT (V5, V10)VMAT & P-VMAT(V30, V20, mean)IMRT (V5, V10) P-VMAT (V30, V20, mean)NSNSNSP-VMAT
      9Stage I NSCLC34 (3–67)8×7.5G −3 × 18GyVMAT, 2 arcs 9–10 coplanar FF-IMRT fieldsVMAT (CI)NSNSVMAT
      20Stages I–IV NSCLC515 (CTV)-13 coplanar FF-IMRT fields 17 noncoplanar FF IMRT fieldsNS17F-IMRT (mean, D30%)NSNSNS13F-IMRT
      • Weyh,
      • 2012
        • Weyh A
        • Konski A
        • Nalichowski A
        • Maier J
        • Lack D
        Lung SBRT: dosimetric and delivery comparison of RapidArc, TomoTherapy, and IMR.
      8Stages I + II NSCLC–4 × 12 GyHelical tomotherapy (HT)FF-IMRT VMATHT (CI)NSNSNSVMAT
       Zhang, 2011
      • Zhang GG
      • Ku L
      • Dilling TJ
      • et al.
      Volumetric modulated arc planning for lung stereotactic body radiotherapy using conventional and unflattened photon beams: a dosimetric comparison with 3D technique.
      15Early stage LC6 (17–161)5×10 GyCoplanar VMAT Noncoplanar VMATFFF VMATFFF VMAT (mean target dose)NS
      IMRT, intensity-modulated radiotherapy; PTV, planning target volume; CI, conformity index; GI, gradient index; HI, homogeneity index; Vx: volume receiving x Gy; max, maximum dose; Dx%, dose to x% of the organ; VMAT, volumetric modulated arc therapy; SS_IMRT, step and shoot IMRT; FFF, flattening filter free; –, no information in the publication; NS, no significant difference

      Clinical Studies

      Early-stage NSCLC

      In 2010, Videtic et al.
      • Videtic GM
      • Stephans K
      • Reddy C
      • et al.
      Intensity-modulated radiotherapy-based stereotactic body radiotherapy for medically inoperable early-stage lung cancer: excellent local control.
      published clinical outcome data of medically inoperable stage I NSCLC patients treated with IMRT-based SABR. In this case series, 26 patients received 50 Gy in 10 fractions, delivered with seven nonopposing, noncoplanar-intensity modulated beams. The median heterogeneity index was 1.08 (range, 1.04–1.2). Seventy-one patients had histological confirmation and 89% of tumors were in a peripheral location (median size 2.2 cm). The treatment was well tolerated, with only one patient (who was on oxygen before commencement of treatment) experiencing grade 3 dyspnoea. Overall, there was no significant change in pulmonary function tests post-treatment and no treatment-related deaths. Three-year local control was comparable to surgical series and 3DCRT-based SABR series at 94.4%, and 3-year OS was 52%.
      Looking further into toxicity of IMRT for stage I NSCLC, Palma et al.
      • Palma DA
      • Senan S
      • Haasbeek CJ
      • Verbakel WF
      • Vincent A
      • Lagerwaard F
      Radiological and clinical pneumonitis after stereotactic lung radiotherapy: a matched analysis of three-dimensional conformal and volumetric-modulated arc therapy techniques.
      compared radiological and clinical patterns of treatment-related pneumonitis (TRP) in patients who received SABR delivered either with VMAT (a rotational form of IMRT using up to 5 arcs) or 3DCRT (8–12 noncoplanar static beams). Seventy-five patients (25 VMAT, 50 3DCRT) were included in the study. Patients between the two arms were matched demographically, for dose, fractionation, PTV size (<100 cc), and tumor location. Interestingly, although 57% patients developed radiological changes in the lung, only 5% developed clinical symptoms. The toxicity profile is similar to that of 3DCRT-based SABR. There was no statistically significant difference between the groups in terms of the rate of clinical TRP.
      Ong et al.
      • Ong CL
      • Verbakel WF
      • Cuijpers JP
      • Slotman BJ
      • Lagerwaard FJ
      • Senan S
      Stereotactic radiotherapy for peripheral lung tumors: a comparison of volumetric modulated arc therapy with 3 other delivery techniques.
      compared VMAT, IMRT, 3DCRT, and dynamic conformal arc techniques for SABR of stage I NSCLC. Although all met the normal tissue dose constraints, IMRT was useful in further shaping the beam around critical organs at risk e.g., chest wall and VMAT had an advantage over other techniques in terms of dose conformity and treatment time. A further paper by the same group reported on a retrospective series of 18 patients with large volume (median PTV 137 cm3), stages I–II lung tumors without nodal metastases treated with VMAT.
      • Ong CL
      • Palma D
      • Verbakel WF
      • Slotman BJ
      • Senan S
      Treatment of large stage I-II lung tumors using stereotactic body radiotherapy (SBRT): planning considerations and early toxicity.
      A risk-adapted fractionation scheme of either five fractions of 11 Gy or eight fractions of 7.5 Gy was used with the following planning objectives: 95% of the PTV should receive at least the nominal fraction dose, 99% of the target volume should receive greater than or equal to 90% of the prescription dose, and the maximum PTV dose was between 110% and 140% of the prescription dose. Five patients developed grade of greater than or equal to 2 radiation pneumonitis (three with grade 2 and two with grade 3), all cases occurred in plans without a high priority optimization objective on contralateral lung. They demonstrated that acute TRP was best predicted by contralateral lung V5 (p < 0.0001).

      Locally advanced NSCLC

      Prospective studies

      A potential advantage of IMRT over 3DCRT is the ability to safely escalate radiotherapy dose. One of the first studies to address this issue was a phase I dose escalation study (84 Gy/35 fractions) of IMRT in stage III NSCLC and induction chemotherapy.
      • Holloway CL
      • Robinson D
      • Murray B
      • et al.
      Results of a phase I study to dose escalate using intensity modulated radiotherapy guided by combined PET/CT imaging with induction chemotherapy for patients with non-small cell lung cancer.
      This study was halted after the enrolment of five patients as one patient died of pneumonitis. This may have been due to an adverse effect of chemotherapy on baseline lung function or the hypofractionated dose regime; however, this study has been criticized for using an inadequate dose calculation algorithm, leading to systematic underestimation of doses to the tumor and organs at risk.
      • De Neve W
      • De Wagter C
      Lethal pneumonitis in a phase I study of chemotherapy and IMRT for NSCLC: the need to investigate the accuracy of dose computation.
      It was widely anticipated that RTOG 0617, a prospective, randomized phase III trial comparing 60 Gy/30 daily fractions with 74 Gy/37 daily fractions (concurrently with paclitaxel/carboplatin), with or without cetuximab would be the first phase III trial to confirm the benefit of dose escalation beyond 60 Gy in stage III NSCLC.
      • Bradley JD
      • Paulus R
      • Komaki R
      • Masters GA
      • et al.
      A randomized phase III comparison of standard-dose (60 Gy) versus high-dose (74 Gy) conformal chemoradiotherapy with or without cetuximab for stage III non-small cell lung cancer: Results on radiation dose in RTOG 0617.
      Surprisingly, at interim analysis the data suggested a survival disadvantage for the high-dose arm as well as inferior local control rates, indicating that dose escalation using conventional fractionation (resulting in increased overall treatment time) is not the ideal approach for NSCLC. The reasons for this are the subject of some debate, but possible explanations include: increased heart dose, extended therapy duration, underreported grade 5 events, compromised target coverage, or likely a combination of these factors. It should be noted that just under half of the patients in this study were treated with IMRT (46.5%). Although patients were stratified by treatment delivery technique and the proportions of patients treated with IMRT were balanced between treatment groups (46.1% in 60 Gy arms and 47.1% in 74 Gy arms), the delivery of 74 Gy was probably challenging, particularly in patients treated without IMRT, given the gross tumor volume (GTV) (mean 124.7 in 60 Gy arms and 128.5 cc in 74 Gy arms). A subsequent analysis on patient reported outcome demonstrated a significantly worse quality of life on the 74 Gy arms at 3 months after treatment.
      • Movsas HCB
      • Sloan J
      • Bradley JD
      • et al.
      Quality of Life (QOL) Analysis of the Randomized Radiation (RT) Dose-Escalation NSCLC Trial (RTOG 0617): The Rest of the Story.
      Interestingly, the decline in quality of life was significantly reduced with the use of IMRT compared to 3DCRT suggesting that the use of improved radiotherapy treatment techniques may be beneficial.
      More recently, results of a phase I trial of hypofractionated, dose escalating IMRT in NSCLC were published.
      • Cannon DM
      • Mehta MP
      • Adkison JB
      • et al.
      Dose-limiting toxicity after hypofractionated dose-escalated radiotherapy in non-small-cell lung cancer.
      Seventy-nine patients received dose escalated treatments based on the patients’ stratified risk for TRP in 25 daily fractions. Patients with all stages of disease were recruited and 62% received chemotherapy in the neoadjuvant or adjuvant setting. Patients were all positron emission tomography staged, planned using four-dimensional (4D) CT and the treatment was delivered with helical tomotherapy. The dose was prescribed such that 95% of the PTV volume received the prescription dose. Despite escalation to doses of up to 85.5 Gy/25 fractions, no grade 3 acute or late esophageal toxicity and no grade 3 pneumonitis was seen; however, six grade 4/5 toxicities were encountered in the form of massive hemoptysis and bronchocavitary fistula. Both these toxicities were associated with centrally based tumors, doses above 75 Gy, and specific 1–3 cc doses to the proximal bronchial tree. No constraints for proximal bronchial tree were specified in the trial protocol. After a median follow-up of 17 months median survival was 16 months and 3-year OS was 29%, which does not appear superior to historical outcome.

      Retrospective studies

      The largest body of evidence for IMRT in locally advanced NSCLC originates from three retrospective publications of patient cohorts from the same cancer center (MD Anderson Cancer Centre, Texas). It should be emphasized that as the treatment groups were not fully balanced and positron emission tomography staging was introduced at the time of recruitment to the IMRT cohorts, the data need to be interpreted with caution. Nevertheless, these studies all suggested improved outcomes with IMRT, reporting less toxicity and a superior OS.
      Yom et al.
      • 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.
      evaluated the rate of TRP in 68 NSCLC patients (85% stage III) treated with IMRT between 2002 and 2005, and compared this to a group of 222 historical controls treated with 3DCRT (2000–2003). Reasons for implementing IMRT included large treatment volume, failure to meet normal tissue dose constraints for 3DCRT, synchronous lung primary tumors, and poor baseline pulmonary function. In both groups, the majority of patients received a treatment dose of 63 Gy in 35 fractions and concurrent platinum-based doublet chemotherapy. Despite a larger GTV in the IMRT group (194 versus 142 cc), patients achieved significantly lower volumes of lung receiving 20 Gy (V20), however had larger volumes of lung receiving 5 Gy (V5) compared to the 3DCRT group. With a median follow-up of eight (0–27) and nine (0–56) months, respectively, the incidence of greater than grade 3 TRP was significantly lower in the IMRT group than in those treated with 3DCRT (8% versus 22% at 6 months). Local control in the IMRT group at 12 months was 55.3% with an estimated OS at 12 months of 57%.
      Liao et al.
      • Liao ZX
      • Komaki RR
      • Thames Jr, HD
      • et al.
      Influence of technologic advances on outcomes in patients with unresectable, locally advanced non-small-cell lung cancer receiving concomitant chemoradiotherapy.
      examined the effect of IMRT, accounting for motion (4DCT), on toxicity and clinical outcome in locally advanced NSCLC. Ninety-one patients (some of whom were also included in the Yom study) were treated with 4DCT/IMRT between 2004 and 2006. These were compared to 318 patients receiving 3DCRT between 1999 and 2004. Both groups received a median dose of 63 Gy using conventional fractionation. The IMRT group contained a greater proportion of patients who were older, current smokers, or staged with positron emission tomography CT (82% 4DCT IMRT versus 49% 3DCTRT). GTV was not reported. Again, this study confirmed a reduced rate of TRP in the IMRT group, with significantly lower V20 percentages (34% versus 37%), at the expense of a higher V5 (65% versus 57%). The authors reported similar rates of local control and distant metastases, but an improvement in OS in the IMRT group (median survival times 1.40 years for the 4DCT/IMRT group and 0.85 year for the 3DCRT group).
      Their most recent study assessed long-term clinical outcome of patients treated with 4DCT IMRT (n = 165; 76% stage III) with or without concurrent chemotherapy. The median radiation dose was 66 Gy given in 33 fractions
      • 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.
      and median GTV was 124.6 cc (range, 4.3–730 cc). Eleven percent of patients developed greater than or equal to grade 3 TRP at 6 months and one patient was affected by grade 3 pulmonary fibrosis at 18 months. The majority of the 29 patients (18%), who experienced grade 3 esophagitis settled within 6 weeks, however four went on to develop an esophageal stricture requiring further intervention. Overall, the incidence and severity of toxicities were lower in IMRT patients than historical control cohorts who received 3DCRT. With a median 16.5 months follow-up, 2-year disease free and OS were 38% and 46%, respectively.
      Other centers have also published encouraging retrospective outcome data for IMRT in locally advanced NSCLC. Memorial Sloan Kettering assessed the toxicity of IMRT in 55 stages Ib–IIIb (62% stage III) NSCLC patients between 2001 and 2005.
      • Sura S
      • Gupta V
      • Yorke E
      • Jackson A
      • Amols H
      • Rosenzweig KE
      Intensity-modulated radiation therapy (IMRT) for inoperable non-small cell lung cancer: the Memorial Sloan-Kettering Cancer Center (MSKCC) experience.
      Patients received a dose of 60 Gy in 30 fractions with either sequential (53%) or concurrent (24%) chemotherapy, unless contraindicated. Mean GTV was 136 cc. With a median follow-up of 12 months, six (11%) patients reported grade 3 pulmonary toxicity, and two (4%) developed grade 3 esophageal toxicity. Two-year OS was 58% with a median survival of 25 months. Govaert et al.
      • Govaert SL
      • Troost EG
      • Schuurbiers OC
      • et al.
      Treatment outcome and toxicity of intensity-modulated (chemo) radiotherapy in stage III non-small cell lung cancer patients.
      experienced similar findings in 71 stages IIb–IIIb NSCLC patients treated with IMRT between 2008 and 2011. Patients received up to a dose of 66 Gy in 33 fractions with chemotherapy. Mean GTV volume was not reported. No grade 3/4 pulmonary or esophageal toxicity was observed, and there were no treatment-related deaths. After median follow-up of 12 months, median survival was 29.7 months, which translated to a 56% two-year OS. A group at the Netherlands Cancer Institute assessed at the rate of acute
      • Uyterlinde W
      • Belderbos J
      • Baas C
      • et al.
      Prediction of acute toxicity grade ≥ 3 in patients with locally advanced non-small-cell lung cancer receiving intensity modulated radiotherapy and concurrent low-dose Cisplatin.
      and late
      • Chen C
      • Uyterlinde W
      • Sonke JJ
      • de Bois J
      • van den Heuvel M
      • Belderbos J
      Severe late esophagus toxicity in NSCLC patients treated with IMRT and concurrent chemotherapy.
      toxicity following hypofractionated IMRT (66 Gy in 24 fractions) and concurrent chemotherapy for NSCLC in two separate papers. Thirty-five percent of patients developed any greater than grade 3 acute toxicity and 7% patients developed TRP. Six percent (11/171) developed severe late esophageal toxicity in the form of stenosis (8/11) or fistula (3/11), which was comparable to historical cohorts treated with 3DCRT. Two-year OS was 52%.

      Population-based studies

      Shirvani et al.
      • Shirvani SM
      • Jiang J
      • Gomez DR
      • Chang JY
      • Buchholz TA
      • Smith BD
      Intensity modulated radiotherapy for stage III non-small cell lung cancer in the United States: predictors of use and association with toxicities.
      investigated predictors of IMRT use in the United States between 2001 and 2007, using the Surveillance, Epidemiology, and End Results (SEER) Medicare database. They reported that the year of diagnosis and treatment in a dedicated radiotherapy center were the only independent predictors of IMRT use. Lung and esophageal toxicity was equal between the IMRT and 3DCRT groups. A further population-based study using the SEER database compared treatment outcomes in stage III NSCLC for IMRT, 3DCRT, and two-dimensional radiotherapy (2DRT) planning techniques.
      • Harris JP
      • Murphy JD
      • Hanlon AL
      • Le QT
      • Loo Jr, BW
      • Diehn M
      A population-based comparative effectiveness study of radiation therapy techniques in stage III non-small cell lung cancer.
      This study was conducted to address fears that IMRT may cause inaccuracies in dose and increased long-term toxicity, which in turn could affect survival. This analysis of nearly 7000 patients confirmed that IMRT was associated with similar toxicities and OS to 3DCRT, with both techniques showing an advantage over 2DRT.

      Challenges in implementing IMRT

      Although the majority of planning studies and limited clinical data support the use of IMRT in lung cancer, implementation comes with clinical and technical challenges. IMRT is a more complex technique than conventional 3DCRT
      • Intensity Modulated Radiation Therapy Collaborative Working Group
      Intensity-modulated radiotherapy: current status and issues of interest.
      and places higher demands on treatment planning, dose calculation algorithms, and delivery systems. As IMRT relies on computerized inverse planning, additional organs at risk such as the heart, brachial plexus, central airways, and esophagus need to be contoured to instruct the system to avoid depositing high dose in these tissues. This is time consuming for the clinician and the treatment planner.
      • Miles EA
      • Clark CH
      • Urbano MT
      • et al.
      The impact of introducing intensity modulated radiotherapy into routine clinical practice.
      ,
      • Moran JM
      • Dempsey M
      • Eisbruch A
      • et al.
      Safety considerations for IMRT: executive summary.
      Dose calculation in lung tissue requires the use of a model-based calculation algorithm (type B), as use of measurement-based algorithms (type A) give rise to inaccurate scatter modeling in lung tissue and deviations of up to 5% between calculated and measured doses.
      • Irvine C
      • Morgan A
      • Crellin A
      • Nisbet A
      • Beange I
      The clinical implications of the collapsed cone planning algorithm.
      • Schiefer H
      • Fogliata A
      • Nicolini G
      • et al.
      The Swiss IMRT dosimetry intercomparison using a thorax phantom.
      • Haedinger U
      • Krieger T
      • Flentje M
      • Wulf J
      Influence of calculation model on dose distribution in stereotactic radiotherapy for pulmonary targets.
      Discrepancies between type A algorithms and measurements are larger for IMRT compared to 3DCRT
      • Fogliata A
      • Clivio A
      • Vanetti E
      • Nicolini G
      • Belosi MF
      • Cozzi L
      Dosimetric evaluation of photon dose calculation under jaw and MLC shielding.
      and so the use of type B algorithms is a prerequisite when planning IMRT for lung patients. The increased complexity of IMRT plans also require additional quality assurance tests to be routinely performed on the delivery system (and commonly across Europe, on individual patient plans).
      • Ezzell GA
      • Galvin JM
      • Low D
      • IMRT Subcommitte
      • AAPM Radiation Therapy Committee
      • et al.
      Guidance document on delivery, treatment planning, and clinical implementation of IMRT: report of the IMRT Subcommittee of the AAPM Radiation Therapy Committee.
      • Langen KM
      • Papanikolaou N
      • Balog J
      • AAPM Task Group 148
      • et al.
      QA for helical tomotherapy: report of the AAPM Task Group 148.

      NCS. . NCS report 22: Code of practice for the Quality Assurance and Control for Intensity Modulated Radiotherapy. 2013

      Breathing motion, especially in lung cancer, influences the dose delivered to the patient. This variation with respiration creates two organ motion effects: the gradient/blurring effect and the interplay effect. The gradient effect occurs as the tumor moves, “blurring” the area in which the tumor is in. This effect can be compensated for by radiating the whole envelope of motion (within an internal target volume),
      • Chavaudra J
      • Bridier A
      Definition of volumes in external radiotherapy: ICRU reports 50 and 62.
      ,
      • Admiraal MA
      • Schuring D
      • Hurkmans CW
      Dose calculations accounting for breathing motion in stereotactic lung radiotherapy based on 4D-CT and the internal target volume.
      by calculating a margin based on the probability distributions of the cumulative dose
      • van Herk M
      • Remeijer P
      • Rasch C
      • Lebesque JV
      The probability of correct target dosage: dose-population histograms for deriving treatment margins in radiotherapy.
      or by a tracking or gating technique.
      • Giraud P
      • Yorke E
      • Jiang S
      • Simon L
      • Rosenzweig K
      • Mageras G
      Reduction of organ motion effects in IMRT and conformal 3D radiation delivery by using gating and tracking techniques.
      ,
      • Guckenberger M
      • Krieger T
      • Richter A
      • et al.
      Potential of image-guidance, gating and real-time tracking to improve accuracy in pulmonary stereotactic body radiotherapy.
      The interplay effect is caused by the lack of synchrony between the moving aperture (e.g., MLC) and tumor motion. There is concern that the highly conformal fields, numerous MLC positions required for IMRT and intra-fractional tumor motion may lead to target miss. Several authors have evaluated the interplay effect for conventional fractionated IMRT treatments using sinusoidal motion
      • 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.
      ,
      • Berbeco RI
      • Pope CJ
      • Jiang SB
      Measurement of the interplay effect in lung IMRT treatment using EDR2 films.
      • Bortfeld T
      • Jiang SB
      • Rietzel E
      Effects of motion on the total dose distribution.
      • Chui CS
      • Yorke E
      • Hong L
      The effects of intra-fraction organ motion on the delivery of intensity-modulated field with a multileaf collimator.
      • Court LE
      • Seco J
      • Lu XQ
      • et al.
      Use of a realistic breathing lung phantom to evaluate dose delivery errors.
      • Li H
      • Park P
      • Liu W
      • et al.
      Patient-specific quantification of respiratory motion-induced dose uncertainty for step-and-shoot IMRT of lung cancer.
      • Riley C
      • Yang Y
      • Li T
      • Zhang Y
      • Heron DE
      • Huq MS
      Dosimetric evaluation of the interplay effect in respiratory-gated RapidArc radiation therapy.
      as well as realistic patient motion.
      • Giraud P
      • Yorke E
      • Jiang S
      • Simon L
      • Rosenzweig K
      • Mageras G
      Reduction of organ motion effects in IMRT and conformal 3D radiation delivery by using gating and tracking techniques.
      • Guckenberger M
      • Krieger T
      • Richter A
      • et al.
      Potential of image-guidance, gating and real-time tracking to improve accuracy in pulmonary stereotactic body radiotherapy.
      • Berbeco RI
      • Pope CJ
      • Jiang SB
      Measurement of the interplay effect in lung IMRT treatment using EDR2 films.
      All reported that the interplay effect could alter the dose distribution of a single fraction, but not a fractionated course of treatment. Jiang et al.
      • 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.
      demonstrated a maximum dose variation of 30% for one field in one fraction, 18% for all five fields after one fraction, and less than 1–2% after 30 fractions. Even with SABR there is a negligible interplay effect as effects average out due to the larger number of monitor units and increased treatment time required.
      • Ong C
      • Verbakel WF
      • Cuijpers JP
      • Slotman BJ
      • Senan S
      Dosimetric impact of interplay effect on RapidArc lung stereotactic treatment delivery.
      • Rao M
      • Wu J
      • Cao D
      • et al.
      Dosimetric impact of breathing motion in lung stereotactic body radiotherapy treatment using intensity modulated radiotherapy and volumetric modulated arc therapy [corrected].
      • Stambaugh C
      • Nelms BE
      • Dilling T
      • et al.
      Experimentally studied dynamic dose interplay does not meaningfully affect target dose in VMAT SBRT lung treatments.
      However, interplay may cause an effect for extreme hypofractionation/SABR combined with very complex IMRT/VMAT deliveries. Strategies to reduce the interplay effect include increasing the number of arcs,
      • Ong C
      • Verbakel WF
      • Cuijpers JP
      • Slotman BJ
      • Senan S
      Dosimetric impact of interplay effect on RapidArc lung stereotactic treatment delivery.
      decreasing the dose rate and therefore prolonging the treatment time
      • 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.
      or avoiding an MLC motion perpendicular to the tumor motion.
      • Ong C
      • Verbakel WF
      • Cuijpers JP
      • Slotman BJ
      • Senan S
      Dosimetric impact of interplay effect on RapidArc lung stereotactic treatment delivery.
      In comparison to 3DCRT, IMRT increases the low-dose bath to the patient as a greater number of beams and monitor units are used (an increase in monitor units is necessary to compensate for large parts of the fields being blocked by MLCs and this increases head leakage and scatter radiation). There are concerns that this low-dose bath may increase the risk of acute and late pulmonary toxicity, as well as the risk of second malignancy.
      • Liu HH
      • Wang X
      • Dong L
      • et al.
      Feasibility of sparing lung and other thoracic structures with intensity-modulated radiotherapy for non-small-cell lung cancer.
      ,
      • Hall EJ
      Intensity-modulated radiation therapy, protons, and the risk of second cancers.
      ,
      • Intensity Modulated Radiation Therapy Collaborative Working Group
      Intensity-modulated radiotherapy: current status and issues of interest.
      ,
      • Yorke ED
      • Jackson A
      • Rosenzweig KE
      • Braban L
      • Leibel SA
      • Ling CC
      Correlation of dosimetric factors and radiation pneumonitis for non-small-cell lung cancer patients in a recently completed dose escalation study.
      The potential survival benefit of IMRT outweighs the secondary cancer risk in NSCLC, however toxicity is of importance. A correlation between low doses to the lung and fatal pneumonitis has been demonstrated in mesothelioma, leading to recommended threshold doses of mean lung dose of less than 8.5–13 Gy, V5 less than 60–75%, and V10 less than 50%.
      • Allen AM
      • Czerminska M
      • Jänne PA
      • et al.
      Fatal pneumonitis associated with intensity-modulated radiation therapy for mesothelioma.
      ,
      • Kristensen CA
      • Nøttrup TJ
      • Berthelsen AK
      • et al.
      Pulmonary toxicity following IMRT after extrapleural pneumonectomy for malignant pleural mesothelioma.
      ,
      • Rice DC
      • Smythe WR
      • Liao Z
      • et al.
      Dose-dependent pulmonary toxicity after postoperative intensity-modulated radiotherapy for malignant pleural mesothelioma.
      However, a clear relationship between V5 lung doses and severe pulmonary toxicity for IMRT in NSCLC is lacking and as yet there is no consensus as to suitable threshold doses.

      DISCUSSION AND FUTURE DIRECTIONS

      By facilitating improved beam shaping around complex structures, IMRT offers the potential to optimize dose delivery to a target volume while sparing surrounding normal tissue. This increases the scope to safely escalate the dose, boost sub-volumes, and treat larger radiotherapy volumes in the radical setting than was previously possible with 3DCRT (Fig. 1).
      Figure thumbnail gr1
      FIGURE 1Patient with large volume disease (T3N3M0) treated with seven fields fixed-beam step and shoot IMRT. 66 Gy in 33 fractions prescribed to PTV_IMRT (PTV edited from the skin by a 0.5 cm isotropic 3D margin and from the spinal canal by a 1.0 cm isotropic 3D margin). Mean lung dose 19.9 Gy, V20 34.5%, maximum spinal cord 48.9 Gy. PTV, planning target volume; V20, percent volume of total lung receiving 20 Gy; IMRT, intensity-modulated radiotherapy; 3D, three dimensional.
      The key clinical question regarding this technique is whether IMRT can lead to an improvement in OS as a result of reduced toxicity and/or isotoxic dose escalation (individualized dose escalation based on predefined safe organs at risk dose constraints) leading to improved local tumor control. Patients with a high burden of disease may relapse both locally and distantly, making outcomes similar whether or not the dose to the primary has been optimized. Robust, randomized evidence demonstrating improved clinical outcomes with IMRT is lacking, and concerns regarding the need for extra resources in terms of treatment planning, delivery time, and financial cost may go some way to explain why the uptake of this technique remains low.
      • Bezjak A
      • Rumble RB
      • Rodrigues G
      • Hope A
      • Warde P
      Members of the IMRT Indications Expert Panel. . Intensity-modulated radiotherapy in the treatment of lung cancer.
      There is little doubt from planning studies that there is a dosimetric advantage of using IMRT for lung cancer, which should justify the increase in time requirements for contouring, planning, and treatment verification. A specific concern about the use of IMRT for lung is the amount of tumor motion during treatment seen in this site compared to, for example, head and neck cancers. This can be partly remedied with 4DCT and advanced planning techniques, and encouragingly the interplay effect does not seem to cause any clinical detriment.
      We would argue that the clinical evidence reviewed in this article demonstrate that IMRT can be delivered safely with acceptable acute and late toxicities. IMRT facilitates lowering of critical dosimetric parameters such as V20, and although lower doses of radiation are delivered to more tissue, concerns that this “low-dose bath” may adversely affect long-term lung function or increase second malignancy risk have not been reported in prospective studies. Crucially retrospective studies report disease-free and OS figures which seem to show an advantage over those achieved with conventional 3DCRT. As these studies were not randomized, there is a likelihood of inherent bias. The IMRT cohorts will have been treated more recently meaning that stage migration may play a part in the improved survival as well as improved patient setup imaging such as Cone Beam CT. Conversely, as IMRT was initially often used for patients unable to meet 3DCRT dose constraints, this group may also contain a higher risk population that would have been expected to have a lower survival.
      The outcome of the recent RTOG 0617 study showing no benefit for the higher dose arm has left some questioning efforts to dose escalate in lung cancer radiotherapy. Although on face value it would seem that the “dose escalation in lung cancer” debate has stalled, we need to be cautious not to dismiss “radiotherapy treatment intensification” as a concept. There are many unanswered questions surrounding RTOG 0617 regarding dose delivery and radiotherapy quality assurance and it is important to acknowledge that less than 50% patients in this trial were treated with IMRT. In addition, there remains good evidence to show that improved local control can improve survival. There is therefore a general consensus that radiotherapy treatment intensification with advanced radiotherapy techniques and image guidance still represents a valuable opportunity to improve outcomes for lung cancer patients. The situation however is complex, with consideration for different fractionation regimes and perhaps a move to greater individualization of treatment. To this end a number of clinical trials to address these issues are open or in set up; examples of these are presented in Table 4.
      Table 4Examples of Ongoing Clinical Trials Utilizing IMRT for Dose Escalation
      Trials Evaluating Personalized Dose Escalation Based on Dose Delivered to OARsTrials Evaluating an Increased Dose to Selected Parts Within the Tumor, Defined by Functional Imaging (Dose Painting)
      Isotoxic IMRT (NCT01836692)PET boost (NCT01024829)
       Prospective multicenter single arm feasibility studyRandomized multicenter phase II study
       Stage III NSCLCT2-4, N0-3, M0 inoperable, NSCLC
       Sequential chemoradiotherapyRT alone, sequential, or concurrent chemoradiotherapy
       Hyperfractionated, accelerated, and dose-escalated radiotherapy with IMRT and image guidance. Dose based on prespecified normal tissue doses66 Gy given in 24 fractions of 2.75 Gy delivered with IMRT +/- integrated boost to whole tumor, or the FDG PET-CT 50% SUVmax area of the primary individualized to meditational organs at risk (with or without chemotherapy)
       Maximum dose 79.4 Gy in 39 twice-daily (BD) fractionsPrimary outcome: delivery of isotoxic IMRT to dose >60 Gy EQD2 (total biologically equivalent in 2 Gy fraction)Proceed to phase II if dose escalation possible in >80% patientsPrimary outcome: local progression-free survival at 1 yearThe planning results of the first 20 patients have been published. It was possible to dose escalate 75% of patients to 72Gy, with dose-limiting organs being the mediastinal structures and the brachial plexus
      • van Elmpt W
      • De Ruysscher D
      • van der Salm A
      • et al.
      The PET-boost randomised phase II dose-escalation trial in non-small cell lung cancer.
      Maastro study (NCT01166204)RTOG (NCT01507428)
       Nonrandomized monocenter phase II studyRandomized multicenter phase II study
       Stages I–III NSCLCStage III NSCLC
       Concurrent chemoradiotherapyConcurrent chemoradiotherapy
      • Radiotherapy delivered with IMRT to an individualized mean lung
      • dose of 20 Gy +/-1
      60 Gy in 30 daily fractions delivered with IMRT +/- adaptive radiotherapy based on FDG-PET/CT scan between fractions 18 and 19
       45Gy/30 BD fractions for first 3 weeks followed by once daily fractions of 2 Gy until the target dose has been reachedMax dose 80.4 Gy in 30 daily fractions, individualized to mean lung dose 20 Gy
       Primary outcome: overall survivalPrimary outcome: local progression-free survival
      IMRT, intensity-modulated radiotherapy
      In conclusion, from the current evidence available, IMRT can achieve better dose conformality, avoid organs at risk and lower treatment toxicity. However, compared to conventional 3D techniques, the planning process and treatment delivery is time consuming and places strain on valuable resources. Our recommendations for the minimum requirements to deliver IMRT safely are presented in Table 5. Further prospective data are needed to strengthen the evidence base for this technique. It is hoped that eventually we may be able to correlate clinical features of the tumor and radiotherapy planning parameters with toxicity and survival. At present IMRT is best indicated when the tumor volume is near to an organ at risk or when treatment volumes are too large to treat to a radical dose with 3DCRT. However, research activity into dose escalation for lung cancer is intensifying and once the optimal approach to this is established, IMRT will undoubtedly play an essential role in radiotherapy treatment delivery.
      Table 5Minimum Requirements for Safe Delivery of IMRT
      Minimum Requirements for the Safe Delivery of IMRT
       4D CT planning scan or equivalent
       Delineation of additional organs at risk for inverse dose plan computation
       Type B algorithm for dose calculation
       Cone beam CT verification
       End-to-end testing using a anthropomorphic or semianthropomorphic phantom before first clinical use
       Risk assessment of interplay effects from the IMRT technique and fractionation employed
       Dedicated machine IMRT QA program
       Patient-specific IMRT QA program including independent MU verification (calculation or measurement based)
       Patient-specific QA of transfer of the treatment plan to the treatment machine
      IMRT, intensity-modulated radiotherapy; QA, quality assurance; MU, monitor unit.

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