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Normal tissue considerations and dose–volume constraints in the moderately hypofractionated treatment of non-small cell lung cancer

      Abstract

      Hypofractionated radiation therapy (RT) regimes in non-small cell lung cancer (NSCLC) have become increasingly popular with a number of international trials currently underway. The majority of the dose–volume-constraints (DVCs) published in the literature refer to conventional 2 Gy per fraction deliveries. Here relevant organs-at-risk (OARs) are identified and available dose–volume constraint data discussed and summarised for moderately hypofractionated NSCLC regimes. The OARs examined include lung, brachial plexus, heart, oesophagus, airway and spinal cord. Where available the toxicity rates are also reported with all data summarised tabulated to aid its use in the clinic.

      Keywords

      In Europe lung cancer represents 15.9% and 7.4% of all invasive cancers diagnosed in males and females respectively and remains a leading cause of cancer deaths accounting for 26.1% in males and 12.7% in females [
      • Ferlay J.
      • Steliarova-Foucher E.
      • Lortet-Tieulent J.
      • Rosso S.
      • Coebergh J.W.W.
      • Comber H.
      • et al.
      Cancer incidence and mortality patterns in Europe: estimates for 40 countries in 2012.
      ]. Stereotactic Ablative Body Radiation Therapy (SABR) has demonstrated the ablative ability of very large doses (>100 Gy biological effective dose (BED)) in small tumours [
      • Timmerman R.
      • Paulus R.
      • Galvin J.
      Stereotactic body radiation therapy for inoperable early stage lung cancer.
      ]. However, in some cases these dose levels cannot be safely delivered in locally advanced (LA) non-small cell lung cancer (NSCLC) due to the size of the target volumes and proximity to nearby structures. Thus, with standard prescription of 60 Gy/30# (fractions) [
      • Perez C.
      • Pajak T.
      • Rubin P.
      • Simpson J.
      • Mohiuddin M.
      • Brady L.
      • et al.
      Long-term observations of the patterns of failure in patients with unresectable non-oat cell carcinoma of the lung treated with definitive radiotherapy. Report of the Radiation Therapy Oncology Group.
      ] 5-year survival rates remain in the region of 10–15% [
      • Sause W.T.
      • Kolesar P.
      • Taylor S.I.V.
      • Johnson D.
      • Livingston R.
      • Komaki R.R.
      • et al.
      Final results of phase III trial in regionally advanced unresectable non-small cell lung cancer: Radiation Therapy Oncology Group, Eastern Cooperative Oncology Group, and Southwest Oncology Group.
      ,
      • Kong F.-M.S.
      • Ten Haken R.K.
      • Schipper M.J.
      • Sullivan M.A.
      • Chen M.
      • Lopez C.
      High-dose radiation improved local tumor control and overall survival in patients with inoperable/unresectable non-small-cell lung cancer: long-term results of a radiation dose escalation study.
      ,
      • Lee C.
      • Stinchcombe T.
      • Moore D.T.
      • Morris D.E.
      • Hayes D.N.
      • Halle J.S.
      • et al.
      Late complications of high-dose (⩾66 Gy) thoracic conformal radiation therapy in combined modality trials in unresectable stage III non-small cell lung cancer.
      ].
      An analysis of a number of RTOG (Radiation Therapy and Oncology Group) trials demonstrated overall treatment time (OTT) to be significantly associated with poorer survival [
      • Machtay M.
      • Hsu C.
      • Komaki R.R.
      • Sause W.T.
      • Swann R.S.
      • Langer C.J.
      • et al.
      Effect of overall treatment time on outcomes after concurrent chemoradiation for locally advanced non-small-cell lung carcinoma: analysis of the Radiation Therapy Oncology Group (RTOG) experience.
      ]. OTT can be reduced through hypofractionation (>2 Gy per #). Thirion et al. have published their experience of 72 Gy/24# in 60 patients, with 1-year overall survival of 68% and thoracic-progression-free survival of 72% [
      • Thirion P.
      • Holmberg O.
      • Collins C.
      • O’Shea C.
      • Moriarty M.
      • Pomeroy M.
      • et al.
      Escalated dose for non-small-cell lung cancer with accelerated hypofractionated three-dimensional conformal radiation therapy.
      ]. A dose of 55 Gy/20# is a NICE (National Institute for Health and Care Excellence) approved schedule in the UK (United Kingdom) [
      • NICE
      CG121: The diagnosis and treatment of lung cancer.
      ]. A review of this regime demonstrated 97% of patients received the prescribed dose (PD), demonstrating deliverability to the majority of patients [
      • Din O.S.
      • Harden S.V.
      • Hudson E.
      • Mohammed N.
      • Pemberton L.S.
      • Lester J.F.
      • et al.
      Accelerated hypo-fractionated radiotherapy for non small cell lung cancer: results from 4 UK centres.
      ]. Low levels of toxicity (no grade 3+ toxicities and radiation pneumonitis rates <20%) suggest that there is space for dose escalation within 20# schedules [
      • Din O.S.
      • Harden S.V.
      • Hudson E.
      • Mohammed N.
      • Pemberton L.S.
      • Lester J.F.
      • et al.
      Accelerated hypo-fractionated radiotherapy for non small cell lung cancer: results from 4 UK centres.
      ]. Long term follow-up of this schedule has shown local tumour control at 3 years of 74.1% [
      • Kelly V.
      • Maguire J.
      Long term local tumour control in inoperable NSCLC treated with accelerated hypofractionated radiotherapy and concurrent cisplatinum and vinorelbine.
      ]. There are a number of current trials in hypofractionated NSCLC treatment, including RTOG 11-06 (30#) [

      Kong F-MS, Machtay M, Bradley JD, Ten Haken RK, Xiao Y, Matuszak MM, et al. RTOG 1106/ACRIN 6697 Randomized phase II trial of individualized adaptive radiotherapy using during treatment FDG-PET/CT and modern technology in locally advanced non-small cell lung cancer (NSCLC). 2013.

      ], I-START (20#) [
      • Nixon L.
      • Lester J.F.
      • Mayles W.P.M.
      • Mayles H.
      • Parsons E.
      • Ionescu A.
      • et al.
      Dose escalation in the I-START trial – ISoToxic Accelerated RadioTherapy in locally advanced non-small cell lung cancer.
      ] and IDEAL-CRT (30#) [
      • Warren S.
      • Panettieri V.
      • Panakis N.
      • Bates N.
      • Lester J.F.
      • Jain P.
      • et al.
      Optimizing collimator margins for isotoxically dose-escalated conformal radiation therapy of non-small cell lung cancer.
      ], while the results of NCIC CTG BR.25 (60 Gy/15#) have recently been published [
      • Cheung P.
      • Faria S.L.
      • Ahmed S.
      • Chabot P.
      • Greenland J.
      • Kurien E.
      • et al.
      Phase II study of accelerated hypofractionated three-dimensional conformal radiotherapy for stage T1-3 N0 M0 non-small cell lung cancer: NCIC CTG BR.25.
      ].
      In 2010 the QUANTEC (Quantitative Analysis of Normal Tissue Effects in the Clinic) review of the literature on normal tissue effects was published, summarising tolerance data on an organ-by-organ basis [
      • Marks L.B.
      • Yorke E.D.
      • Jackson A.
      • Ten Haken R.K.
      • Constine L.S.
      • Eisbruch A.
      • et al.
      Use of normal tissue complication probability models in the clinic.
      ]. However, it is primarily focussed on conventional fractionation and the lack of established constraints for hypofractionated treatment of NSCLC was highlighted in a recent study from Swanick et al. [
      • Swanick C.W.
      • Lin S.H.
      • Sutton J.
      • Naik N.S.
      • Allen P.K.
      • Levy L.B.
      • et al.
      Use of simultaneous radiation boost achieves high control rates in patients with non-small-cell lung cancer who are not candidates for surgery or conventional chemoradiation.
      ]. A number of authors have also summarised tolerance doses for SABR [
      • Grimm J.
      • LaCouture T.
      • Croce R.
      • Yeo I.
      • Zhu Y.
      • Xue J.
      Dose tolerance limits and dose volume histogram evaluation for stereotactic body radiotherapy.
      ,
      • Gay H.A.
      • Sibata C.H.
      • Allison R.R.
      • Jeremic B.
      Isodose-based methodology for minimizing the morbidity and mortality of thoracic hypofractionated radiotherapy.
      ]. In a dose escalation planning study by Warren et al. the proximal bronchial tree and great vessels limited escalation [
      • Warren M.
      • Webster G.
      • Ryder D.
      • Rowbottom C.
      • Faivre-Finn C.
      An isotoxic planning comparison study for stage II–III non-small cell lung cancer: Is intensity-modulated radiotherapy the answer?.
      ], organs that are not typically contoured or considered in conventional NSCLC radiation therapy (RT). At doses above 80 Gy EQD2 (Equivalent Dose in 2 Gy) toxicities can be observed related to high point-doses (oesophageal fistula, bronchial stenosis) [
      • Thirion P.
      • Holmberg O.
      • Collins C.
      • O’Shea C.
      • Moriarty M.
      • Pomeroy M.
      • et al.
      Escalated dose for non-small-cell lung cancer with accelerated hypofractionated three-dimensional conformal radiation therapy.
      ,
      • Belderbos J.S.
      • Heemsbergen W.D.
      • De Jaeger K.
      • Baas P.
      • Lebesque J.V.
      Final results of a phase I/II dose escalation trial in non-small-cell lung cancer using three-dimensional conformal radiotherapy.
      ,
      • Bradley J.D.
      • Graham M.V.
      • Winter K.
      • Purdy J.A.
      • Komaki R.R.
      • Roa W.H.
      • et al.
      Toxicity and outcome results of RTOG 9311: a phase I–II dose–escalation study using three-dimensional conformal radiotherapy in patients with inoperable non-small-cell lung carcinoma.
      ,
      • Miller K.L.
      • Shafman T.D.
      • Anscher M.S.
      • Zhou S.-M.
      • Clough R.W.
      • Garst J.L.
      • et al.
      Bronchial stenosis: an underreported complication of high-dose external beam radiotherapy for lung cancer?.
      ]. In accelerated hypofractionated schedules in LA-NSCLC there are additional organs-at-risk (OARs) and toxicities to be considered. The motivation of this systematic review is to discuss and summarise dose–volume constraints (DVCs) for moderately hypofractionated (2.1–5 Gy per #) regimes in LA-NSCLC in order to aid those intending to treat with a hypofractionated regime to select appropriate evidence based DVCs.

      Materials and methods

      A literature search was performed using PubMed, Science Direct, Google Scholar and ClinicalTrials.Gov including the terms ‘hypofractionation’, ‘lung cancer,’ ‘NSCLC’, ‘DVCs’, ‘dose volume constraints’, ‘toxicity’ and incorporated Boolean logic to narrow the results. Secondary related articles were selected from the reference lists of articles found to be relevant. The search yielded both clinical trial schema and publications on clinical treatment. The organs-at-risk identified include lung, brachial plexus, heart, oesophagus, airway and spinal cord. Particular attention has been paid to reported cases of grade 4 and 5 toxicities and their relationship to dose delivered. Only studies including 3DCRT (3-dimensional conformal radiation therapy) or IMRT (intensity modulated radiation therapy) were included. Schedules other than 5# per week, greater than 5 Gy per #, where patients had previous thoracic RT or where a scheduled break was present in RT were also excluded. A CONSORT diagram illustrates the number of papers identified and how the inclusion/exclusion criteria resulted in the final number of studies (see Fig. 1).
      Figure thumbnail gr1
      Fig. 1CONSORT diagram indicating the selection process for including papers/protocols in this review.

      Results

      Lung

      V20Gy (% volume receiving 20 Gy) <30–35% is commonly used in conventional fractionation [
      • Graham M.V.
      • Purdy J.A.
      • Emami B.
      • Harms W.B.
      • Bosch W.
      • Lockett M.
      • et al.
      Clinical dose–volume histogram analysis for pneumonitis after 3D treatment for non-small cell lung cancer.
      ] and many of the studies analysed here have used this metric without accounting for differences in fraction number, fraction size or dose distribution due to delivery technique [
      • Thirion P.
      • Holmberg O.
      • Collins C.
      • O’Shea C.
      • Moriarty M.
      • Pomeroy M.
      • et al.
      Escalated dose for non-small-cell lung cancer with accelerated hypofractionated three-dimensional conformal radiation therapy.
      ]. A number of the studies use a mean lung dose (MLD) constraint as detailed in the QUANTEC report [
      • Marks L.B.
      • Yorke E.D.
      • Jackson A.
      • Ten Haken R.K.
      • Constine L.S.
      • Eisbruch A.
      • et al.
      Use of normal tissue complication probability models in the clinic.
      ], with five utilising a LQ (linear quadratic) correction on the DVH (dose–volume histogram) before generating a MLD or rNTDmean (mean fraction-normalised lung dose divided by the normalised prescription dose) [
      • Nixon L.
      • Lester J.F.
      • Mayles W.P.M.
      • Mayles H.
      • Parsons E.
      • Ionescu A.
      • et al.
      Dose escalation in the I-START trial – ISoToxic Accelerated RadioTherapy in locally advanced non-small cell lung cancer.
      ,
      • Warren S.
      • Panettieri V.
      • Panakis N.
      • Bates N.
      • Lester J.F.
      • Jain P.
      • et al.
      Optimizing collimator margins for isotoxically dose-escalated conformal radiation therapy of non-small cell lung cancer.
      ,
      • Chen C.
      • Uyterlinde W.
      • Sonke J.-J.
      • de Bois J.
      • van den Heuvel M.
      • Belderbos J.S.
      Severe late esophagus toxicity in NSCLC patients treated with IMRT and concurrent chemotherapy.
      ,
      • Cannon D.M.
      • Mehta M.P.
      • Adkison J.B.
      • Khuntia D.
      • Traynor A.M.
      • Tomé W.A.
      • et al.
      Dose-limiting toxicity after hypofractionated dose-escalated radiotherapy in non-small-cell lung cancer.
      ,
      • Adkison J.B.
      • Khuntia D.
      • Bentzen S.M.
      • Cannon G.M.
      • Tomé W.A.
      • Jaradat H.
      • et al.
      Dose escalated, hypofractionated radiotherapy using helical tomotherapy for inoperable non-small cell lung cancer: preliminary results of a risk-stratified phase I.
      ]. In three studies the lung dose is the basis for deciding the prescription dose level [
      • Cannon D.M.
      • Mehta M.P.
      • Adkison J.B.
      • Khuntia D.
      • Traynor A.M.
      • Tomé W.A.
      • et al.
      Dose-limiting toxicity after hypofractionated dose-escalated radiotherapy in non-small-cell lung cancer.
      ,
      • Adkison J.B.
      • Khuntia D.
      • Bentzen S.M.
      • Cannon G.M.
      • Tomé W.A.
      • Jaradat H.
      • et al.
      Dose escalated, hypofractionated radiotherapy using helical tomotherapy for inoperable non-small cell lung cancer: preliminary results of a risk-stratified phase I.
      ,
      • Kong F-.M.S.
      • Hayman J.
      • Griffith K.A.
      • Kalemkerian G.P.
      • Arenberg D.
      • Lyons S.
      • et al.
      Final toxicity results of a radiation-dose escalation study in patients with non-small-cell lung cancer (NSCLC): predictors for radiation pneumonitis and fibrosis.
      ]. A summary of the data gathered is presented in Table 1, Table 2, this represents data from 1845 patients and there were 13 deaths as a result of toxicity (crude rate 0.7%). Two patients with T4 disease died during treatment; they had received 12 Gy/5# and 31.2 Gy/13# respectively [
      • Cho K.H.
      • Ahn S.J.
      • Pyo H.R.
      • Kim K.-S.
      • Kim Y.-C.
      • Moon S.H.
      • et al.
      A Phase II study of synchronous three-dimensional conformal boost to the gross tumor volume for patients with unresectable Stage III non-small-cell lung cancer: results of Korean Radiation Oncology Group 0301 study.
      ]. Three patients died from lung toxicity within 90 days of RT, one of these received 59 Gy of 70.5 Gy, the second died after completing RT (70.5 Gy/30#) with autopsy revealing the presence of radiation fibrosis [
      • Bral S.
      • Duchateau M.
      • Versmessen H.
      • Engels B.
      • Tournel K.
      • Vinh-Hung V.
      • et al.
      Toxicity and outcome results of a class solution with moderately hypofractionated radiotherapy in inoperable Stage III non-small cell lung cancer using helical tomotherapy.
      ] and the third received 63.25 Gy/25# [
      • Cannon D.M.
      • Mehta M.P.
      • Adkison J.B.
      • Khuntia D.
      • Traynor A.M.
      • Tomé W.A.
      • et al.
      Dose-limiting toxicity after hypofractionated dose-escalated radiotherapy in non-small-cell lung cancer.
      ]. Three deaths were reported by Kepka et al., two of these were at their highest dose level of 58.8 Gy/21# leading them to reduce the dose to the previous level of 56.7 Gy/21# [
      • Kepka L.
      • Tyc-Szczepaniak D.
      • Bujko K.
      Dose-per-fraction escalation of accelerated hypofractionated three-dimensional conformal radiotherapy in locally advanced non-small cell lung cancer.
      ]. None of these three patients had exceeded the DVCs (V20Gy < 35% and MLD < 20 Gy) [
      • Kepka L.
      • Tyc-Szczepaniak D.
      • Bujko K.
      Dose-per-fraction escalation of accelerated hypofractionated three-dimensional conformal radiotherapy in locally advanced non-small cell lung cancer.
      ]. Three patient deaths were reported at 60 Gy/25# [
      • Kerner G.S.M.A.
      • van Dullemen L.F.A.
      • Wiegman E.M.
      • Widder J.
      • Blokzijl E.
      • Driever E.M.
      • et al.
      Concurrent gemcitabine and 3D radiotherapy in patients with stage III unresectable non-small cell lung cancer.
      ], and one at both 54/18# [
      • Oh D.
      • Ahn Y.C.
      • Kim B.
      • Pyo H.R.
      Hypofractionated three-dimensional conformal radiation therapy alone for centrally located cT1-3N0 Non-Small-Cell Lung Cancer.
      ] and 60 Gy/15# [
      • Cheung P.
      • Faria S.L.
      • Ahmed S.
      • Chabot P.
      • Greenland J.
      • Kurien E.
      • et al.
      Phase II study of accelerated hypofractionated three-dimensional conformal radiotherapy for stage T1-3 N0 M0 non-small cell lung cancer: NCIC CTG BR.25.
      ]. There is considerable heterogeneity in the reporting of toxicity across the studies, with some only reporting toxicity by group (e.g. grade 2+), others did not distinguish between acute and late lung toxicity or by chemotherapy schedule. Thus not all data could be included in overall toxicity summaries. The crude incidence of grade 3+ toxicity in the sequential studies reported here was 2.9% (15/516) for acute and 4.7% (24/516) for late toxicity. In the concurrent studies the crude incidences of grade 3+ acute and late toxicity were 6.3% (10/158) and 10.1% (16/158) respectively. Three of the concurrent studies did not distinguish between acute and late toxicity and they reported grade 3+ rate of 3.3% (13/400) [
      • Kerner G.S.M.A.
      • van Dullemen L.F.A.
      • Wiegman E.M.
      • Widder J.
      • Blokzijl E.
      • Driever E.M.
      • et al.
      Concurrent gemcitabine and 3D radiotherapy in patients with stage III unresectable non-small cell lung cancer.
      ,
      • Maguire J.
      • Khan I.
      • McMenemin R.
      • O’Rourke N.
      • McNee S.G.
      • Kelly V.
      • et al.
      SOCCAR: A randomised phase II trial comparing sequential versus concurrent chemotherapy and radical hypofractionated radiotherapy in patients with inoperable stage III Non-Small Cell Lung Cancer and good performance status.
      ,
      • Lin Q.
      • Liu Y.
      • Ren X.
      • Wang N.
      • Chen X.
      • Wang D.
      • et al.
      Dose escalation of accelerated hypofractionated three-dimensional conformal radiotherapy (at 3 Gy/fraction) with concurrent vinorelbine and carboplatin chemotherapy in unresectable stage III non-small-cell lung cancer : a phase I trial.
      ].
      Table 1Summary of dose–volume constraints and reported toxicities (with sequential or no chemotherapy) for the combined lung in hypofractionated NSCLC studies.
      No. of #Treatment planning limitAcute toxicity

      (Scale)
      Late toxicity

      (Scale)
      References
      Initially contralateral lung NTCP < 2%, then Veff < 0.40A(Combined SWOG, RTOG and CTCAE)
      30–4931 GI RP (28.4%)31 GI (28.4%) – fibrosisKong
      • Kong F-.M.S.
      • Hayman J.
      • Griffith K.A.
      • Kalemkerian G.P.
      • Arenberg D.
      • Lyons S.
      • et al.
      Final toxicity results of a radiation-dose escalation study in patients with non-small-cell lung cancer (NSCLC): predictors for radiation pneumonitis and fibrosis.
      109 patients
      12 GII RP (11%)11 GII (10.1%) – fibrosis
      5 GIII RP (4.6%)4 GIII (3.7%) – fibrosis
      30V19Gy < 30%A(RTOG)

      6 GIII RP (10%)
      (RTOG)

      3 GIII RP (5%)


      Donato
      • Donato V.
      • Arcangeli S.
      • Monaco A.
      • Caruso C.
      • Cianciulli M.
      • Boboc G.
      • et al.
      Moderately escalated hypofractionated (chemo) radiotherapy delivered with helical intensity-modulated technique in stage III unresectable non-small cell lung cancer.


      32 patients
      MLD < 19 GyOverall toxicity for 61 patients, not separated by concurrent/sequential chemotherapy schedule
      30V20Gy < 30% (35%)C(RTOG)(RTOG)Bral
      • Bral S.
      • Duchateau M.
      • Versmessen H.
      • Engels B.
      • Tournel K.
      • Vinh-Hung V.
      • et al.
      Toxicity and outcome results of a class solution with moderately hypofractionated radiotherapy in inoperable Stage III non-small cell lung cancer using helical tomotherapy.


      40 patients
      MLD < 17 Gy (20 Gy)17 GII + (43%)7 GII (23%)
      2 GV (5%)5 GIII (16%)
      25rNTDmean for <20% risk of RP(CTCAE$)

      32 GI RP (70%)

      6 GII RP (13%)

      No GIII+
      Adkison
      • Adkison J.B.
      • Khuntia D.
      • Bentzen S.M.
      • Cannon G.M.
      • Tomé W.A.
      • Jaradat H.
      • et al.
      Dose escalated, hypofractionated radiotherapy using helical tomotherapy for inoperable non-small cell lung cancer: preliminary results of a risk-stratified phase I.


      46 patients
      25Binned according to rNTDmeanC(CTCAE$)

      12 GII RP (16%)

      No GIII + RP

      6 GIV–V toxicities (1 at 1 month, 1 at 1.6 months and 3 at <8 months)
      Cannon
      • Cannon D.M.
      • Mehta M.P.
      • Adkison J.B.
      • Khuntia D.
      • Traynor A.M.
      • Tomé W.A.
      • et al.
      Dose-limiting toxicity after hypofractionated dose-escalated radiotherapy in non-small-cell lung cancer.


      79 patients

      (75 evaluable for toxicity)
      24Not reportedC(RTOG/EORTC)

      6 GIII–IV (8%) – shortness of breath
      (RTOG/EORTC)

      11 GIII–IV (14%)

      1 fatal lung haemorrhage
      Belderbos
      • Belderbos J.S.
      • Uitterhoeve L.
      • van Zandwijk N.
      • Belderbos H.
      • Rodrigus P.
      • van de Vaart P.
      • et al.
      Randomised trial of sequential versus concurrent chemo-radiotherapy in patients with inoperable non-small cell lung cancer (EORTC 08972-22973).


      78 patients (76 RT started)
      24V25Gy < 30%C(RTOG/EORTC)

      23 GI (50%)

      3 GII (6.5%)
      (SWOG)

      9 GI RP

      1 GIII RP
      Thirion
      • Thirion P.
      • Brennan S.
      • Fitzpatrick D.
      • Armstrong J.
      • Dunne M.
      • O’Shea C.
      • et al.
      Escalated dose for Non-Small-Cell Lung Cancer with accelerated hypofractionated three-dimensional conformal radiation therapy.


      46 patients
      21V20Gy < 35%C

      MLD < 20 Gy
      (SWOG)

      21 GI RP (12%)

      9 GII RP (5%)

      3 GV (2%)
      (RTOG/EORTC)

      6 GIII (4%)
      Kepka
      • Kepka L.
      • Tyc-Szczepaniak D.
      • Bujko K.
      Dose-per-fraction escalation of accelerated hypofractionated three-dimensional conformal radiotherapy in locally advanced non-small cell lung cancer.


      173 patients
      20–25MLD < 18 GyC(CTCAE$)

      3 GII RP (5%)

      No GIII+
      Yung
      • Yung T.
      • Giuliani M.
      • Le L.
      • Sun A.
      Outcomes of accelerated hypofractionated radiotherapy in stage I non-small-cell lung cancer.


      60 patients
      20V20Gy < 30%A(CTCAE$)

      3 GIII + RP (5.2%)
      Maguire
      • Maguire J.
      • Khan I.
      • McMenemin R.
      • O’Rourke N.
      • McNee S.G.
      • Kelly V.
      • et al.
      SOCCAR: A randomised phase II trial comparing sequential versus concurrent chemotherapy and radical hypofractionated radiotherapy in patients with inoperable stage III Non-Small Cell Lung Cancer and good performance status.


      59 patients
      20MLD < 17GyA (with EQD2 correction)I-START
      • Nixon L.
      • Lester J.F.
      • Mayles W.P.M.
      • Mayles H.
      • Parsons E.
      • Ionescu A.
      • et al.
      Dose escalation in the I-START trial – ISoToxic Accelerated RadioTherapy in locally advanced non-small cell lung cancer.
      ,

      ISoToxic Accelerated RadioTherapy in Locally Advanced Non-small Cell Lung Cancer: The Phase I/II I-START Trial (I-START) n.d. https://clinicaltrials.gov/ct2/show/NCT01537991.



      Trial Protocol
      20V20Gy < 25–30%C

      MLD < 15 Gy
      (RTOG)

      6 GI–II RP (20%)

      1 GIII RP (3%)

      No GIV+
      (RTOG)

      2 GIII (7%)

      No GIV+

      Osti
      • Osti M.F.
      • Agolli L.
      • Valeriani M.
      • Falco T.
      • Bracci S.
      • De Sanctis V.
      • et al.
      Image guided hypofractionated 3-dimensional radiation therapy in patients with inoperable advanced stage non-small cell lung cancer.


      30 patients
      20V16Gy < 22%C(RTOG/EORTC)

      No GII+
      (RTOG/EORTC)

      1 GI (2.7%)
      Bonfili
      • Bonfili P.
      • Di Staso M.
      • Gravina G.L.
      • Franzese P.
      • Buonopane S.
      • Soldà F.
      • et al.
      Hypofractionated radical radiotherapy in elderly patients with medically inoperable stage I-II non-small-cell lung cancer.


      36 patients
      18–20V20Gy < 27.5%C

      MLD < 16Gy

      Preferred rather than required
      (CTCAE$)

      6 GII RP (10.0%)

      2 GIII RP (3.3%)

      1 GV RP (1.7%) – treated to 54 Gy
      Oh
      • Oh D.
      • Ahn Y.C.
      • Kim B.
      • Pyo H.R.
      Hypofractionated three-dimensional conformal radiation therapy alone for centrally located cT1-3N0 Non-Small-Cell Lung Cancer.


      60 patients
      15V20Gy < 30%C

      MLD < 20 Gy
      (CTCAE$)

      56 G0 RP (79%)

      10 GI RP (14%)

      4 GII RP (6%)

      1 GIII RP (1%)

      0 GIV- GV RP
      Swanick
      • Swanick C.W.
      • Lin S.H.
      • Sutton J.
      • Naik N.S.
      • Allen P.K.
      • Levy L.B.
      • et al.
      Use of simultaneous radiation boost achieves high control rates in patients with non-small-cell lung cancer who are not candidates for surgery or conventional chemoradiation.


      71 patients

      (4 received concurrent)
      15No DVCC applied(CTCAE$)

      Cough: 39 GI (48.8%), 3 GII (3.8%), 6 GIII (7.5%)

      Dyspnoea: 24 GI (30%), 21 GII (26.3%), 8 GIII (10%), 3 GIV (3.8%)

      Pneumonitis: 5 GI (6.3%), 4 GII (5%), 7 GIII (8.8%), 1 GIV (1.3%)

      1 GV pulmonary haemorrhage
      Cheung
      • Cheung P.
      • Faria S.L.
      • Ahmed S.
      • Chabot P.
      • Greenland J.
      • Kurien E.
      • et al.
      Phase II study of accelerated hypofractionated three-dimensional conformal radiotherapy for stage T1-3 N0 M0 non-small cell lung cancer: NCIC CTG BR.25.


      80 patients
      # = fraction,, ‡ = two patients with T4 disease died from haemoptysis, $ = paper does not differentiate between acute and late toxicity, RP = radiation pneumonitis, VXGy = % volume receiving X dose, MLD = mean lung dose, rNTDmean = mean fraction-normalised lung dose divided by the normalised prescription dose, NTCP = normal tissue complication probability, A = combined lung – GTV, B = combined lung – PTV, C = specific combined lung volume not detailed, D = combined lung – CTV, E = total lung.
      Table 2Summary of dose–volume constraints and reported toxicities (with concurrent chemotherapy) for the combined lung in hypofractionated NSCLC studies.
      No. of #Treatment Planning LimitAcute toxicity

      (Scale)
      Late toxicity

      (Scale)
      References
      30V19Gy < 30%A(RTOG)

      6 GIII (10%)
      (RTOG)

      3 GIII (5%)
      Donato
      • Donato V.
      • Arcangeli S.
      • Monaco A.
      • Caruso C.
      • Cianciulli M.
      • Boboc G.
      • et al.
      Moderately escalated hypofractionated (chemo) radiotherapy delivered with helical intensity-modulated technique in stage III unresectable non-small cell lung cancer.
      MLD < 19 GyOverall toxicity for 61 patients, not separated by concurrent/sequential chemotherapy schedule29 patients
      3020% risk of GII–V RPIDEAL-CRT
      • Warren S.
      • Panettieri V.
      • Panakis N.
      • Bates N.
      • Lester J.F.
      • Jain P.
      • et al.
      Optimizing collimator margins for isotoxically dose-escalated conformal radiation therapy of non-small cell lung cancer.


      Trial Protocol
      30D0.03cc < 110%A Rx Dose

      V5Gy < 65%

      V20Gy < 35%

      MLD < 20 Gy
      RTOG 11–06

      Kong F-MS, Machtay M, Bradley JD, Ten Haken RK, Xiao Y, Matuszak MM, et al. RTOG 1106/ACRIN 6697 Randomized phase II trial of individualized adaptive radiotherapy using during treatment FDG-PET/CT and modern technology in locally advanced non-small cell lung cancer (NSCLC). 2013.



      Trial Protocol
      25V20Gy < 35%C(RTOG)

      12 GI (24.5%)

      3 GII (6.1%)

      2 GIII (4.1%)

      0 GIV (0%)

      2 GV (4.1%)
      (EORTC)

      15 GI (34.1%)

      6 GII (13.6%)

      3 GIII (6.8%)

      1 GIV (2.3%)

      Cho
      • Cho K.H.
      • Ahn S.J.
      • Pyo H.R.
      • Kim K.-S.
      • Kim Y.-C.
      • Moon S.H.
      • et al.
      A Phase II study of synchronous three-dimensional conformal boost to the gross tumor volume for patients with unresectable Stage III non-small-cell lung cancer: results of Korean Radiation Oncology Group 0301 study.


      49 patients
      25V20Gy < 30%C

      MLD < 20 Gy
      (CTCAE$)

      52 GII (17.7%)

      6 GIII (2.0%)

      1 GIV (0.3%)

      3 GV (0.9%)
      Kerner
      • Kerner G.S.M.A.
      • van Dullemen L.F.A.
      • Wiegman E.M.
      • Widder J.
      • Blokzijl E.
      • Driever E.M.
      • et al.
      Concurrent gemcitabine and 3D radiotherapy in patients with stage III unresectable non-small cell lung cancer.


      318 patients
      25MLD < 14 GyC

      V20Gy < 25%
      (CTCAE)

      No RP reported
      Bearz
      • Bearz A.
      • Minatel E.
      • Rumeileh I.
      Concurrent chemoradiotherapy with tomotherapy in locally advanced non-small cell lung cancer: a phase I, docetaxel dose-escalation study, with hypofractionated radiation regimen.


      33 patients
      22–28V20Gy < 30%D(CTCAE)

      2 GI (20%)

      No GII+
      (CTCAE)

      4 GI (40%)

      No GII+
      Matsuura
      • Matsuura K.
      • Kimura T.
      • Kashiwado K.
      • Fujita K.
      • Akagi Y.
      • Yuki S.
      • et al.
      Results of a preliminary study using hypofractionated involved-field radiation therapy and concurrent carboplatin/paclitaxel in the treatment of locally advanced non-small-cell lung cancer.


      10 patients
      24Not reportedC(RTOG/EORTC)

      6 GIII–IV (9%) – shortness of breath
      (RTOG/EORTC)

      12 GIII–IV (18%)

      1 fatal lung haemorrhage
      Belderbos
      • Belderbos J.S.
      • Uitterhoeve L.
      • van Zandwijk N.
      • Belderbos H.
      • Rodrigus P.
      • van de Vaart P.
      • et al.
      Randomised trial of sequential versus concurrent chemo-radiotherapy in patients with inoperable non-small cell lung cancer (EORTC 08972-22973).


      80 patients (66 chemo-RT started)
      24LQ correctedC (α/β = 3)

      MLD < 20 Gy
      Not reportedNot reportedChen
      • Chen C.
      • Uyterlinde W.
      • Sonke J.-J.
      • de Bois J.
      • van den Heuvel M.
      • Belderbos J.S.
      Severe late esophagus toxicity in NSCLC patients treated with IMRT and concurrent chemotherapy.


      231 patients
      22–24V20Gy < 30%B(CTCAE$)

      4 GI RP (30.8%)

      5 GII RP (38.5%)

      1 GIII RP (7.7%)
      Lin
      • Lin Q.
      • Liu Y.
      • Ren X.
      • Wang N.
      • Chen X.
      • Wang D.
      • et al.
      Dose escalation of accelerated hypofractionated three-dimensional conformal radiotherapy (at 3 Gy/fraction) with concurrent vinorelbine and carboplatin chemotherapy in unresectable stage III non-small-cell lung cancer : a phase I trial.


      13 patients
      20V20Gy < 40%ANot reportedNot reportedMaguire
      • Maguire J.
      • Kelly V.
      • Ledson M.
      • Smyth C.
      • Walshaw M.
      Changes in pulmonary functions after radical accelerated hypofractionatad radiotherapy concurrent with cisplatinum and vinoraibine.


      30 patients
      20V20Gy < 30%A(CTCAE$)

      2 GIII+ (3.1%)
      Maguire
      • Maguire J.
      • Khan I.
      • McMenemin R.
      • O’Rourke N.
      • McNee S.G.
      • Kelly V.
      • et al.
      SOCCAR: A randomised phase II trial comparing sequential versus concurrent chemotherapy and radical hypofractionated radiotherapy in patients with inoperable stage III Non-Small Cell Lung Cancer and good performance status.


      69 patients
      # = fraction,, ‡ = two patients with T4 disease died from haemoptysis, $ = paper does not differentiate between acute and late toxicity, RP = radiation pneumonitis, VXgy = % volume receiving X dose, MLD = mean lung dose, rNTDmean = mean fraction-normalised lung dose divided by the normalised prescription dose, NTCP = normal tissue complication probability, A = combined lung – GTV, B = combined lung – PTV, C = specific combined lung volume not detailed, D = combined lung – CTV.

      Brachial plexus

      None of the clinical studies reviewed applied a constraint to the brachial plexus but three of the trial protocols did. I-START imposed D1cc < 55 Gy/20# [
      • Nixon L.
      • Lester J.F.
      • Mayles W.P.M.
      • Mayles H.
      • Parsons E.
      • Ionescu A.
      • et al.
      Dose escalation in the I-START trial – ISoToxic Accelerated RadioTherapy in locally advanced non-small cell lung cancer.
      ], while IDEAL-CRT utilised both D0.1cc < 65 Gy/30# and D30% < 60 Gy/30# [
      • Warren S.
      • Panettieri V.
      • Panakis N.
      • Bates N.
      • Lester J.F.
      • Jain P.
      • et al.
      Optimizing collimator margins for isotoxically dose-escalated conformal radiation therapy of non-small cell lung cancer.
      ], these correspond to EQD2 limits of D1cc < 65.3 Gy2, D0.1cc < 67.7 Gy2 and D30% < 60 Gy2 respectively. As RTOG 11-06 is a 2-phase regime an EQD2 correction of D0.03cc < 63 Gy is not appropriate. Cannon et al. [
      • Cannon D.M.
      • Mehta M.P.
      • Adkison J.B.
      • Khuntia D.
      • Traynor A.M.
      • Tomé W.A.
      • et al.
      Dose-limiting toxicity after hypofractionated dose-escalated radiotherapy in non-small-cell lung cancer.
      ] reported one patient developing brachial plexopathy following 57 Gy/25#, (EQD2 = 61Gy2), to a right upper lobe tumour and axillary node.

      Heart

      A summary of the heart data gathered is included in the Supplementary material. There is considerable heterogeneity in the DVCs applied: from maximum dose [

      Kong F-MS, Machtay M, Bradley JD, Ten Haken RK, Xiao Y, Matuszak MM, et al. RTOG 1106/ACRIN 6697 Randomized phase II trial of individualized adaptive radiotherapy using during treatment FDG-PET/CT and modern technology in locally advanced non-small cell lung cancer (NSCLC). 2013.

      ,
      • Cheung P.
      • Faria S.L.
      • Ahmed S.
      • Chabot P.
      • Greenland J.
      • Kurien E.
      • et al.
      Phase II study of accelerated hypofractionated three-dimensional conformal radiotherapy for stage T1-3 N0 M0 non-small cell lung cancer: NCIC CTG BR.25.
      ], to mean heart dose [

      Kong F-MS, Machtay M, Bradley JD, Ten Haken RK, Xiao Y, Matuszak MM, et al. RTOG 1106/ACRIN 6697 Randomized phase II trial of individualized adaptive radiotherapy using during treatment FDG-PET/CT and modern technology in locally advanced non-small cell lung cancer (NSCLC). 2013.

      ,
      • Chen C.
      • Uyterlinde W.
      • Sonke J.-J.
      • de Bois J.
      • van den Heuvel M.
      • Belderbos J.S.
      Severe late esophagus toxicity in NSCLC patients treated with IMRT and concurrent chemotherapy.
      ], to minimum dose [
      • Nixon L.
      • Lester J.F.
      • Mayles W.P.M.
      • Mayles H.
      • Parsons E.
      • Ionescu A.
      • et al.
      Dose escalation in the I-START trial – ISoToxic Accelerated RadioTherapy in locally advanced non-small cell lung cancer.
      ,
      • Warren S.
      • Panettieri V.
      • Panakis N.
      • Bates N.
      • Lester J.F.
      • Jain P.
      • et al.
      Optimizing collimator margins for isotoxically dose-escalated conformal radiation therapy of non-small cell lung cancer.
      ,
      • Kong F-.M.S.
      • Hayman J.
      • Griffith K.A.
      • Kalemkerian G.P.
      • Arenberg D.
      • Lyons S.
      • et al.
      Final toxicity results of a radiation-dose escalation study in patients with non-small-cell lung cancer (NSCLC): predictors for radiation pneumonitis and fibrosis.
      ]. Late heart toxicity tends not to be reported in the NSCLC literature, perhaps a reflection of the time taken for it to develop and poor overall survival in this patient population. Belderbos et al. [
      • Belderbos J.S.
      • Uitterhoeve L.
      • van Zandwijk N.
      • Belderbos H.
      • Rodrigus P.
      • van de Vaart P.
      • et al.
      Randomised trial of sequential versus concurrent chemo-radiotherapy in patients with inoperable non-small cell lung cancer (EORTC 08972-22973).
      ] treated 142 NSCLC patients to 66 Gy/24# and observed two cases of grade 4 toxicity. A study on pericardial effusions initially only identified fraction size as a toxicity predictor however, once a correction for fraction size was applied only the ‘bio-average’ and ‘bio-maximum’ dose (LQ corrected average and maximum dose) were significant [
      • Martel M.K.
      • Sahijdak W.
      • Ten Haken R.K.
      • Kessler M.
      • Turrisi A.T.
      Fraction size and dose parameters related to the incidence of pericardial effiusions.
      ]. There are some data also on the effect of irradiation of the great vessels. In a review of 100 NSCLC patients treated with 60–85.5 Gy in 30–37# Han et al. demonstrated that pulmonary artery invasion and the volume of pulmonary artery receiving 45–60 Gy were associated with reduced overall survival [
      • Han C.-B.
      • Wang W.-L.
      • Quint L.
      • Xue J.-X.
      • Matuszak M.M.
      • Ten Haken R.K.
      • et al.
      Pulmonary artery invasion, high-dose radiation, and overall survival in patients with non-small cell lung cancer.
      ].

      Oesophagus

      Table 3, Table 4 summarise the oesophageal DVCs utilised and toxicities reported, stratified by chemotherapy. Cannon et al. established a maximum tolerated dose (MTD) of 63.25 Gy/25# (EQD2 = 70Gy3, 58.9 Gy/20#) [
      • Cannon D.M.
      • Mehta M.P.
      • Adkison J.B.
      • Khuntia D.
      • Traynor A.M.
      • Tomé W.A.
      • et al.
      Dose-limiting toxicity after hypofractionated dose-escalated radiotherapy in non-small-cell lung cancer.
      ]. A similar study in a concurrent chemotherapy setting established a MTD of 69 Gy/23# (EQD2 = 70Gy3, 56.58 Gy/20#) [
      • Lin Q.
      • Liu Y.
      • Ren X.
      • Wang N.
      • Chen X.
      • Wang D.
      • et al.
      Dose escalation of accelerated hypofractionated three-dimensional conformal radiotherapy (at 3 Gy/fraction) with concurrent vinorelbine and carboplatin chemotherapy in unresectable stage III non-small-cell lung cancer : a phase I trial.
      ]. I-START have stratified dose escalation groups according to the length of oesophagus within the PTV (planning target volume) [
      • Nixon L.
      • Lester J.F.
      • Mayles W.P.M.
      • Mayles H.
      • Parsons E.
      • Ionescu A.
      • et al.
      Dose escalation in the I-START trial – ISoToxic Accelerated RadioTherapy in locally advanced non-small cell lung cancer.
      ]. Chen et al. utilised LQ corrected DVHs in their dosimetric analysis and reported values in terms of EQD2 (acute: α/β = 10, late: α/β = 3). Three of their patients developed a fistula and all subsequently died. A higher grade or acute toxicity was significantly associated with a lower recovery rate from late toxicity. The most predictive dosimetric variables of toxicity rates were n = 0.03 for EUD (equivalent uniform dose) and V76.7Gy [
      • Chen C.
      • Uyterlinde W.
      • Sonke J.-J.
      • de Bois J.
      • van den Heuvel M.
      • Belderbos J.S.
      Severe late esophagus toxicity in NSCLC patients treated with IMRT and concurrent chemotherapy.
      ]. Following two deaths due to toxicity Thirion et al. amended their protocol to include an additional DVC of ‘98% of circumferential oesophagus ⩽1 cm’. Ten patients were subsequently treated with single instances of both grade 2 and grade 3 toxicity reported [
      • Thirion P.
      • Brennan S.
      • Fitzpatrick D.
      • Armstrong J.
      • Dunne M.
      • O’Shea C.
      • et al.
      Escalated dose for Non-Small-Cell Lung Cancer with accelerated hypofractionated three-dimensional conformal radiation therapy.
      ]. The crude incidence of grade 3+ toxicity in the sequential studies reported here was 3.8% (25/663) for acute and 0.9% (6/663) for late toxicity. In the concurrent studies the crude incidences of grade 3+ acute and late toxicity were 10.7% (20/187) and 4.7% (17/358) respectively. Three concurrent studies did not distinguish between acute and late toxicity and reported grade 3+ rates of 10% (40/400) [
      • Kerner G.S.M.A.
      • van Dullemen L.F.A.
      • Wiegman E.M.
      • Widder J.
      • Blokzijl E.
      • Driever E.M.
      • et al.
      Concurrent gemcitabine and 3D radiotherapy in patients with stage III unresectable non-small cell lung cancer.
      ,
      • Maguire J.
      • Khan I.
      • McMenemin R.
      • O’Rourke N.
      • McNee S.G.
      • Kelly V.
      • et al.
      SOCCAR: A randomised phase II trial comparing sequential versus concurrent chemotherapy and radical hypofractionated radiotherapy in patients with inoperable stage III Non-Small Cell Lung Cancer and good performance status.
      ,
      • Lin Q.
      • Liu Y.
      • Ren X.
      • Wang N.
      • Chen X.
      • Wang D.
      • et al.
      Dose escalation of accelerated hypofractionated three-dimensional conformal radiotherapy (at 3 Gy/fraction) with concurrent vinorelbine and carboplatin chemotherapy in unresectable stage III non-small-cell lung cancer : a phase I trial.
      ].
      Table 3Summary of dose–volume constraints and reported toxicities (with sequential or no chemotherapy) for the oesophagus in hypofractionated NSCLC studies.
      No. of #Treatment planning limitAcute toxicity

      (scale)
      Late toxicity

      (scale)
      References
      30–49Veff < 0.33

      Ref doses 65, 72 and 80 Gy
      (CTCAE)

      43 GI (39.5%) – oesophagitis

      18 GII (16.5%) – oesophagitis

      3 GIII (2.7%) – oesophagitis
      (CTCAE)

      10 GI (9.2%) – oesophageal stricture

      1 GII (0.9%) – oesophageal stricture

      No GIII+
      Kong
      • Kong F-.M.S.
      • Hayman J.
      • Griffith K.A.
      • Kalemkerian G.P.
      • Arenberg D.
      • Lyons S.
      • et al.
      Final toxicity results of a radiation-dose escalation study in patients with non-small-cell lung cancer (NSCLC): predictors for radiation pneumonitis and fibrosis.


      109 patients
      30Mean < 32Gy

      V33Gy < 50%

      V47Gy < 40%
      (RTOG)

      No GIII+
      (RTOG)

      No GIII+
      Donato
      • Donato V.
      • Arcangeli S.
      • Monaco A.
      • Caruso C.
      • Cianciulli M.
      • Boboc G.
      • et al.
      Moderately escalated hypofractionated (chemo) radiotherapy delivered with helical intensity-modulated technique in stage III unresectable non-small cell lung cancer.


      32 patients
      30Dmax < 70Gy

      D33% < 66Gy

      D50% < 35 Gy
      (RTOG)

      13 GII (33%)

      1 GIII (2.5%) – dysphagia
      (RTOG)

      No persisting GII+
      Bral
      • Bral S.
      • Duchateau M.
      • Versmessen H.
      • Engels B.
      • Tournel K.
      • Vinh-Hung V.
      • et al.
      Toxicity and outcome results of a class solution with moderately hypofractionated radiotherapy in inoperable Stage III non-small cell lung cancer using helical tomotherapy.


      40 patients
      25Veff < 0.30

      D0.5cc (EQD2) < 64 Gy
      (RTOG)

      11 GI (24%)

      7 GII (15%)

      No GIII+
      Adkison
      • Adkison J.B.
      • Khuntia D.
      • Bentzen S.M.
      • Cannon G.M.
      • Tomé W.A.
      • Jaradat H.
      • et al.
      Dose escalated, hypofractionated radiotherapy using helical tomotherapy for inoperable non-small cell lung cancer: preliminary results of a risk-stratified phase I.


      46 patients
      25Veff < 0.3

      D5cc < 64 Gy (was Dmax) (EQD2 equivalent)
      (CTCAE)

      36 GII (48%) – oesophagitis

      No GIII+
      (CTCAE)

      21 GII (28%)

      No GIII+
      Cannon
      • Cannon D.M.
      • Mehta M.P.
      • Adkison J.B.
      • Khuntia D.
      • Traynor A.M.
      • Tomé W.A.
      • et al.
      Dose-limiting toxicity after hypofractionated dose-escalated radiotherapy in non-small-cell lung cancer.


      79 patients

      (75 evaluable for toxicity)
      24<18 cm in elective fields

      <12 cm in boost fields
      (RTOG/EORTC)

      4 GIII (5%)

      no GIV
      (RTOG/EORTC)

      GI–II (11%)

      GIII (4%)

      no GIV
      Belderbos
      • Belderbos J.S.
      • Uitterhoeve L.
      • van Zandwijk N.
      • Belderbos H.
      • Rodrigus P.
      • van de Vaart P.
      • et al.
      Randomised trial of sequential versus concurrent chemo-radiotherapy in patients with inoperable non-small cell lung cancer (EORTC 08972-22973).


      78 patients (76 RT started)
      24Protocol revision: <1 cm circumferential oesophagus in 98% isodose line(RTOG/EORTC)

      28 GI (77.8%)

      5 GII (13.8%)

      3 GIII (8.3%)
      (RTOG/EORTC)

      2 GV

      10 pts post-DVC

      1 GI (10%)

      1 GII (10%)

      1 GIII (10%)
      Thirion
      • Thirion P.
      • Brennan S.
      • Fitzpatrick D.
      • Armstrong J.
      • Dunne M.
      • O’Shea C.
      • et al.
      Escalated dose for Non-Small-Cell Lung Cancer with accelerated hypofractionated three-dimensional conformal radiation therapy.


      46 patients
      21None utilised(RTOG/EORTC)

      12 GIII (7%)
      (RTOG/EORTC)

      1 GI (0.5%)

      3 GII (2%)
      Kepka
      • Kepka L.
      • Tyc-Szczepaniak D.
      • Bujko K.
      Dose-per-fraction escalation of accelerated hypofractionated three-dimensional conformal radiotherapy in locally advanced non-small cell lung cancer.


      173 patients
      20–25None utilised(CTCAE$)

      3 GII (5%)

      No GIII+
      Yung
      • Yung T.
      • Giuliani M.
      • Le L.
      • Sun A.
      Outcomes of accelerated hypofractionated radiotherapy in stage I non-small-cell lung cancer.


      60 patients
      20<12 cm in the PTV(CTCAE$)

      5 GIII (8.5%)

      No GIV–V
      Maguire
      • Maguire J.
      • Khan I.
      • McMenemin R.
      • O’Rourke N.
      • McNee S.G.
      • Kelly V.
      • et al.
      SOCCAR: A randomised phase II trial comparing sequential versus concurrent chemotherapy and radical hypofractionated radiotherapy in patients with inoperable stage III Non-Small Cell Lung Cancer and good performance status.


      59 patients
      20<Rx DoseI-START
      • Nixon L.
      • Lester J.F.
      • Mayles W.P.M.
      • Mayles H.
      • Parsons E.
      • Ionescu A.
      • et al.
      Dose escalation in the I-START trial – ISoToxic Accelerated RadioTherapy in locally advanced non-small cell lung cancer.
      ,

      ISoToxic Accelerated RadioTherapy in Locally Advanced Non-small Cell Lung Cancer: The Phase I/II I-START Trial (I-START) n.d. https://clinicaltrials.gov/ct2/show/NCT01537991.



      Trial Protocol
      20V42Gy < 32%(RTOG)

      12 GI–II (40%)

      2 GIII (7%)

      No GIV+
      (RTOG)

      1 GIII (3%)

      No GIV+
      Osti
      • Osti M.F.
      • Agolli L.
      • Valeriani M.
      • Falco T.
      • Bracci S.
      • De Sanctis V.
      • et al.
      Image guided hypofractionated 3-dimensional radiation therapy in patients with inoperable advanced stage non-small cell lung cancer.


      30 patients
      20V41Gy < 32%(RTOG/EORTC)

      7 GII (19.4%)
      (RTOG/EORTC)

      No late toxicity
      Bonfili
      • Bonfili P.
      • Di Staso M.
      • Gravina G.L.
      • Franzese P.
      • Buonopane S.
      • Soldà F.
      • et al.
      Hypofractionated radical radiotherapy in elderly patients with medically inoperable stage I-II non-small-cell lung cancer.


      36 patients
      18–20None(CTCAE$)

      10 GII (16.7%)

      No GIII+
      Oh
      • Oh D.
      • Ahn Y.C.
      • Kim B.
      • Pyo H.R.
      Hypofractionated three-dimensional conformal radiation therapy alone for centrally located cT1-3N0 Non-Small-Cell Lung Cancer.


      60 patients
      15Mean < 34 Gy(CTCAE$)

      39 G0 (55%) – oesophagitis

      0 GI (0%) – oesophagitis

      28 GII (39%) – oesophagitis

      3 GIII (5%) – oesophagitis

      0 GIV (0%)– oesophagitis

      1 GV (1%) – oesophagitis
      Swanick
      • Swanick C.W.
      • Lin S.H.
      • Sutton J.
      • Naik N.S.
      • Allen P.K.
      • Levy L.B.
      • et al.
      Use of simultaneous radiation boost achieves high control rates in patients with non-small-cell lung cancer who are not candidates for surgery or conventional chemoradiation.


      71 patients

      (4 received concurrent)
      15Dmax < 40 Gy (45 Gy)(CTCAE$)

      11 GI (13.8%) – oesophagitis

      5 GII (6.3%) – oesophagitis

      No GIII+
      Cheung
      • Cheung P.
      • Faria S.L.
      • Ahmed S.
      • Chabot P.
      • Greenland J.
      • Kurien E.
      • et al.
      Phase II study of accelerated hypofractionated three-dimensional conformal radiotherapy for stage T1-3 N0 M0 non-small cell lung cancer: NCIC CTG BR.25.


      80 patients
      # = fraction, PD = prescribed dose, $ = paper does not differentiate between acute and late toxicity, VXgy = % volume receiving X dose, MED = mean oesophageal dose, Dycm = dose (in Gy) received by y cm of the oesophagus.
      Table 4Summary of dose–volume constraints and reported toxicities (with concurrent chemotherapy) for the oesophagus in hypofractionated NSCLC studies.
      No. of #Treatment planning limitAcute toxicity

      (scale)
      Late toxicity

      (scale)
      References
      30Mean < 32Gy

      V33Gy < 50%

      V47Gy < 40%
      (RTOG)

      2 GIII

      (RTOG)

      No GIII + 

      Donato
      • Donato V.
      • Arcangeli S.
      • Monaco A.
      • Caruso C.
      • Cianciulli M.
      • Boboc G.
      • et al.
      Moderately escalated hypofractionated (chemo) radiotherapy delivered with helical intensity-modulated technique in stage III unresectable non-small cell lung cancer.


      29 patients
      30D1cc < PDIDEAL-CRT
      • Warren S.
      • Panettieri V.
      • Panakis N.
      • Bates N.
      • Lester J.F.
      • Jain P.
      • et al.
      Optimizing collimator margins for isotoxically dose-escalated conformal radiation therapy of non-small cell lung cancer.


      Trial Protocol
      30D0.03cc < 74 Gy

      MED < 34Gy
      RTOG 11–06

      Kong F-MS, Machtay M, Bradley JD, Ten Haken RK, Xiao Y, Matuszak MM, et al. RTOG 1106/ACRIN 6697 Randomized phase II trial of individualized adaptive radiotherapy using during treatment FDG-PET/CT and modern technology in locally advanced non-small cell lung cancer (NSCLC). 2013.



      Trial Protocol
      25V55Gy < 30%(RTOG)

      11 GI (22.5%)

      22 GII (44.9%)

      5 GIII (10.2%)

      2 GIV (4.1%)

      No GV
      (EORTC)

      1 GI (2.3%)

      2 GII (4.5%)

      3 GIII (6.8%)

      No GIV+
      Cho
      • Cho K.H.
      • Ahn S.J.
      • Pyo H.R.
      • Kim K.-S.
      • Kim Y.-C.
      • Moon S.H.
      • et al.
      A Phase II study of synchronous three-dimensional conformal boost to the gross tumor volume for patients with unresectable Stage III non-small-cell lung cancer: results of Korean Radiation Oncology Group 0301 study.


      49 patients
      25None utilised(CTCAE$)

      43 GII (13.6%)

      29 GIII (9. 1%)

      1 GIV (0.3%)

      2 GV (0.6%)
      Kerner
      • Kerner G.S.M.A.
      • van Dullemen L.F.A.
      • Wiegman E.M.
      • Widder J.
      • Blokzijl E.
      • Driever E.M.
      • et al.
      Concurrent gemcitabine and 3D radiotherapy in patients with stage III unresectable non-small cell lung cancer.


      318 patients
      25None utilised(CTCAE)

      7 GII (21%)
      (CTCAE)

      No late toxicity reported
      Bearz
      • Bearz A.
      • Minatel E.
      • Rumeileh I.
      Concurrent chemoradiotherapy with tomotherapy in locally advanced non-small cell lung cancer: a phase I, docetaxel dose-escalation study, with hypofractionated radiation regimen.


      33 patients
      24–28None utilised(CTCAE)

      3 GI (30%)

      4 GII (40%)

      no GIII+
      (CTCAE)

      No late G2 + toxicity reported
      Matsuura
      • Matsuura K.
      • Kimura T.
      • Kashiwado K.
      • Fujita K.
      • Akagi Y.
      • Yuki S.
      • et al.
      Results of a preliminary study using hypofractionated involved-field radiation therapy and concurrent carboplatin/paclitaxel in the treatment of locally advanced non-small-cell lung cancer.


      10 patients
      24<18 cm in elective fields

      <12 cm in boost fields
      (RTOG/EORTC)

      9 GIII (13.6%)

      2 GIV (3%)
      (RTOG/EORTC)

      GI-II (22%)

      GIII (5%)
      Belderbos
      • Martel M.K.
      • Sahijdak W.
      • Ten Haken R.K.
      • Kessler M.
      • Turrisi A.T.
      Fraction size and dose parameters related to the incidence of pericardial effiusions.


      80 patients (66 chemo-RT started)
      24LQ corrected (α/β = 10)

      V35Gy < 65%
      (CTCAE)

      Not reported
      (RTOG)

      8 GIII (4.7%)

      3 GV (1.75%)
      Chen
      • Chen C.
      • Uyterlinde W.
      • Sonke J.-J.
      • de Bois J.
      • van den Heuvel M.
      • Belderbos J.S.
      Severe late esophagus toxicity in NSCLC patients treated with IMRT and concurrent chemotherapy.


      171 patients
      22–24Dmax < 70Gy

      D10cm < 60 Gy
      (CTCAE$)

      4 GI (30.8%) – oesophagitis

      5 GII (38.5%) – oesophagitis

      2 GIII (15.4%) – oesophagitis
      Lin
      • Lin Q.
      • Liu Y.
      • Ren X.
      • Wang N.
      • Chen X.
      • Wang D.
      • et al.
      Dose escalation of accelerated hypofractionated three-dimensional conformal radiotherapy (at 3 Gy/fraction) with concurrent vinorelbine and carboplatin chemotherapy in unresectable stage III non-small-cell lung cancer : a phase I trial.


      13 patients
      20<12 cm in the PTV(CTCAE$)

      6 GIII (8.8%)

      No GIV–V
      Maguire
      • Maguire J.
      • Khan I.
      • McMenemin R.
      • O’Rourke N.
      • McNee S.G.
      • Kelly V.
      • et al.
      SOCCAR: A randomised phase II trial comparing sequential versus concurrent chemotherapy and radical hypofractionated radiotherapy in patients with inoperable stage III Non-Small Cell Lung Cancer and good performance status.


      69 patients
      # = fraction, PD = prescribed dose, $ = paper does not differentiate between acute and late toxicity, VXgy = % volume receiving X dose, MED = mean oesophageal dose, Dycm = dose (in Gy) received by y cm of the oesophagus.

      Airway

      Cho et al. treated 49 patients to 60 Gy/25# with no bronchial stenosis [
      • Cho K.H.
      • Ahn S.J.
      • Pyo H.R.
      • Kim K.-S.
      • Kim Y.-C.
      • Moon S.H.
      • et al.
      A Phase II study of synchronous three-dimensional conformal boost to the gross tumor volume for patients with unresectable Stage III non-small-cell lung cancer: results of Korean Radiation Oncology Group 0301 study.
      ]. Only two studies specified an airway DVC in treatment planning. Cheung et al. limited the dose to the trachea/main-stem bronchus to 50 Gy in 15# (EQD2 = 63.33Gy3) with no toxicity reported. Cannon et al. imposed two dose limits on the proximal bronchial tree: D3cc < 75 Gy and Dmax < 83 Gy. Six of the 79 patients had grade 4/5 toxicities that could possibly be attributed to RT with an increased incidence in those that received greater than 75 Gy. Doses received by small portions of the proximal bronchial tree were significantly associated with these grade 4/5 toxicities [
      • Cannon D.M.
      • Mehta M.P.
      • Adkison J.B.
      • Khuntia D.
      • Traynor A.M.
      • Tomé W.A.
      • et al.
      Dose-limiting toxicity after hypofractionated dose-escalated radiotherapy in non-small-cell lung cancer.
      ].

      Spinal cord

      Analysis by Macbeth et al. [
      • Macbeth F.R.
      • Wheldon T.E.
      • Girling D.J.
      • Stephens R.J.
      • Machin D.
      • Bleehen N.M.
      • et al.
      Radiation myelopathy: estimates of risk in 1048 patients in three randomized trials of palliative radiotherapy for non-small cell lung cancer. The medical research council lung cancer working party.
      ] shows that the α/β ratio for the thoracic spinal cord is lower that the 3 Gy commonly assumed and is possibly close to 2 Gy. For DVCs reported in the literature (full Table in Supplementary materials) the EQD2 values range from 34.56–52 Gy2, with the majority in the range 42.2–46.2 Gy2. There was a single grade 4 toxicity reported, a diabetic patient developing paraparesis 6-years post-RT (spinal cord dose of 44 Gy/21#) [
      • Kepka L.
      • Tyc-Szczepaniak D.
      • Bujko K.
      Dose-per-fraction escalation of accelerated hypofractionated three-dimensional conformal radiotherapy in locally advanced non-small cell lung cancer.
      ].

      Discussion

      When interpreting DVCs for use in the clinic factors including inhomogeneity corrections, treatment delivery technique, dose calculation algorithm, number of fractions and OAR delineation must be considered. Vogelius et al. examined the risk of radiation pneumonitis via NTCP (normal tissue complication probability) modelling and concluded that, in the case of hypofractionation, modern dose distributions are radiobiologically more forgiving as much of the normal tissue receives lower doses per # than the tumour [
      • Vogelius I.S.
      • Westerly D.C.
      • Cannon G.M.
      • Bentzen S.M.
      Hypofractionation does not increase radiation pneumonitis risk with modern conformal radiation delivery techniques.
      ]. Five studies and two protocols reviewed here utilised biological correction to the DVH. The studies reviewed use α/β = 3 however, recent laboratory data suggest that α/β for normal lung could be as low as 1.3 Gy [
      • Scheenstra A.E.H.
      • Rossi M.M.G.
      • Belderbos J.S.
      • Damen E.M.F.
      • Lebesque J.V.
      • Sonke J.-J.
      Alpha/beta ratio for normal lung tissue as estimated from lung cancer patients treated with stereotactic body and conventionally fractionated radiation therapy.
      ], contrasting with clinical data of 4.0 ± 0.9 Gy [
      • Bentzen S.M.
      • Skoczylas J.Z.
      • Bernier J.
      Quantitative clinical radiobiology of early and late lung reactions.
      ]. Over time, biologically corrected constraints may become obsolete due to a shift in the parameters used to derive them.
      Doses to normal tissue in modern NSCLC RT are lower than previously due to: steep dose fall-off and highly conformal distributions in IMRT/VMAT (volume modulated arc therapy); a move away from treatment of elective nodal volumes; image guided radiation therapy (IGRT) and gating. An evaluation of radiation pneumonitis since the move to IMRT from 3DCRT has shown a lower rate [
      • Yom S.S.
      • Liao Z.
      • Liu H.H.
      • Tucker S.L.
      • Hu C.-S.
      • Wei X.
      • 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.
      ]. With arc or multi-field IMRT the spatial distribution of lung dose changes with fields entering through the contralateral lung but the region of the ipsilateral lung receiving the prescription dose can been reduced. The importance of considering more than one single lung metric was illustrated in a report on fatal RP after IMRT treatment for mesothelioma [
      • Allen A.M.
      • Czerminska M.
      • Jänne P.A.
      • Sugarbaker D.J.
      • Bueno R.
      • Harris J.R.
      Fatal pneumonitis associated with intensity-modulated radiation therapy for mesothelioma.
      ]. The QUANTEC publication also warned about the use of a single metric in inverse planning due to the possibility of introducing a ‘kink’ into the DVH [
      • Marks L.B.
      • Yorke E.D.
      • Jackson A.
      • Ten Haken R.K.
      • Constine L.S.
      • Eisbruch A.
      • et al.
      Use of normal tissue complication probability models in the clinic.
      ] whereas DVCs such as MLD and rNTDmean inherently include the entire DVH. However, rNTDmean is a post hoc calculation and can’t be used as an objective in inverse planning. Modern dose calculation algorithms model transport in lung tissue more accurately, producing a different DVH than older algorithms for the same treatment plan. Four of the twenty-two papers reviewed reported the dose calculation algorithm used [
      • Kong F.-M.S.
      • Ten Haken R.K.
      • Schipper M.J.
      • Sullivan M.A.
      • Chen M.
      • Lopez C.
      High-dose radiation improved local tumor control and overall survival in patients with inoperable/unresectable non-small-cell lung cancer: long-term results of a radiation dose escalation study.
      ,
      • Swanick C.W.
      • Lin S.H.
      • Sutton J.
      • Naik N.S.
      • Allen P.K.
      • Levy L.B.
      • et al.
      Use of simultaneous radiation boost achieves high control rates in patients with non-small-cell lung cancer who are not candidates for surgery or conventional chemoradiation.
      ,
      • Belderbos J.S.
      • Uitterhoeve L.
      • van Zandwijk N.
      • Belderbos H.
      • Rodrigus P.
      • van de Vaart P.
      • et al.
      Randomised trial of sequential versus concurrent chemo-radiotherapy in patients with inoperable non-small cell lung cancer (EORTC 08972-22973).
      ,
      • Yom S.S.
      • Liao Z.
      • Liu H.H.
      • Tucker S.L.
      • Hu C.-S.
      • Wei X.
      • 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.
      ] with a further five treating with Tomotherapy, which utilises a convolution/superposition algorithm. Three calculated without inhomogeneity corrections [
      • Cheung P.
      • Faria S.L.
      • Ahmed S.
      • Chabot P.
      • Greenland J.
      • Kurien E.
      • et al.
      Phase II study of accelerated hypofractionated three-dimensional conformal radiotherapy for stage T1-3 N0 M0 non-small cell lung cancer: NCIC CTG BR.25.
      ,
      • Cho K.H.
      • Ahn S.J.
      • Pyo H.R.
      • Kim K.-S.
      • Kim Y.-C.
      • Moon S.H.
      • et al.
      A Phase II study of synchronous three-dimensional conformal boost to the gross tumor volume for patients with unresectable Stage III non-small-cell lung cancer: results of Korean Radiation Oncology Group 0301 study.
      ,
      • Thirion P.
      • Brennan S.
      • Fitzpatrick D.
      • Armstrong J.
      • Dunne M.
      • O’Shea C.
      • et al.
      Escalated dose for Non-Small-Cell Lung Cancer with accelerated hypofractionated three-dimensional conformal radiation therapy.
      ]. The impact of the dose calculation algorithm on the normal tissue DVH has been reported to be of the order of 5% [
      • Allen A.M.
      • Czerminska M.
      • Jänne P.A.
      • Sugarbaker D.J.
      • Bueno R.
      • Harris J.R.
      Fatal pneumonitis associated with intensity-modulated radiation therapy for mesothelioma.
      ,
      • Nisbet A.
      • Beange I.
      • Vollmar H.-S.
      • Irvine C.
      • Morgan A.M.
      • Thwaites D.I.
      Dosimetric verification of a commercial collapsed cone algorithm in simulated clinical situations.
      ,
      • Hedin E.
      • Bäck A.
      Influence of different dose calculation algorithms on the estimate of NTCP for lung complications.
      ,
      • De Jaeger K.
      • Hoogeman M.S.
      • Engelsman M.
      • Seppenwoolde Y.
      • Damen E.M.F.
      • Mijnheer B.J.
      • et al.
      Incorporating an improved dose-calculation algorithm in conformal radiotherapy of lung cancer: re-evaluation of dose in normal lung tissue.
      ] with, usually a decrease in the maximum dose and an increase in the volume irradiated to higher dose [
      • Irvine C.
      • Morgan A.
      • Crellin A.
      • Nisbet A.
      • Beange I.
      The clinical Implications of the collapsed cone planning algorithm.
      ].
      Analysis of the toxicity related deaths show thirteen due to lung toxicity and seven due to oesophageal toxicity. Four patients died from lung toxicity without completing their RT, suggesting that underlying disease may be a contributory factor. The three patients who died from radiation pneumonitis in one study were all aged over seventy, they also had PTV volumes on the larger end of the scale (508–600 cc) and two had a V20Gy of 30% and 34% [
      • Kerner G.S.M.A.
      • van Dullemen L.F.A.
      • Wiegman E.M.
      • Widder J.
      • Blokzijl E.
      • Driever E.M.
      • et al.
      Concurrent gemcitabine and 3D radiotherapy in patients with stage III unresectable non-small cell lung cancer.
      ], above their dose constraint. In another study all three deaths followed the development of an oesophageal fistula. No maximum dose constraint was applied to these patients, only a volume based constraint of V35Gy < 65% [
      • Chen C.
      • Uyterlinde W.
      • Sonke J.-J.
      • de Bois J.
      • van den Heuvel M.
      • Belderbos J.S.
      Severe late esophagus toxicity in NSCLC patients treated with IMRT and concurrent chemotherapy.
      ]. Two oesophageal deaths were reported by Kerner et al. who did not apply any dose constraint to the oesophagus. The protocol was then amended to include an oesophageal constraint so that less that 1 cm of the circumferential oesophagus could lie within the 98% isodose line. They subsequently treated ten more patients with a single instance of each of grade I–III oesophageal toxicity [
      • Kerner G.S.M.A.
      • van Dullemen L.F.A.
      • Wiegman E.M.
      • Widder J.
      • Blokzijl E.
      • Driever E.M.
      • et al.
      Concurrent gemcitabine and 3D radiotherapy in patients with stage III unresectable non-small cell lung cancer.
      ]. Nine of the studies reviewed here do not report specific dose volume constraints to the oesophagus in the treatment planning process with a some using generic statements such as ‘special attention was paid to minimise the maximum doses applied to this structure’ [
      • Kepka L.
      • Tyc-Szczepaniak D.
      • Bujko K.
      Dose-per-fraction escalation of accelerated hypofractionated three-dimensional conformal radiotherapy in locally advanced non-small cell lung cancer.
      ]. In the single instance of severe spinal cord toxicity reported the dose of 44 Gy/21# was within the level conventionally given safely to the spinal cord. However, this patient was a diabetic and vascular damage post-RT was observed at the level of the spinal cord damage with dose in this region varying from 45 to 50 Gy in 21# [
      • Kepka L.
      • Tyc-Szczepaniak D.
      • Bujko K.
      Dose-per-fraction escalation of accelerated hypofractionated three-dimensional conformal radiotherapy in locally advanced non-small cell lung cancer.
      ]. Considerably heterogeneity in the methods of toxicity reporting e.g. not specifying acute vs. late, reporting grade 2+ rather than each individual grade makes combining the data presented in the tables into an overall summary quite difficult.
      Concurrent chemotherapy has been shown to result in rates of acute oesophagitis of 15–25% (in the setting of both conventional and hypofractionated treatment [
      • Werner-Wasik M.
      • Yorke E.D.
      • Deasy J.O.
      • Nam J.
      • Marks L.B.
      Radiation dose–volume effects in the esophagus.
      ]. A review of oesophagitis following chemoradiotherapy by Palma et al. [
      • Palma D.A.
      • Senan S.
      • Oberije C.J.G.
      • Belderbos J.S.
      • de Dios N.R.
      • Bradley J.D.
      • et al.
      Predicting esophagitis after chemoradiation therapy for non-small cell lung cancer: an individual patient data meta-analysis.
      ] found that just over 50% of patients treated with concurrent chemoradiotherapy experienced radiation oesophagitis although the majority (85.2%) of their patients received ⩽2 Gy per #. In the hypofractionated studies here the rate of acute grade 3+ oesophagitis in the concurrent studies was 13.2%. A group from the West of Scotland Cancer Centre found a strong relationship between dose volume parameters and oesophagitis in sequential chemoradiotherapy but no such relationship in concurrent chemoradiotherapy [
      • Tho L.M.
      • Mahmood R.
      • Leitch M.
      • Brisbane I.
      • Kakumanu S.
      • Mohammed N.
      Oesophageal toxicity and hypofractionated concurrent chemoradiotherapy for non-small cell lung cancer.
      ]. In the recent SOCCAR trial (55 Gy/20#) treatment related mortality was higher in the concurrent arm (2.9%) versus the sequential arm (1.7%). However, serious adverse events were lower in the concurrent arm (34%) versus the sequential arm (41%) [
      • Maguire J.
      • Khan I.
      • McMenemin R.
      • O’Rourke N.
      • McNee S.G.
      • Kelly V.
      • et al.
      SOCCAR: A randomised phase II trial comparing sequential versus concurrent chemotherapy and radical hypofractionated radiotherapy in patients with inoperable stage III Non-Small Cell Lung Cancer and good performance status.
      ]. In the hypofractionated literature Adkinson et al. have shown that adjuvant chemotherapy after RT gives a significantly higher risk of grade 2 pneumonitis, in comparison to induction or no chemotherapy [
      • Adkison J.B.
      • Khuntia D.
      • Bentzen S.M.
      • Cannon G.M.
      • Tomé W.A.
      • Jaradat H.
      • et al.
      Dose escalated, hypofractionated radiotherapy using helical tomotherapy for inoperable non-small cell lung cancer: preliminary results of a risk-stratified phase I.
      ]. The Palma et al. study demonstrated a symptomatic pneumonitis rate of 29.8% post chemoradiotherapy and found total daily dose >2 Gy to be significantly associated with fatal pneumonitis [
      • Palma D.A.
      • Senan S.
      • Tsujino K.
      • Barriger R.B.
      • Rengan R.
      • Moreno M.
      • et al.
      Predicting radiation pneumonitis after chemoradiation therapy for lung cancer: an international individual patient data meta-analysis.
      ]. In the hypofractionated studies reported here the rate of acute grade 3+ pneumonitis in the concurrent studies was 8.0%. A significant relationship between V20Gy and the risk of fatal pneumonitis has been shown [
      • Palma D.A.
      • Senan S.
      • Tsujino K.
      • Barriger R.B.
      • Rengan R.
      • Moreno M.
      • et al.
      Predicting radiation pneumonitis after chemoradiation therapy for lung cancer: an international individual patient data meta-analysis.
      ]. The most common lung DVC reported in this review was V20Gy < 30%, with few correcting for fractionation.
      Applying any DVC is dependent on the method used to contour the volume. The QUANTEC report suggests contouring the oesophagus from the cricoid cartilage to the gastro-oesophageal junction and notes that methods used in some other works result in oesophageal volumes up to 20% smaller [
      • Werner-Wasik M.
      • Yorke E.D.
      • Deasy J.O.
      • Nam J.
      • Marks L.B.
      Radiation dose–volume effects in the esophagus.
      ]. Delineation was according to QUANTEC in Chen et al. and Kong et al. whereas Maguire et al. only contoured at the level of the PTV (with no DVC applied to the oesophagus). Donato et al. added a 5 mm planning-at-risk volume (PRV) to their oesophageal contour, none of the remaining studies detailed their contouring method. There is a broad spectrum of DVCs used for the oesophagus in the literature with maximum doses, lengths in PTV and volume based constraints applied. This may reflect different toxicity endpoints that result from point-dose versus volume irradiations. A meta-analysis of examining the best predictors for radiation oesophagitis by Palma et al. established the oesophageal volume receiving ⩾60 Gy as the best predictor, however their data were not corrected for dose per fraction and the majority of patients received conventional 1.8–2 Gy per fraction [
      • Palma D.A.
      • Senan S.
      • Oberije C.J.G.
      • Belderbos J.S.
      • de Dios N.R.
      • Bradley J.D.
      • et al.
      Predicting esophagitis after chemoradiation therapy for non-small cell lung cancer: an individual patient data meta-analysis.
      ]. A comprehensive review of the literature on the relationship between dose–volume histogram metrics and oesophageal toxicity was performed by Rose et al. [
      • Rose J.
      • Rodrigues G.B.
      • Yaremko B.
      • Lock M.
      • D’Souza D.
      Systematic review of dose–volume parameters in the prediction of esophagitis in thoracic radiotherapy.
      ] and they found high levels of association for MED (mean oesophageal dose), V20Gy, V30Gy, V40Gy, V45Gy and V50Gy. However, they included patients both with and without chemotherapy. In a concurrent chemotherapy group receiving 66 Gy in 24 fractions the oesophageal V50Gy has been associated with a higher incidence of acute oesophageal toxicity [
      • Uyterlinde W.
      • van den Heuvel M.
      • Van Werkhoven E.
      • Belderbos J.S.
      • Baas P.
      • Kwint M.
      • et al.
      Clinical prediction for acute toxicity in patients with locally advanced non-small cell lung cancer receiving concurrent chemoradiation.
      ].
      The majority of the papers reviewed here neither imposed a constraint on the brachial plexus nor reported any toxicity. The inclusion of a brachial plexus constraint in the trial protocols is perhaps an indication of an increased awareness of the potential for brachial plexus injury in hypofractionated regimes. An IMRT planning study in NSCLC by Warren et al. [
      • Warren M.
      • Webster G.
      • Ryder D.
      • Rowbottom C.
      • Faivre-Finn C.
      An isotoxic planning comparison study for stage II–III non-small cell lung cancer: Is intensity-modulated radiotherapy the answer?.
      ] incorporated a brachial plexus PRV as an OAR, as recommended by ICRU-83 for serial organs [
      • Gregoire V.
      • Mackie T.R.
      • De Neve W.
      • Gospodarowicz M.K.
      • Purdy J.A.
      • Van Herk M.B.
      ICRU 83. Prescribing, recording, and reporting photon-beam intensity-modulated radiation therapy (IMRT).
      ]. The value of a point Dmax dose can be dependent on the calculation grid size, the CT slice interval, the dose calculation algorithm, the configuration of the dose calculation model and statistical uncertainty in the dose calculation, thus it can be more appropriate to specify and report volume rather than point doses, for example RTOG specifies D0.03cc instead of Dmax across its trials. It is important when reviewing spinal cord constraints to be aware of the volume to which they are specified; (a) spinal cord, (b) bony spinal canal or (c) PRV volume and the IGRT correction strategy employed. IMRT and VMAT techniques have the potential to generate dose gradients in excess of 10% per mm and a PRV on serial organs may be more appropriate in these situations [
      • Gregoire V.
      • Mackie T.R.
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      • Van Herk M.B.
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      ].

      Conclusions

      For some OARs (e.g. lung and spinal cord) there is consensus in the literature as to the relevant dose–volume metrics to apply in hypofractionated RT. For other organs, such as the oesophagus, there is heterogeneity in the data and the mechanisms of toxicity may not be fully understood. When treating NSCLC with hypofractionated RT it is important to be aware of normal tissue considerations that may not be of concern in conventional fractionation and to widen the toxicity assessment processes accordingly. In changing RT technique the DVCs to be considered may need to be adjusted in light of the altered dose distribution. The dose calculation algorithm utilised should reported in all clinical thoracic papers and efforts should be made to ensure homogeneity in delivered dose across institutions in clinical trials. When reporting toxicity all grades experienced as well as number of patients and number evaluable at that time-point should be reported to allow comparison between studies. We consider it worth investigating the benefits that new technology (4 dimensional computed tomography, intensity modulated techniques, gating) along with hypofractionated dose escalation could potentially bring to LA-NSCLC patients.

      Conflict of interest statement

      There are no conflicts of interest to be declared for any authors.

      Appendix A. Supplementary data

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