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PET-CT use and the occurrence of elective nodal failure in involved field radiotherapy for non-small cell lung cancer: A systematic review

  • Lucyna Kepka
    Correspondence
    Corresponding author at: Independent Public Health Care Facility of the Ministry of the Interior and Warmian & Mazurian Oncology Centre, Al. Wojska Polskiego 37, 10-228 Olsztyn, Poland.
    Affiliations
    Radiation Oncology Department, Independent Public Health Care Facility of the Ministry of the Interior and Warmian & Mazurian Oncology Centre, Olsztyn, Poland
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  • Joanna Socha
    Affiliations
    Radiation Oncology Department, Regional Oncology Centre, Czestochowa, Poland
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      Abstract

      Aim

      Current guidelines do not recommend the use of elective nodal irradiation for NSCLC, for several reasons. One of these is that PET-CT provides adequate nodal staging. We compared the published rates of elective nodal failures (ENFs) defined as regional failures that occur without local recurrence irrespectively of distant metastases status in patients who did or did not undergo PET-CT for staging.

      Methods

      Reports of the occurrence of ENFs were considered. Only studies that used involved fields and specified the number of ENFs in patients with and without PET-CT use were included. A chi-squared test was used for the comparison of the risk of ENF in patients staged with and without PET.

      Results

      Forty-eight studies were included; 2158 and 1487 patients with and without PET-CT performed before radiotherapy were identified. The proportion of patients treated with SBRT was higher in the group with PET-CT (71%) than it was in the group without PET-CT (20%; p < .001). There were 136 (6.3%) and 98 (6.6%) ENFs in patients with and without PET-CT, respectively (p = .74).

      Conclusion

      The failure to reduce ENF by PET-CT was demonstrated. These data should be regarded in the context of the adequacy of reporting the rate of ENF and recognized value of PET-CT in NSCLC treatment.

      Keywords

      Most current treatment guidelines do not recommend the use of elective nodal irradiation (ENI) in non-small cell lung cancer (NSCLC), for several reasons [

      NCCN clinical practice guidelines in oncology. Non-small cell lung cancer. Version 3, <www.nccn.org>; 2014 [accessed 30.07.2014].

      ,
      • De Ruysscher D.
      • Faivre-Finn C.
      • Nestle U.
      • et al.
      European Organization for Research and Treatment of Cancer recommendations for planning and delivery of high dose, high-precision of radiotherapy for lung cancer.
      ]. Shortly, these recommendations are funded on the basis that involved-field radiotherapy (IFRT) allows dose escalation and the rate of elective nodal failures (ENFs) is low in this technique, which is especially true for contemporary imaging, including positron-emission tomography–computed tomography (PET-CT) [

      NCCN clinical practice guidelines in oncology. Non-small cell lung cancer. Version 3, <www.nccn.org>; 2014 [accessed 30.07.2014].

      ,
      • De Ruysscher D.
      • Faivre-Finn C.
      • Nestle U.
      • et al.
      European Organization for Research and Treatment of Cancer recommendations for planning and delivery of high dose, high-precision of radiotherapy for lung cancer.
      ,
      • Van Houtte P.
      • Roelandts M.
      • Mornex F.
      Radiotherapy of lung cancer: any room left for elective mediastinal irradiation in 2011.
      ,
      • Toloza E.M.
      • Harpole L.
      • McCrory D.C.
      Noninvasive staging of non-small cell lung cancer. A review of the current evidence.
      ,
      • van Loon J.
      • van Baardwijk A.
      • Boersma L.
      • et al.
      Therapeutic implications of molecular imaging with PET in the combined modality of lung cancer.
      ].
      PET-CT has higher sensitivity and specificity than CT in the detection of mediastinal and hilar nodal metastases [
      • Toloza E.M.
      • Harpole L.
      • McCrory D.C.
      Noninvasive staging of non-small cell lung cancer. A review of the current evidence.
      ]. The value of PET-CT in radiotherapy for NSCLC with regard to the determination of target volumes is recognized [
      • De Ruysscher D.
      • Faivre-Finn C.
      • Nestle U.
      • et al.
      European Organization for Research and Treatment of Cancer recommendations for planning and delivery of high dose, high-precision of radiotherapy for lung cancer.
      ]. It is claimed also that this may be an additional tool that facilitates IFRT in NSCLC. Better imaging is supposed to lead to better (i.e., more limited) treatment volume tailoring. Thus, the occurrence of ENF should be reduced with the use of PET-CT for staging, which supports the omission of ENI [
      • van Loon J.
      • van Baardwijk A.
      • Boersma L.
      • et al.
      Therapeutic implications of molecular imaging with PET in the combined modality of lung cancer.
      ]. Historically, in the largest-ever published study on the occurrence of ENF, which did not employ ENI, there was no statistically significant difference in the risk of ENF between patients who had PET-CT for staging and those who did not. Among 524 patients, 32 ENFs (6.1%) were identified. Three hundred twelve patients with pretreatment PET-CT had an actuarial 2-year ENF risk of 8.6% compared with 6% in 212 patients who were staged without PET-CT (p = .73) [
      • Rosenzweig K.E.
      • Sura S.
      • Jackson A.
      • Yorke E.
      Involved-field radiation therapy for inoperable non-small-cell lung cancer.
      ]. Recently, in the report of the outcome of a large pooled cohort of patients undergoing stereotactic body radiation therapy (SBRT), no impact of PET-CT on the occurrence of ENF was demonstrated. Among 505 patients with early-stage lung cancer, 88% had PET-CT for staging. There were 12% and 3% regional recurrences in patients who did or did not undergo PET-CT staging, respectively (p = .06) [
      • Grills I.S.
      • Hope A.J.
      • Guckenberger M.
      • et al.
      A collaborative analysis of stereotactic lung radiotherapy outcomes for early-stage non-small cell lung cancer using daily cone-beam computed tomography image-guided radiotherapy.
      ]. These conflicting data regarding the value of PET-CT in the reduction of the risk of ENF incited us to perform a search of the literature to compare the frequency of the occurrence of ENF after IFRT between patients who had and those who did not have PET-CT for staging.

      Methods

      Studies that reported the occurrence of ENF were selected via a comprehensive literature search using the “PubMed” and “Google Scholar” databases. The search terms included were: “Elective nodal failure,” “Isolated nodal failure,” “Non-small cell lung cancer,” “Involved-field radiotherapy,” “PET-CT and radiotherapy,” “Radiotherapy and NSCLC,” “pattern of failure,” “SBRT and NSCLC,” and “ENI and NSCLC.” The reference lists of relevant articles were further explored.
      For the purpose of this review, ENF was defined as the relapse in initially uninvolved lymph nodes that were not intentionally included in the radiation volume, without simultaneous or previous local relapse. Regional relapses in the initially uninvolved lymph nodes that occurred simultaneously with distant metastases without local relapse were also considered as ENF.
      Only studies that included clear statements regarding the use (or not) of PET-CT for staging (±planning) were included. In a few cases, e-mails were sent to the corresponding authors with a request of details on the number of patients in whom PET-CT was used for staging before radiotherapy and its relation to the reported number of ENFs. Studies in which the exact number of patients and ENFs in groups with and without PET-CT was not established were excluded. Patients who received ENI were excluded. The crude number of ENFs was derived from respective studies with and without PET-CT. A chi-squared test was used to compare the rate of ENF in patients for whom PET-CT was performed before radiotherapy with that observed in patients who did not have PET-CT for baseline staging or planning. In addition, the rate of ENF in patients who underwent SBRT was compared between groups of patients with and without PET-CT. A similar comparison was performed after excluding patients treated with SBRT.

      Results

      In total, 65 studies that reported the occurrence of ENF after radiotherapy for NSCLC were found. Seventeen studies were excluded for the following reasons: use of ENI in all patients (2) [
      • Kepka L.
      • Bujko K.
      • Zolciak-Siwinska A.
      Risk of isolated nodal failure for non-small cell lung cancer (NSCLC) treated with the elective nodal irradiation (ENI) using 3D-conformal radiotherapy (3D-CRT) techniques.
      ,
      • Sanuki-Fujimoto N.
      • Sumi M.
      • Ito Y.
      • et al.
      Relation between elective nodal failure and irradiated volume in non-small-cell lung cancer (NSCLC) treated with radiotherapy using conventional fields and doses.
      ]; lack of information on the occurrence of ENF in relation to the use (or not) of ENI (2) [
      • Uematsu M.
      • Shioda A.
      • Suda A.
      • et al.
      Computed tomography-guided frameless stereotactic radiotherapy for stage I non-small-cell lung cancer: a 5-year experience.
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      • Marks L.B.
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      • Prosnitz L.R.
      Radiotherapy alone for medically inoperable stage I non-small-cell lung cancer: the Duke experience.
      ]; the exact number of ENFs in groups of patients with and without PET-CT or the number of patients with PET-CT performed before radiotherapy was not specified (10) [
      • Rosenzweig K.E.
      • Sura S.
      • Jackson A.
      • Yorke E.
      Involved-field radiation therapy for inoperable non-small-cell lung cancer.
      ,
      • Grills I.S.
      • Hope A.J.
      • Guckenberger M.
      • et al.
      A collaborative analysis of stereotactic lung radiotherapy outcomes for early-stage non-small cell lung cancer using daily cone-beam computed tomography image-guided radiotherapy.
      ,
      • Soliman H.
      • Cheung P.C.F.
      • Yeung L.T.F.
      • et al.
      Accelerated hypofractionation for early stage non-small cell lung cancer: long-term results.
      ,
      • Zhu Z.F.
      • Fan M.
      • Wu K.L.
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      A phase II trial of accelerated hypofractionated three-dimensional conformal radiation therapy in locally advanced non-small cell lung cancer.
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      • Papiez L.
      • Williams M.
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      Stereotactic body radiation therapy of early stage non-small cell lung carcinoma: a phase I study.
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      • Satoh H.
      • Sugahara S.
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      Proton beam therapy of stage II and III non-small cell lung cancer.
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      • Baumann P.
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      ]; repeated reports on subgroups of patients from previous publications (2) [
      • Chen M.
      • Hayman J.A.
      • Ten Haken R.K.
      • et al.
      Long-term results of high-dose conformal radiotherapy for patients with medically inoperable T1-3N0 non-small-cell lung cancer: is low incidence of regional failure due to incidental nodal irradiation?.
      ,
      • Henderson M.A.
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      ]; and doubt on the isolated character of regional relapse in a small subgroup of patients without PET-CT (1) [
      • Lagerwaard F.J.
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      • Smit E.F.
      • Slotman B.J.
      • Senan S.
      Outcomes of risk-adapted fractionated stereotactic radiotherapy for stage I non-small cell lung cancer.
      ]. Finally, 48 studies were included in this review [
      • Lao L.
      • Hope A.J.
      • Maganti M.
      • et al.
      Incidental prophylactic nodal irradiation and patterns of nodal relapse in inoperable early stage NSCLC patients treated with SBRT: a case-matched analysis.
      ,
      • Slotman B.J.
      • Antonisse I.E.
      • Nio K.H.
      Limited field irradiation in early stage (T1–2N0) non-small cell lung cancer.
      ,
      • Krol A.
      • Aussems P.
      • Noordijk E.M.
      • Hermans J.
      • Leer J.W.H.
      Local irradiation alone for peripheral stage I lung cancer: could we omit the elective regional nodal irradiation?.
      ,
      • Robertson J.M.
      • Ten Haken R.K.
      • Hazuka M.B.
      • et al.
      Dose escalation for non-small cell lung cancer using conformal radiation therapy.
      ,
      • Hayakawa K.
      • Mitsuhashi N.
      • Saito Y.
      • et al.
      Limited field irradiation for medically inoperable patients with stage I non-small cell lung cancer.
      ,
      • Cheung P.C.F.
      • Mackillop W.J.
      • Dixon P.
      • et al.
      Involved-field radiotherapy alone for early-stage non-small cell lung cancer.
      ,
      • Rosenzweig K.E.
      • Sim S.E.
      • Mychalczak B.
      • et al.
      Elective nodal irradiation in the treatment of non-small cell lung cancer with three-dimensional conformal radiation therapy.
      ,
      • Hayman J.A.
      • Martel M.K.
      • Ten Haken R.K.
      • et al.
      Dose escalation in non-small cell lung cancer using three-dimensional conformal radiation therapy: update of a phase I trial.
      ,
      • Cheung P.C.F.
      • Yeung L.T.F.
      • Basrur V.
      • et al.
      Accelerated hypofractionation for early stage non-small cell lung cancer.
      ,
      • Senan S.
      • Burgers S.
      • Samson M.J.
      • et al.
      Can elective nodal irradiation be omitted in stage III non-small-cell lung cancer? Analysis of recurrences in a phase II study of induction chemotherapy and involved-field radiotherapy.
      ,
      • Hof H.
      • Herfarth K.K.
      • Unter M.M.
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      Stereotactic single-dose radiotherapy of stage I non-small cell lung cancer (NSCLC).
      ,
      • Bradley J.D.
      • Wahab S.
      • Lockett M.A.
      • et al.
      Elective nodal failures are uncommon in medically inoperable patients with stage I non-small-cell lung carcinoma treated with limited radiotherapy fields.
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      • Onishi H.
      • Kuriyama K.
      • Komiyama T.
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      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.
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      • Heemsbergen W.D.
      • De Jaeger K.
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      Final results of a Phase I/II dose escalation trial in non-small-cell lung cancer using three dimensional conformal radiotherapy.
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      • Lax I.
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      • Turrisi 3rd, A.T.
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      • et al.
      Conformal high dose external radiation therapy, 80.5 Gy, alone for medically inoperable non-small cell lung cancer: a retrospective analysis.
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      • Yuan S.
      • Sun X.
      • Li M.
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      A randomized study of involved-field irradiation versus elective nodal irradiation in combination with concurrent chemotherapy for inoperable stage III non-small cell lung cancer.
      ,
      • Mostafa E.
      • Khatab A.
      • Al-Adwy E.R.
      • Al-Assal G.M.
      Limited field radiotherapy concomitant with cisplatin/etoposide followed by consolidation docetaxel for the treatment of inoperable stage III non-small cell lung cancer.
      ,
      • Yu H.M.
      • Liu Y.F.
      • Yu J.M.
      • Liu J.
      • Zhao Y.
      • Hou M.
      Involved-field radiotherapy is effective for patients 70 years old or more with early stage non-small cell lung cancer.
      ,
      • Sulman E.P.
      • Komaki R.
      • Klopp A.H.
      • et al.
      Exclusion of elective nodal irradiation is associated with minimal elective nodal failure in non-small cell lung cancer.
      ,
      • Nakayama H.
      • Satoh H.
      • Kurishima K.
      • et al.
      High-dose conformal radiotherapy for patients with stage III non-small cell lung carcinoma.
      ,
      • Onishi H.
      • Shirato H.
      • Nagata Y.
      • et al.
      Stereotactic body radiotherapy (SBRT) for operable stage I non-small-cell lung cancer: can SBRT be comparable to surgery?.
      ,
      • Chen M.
      • Bao Y.
      • Ma H.L.
      Involved-field radiotherapy versus elective nodal irradiation in combination with concurrent chemotherapy for locally advanced non-small cell lung cancer: a prospective randomized study.
      ,
      • Zimmermann F.
      • Geinitz H.
      • Schill S.
      • et al.
      Stereotactic hypofractionated radiation therapy for stage I non-small cell lung cancer.
      ,
      • De Ruysscher D.
      • Wanders S.
      • van Haren E.
      • et al.
      Selective mediastinal node irradiation based on FDG-PET scan data in patients with non-small-cell lung cancer: a prospective clinical study.
      ,
      • Hoopes D.J.
      • Tann M.
      • Fletcher J.W.
      • et al.
      FDG-PET and stereotactic body radiotherapy (SBRT) for stage I non-small-cell lung cancer.
      ,
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      • Chang J.Y.
      • Tucker S.L.
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      Intrathoracic patterns of failure for non-small-cell lung cancer with positron-emission tomography/computed tomography-defined target delineation.
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      • Chang J.Y.
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      • Dong L.
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      Stereotactic body radiation therapy in centrally and superiorly located stage I or isolated recurrent non-small cell lung cancer.
      ,
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      • Djemil T.
      • Reddy C.A.
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      A comparison of two stereotactic body radiation fractionation schedules for medically inoperable stage I non-small cell lung cancer: the Cleveland Clinic experience.
      ,
      • Collins B.T.
      • Vahdat S.
      • Erickson K.
      Radical cyberknife radiosurgery with tumor tracking: an effective treatment for inoperable small peripheral stage I non-small cell lung cancer.
      ,
      • Fakiris A.J.
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      • et al.
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      ,
      • Bradley J.D.
      • El Naqa I.
      • Drzymala R.E.
      • et al.
      Stereotactic body radiation therapy for early stage non-small cell lung cancer: the pattern of failure is distant.
      ,
      • Fernandes A.T.
      • Shen J.
      • Finlay J.
      • et al.
      Elective nodal irradiation (ENI) vs. involved field radiotherapy (IFRT) for locally advanced non-small cell lung cancer (NSCLC): a comparative analysis of toxicities and clinical outcomes.
      ,
      • Kimura T.
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      Impact of incidental irradiation on clinically uninvolved nodal regions in patients with advanced non-small cell lung cancer treated with involved-field radiation therapy: does incidental irradiation contribute to the low incidence of elective nodal failure?.
      ,
      • Ricardi U.
      • Filippi A.R.
      • Guarneri A.
      • et al.
      Stereotactic body radiation therapy for early stage non-small cell lung cancer: results of a prospective trial.
      ,
      • Timmerman R.
      • Paulus R.
      • Galvin J.
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      Stereotactic body radiation therapy for inoperable early stage lung cancer.
      ,
      • Grills I.S.
      • Mangona V.S.
      • Welsh R.
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      ,
      • Fleckenstein J.
      • Hellwig D.
      • Kremp S.
      • et al.
      F-18-FDG-PET confined radiotherapy of locally advanced NSCLC with concomitant chemotherapy: results of the PET-PLAN pilot trial.
      ,
      • Bral S.
      • Gevaert T.
      • Linthout N.
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      ,
      • Kolodziejczyk M.
      • Bujko K.
      • Michalski K.
      • Kepka L.
      Incidence of isolated nodal failure in non-small cell lung cancer patients included in a prospective study of the value of PET-CT.
      ,
      • Bradley J.
      • Bae K.
      • Choi N.
      • et al.
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      ,
      • Tada T.
      • Chiba Y.
      • Tsujino K.
      • et al.
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      ,
      • Senthi S.
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      • Senan S.
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      ,
      • Kim M.J.
      • Yeo S.G.
      • Kim E.S.
      • Min C.K.
      • Se An P.
      Intensity-modulated stereotactic body radiotherapy for stage I non-small cell lung cancer.
      ]. For one study, details on the use of PET-CT in relation to the occurrence of ENF were provided by personal communication from the corresponding author [
      • Lao L.
      • Hope A.J.
      • Maganti M.
      • et al.
      Incidental prophylactic nodal irradiation and patterns of nodal relapse in inoperable early stage NSCLC patients treated with SBRT: a case-matched analysis.
      ].
      The characteristics of the studies included in this review are provided in Table 1. There were 28 groups (2158 patients) with PET-CT and in 24 groups (1487 patients) without PET-CT performed before radiotherapy. The distribution of clinical stages in patients with and without PET-CT performed before radiotherapy was: early (stage I or II): 1605 (74%) and 856 (57.5%); locally advanced (stage III): 400 (19%) and 486 (32.5%); and unknown: 153 (7%) and 145 (10%), respectively. The provided follow-up period for patients staged with PET-CT ranged from 12.4 to 50.2 months (median: 18 months) and for patients staged without PET-CT ranged from 9.4 to 86 months (median: 20.5 months).
      Table 1Studies included in the review that reported on the risk of ENF (elective nodal failure) in patients staged with or without PET.
      Study: First author [Ref.]; type of the studyNumber of patients evaluatedNumber of ENF (%)Details on treatmentPatient/tumor characteristicsMedian follow-up [in months]; unless otherwise stated
      Patients staged without PET
      Lao
      • Lao L.
      • Hope A.J.
      • Maganti M.
      • et al.
      Incidental prophylactic nodal irradiation and patterns of nodal relapse in inoperable early stage NSCLC patients treated with SBRT: a case-matched analysis.
      ; prospective
      23
      Numbers provided by personal communication of Dr. Cho [23].
      0 (0)SBRT
      SBRT – Stereotactic-body Radiotherapy.
      T1-T2N020 months
      Slotman
      • Slotman B.J.
      • Antonisse I.E.
      • Nio K.H.
      Limited field irradiation in early stage (T1–2N0) non-small cell lung cancer.
      ; retrospective
      311 (3.2)12 × 4 Gy;T1-T2N0Not specified
      Krol
      • Krol A.
      • Aussems P.
      • Noordijk E.M.
      • Hermans J.
      • Leer J.W.H.
      Local irradiation alone for peripheral stage I lung cancer: could we omit the elective regional nodal irradiation?.
      ; retrospective
      1082 (1.9)2.5–3.0 Gy/fraction to 60–65 GyPeripheral tumorsNot specified
      Robertson
      • Robertson J.M.
      • Ten Haken R.K.
      • Hazuka M.B.
      • et al.
      Dose escalation for non-small cell lung cancer using conformal radiation therapy.
      ; prospective
      301 (3.3)Dose escalation up to 92.4 GyStage II and IIINot specified
      Hayakawa
      • Hayakawa K.
      • Mitsuhashi N.
      • Saito Y.
      • et al.
      Limited field irradiation for medically inoperable patients with stage I non-small cell lung cancer.
      ; retrospective
      261 (3.8)60–81 GyStage IRange: 3–18 years
      Cheung
      • Cheung P.C.F.
      • Mackillop W.J.
      • Dixon P.
      • et al.
      Involved-field radiotherapy alone for early-stage non-small cell lung cancer.
      ; retrospective
      1034 (3.8)52.5 Gy in 20 frT1-T4N0 (5 × N1)86
      Rosenzweig
      • Rosenzweig K.E.
      • Sim S.E.
      • Mychalczak B.
      • et al.
      Elective nodal irradiation in the treatment of non-small cell lung cancer with three-dimensional conformal radiation therapy.
      ; retrospective
      17111 (6.4)Dose escalation up to 81 Gy86% stage III; 14% stage I and II21
      Hayman
      • Hayman J.A.
      • Martel M.K.
      • Ten Haken R.K.
      • et al.
      Dose escalation in non-small cell lung cancer using three-dimensional conformal radiation therapy: update of a phase I trial.
      ; prospective
      632 (3.2)Dose escalation up to 102.9 GyAll stages9.4
      Cheung
      • Cheung P.C.F.
      • Yeung L.T.F.
      • Basrur V.
      • et al.
      Accelerated hypofractionation for early stage non-small cell lung cancer.
      ; retrospective
      332 (6.1)48 Gy in 12 fractionsT1T2N022.5
      Senan
      • Senan S.
      • Burgers S.
      • Samson M.J.
      • et al.
      Can elective nodal irradiation be omitted in stage III non-small-cell lung cancer? Analysis of recurrences in a phase II study of induction chemotherapy and involved-field radiotherapy.
      ; prospective
      430 (0)Sequential CHT-RTStage III; only patients who received at least 50 Gy16
      Hof
      • Hof H.
      • Herfarth K.K.
      • Unter M.M.
      • et al.
      Stereotactic single-dose radiotherapy of stage I non-small cell lung cancer (NSCLC).
      ; retrospective
      100 (0)SBRT single fractionStage I14.9
      Bradley
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      • Wahab S.
      • Lockett M.A.
      • et al.
      Elective nodal failures are uncommon in medically inoperable patients with stage I non-small-cell lung carcinoma treated with limited radiotherapy fields.
      ; prospective
      332 (6)Dose escalation (median dose: 70 Gy)Stage I20
      Onishi
      • Onishi H.
      • Kuriyama K.
      • Komiyama T.
      • et al.
      Clinical outcomes of stereotactic radiotherapy for stage I non-small cell lung cancer using a novel irradiation technique: patient self-controlled breath-hold and beam switching using a combination of linear accelerator and CT scanner.
      ; prospective
      352 (5.7%)SBRTStage I13
      Bradley
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      • Winter K.
      • 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.
      ; prospective
      17914 (8)Dose escalation up to 70–90 Gy; in stage III combined with sequential CHTStage I–IIIRange of median for subgroups: 13.3–18.7
      Belderbos
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      ; prospective
      210 (0)Dose escalation from 50 to 94 Gy (median: 80 Gy); 18% induction CHTStage I–III17
      Baumann
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      ; retrospective
      1386 (4.3)SBRTStage I33
      Urbanic
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      Conformal high dose external radiation therapy, 80.5 Gy, alone for medically inoperable non-small cell lung cancer: a retrospective analysis.
      ;
      350 (0)80.5 Gy in 35 fractionsStage I and II33
      Yuan
      • Yuan S.
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      • Li M.
      • et al.
      A randomized study of involved-field irradiation versus elective nodal irradiation in combination with concurrent chemotherapy for inoperable stage III non-small cell lung cancer.
      ; prospective
      1007 (7)68–74 Gy with concomitant CHTStage III27
      Mostafa
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      ; prospective
      321 (3.1)66 Gy with concomitant CHTStage III13.5
      Yu
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      8029 (36.3)66.6 Gy; IMRTStage I and II72
      Sulman
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      Exclusion of elective nodal irradiation is associated with minimal elective nodal failure in non-small cell lung cancer.
      ; retrospective
      290 (0)Most concurrent RT (64 Gy)-CHTAll stages18
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      ; retrospective
      452 (4.4)66–84 Gy with sequential or concomitant CHTStage IIINot specified
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      ; retrospective
      8711(12.6)SBRTStage I55
      Chen
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      • Bao Y.
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      Involved-field radiotherapy versus elective nodal irradiation in combination with concurrent chemotherapy for locally advanced non-small cell lung cancer: a prospective randomized study.
      ; prospective
      320 (0)Median RT dose of 60 Gy with induction and concomitant CHTStage III33
      Patients staged with PET
      Lao
      • Lao L.
      • Hope A.J.
      • Maganti M.
      • et al.
      Incidental prophylactic nodal irradiation and patterns of nodal relapse in inoperable early stage NSCLC patients treated with SBRT: a case-matched analysis.
      ; prospective
      156
      Numbers provided by personal communication of Dr. Cho [23].
      19 (12.2)SBRTStage I20
      Zimmermann
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      • Geinitz H.
      • Schill S.
      • et al.
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      ; retrospective
      302 (6.7)SBRTStage I18
      De Ruysscher
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      • et al.
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      ; prospective
      441 (2.3)61.2–64.7 Gy in 34/37 fractionsAll stages16
      Belderbos
      • Belderbos J.S.
      • Heemsbergen W.D.
      • De Jaeger K.
      • et al.
      Final results of a Phase I/II dose escalation trial in non-small-cell lung cancer using three dimensional conformal radiotherapy.
      ; prospective
      672 (3)Dose escalation from 50 to 94 Gy (median: 80 Gy); 18% induction CHTAll stages17
      Hoopes
      • Hoopes D.J.
      • Tann M.
      • Fletcher J.W.
      • et al.
      FDG-PET and stereotactic body radiotherapy (SBRT) for stage I non-small-cell lung cancer.
      ; prospective
      576 (10.5)SBRTStage I42.5
      Klopp
      • Klopp A.H.
      • Chang J.Y.
      • Tucker S.L.
      • et al.
      Intrathoracic patterns of failure for non-small-cell lung cancer with positron-emission tomography/computed tomography-defined target delineation.
      ; retrospective
      353 (8.5)60–70 Gy; 70% with concurrent CHTAll stages13
      Chang
      • Chang J.Y.
      • Balter P.A.
      • Dong L.
      • et al.
      Stereotactic body radiation therapy in centrally and superiorly located stage I or isolated recurrent non-small cell lung cancer.
      ; retrospective
      131 (7.7)SBRTStage I17
      Sulman
      • Sulman E.P.
      • Komaki R.
      • Klopp A.H.
      • et al.
      Exclusion of elective nodal irradiation is associated with minimal elective nodal failure in non-small cell lung cancer.
      ; retrospective
      862 (2.3)Most concurrent RT (mean: 64 Gy)-CHTAll stages18
      Stephans
      • Stephans K.L.
      • Djemil T.
      • Reddy C.A.
      • et al.
      A comparison of two stereotactic body radiation fractionation schedules for medically inoperable stage I non-small cell lung cancer: the Cleveland Clinic experience.
      ; retrospective
      867 (8.1)SBRTStage I15.3
      Collins
      • Collins B.T.
      • Vahdat S.
      • Erickson K.
      Radical cyberknife radiosurgery with tumor tracking: an effective treatment for inoperable small peripheral stage I non-small cell lung cancer.
      ; retrospective
      200 (0)SBRT (cyberknife)Stage I (“small, peripheral”)25
      Fakiris
      • Fakiris A.J.
      • McGarry R.C.
      • Yiannoutsos C.T.
      • et al.
      Stereotactic body radiation therapy for early-stage non-small cell lung carcinoma: four-year results of a prospective phase II study.
      ; prospective
      704 (5.7)SBRTStage I50.2
      Bradley
      • Bradley J.D.
      • El Naqa I.
      • Drzymala R.E.
      • et al.
      Stereotactic body radiation therapy for early stage non-small cell lung cancer: the pattern of failure is distant.
      ; retrospective
      914 (4.4)SBRTStage I and II (+6 T1N0M1)18
      Fernandes
      • Fernandes A.T.
      • Shen J.
      • Finlay J.
      • et al.
      Elective nodal irradiation (ENI) vs. involved field radiotherapy (IFRT) for locally advanced non-small cell lung cancer (NSCLC): a comparative analysis of toxicities and clinical outcomes.
      ; retrospective
      486 (12.5)60–84 Gy with concurrent or sequential CHTStage III (including 3 oligometastatic)16.2
      Kimura
      • Kimura T.
      • Togami T.
      • Nishiyama Y.
      • et al.
      Impact of incidental irradiation on clinically uninvolved nodal regions in patients with advanced non-small cell lung cancer treated with involved-field radiation therapy: does incidental irradiation contribute to the low incidence of elective nodal failure?.
      ; retrospective
      504 (8)60–80 Gy; in 72% with sequential or concurrent CHTStage II – 28% Stage III – 72%Not specified
      Ricardi
      • Ricardi U.
      • Filippi A.R.
      • Guarneri A.
      • et al.
      Stereotactic body radiation therapy for early stage non-small cell lung cancer: results of a prospective trial.
      ; prospective
      627 (11.3)SBRTStage I28
      Timmerman
      • Timmerman R.
      • Paulus R.
      • Galvin J.
      • et al.
      Stereotactic body radiation therapy for inoperable early stage lung cancer.
      ; prospective
      552 (3.6)SBRTStage I34.4
      Grills
      • Grills I.S.
      • Mangona V.S.
      • Welsh R.
      • et al.
      Outcomes after stereotactic lung radiotherapy or wedge resection for stage I non-small-cell lung cancer.
      ; retrospective
      554 (7.3)SBRTStage I30
      Fleckenstein
      • Fleckenstein J.
      • Hellwig D.
      • Kremp S.
      • et al.
      F-18-FDG-PET confined radiotherapy of locally advanced NSCLC with concomitant chemotherapy: results of the PET-PLAN pilot trial.
      ; prospective
      231 (4.3)66.6 Gy with concurrent CHTStages II and III27.2
      Bral
      • Bral S.
      • Gevaert T.
      • Linthout N.
      • et al.
      Prospective, risk-adapted strategy of stereotactic body radiotherapy for early-stage non-small cell lung cancer: results of a phase II trial.
      ; prospective
      402 (5)SBRTT1-T3N016
      Kolodziejczyk
      • Kolodziejczyk M.
      • Bujko K.
      • Michalski K.
      • Kepka L.
      Incidence of isolated nodal failure in non-small cell lung cancer patients included in a prospective study of the value of PET-CT.
      ; prospective
      503 (6)RT 58.7 – 66 Gy with or without sequential CHTAll stages32
      Bradley
      • Bradley J.
      • Bae K.
      • Choi N.
      • et al.
      A Phase II comparative study of gross tumor volume definition with or without PET/CT Fusion in Dosimetric Planning for Non-small-cell (RTOG) 0515.
      ; prospective
      471 (2)Different curative doses with or without CHTStages II (6%) and III (94%)12.9
      Tada
      • Tada T.
      • Chiba Y.
      • Tsujino K.
      • et al.
      A phase I study of chemoradiotherapy with use of involved-field conformal radiotherapy and accelerated hyperfractionation for stage III non-small cell lung cancer: WJTOG 3305.
      ; prospective
      221 (4.5)Hyperfractionated dose escalation concurrent CHTStage IIINot specified
      Senthi
      • Senthi S.
      • Lagerwaard F.J.
      • Haasbeek C.J.A.
      • Slotman B.J.
      • Senan S.
      Patterns of disease recurrence after stereotactic ablative radiotherapy for early stage non-small-cell lung cancer: a retrospective analysis.
      ; retrospective
      67637 (5.5)SBRTStage I and II32.9
      Van Baardwijk
      • Van Baardwijk A.
      • Reymen B.
      • Wanders S.
      • et al.
      Mature results of a phase II trial on individualised accelerated radiotherapy based on normal tissue constraints in concurrent chemo-radiation for stage III non-small cell lung cancer.
      ; prospective
      1326 (4.5)Concurrent RT-CHTStage III30.9
      Zhang
      • Zhang X.
      • Liu H.
      • Balter P.
      • et al.
      Positron emission tomography for assessing local failure after stereotactic body radiotherapy for non-small-cell lung cancer.
      ; retrospective
      686 (8.8)SBRTStage I31
      Chen
      • Chen M.
      • Bao Y.
      • Ma H.L.
      Involved-field radiotherapy versus elective nodal irradiation in combination with concurrent chemotherapy for locally advanced non-small cell lung cancer: a prospective randomized study.
      ; prospective
      130 (0)Median RT dose of 60 Gy with induction and concomitant CHTStage III33
      Samuels
      • Samuels M.A.
      • Kandula S.
      • Koru-Sengul T.
      • et al.
      Stereotactic body radiotherapy in patients with stage I non-small-cell lung cancer aged 75 years and older: retrospective results from a multicentre consortium.
      ; retrospective
      464 (8.7)SBRTStage I12.4
      Kim
      • Kim M.J.
      • Yeo S.G.
      • Kim E.S.
      • Min C.K.
      • Se An P.
      Intensity-modulated stereotactic body radiotherapy for stage I non-small cell lung cancer.
      ; retrospective
      161 (6)SBRTStage I14
      low asterisk Numbers provided by personal communication of Dr. Cho
      • Lao L.
      • Hope A.J.
      • Maganti M.
      • et al.
      Incidental prophylactic nodal irradiation and patterns of nodal relapse in inoperable early stage NSCLC patients treated with SBRT: a case-matched analysis.
      .
      low asterisklow asterisk SBRT – Stereotactic-body Radiotherapy.
      The crude occurrence of ENF varied among these studies from 0% to 12.5% (median: 5.9%) in patients staged with PET-CT and from 0% to 36.3% (median: 3.6%) in patients staged without PET-CT (Fig. 1). There were 136 (6.3%) and 98 (6.6%) ENFs in patients with and without PET-CT performed for staging before IFRT, respectively (p = .74). In relation to the technique of radiotherapy used, 1541 (71.4%) patients with PET-CT and 293 (19.7%) without PET-CT received SBRT (p < .001). There were 125 ENF (6.8%) in 1834 patients treated with SBRT and 109 ENF (6%) in 1811 patients treated with other techniques. In the group of patients who were treated with SBRT without PET-CT, there were 19 (6.5%) ENFs compared with 106 (6.9%) ENFs in SBRT patients with PET-CT (p = .82). After excluding patients who were treated with SBRT, we detected 79 ENFs (6.6%) in 1194 patients without PET-CT, and 30 (4.9%) ENFs in 617 patients with PET-CT performed before radiotherapy (p = .16).
      Figure thumbnail gr1
      Fig. 1Median and range values of the rate of elective nodal failures (ENF) in 28 groups (2158 patients) with PET-CT and in 24 groups (1487 patients) without PET-CT performed before radiotherapy.

      Discussion

      No difference in the reported rate of ENF between patients who had PET-CT for staging before IFRT and those who did not was demonstrated in this literature review. This indicates that, despite the recognized higher sensitivity and specificity of PET-CT over CT for mediastinal and hilar nodal staging of lung cancer [
      • Toloza E.M.
      • Harpole L.
      • McCrory D.C.
      Noninvasive staging of non-small cell lung cancer. A review of the current evidence.
      ], the pattern of regional failure after IFRT for NSCLC may not be modified by the use of PET-CT. In other words, the safety of ENI omission is not strongly supported by the use of PET-CT itself for staging.
      On the other hand, the findings of our study support neither the use of ENI nor its omission. The dilemmas that are usually pointed out by the debaters of ENI persist, one of which is the risk of an underestimation of the rate of ENF (ascertainment bias, e.g., in the case of distant relapse) [
      • Van Houtte P.
      • Roelandts M.
      • Mornex F.
      Radiotherapy of lung cancer: any room left for elective mediastinal irradiation in 2011.
      ,
      • Kelsey C.R.
      • Marks L.B.
      • Glatstein E.
      Elective nodal irradiation for locally advanced non-small cell lung cancer; it’s called cancer for a reason.
      ]. One may argue that the rate of ENF, which appears to be independent of the diagnostic tool used, undermines the estimation of the value of PET-CT using the evaluation of the risk of ENF. We agree with this reasoning; however, the purpose of our study was limited to this end-point only, and we acknowledge all limitations related to the complexity of the detection of ENF. Nevertheless, we conclude that the use of PET-CT does not change this risk, as postulated in the guidelines [

      NCCN clinical practice guidelines in oncology. Non-small cell lung cancer. Version 3, <www.nccn.org>; 2014 [accessed 30.07.2014].

      ,
      • De Ruysscher D.
      • Faivre-Finn C.
      • Nestle U.
      • et al.
      European Organization for Research and Treatment of Cancer recommendations for planning and delivery of high dose, high-precision of radiotherapy for lung cancer.
      ,
      • van Loon J.
      • van Baardwijk A.
      • Boersma L.
      • et al.
      Therapeutic implications of molecular imaging with PET in the combined modality of lung cancer.
      ]. The risk of 5–12% associated with this type of relapse is considered by some as being low, especially in the context of high risk of local relapse [
      • van Loon J.
      • van Baardwijk A.
      • Boersma L.
      • et al.
      Therapeutic implications of molecular imaging with PET in the combined modality of lung cancer.
      ,
      • Sulman E.P.
      • Komaki R.
      • Klopp A.H.
      • et al.
      Exclusion of elective nodal irradiation is associated with minimal elective nodal failure in non-small cell lung cancer.
      ], and by others as being meaningful, thus precluding an opportunity for a cure in a proportion of patients, because an even lesser survival benefit associated with the addition of chemotherapy to radiotherapy changed clinical practice guidelines [
      • Kelsey C.R.
      • Marks L.B.
      • Glatstein E.
      Elective nodal irradiation for locally advanced non-small cell lung cancer; it’s called cancer for a reason.
      ,
      • Belderbos J.S.A.
      • Kepka L.
      • Kong F.-M.
      • Martel M.K.
      • Videtic G.M.M.
      • Jeremic B.
      Report from the International Atomic Energy Agency (IAEA) consultants’ meeting on elective nodal irradiation in lung cancer: Non-Small Cell Lung Cancer (NSCLC).
      ].
      We should acknowledge a number of limitations of our analysis. Besides limitations related to the reporting of ENF we acknowledge that we were not able to derive from most studies included in the review any data on the diagnostic tools used in the follow-up period. One may only speculate that patients staged with PET-CT before radiotherapy had more often PET-CT performed during follow-up and this contributed to the higher number of detection of regional relapses in such patients. Also, due to the growing evidence of the value of PET-CT for radiotherapy planning and its increased availability, patients treated without PET-CT were treated in the higher proportion in earlier era. Thus patients with PET-CT used for staging would have falsely higher rate of ENF due to better post-treatment staging. This may undermine the value of our findings. Nevertheless, also in the studies in which patients were treated with and without PET-CT for staging in the same time period, there was no difference in the rate of ENF in favor of the PET-CT use [
      • Rosenzweig K.E.
      • Sura S.
      • Jackson A.
      • Yorke E.
      Involved-field radiation therapy for inoperable non-small-cell lung cancer.
      ,
      • Lao L.
      • Hope A.J.
      • Maganti M.
      • et al.
      Incidental prophylactic nodal irradiation and patterns of nodal relapse in inoperable early stage NSCLC patients treated with SBRT: a case-matched analysis.
      ,
      • Belderbos J.S.
      • Heemsbergen W.D.
      • De Jaeger K.
      • et al.
      Final results of a Phase I/II dose escalation trial in non-small-cell lung cancer using three dimensional conformal radiotherapy.
      ,
      • Kolodziejczyk M.
      • Bujko K.
      • Michalski K.
      • Kepka L.
      Incidence of isolated nodal failure in non-small cell lung cancer patients included in a prospective study of the value of PET-CT.
      ]. One may think also that patients staged with PET-CT survived longer than patients without PET-CT due to stage migration thus a rate of detected ENF would be higher. However, the lengths of follow-up period of patients in the groups with and without PET-CT were similar in our study.
      We reported the significantly higher proportion of PET-CT staging for SBRT patients than for patients treated with conventional techniques. However, the benefit of the use of PET-CT for staging was not disclosed for any techniques used. Patients treated with SBRT have probably a lower risk of ENF due to the earlier stages of their disease. Surprisingly, the rate of ENF was very similar in patients treated with SBRT and in those treated with conventional techniques. This may be related to the steeper dose distribution and related to that a lack of incidental irradiation [
      • Salguero F.J.
      • Belderbos J.S.
      • Rossi M.
      • et al.
      Microscopic disease extension as a risk factor for loco-regional recurrence of NSCLC after SBRT.
      ]. We still do not have firm data that enable us to incorporate the phenomenon of incidental irradiation into treatment planning, to prevent regional failures. However, there is growing evidence that, in the absence of ENI, incidental irradiation reduces the risk of ENF. Recently, it was demonstrated that doses higher than 20 Gy delivered to ipsilateral hilum decreased the rate of ENF in patients treated with SBRT [
      • Lao L.
      • Hope A.J.
      • Maganti M.
      • et al.
      Incidental prophylactic nodal irradiation and patterns of nodal relapse in inoperable early stage NSCLC patients treated with SBRT: a case-matched analysis.
      ]. This may explain the absence of differences in the reported rate of ENF between patients with early peripheral tumours who were treated with SBRT and patients treated with other techniques, in whom central and larger tumors are at a potentially higher risk of regional relapse. Even low radiation doses (i.e., lower than 40 Gy) may reduce regional relapses in both SBRT and non-SBRT techniques [
      • Lao L.
      • Hope A.J.
      • Maganti M.
      • et al.
      Incidental prophylactic nodal irradiation and patterns of nodal relapse in inoperable early stage NSCLC patients treated with SBRT: a case-matched analysis.
      ,
      • Kepka L.
      • Maciejewski B.
      • Withers H.R.
      Does incidental irradiation with doses lower than 50 Gy effectively reduce isolated nodal recurrences in non-small-cell lung cancer: dose-response relationship.
      ]. Probably, a rapid dose decrease outside PTV in the SBRT technique led to the increased risk of ENF. PET-CT should not render us overconfident about the real disease extent, because this diagnostic tool is not able to detect microscopic disease. Here, we do not promote ENI use in SBRT, because the results obtained with this technique to date are very encouraging; however, we should still closely monitor such patients and continue to gather data on this issue [
      • Brada M.
      • Pope A.
      • Baumann M.
      SABR in NSCLC – the beginning of the end or the end of the beginning?.
      ,
      • Louie A.V.
      • Palma D.A.
      • Dahele M.
      • Rodrigues G.B.
      • Senan S.
      Management of early-stage non-small cell lung cancer using stereotactic ablative radiotherapy: controversies, insights and changing horizons.
      ].
      Unfortunately, we were not able to demonstrate the proportion of ENF in relation to the clinical stage of the disease. Most reports included in this review did not specify the exact distribution of ENF in this regard. One may expect that the risk of ENF increases with more advanced clinical stage, as it was demonstrated in other reports [
      • Kepka L.
      • Bujko K.
      • Zolciak-Siwinska A.
      Risk of isolated nodal failure for non-small cell lung cancer (NSCLC) treated with the elective nodal irradiation (ENI) using 3D-conformal radiotherapy (3D-CRT) techniques.
      ]. Also, the value of PET-CT may be more limited in more locoregionally advanced NSCLC. Videtic et al. [
      • Videtic G.M.
      • Rice T.W.
      • Murthy S.
      • et al.
      Utility of positron emission tomography compared with mediastinoscopy for delineating involved lymph nodes in stage III lung cancer: insights for radiotherapy planning from a surgical cohort.
      ] demonstrated that 39% of 87 stage III NSCLC patients had nodal metastases identified by mediastinoscopy that were undetected by PET-CT.
      The heterogeneity of included studies is another limitation of our findings. We have included prospective and retrospective studies performed within different periods of time. However, we were not able to find better way of looking for these data, because even in the prospective studies, the pattern of failure was not usually considered as the main end-point of the study and these data were also often recorded retrospectively. Different times of performing radiotherapy might have led to the use of different types and techniques of PET scanning. We cannot exclude that the modern PET-CT machines would contribute to the higher accuracy of mediastinal staging. Also, most studies did not provide details on delineation, i.e. how the PET-CT findings modified radiation target volumes. Included studies did not provide data on the policy of pathologic verification of PET-CT findings. However, pathologic staging is not mandatory for radiotherapy purposes and is not routinely used in clinical practice [
      • De Ruysscher D.
      • Faivre-Finn C.
      • Nestle U.
      • et al.
      European Organization for Research and Treatment of Cancer recommendations for planning and delivery of high dose, high-precision of radiotherapy for lung cancer.
      ]. We are aware that if we had all these data our analysis would have more scientific impact. On the other, we think that a large number of included studies compensates for these uncertainties.
      Our rate of ENFs (6.5%) differs slightly from this provided in the guidelines (usually below 5%). This may be related to our definition of ENF in which regional failures were not excluded if they occurred simultaneously with distant metastases. The guidelines refer to the reports in which, mostly, isolated nodal failures (INFs) instead of ENFs were considered. INFs were defined as outside clinical target volume regional failures that occurred in the absence of local and distant relapse. We consider that regional failures may be a source of distant seeding and, at times, distant metastases represent failure in regional control. For that reason, our definition of ENF seems to be more suitable for evaluation of the value of PET-CT in terms of regional control.
      In conclusion, we have demonstrated that, despite the recognized value of PET-CT in the diagnostic and radiotherapy of NSCLC, its value in the reduction of ENF in radiotherapy of lung cancer should not be overestimated.

      Conflict of interest statement

      No conflict of interest from any authors. No financial funding received for this study.

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