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Hypofractionated proton therapy for non-small cell lung cancer: Ready for prime time? A systematic review and meta-analysis

  • Author Footnotes
    1 These Authors contributed equally to the manuscript and should be considered as Co-first Authors.
    Stefania Volpe
    Correspondence
    Corresponding authors at: IEO, Via Ripamonti 435, 20141 Milan, Italy.
    Footnotes
    1 These Authors contributed equally to the manuscript and should be considered as Co-first Authors.
    Affiliations
    Department of Radiation Oncology, European Institute of Oncology (IEO) IRCCS, Milan, Italy

    Department of Oncology and Hemato-Oncology (DIPO), University of Milan, Milan, Italy
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    1 These Authors contributed equally to the manuscript and should be considered as Co-first Authors.
    Gaia Piperno
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    1 These Authors contributed equally to the manuscript and should be considered as Co-first Authors.
    Affiliations
    Department of Radiation Oncology, European Institute of Oncology (IEO) IRCCS, Milan, Italy
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  • Francesca Colombo
    Correspondence
    Corresponding authors at: IEO, Via Ripamonti 435, 20141 Milan, Italy.
    Affiliations
    Department of Radiation Oncology, European Institute of Oncology (IEO) IRCCS, Milan, Italy

    Department of Oncology and Hemato-Oncology (DIPO), University of Milan, Milan, Italy
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  • Annalisa Biffi
    Affiliations
    National Centre of Healthcare Research and Pharmacoepidemiology, University of Milano-Bicocca, Milan, Italy

    Department of Statistics and Quantitative Methods, University of Milano-Bicocca, Milan, Italy
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  • Stefania Comi
    Affiliations
    Unit of Medical Physics, European Institute of Oncology (IEO) IRCCS, Milan, Italy
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  • Federico Mastroleo
    Affiliations
    Department of Radiation Oncology, European Institute of Oncology (IEO) IRCCS, Milan, Italy

    University of Piemonte Orientale, Novara, Italy
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  • Author Footnotes
    3 Affiliation at the time of the study.
    Anna Maria Camarda
    Footnotes
    3 Affiliation at the time of the study.
    Affiliations
    Department of Radiation Oncology, European Institute of Oncology (IEO) IRCCS, Milan, Italy

    Department of Oncology and Hemato-Oncology (DIPO), University of Milan, Milan, Italy
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    3 Affiliation at the time of the study.
    Alessia Casbarra
    Footnotes
    3 Affiliation at the time of the study.
    Affiliations
    Department of Radiation Oncology, European Institute of Oncology (IEO) IRCCS, Milan, Italy

    Department of Oncology and Hemato-Oncology (DIPO), University of Milan, Milan, Italy
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  • Federica Cattani
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    Unit of Medical Physics, European Institute of Oncology (IEO) IRCCS, Milan, Italy
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  • Giulia Corrao
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    Department of Radiation Oncology, European Institute of Oncology (IEO) IRCCS, Milan, Italy
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  • Filippo de Marinis
    Affiliations
    Thoracic Oncology Division, European Institute of Oncology (IEO), IRCCS, Milan, Italy
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  • Lorenzo Spaggiari
    Affiliations
    Department of Oncology and Hemato-Oncology (DIPO), University of Milan, Milan, Italy

    Division of Thoracic Surgery, European Institute of Oncology (IEO), IRCSS, Milan, Italy
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  • Matthias Guckenberger
    Affiliations
    Department of Radiation Oncology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
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  • Roberto Orecchia
    Affiliations
    Department of Radiation Oncology, European Institute of Oncology (IEO) IRCCS, Milan, Italy

    Scientific Direction, IEO, European Institute of Oncology (IEO), IRCCS, Milan, Italy
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    2 These Authors contributed equally to the manuscript and should be considered as Co-last Authors.
    Daniela Alterio
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    2 These Authors contributed equally to the manuscript and should be considered as Co-last Authors.
    Affiliations
    Department of Radiation Oncology, European Institute of Oncology (IEO) IRCCS, Milan, Italy
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  • Author Footnotes
    2 These Authors contributed equally to the manuscript and should be considered as Co-last Authors.
    Barbara Alicja Jereczek-Fossa
    Footnotes
    2 These Authors contributed equally to the manuscript and should be considered as Co-last Authors.
    Affiliations
    Department of Radiation Oncology, European Institute of Oncology (IEO) IRCCS, Milan, Italy

    Department of Oncology and Hemato-Oncology (DIPO), University of Milan, Milan, Italy
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  • Author Footnotes
    1 These Authors contributed equally to the manuscript and should be considered as Co-first Authors.
    2 These Authors contributed equally to the manuscript and should be considered as Co-last Authors.
    3 Affiliation at the time of the study.
Published:September 20, 2022DOI:https://doi.org/10.1016/j.ctrv.2022.102464

      Highlights

      • Hypofractionated proton beam radiotherapy for early-stage non-small cell lung cancer is gaining attention.
      • The optimal treatment schedule in terms of oncological outcomes and toxicities has not been defined.
      • The delivery of BED ≥ 105.6 Gy(RBE) is associated with improved survival, disease-free survival and local control.
      • Dose escalation may be associated with a slight increase in late toxicities, albeit medically manageable and non life-threatening.
      • Optimized patients’ selection and the use of advance uncertainty management techniques are mandatory.

      Abstract

      Background

      Hypofractionated proton beam radiotherapy (PBT) is gaining attention in early-stage non-small cell lung cancer (ES-NSCLC). However, there is a large unmet need to define indications, prescription doses and potential adverse events of protons in this clinical scenario. Hence, the present work aims to provide a critical literature revision, and to investigate associations between fractionation schedules/ biological effective doses (BEDs), oncological outcomes and toxicities.

      Materials and methods

      This systematic review and meta-analysis complied with the PRISMA recommendations. Inclusion criteria were: 1) curative-intent hypofractionated PBT for ES-NSCLC (≥3 Gy(RBE)/fraction), 2) report of the clinical outcomes of interest, 3) availability of full-text written in English. The bibliographic search was performed on the NCBI Pubmed, Embase and Scopus in September 2021; no other limitations were applied. The BED was calculated for each included study (α/β = 10 Gy); the median BED for all studies was used as a threshold for stratifying selected evidence into “high” and “low”-dose subgroups. Heterogeneity was tested using chi-square statistics; inconsistency was measured with the I2 index. Pooled estimate was obtained by fitting both the fixed-effect and the DerSimonian and Laird random-effect model.

      Results

      Eight studies and 401 patients were available for the meta-analysis; median follow-up was 32.8 months. The median delivered BED was 105.6 Gy(RBE). A BED ≥ 105.6 Gy(RBE) consistently provided superior OS, CSS, DFS and LC rates (i.e.: 4-year OS: 0.56 [0.34–0.76] for BED < 105.6 Gy(RBE) and 0.78 [0.64–0.88] for BED ≥ 105.6 Gy(RBE)). The meta-analysis of proportions showed a comparable probability of developing acute grade ≥ 2 toxicity between the two groups, while the probability of any late grade ≥ 2 event was almost three-times greater for BED ≥ 105.6 Gy(RBE), with rib fractures being more common in the high dose group.

      Conclusion

      Hypofractionated PBT is a safe and effective treatment option for ES-NSCLC; the delivery of BED ≥ 105.6 Gy(RBE) with advanced techniques for uncertainty management has been associated with improved oncological outcomes across all considered time points.

      Keywords

      Abbreviations:

      BED (Biologically effective dose), CI (Confidence interval), CSS (Cancer-specific survival), CT (Computed tomography), CTV (Clinical target volume), DNA (Deoxyribonucleic Acid), ES (Early-stage), ESMO (European society of medical oncology), GTV (Gross tumor volume), IQR (Interquartile range), LC (Local control), NCCN (National comprehensive cancer network), NSCLC (Non-small cell lung cancer), OS (Overall survival), PBT (Proton beam therapy), PFS (Progression-free survival), PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses), PTV (Planning target volume), RF (Rib fracture), RT (Radiotherapy), SBPT (Stereotactic body proton therapy), SBRT (Stereotactic body radiation therapy)

      Introduction

      With an estimated number of deaths of almost 1.8 million in 2020, lung cancer is the most common cause of cancer-related death worldwide [

      Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA A Cancer J Clin 2021; caac.21660.

      ]. Of these, up to 85% are non-small cell lung cancers (NSCLCs), a disease entity which encompasses distinct mutational and histological subtypes, [
      • Thomas A.
      • Liu S.V.
      • Subramaniam D.S.
      • et al.
      Refining the treatment of NSCLC according to histological and molecular subtypes.
      ]. Given the extremely poor survival rates of advanced and metastatic NSCLC, increasing efforts have been made to design screening programs for high-risk populations (e.g. heavy smokers). Therefore, other than a mortality benefit [
      • Dziedzic R.
      • Marjański T.
      • Rzyman W.
      A narrative review of invasive diagnostics and treatment of early lung cancer.
      ], it is expected that the prevalence of early-stage NSCLC (ES-NSCLC) will increase in the upcoming years.
      In the absence of conclusive data from randomized clinical trials, surgery remains the primary treatment option for newly-diagnosed ES-NSCLCs, and radiotherapy (RT) is mainly reserved as an option in case of significant comorbidities contraindicating general anesthesia, or if the patient refuses surgical intervention after thoracic surgery evaluation [

      NCCN- National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines)- Non-Small Cell Lung Cancer. Version 4.2021- March 3, 2021, https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf.

      ,
      • Guckenberger M.
      • Andratschke N.
      • Dieckmann K.
      • et al.
      ESTRO ACROP consensus guideline on implementation and practice of stereotactic body radiotherapy for peripherally located early stage non-small cell lung cancer.
      ]. However, despite negative patients’ selection, stereotactic body RT (SBRT) allows for excellent disease control, with survival rates matching those of surgical series in comparable cohorts [
      • Chang J.Y.
      • Senan S.
      • Paul M.A.
      • et al.
      Stereotactic ablative radiotherapy versus lobectomy for operable stage I non-small-cell lung cancer: a pooled analysis of two randomised trials.
      ,
      • Zheng X.
      • Schipper M.
      • Kidwell K.
      • et al.
      Survival outcome after stereotactic body radiation therapy and surgery for stage I non-small cell lung cancer: a meta-analysis.
      ,
      • Wrona A.
      • Mornex F.
      Hypofractionation in Early Stage Non-Small Cell Lung Cancer.
      ,
      • Chang J.Y.
      • Mehran R.J.
      • Feng L.
      • et al.
      Stereotactic ablative radiotherapy for operable stage I non-small-cell lung cancer (revised STARS): long-term results of a single-arm, prospective trial with prespecified comparison to surgery.
      ]. To date, international guidelines recommend the use of SBRT over more modestly hypofractionated regimens, and the delivery of biological effective doses (BEDs) greater than 100 Gy is advised to maximize local control and overall survival, especially in case of tumors up to 5 cm in size [

      NCCN- National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines)- Non-Small Cell Lung Cancer. Version 4.2021- March 3, 2021, https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf.

      ,
      • Wrona A.
      • Mornex F.
      Hypofractionation in Early Stage Non-Small Cell Lung Cancer.
      ,
      • Onishi H.
      • Shirato H.
      • Nagata Y.
      • et al.
      Hypofractionated Stereotactic Radiotherapy (HypoFXSRT) for Stage I Non-small Cell Lung Cancer: Updated Results of 257 Patients in a Japanese Multi-institutional Study.
      ,
      • Olsen J.R.
      • Robinson C.G.
      • El Naqa I.
      • et al.
      Dose-Response for Stereotactic Body Radiotherapy in Early-Stage Non–Small-Cell Lung Cancer.
      ]. However, a recent analysis of real-world data from the American National Cancer Dataset has underlined that the delivery of a BED greater or equal to 130 Gy (α/β = 10 Gy) may lead greater 5–5-years overall survival rates in stage I NSCLC [
      • Moreno A.C.
      • Fellman B.
      • Hobbs B.P.
      • et al.
      Biologically Effective Dose in Stereotactic Body Radiotherapy and Survival for Patients With Early-Stage NSCLC.
      ]. As a part of the debate on optimal BED identification, a meta-analysis by Zhang et al. has suggested that BED should be maintained below 146 Gy (α/β = 10 Gy) to avoid a detrimental effect on patients’ survival in case of peripheral tumors [
      • Zhang J.
      • Yang F.
      • Li B.
      • et al.
      Which is the optimal biologically effective dose of stereotactic body radiotherapy for Stage I non-small-cell lung cancer? A meta-analysis.
      ], while a systematic review focusing on central NSCLCs has shown that a threshold of 210 Gy BED (α/β = 3 Gy) should be respected to lower the risk of potentially severe radiation-related adverse events [
      • Senthi S.
      • Haasbeek C.J.A.
      • Slotman B.J.
      • et al.
      Outcomes of stereotactic ablative radiotherapy for central lung tumours: A systematic review.
      ].
      As this body of evidence claims for a cautious approach to dose escalation in SBRT, the use of proton beam therapy (PBT) may represent an appealing option in order not only to further improve oncological outcomes, but also to reduce toxicity in patients with severe comorbidities and/or centrally-located lesions. Indeed, PBT is gaining increasing attention, and facilities are becoming more available worldwide [
      • Ramella S.
      • D’Angelillo R.M.
      Proton beam or photon beam radiotherapy in the treatment of non-small-cell lung cancer.
      ]. Thanks to the depth-dose distribution, and a clear dose fall-off after the Bragg peak, particles allow for a better dose distribution, with less dose delivered to the healthy structures [
      • Durante M.
      • Orecchia R.
      • Loeffler J.S.
      Charged-particle therapy in cancer: clinical uses and future perspectives.
      ,
      • Paganetti H.
      • Grassberger C.
      • Sharp G.C.
      Physics of Particle Beam and Hypofractionated Beam Delivery in NSCLC.
      ]. While these advantages are supported by in silico studies [
      • Ramella S.
      • D’Angelillo R.M.
      Proton beam or photon beam radiotherapy in the treatment of non-small-cell lung cancer.
      ,
      • Register S.P.
      • Zhang X.
      • Mohan R.
      • et al.
      Proton Stereotactic Body Radiation Therapy for Clinically Challenging Cases of Centrally and Superiorly Located Stage I Non-Small-Cell Lung Cancer.
      ], randomized evidence is lacking to favor the use of either SBRT or PBT in clinical practice [
      • Nantavithya C.
      • Gomez D.R.
      • Wei X.
      • et al.
      Phase 2 Study of Stereotactic Body Radiation Therapy and Stereotactic Body Proton Therapy for High-Risk, Medically Inoperable, Early-Stage Non-Small Cell Lung Cancer.
      ]. The only currently-available systematic review and meta-analysis comparing these two treatment modalities for ES-NSCLC has led to inconclusive results, mainly due to a severe selection bias between patients’ groups [
      • Chi A.
      • Chen H.
      • Wen S.
      • et al.
      Comparison of particle beam therapy and stereotactic body radiotherapy for early stage non-small cell lung cancer: A systematic review and hypothesis-generating meta-analysis.
      ]. Moreover, the use of PBT in this clinical setting is still facing several technical challenges, such as the full management respiratory motion and more efficient dose calculation algorithms, which would minimize the range uncertainties inherent in small-sized targets moving in a low-density tissue.
      Currently, there is a large unmet need to define indication, prescription doses and potential side effects of protons in this clinical scenario. Specifically, hypofractionated PBT represents an attractive choice to reduce overall-treatment time, improve patients’ quality of life and lower treatment-related costs. Moreover, from a technical perspective, adequately delivered hypofractionated PBT is expected to reduce the effects of inter-fractional variations (i.e. patient’s positioning, anatomical modifications, tumor shrinkage, interplay effect) [
      • Paganetti H.
      • Grassberger C.
      • Sharp G.C.
      Physics of Particle Beam and Hypofractionated Beam Delivery in NSCLC.
      ]. Other than physics properties, radiobiological characteristics of PBT are gaining increasing attention, both at pre-clinical and clinical level. Several immunological, genetic, and molecular mechanisms have been associated with radiation quality [
      • Marcus D.
      • Lieverse R.I.Y.
      • Klein C.
      • et al.
      Charged Particle and Conventional Radiotherapy: Current Implications as Partner for Immunotherapy.
      ,
      • Tommasino F.
      • Durante M.
      Proton Radiobiology.
      ]. In detail, high-energy protons seem to elicit specific alterations of cell cycle regulation, DNA damage response and apoptosis signaling [
      • Ding L.-H.
      • Park S.
      • Peyton M.
      • et al.
      Distinct transcriptome profiles identified in normal human bronchial epithelial cells after exposure to γ-rays and different elemental particles of high Z and energy.
      ,
      • Finnberg N.
      • Wambi C.
      • Ware J.H.
      • et al.
      Gamma-radiation (GR) triggers a unique gene expression profile associated with cell death compared to proton radiation (PR) in mice in vivo.
      ,
      • Zhang X.
      • Lin S.H.
      • Fang B.
      • et al.
      Therapy-Resistant Cancer Stem Cells Have Differing Sensitivity to Photon versus Proton Beam Radiation.
      ], as well as the activation of genes related to inflammatory response, angiogenetic control, and migration effects [
      • Tommasino F.
      • Durante M.
      Proton Radiobiology.
      ,
      • Girdhani S.
      • Lamont C.
      • Hahnfeldt P.
      • et al.
      Proton Irradiation Suppresses Angiogenic Genes and Impairs Cell Invasion and Tumor Growth.
      ]. Moreover, the genomic instability induced by PBT may lead to a higher release of antigens and an enhanced T-cell- mediated immune response [
      • Marcus D.
      • Lieverse R.I.Y.
      • Klein C.
      • et al.
      Charged Particle and Conventional Radiotherapy: Current Implications as Partner for Immunotherapy.
      ,
      • Alan Mitteer R.
      • Wang Y.
      • Shah J.
      • et al.
      Proton beam radiation induces DNA damage and cell apoptosis in glioma stem cells through reactive oxygen species.
      ]. These radiobiological effects may be further enhanced by hypofractionation, as suggested by a recent in vitro study led by Zhang et al. on two different NSCLC cell lines [
      • Zhang H.
      • Wan C.
      • Huang J.
      • et al.
      In Vitro Radiobiological Advantages of Hypofractionation Compared with Conventional Fractionation: Early-Passage NSCLC Cells are Less Aggressive after Hypofractionation.
      ].
      Hence, given the importance of the topic in current Radiation Oncology, we have performed the present systematic review and meta-analysis, aiming to:
      • -
        Collect currently-available evidence on the use of hypofractionated PBT in NSCLC, with a dedicated focus on the curative-intent treatment of early-stages.
      • -
        Assess whether any fractionation schedule/ BED results in better oncological outcomes in terms of overall survival (OS), cancer-specific survival (CSS), progression-free survival (PFS) and local control (LC), and evaluate the associated toxicity profile.
      • -
        Provide a hypothesis-generating framework for further studies in the field.

      Materials and methods

      Search strategy

      The methodology complied with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendations [
      • Page M.J.
      • McKenzie J.E.
      • Bossuyt P.M.
      • et al.
      The PRISMA 2020 statement: An updated guideline for reporting systematic reviews.
      ]. All manuscripts in English were considered eligible provided that the following inclusion criteria were fulfilled: 1) curative-intent PBT for NSCLC, delivered with hypofractionated schemes (≥3 Gy(RBE)/fraction), 2) report of clinical outcomes (e.g. overall survival, local control, acute and late treatment-related toxicities) and 3) availability of full-text. Studies comparing PBT and photon-based RT were considered eligible only if it was possible to retrieve information on PBT doses, oncological outcomes, and toxicities. The bibliographic search was performed on the NCBI PubMed, Embase and Scopus databases in September 2021; no limitations other than language were used not to miss potentially relevant publications. Narrative and systematic reviews were considered for cross-reference. The full search strategy is provided in the Supplementary Material 1.

      Evidence acquisition

      Article selection was performed by two authors (FC and MC); a third author (SV) was interrogated in case of discrepancies. The whole article selection process is shown in Supplementary Fig. 1. As a further specification, two works were excluded because of significant population overlap with more recent series, which were included in the final analysis [
      • Kanemoto A.
      • Okumura T.
      • Ishikawa H.
      • et al.
      Outcomes and Prognostic Factors for Recurrence After High-Dose Proton Beam Therapy for Centrally and Peripherally Located Stage I Non–Small-Cell Lung Cancer.
      ,
      • Kharod S.M.
      • Nichols R.C.
      • Henderson R.H.
      • et al.
      Image-Guided Hypofractionated Proton Therapy in Early-Stage Non-Small Cell Lung Cancer: A Phase 2 Study.
      ]. For each study meeting the inclusion criteria, the following patient-, tumor- and treatment- related characteristics were considered: type of study, number of included patients, median/mean patient’s age, tumor histology, tumor size, type of intervention (±control), use of any concomitant systemic treatment, fractionation scheme (dose/fraction, total dose, number of fractions), follow-up duration, oncological outcomes, onset of any moderate-to-severe acute and late toxicities (grade ≥ 2 per the Common Terminology Criteria for Adverse Events). If multiple fractionation schemes were used, separate information was retrieved for each fractionation scheme, whenever possible. In this case, the studies were considered for quantitative synthesis. Either prior or concomitant use of systemic treatment was allowed. To allow for a fair comparison among studies, the total BED was calculated for each study. A α/β ratio of 10 Gy was assumed for the primary tumor control [
      • Klement R.J.
      • Sonke J.-J.
      • Allgäuer M.
      • et al.
      Estimation of the α/β ratio of non-small cell lung cancer treated with stereotactic body radiotherapy.
      ].
      Figure thumbnail gr1
      Fig. 1Forrest plots with study-specific data and summary proportions for overall survival at 3-years.

      Statistical analysis

      Extracted data included author and year, study design, number of included patients, fractionation and median BED, median follow-up duration, oncological outcomes (overall survival, local control, progression-free survival, cause specific survival) and toxicities (acute or late). Data were processed and portrayed in the corresponding forest plots by an author (AB). Oncological outcomes and toxicities were expressed as proportions with 95% confidence intervals (CIs). For the stratification of patients, a median BED was calculated on the total doses of included studies.
      Heterogeneity between study-specific estimates was tested using chi-square statistics [
      • Cochran W.G.
      The Combination of Estimates from Different Experiments.
      ]; inconsistency was measured with the I2 index [
      • Higgins J.P.T.
      Measuring inconsistency in meta-analyses.
      ]. Pooled estimate was obtained by fitting both the fixed-effect and the DerSimonian and Laird random-effect model [
      • DerSimonian R.
      • Laird N.
      Meta-analysis in clinical trials.
      ]. All tests were considered statistically significant for p < 0.05. All analyses were performed by using R x64 (version 4.1.0) with the package “Meta”.

      Results

      Qualitative synthesis

      Overall, 15 studies were included in the qualitative synthesis; of these, 5 were prospective trials. Two retrospective series considered a mixed population of early-stage cases and locally-advanced and/or recurrent disease [
      • Lee S.U.
      • Moon S.H.
      • Cho K.H.
      • et al.
      Ablative dose proton beam therapy for stage I and recurrent non-small cell lung carcinomas: Ablative dose PBT for NSCLC.
      ,
      • Shioyama Y.
      • Tokuuye K.
      • Okumura T.
      • et al.
      Clinical evaluation of proton radiotherapy for non–small-cell lung cancer.
      ]. The total number of analyzed patients was 665, with a median sample size per study of 50 (interquartile range, IQR: 22–57), and a median age of 75 years. Poor performance status was explicitly reported an exclusion criterion for patients’ inclusion/enrollment in 12/15 studies ([
      • Nantavithya C.
      • Gomez D.R.
      • Wei X.
      • et al.
      Phase 2 Study of Stereotactic Body Radiation Therapy and Stereotactic Body Proton Therapy for High-Risk, Medically Inoperable, Early-Stage Non-Small Cell Lung Cancer.
      ,
      • Kanemoto A.
      • Okumura T.
      • Ishikawa H.
      • et al.
      Outcomes and Prognostic Factors for Recurrence After High-Dose Proton Beam Therapy for Centrally and Peripherally Located Stage I Non–Small-Cell Lung Cancer.
      ,
      • Kharod S.M.
      • Nichols R.C.
      • Henderson R.H.
      • et al.
      Image-Guided Hypofractionated Proton Therapy in Early-Stage Non-Small Cell Lung Cancer: A Phase 2 Study.
      ,
      • Lee S.U.
      • Moon S.H.
      • Cho K.H.
      • et al.
      Ablative dose proton beam therapy for stage I and recurrent non-small cell lung carcinomas: Ablative dose PBT for NSCLC.
      ,
      • Shioyama Y.
      • Tokuuye K.
      • Okumura T.
      • et al.
      Clinical evaluation of proton radiotherapy for non–small-cell lung cancer.
      ,
      • Hata M.
      • Tokuuye K.
      • Kagei K.
      • et al.
      Hypofractionated High-Dose Proton Beam Therapy for Stage I Non–Small-Cell Lung Cancer: Preliminary Results of A Phase I/II Clinical Study.
      ,
      • Iwata H.
      • Murakami M.
      • Demizu Y.
      • et al.
      High-dose proton therapy and carbon-ion therapy for stage I nonsmall cell lung cancer.
      ,
      • Makita C.
      • Nakamura T.
      • Takada A.
      • et al.
      High-dose proton beam therapy for stage I non-small cell lung cancer: Clinical outcomes and prognostic factors.
      ,
      • Nakamura N.
      • Hotta K.
      • Zenda S.
      • et al.
      Hypofractionated proton beam therapy for centrally located lung cancer.
      ,
      • Nihei K.
      • Ogino T.
      • Ishikura S.
      • et al.
      High-dose proton beam therapy for Stage I non–small-cell lung cancer.
      ,
      • Ono T.
      • Yabuuchi T.
      • Nakamura T.
      • et al.
      High dose hypofractionated proton beam therapy is a safe and feasible treatment for central lung cancer.
      ,
      • Westover K.D.
      • Seco J.
      • Adams J.A.
      • et al.
      Proton SBRT for Medically Inoperable Stage I NSCLC.
      ]; and detailed information on comorbidities deeming inoperability were present in one third of cases ([
      • Kanemoto A.
      • Okumura T.
      • Ishikawa H.
      • et al.
      Outcomes and Prognostic Factors for Recurrence After High-Dose Proton Beam Therapy for Centrally and Peripherally Located Stage I Non–Small-Cell Lung Cancer.
      ,
      • Hata M.
      • Tokuuye K.
      • Kagei K.
      • et al.
      Hypofractionated High-Dose Proton Beam Therapy for Stage I Non–Small-Cell Lung Cancer: Preliminary Results of A Phase I/II Clinical Study.
      ,
      • Iwata H.
      • Murakami M.
      • Demizu Y.
      • et al.
      High-dose proton therapy and carbon-ion therapy for stage I nonsmall cell lung cancer.
      ,
      • Makita C.
      • Nakamura T.
      • Takada A.
      • et al.
      High-dose proton beam therapy for stage I non-small cell lung cancer: Clinical outcomes and prognostic factors.
      ,
      • Westover K.D.
      • Seco J.
      • Adams J.A.
      • et al.
      Proton SBRT for Medically Inoperable Stage I NSCLC.
      ]. These were mainly concomitant lung disease (e.g. chronic obstructive pulmonary disease, interstitial pneumonia), cardiac dysfunction and advanced age. Only 9/15 works provided information on median tumor size [
      • Nantavithya C.
      • Gomez D.R.
      • Wei X.
      • et al.
      Phase 2 Study of Stereotactic Body Radiation Therapy and Stereotactic Body Proton Therapy for High-Risk, Medically Inoperable, Early-Stage Non-Small Cell Lung Cancer.
      ,
      • Kanemoto A.
      • Okumura T.
      • Ishikawa H.
      • et al.
      Outcomes and Prognostic Factors for Recurrence After High-Dose Proton Beam Therapy for Centrally and Peripherally Located Stage I Non–Small-Cell Lung Cancer.
      ,
      • Lee S.U.
      • Moon S.H.
      • Cho K.H.
      • et al.
      Ablative dose proton beam therapy for stage I and recurrent non-small cell lung carcinomas: Ablative dose PBT for NSCLC.
      ,
      • Hata M.
      • Tokuuye K.
      • Kagei K.
      • et al.
      Hypofractionated High-Dose Proton Beam Therapy for Stage I Non–Small-Cell Lung Cancer: Preliminary Results of A Phase I/II Clinical Study.
      ,
      • Iwata H.
      • Murakami M.
      • Demizu Y.
      • et al.
      High-dose proton therapy and carbon-ion therapy for stage I nonsmall cell lung cancer.
      ,
      • Ono T.
      • Yabuuchi T.
      • Nakamura T.
      • et al.
      High dose hypofractionated proton beam therapy is a safe and feasible treatment for central lung cancer.
      ,
      • Westover K.D.
      • Seco J.
      • Adams J.A.
      • et al.
      Proton SBRT for Medically Inoperable Stage I NSCLC.
      ,
      • Bush D.A.
      • Cheek G.
      • Zaheer S.
      • et al.
      High-Dose Hypofractionated Proton Beam Radiation Therapy Is Safe and Effective for Central and Peripheral Early-Stage Non-Small Cell Lung Cancer: Results of a 12-Year Experience at Loma Linda University Medical Center.
      ,
      • Iwata H.
      • Demizu Y.
      • Fujii O.
      • et al.
      Long-Term Outcome of Proton Therapy and Carbon-Ion Therapy for Large (T2a–T2bN0M0) Non–Small-Cell Lung Cancer.
      ], which was 2.5 (IQR: 2.0–3.7) cm for the whole population. The median dose/fraction was 6.0 Gy(RBE), with a median prescribed total dose of 63 Gy(RBE), resulting in a median BED of 105.6 Gy(RBE) to the target volumes. Only one patient in the whole examined population had received concomitant systemic therapy with Cetuximab [
      • Gomez D.R.
      • Gillin M.
      • Liao Z.
      • et al.
      Phase 1 Study of Dose Escalation in Hypofractionated Proton Beam Therapy for Non-Small Cell Lung Cancer.
      ]. Positron emission tomography was a required staging examination in 9/15 cases [
      • Kanemoto A.
      • Okumura T.
      • Ishikawa H.
      • et al.
      Outcomes and Prognostic Factors for Recurrence After High-Dose Proton Beam Therapy for Centrally and Peripherally Located Stage I Non–Small-Cell Lung Cancer.
      ,
      • Lee S.U.
      • Moon S.H.
      • Cho K.H.
      • et al.
      Ablative dose proton beam therapy for stage I and recurrent non-small cell lung carcinomas: Ablative dose PBT for NSCLC.
      ,
      • Hata M.
      • Tokuuye K.
      • Kagei K.
      • et al.
      Hypofractionated High-Dose Proton Beam Therapy for Stage I Non–Small-Cell Lung Cancer: Preliminary Results of A Phase I/II Clinical Study.
      ,
      • Iwata H.
      • Murakami M.
      • Demizu Y.
      • et al.
      High-dose proton therapy and carbon-ion therapy for stage I nonsmall cell lung cancer.
      ,
      • Ono T.
      • Yabuuchi T.
      • Nakamura T.
      • et al.
      High dose hypofractionated proton beam therapy is a safe and feasible treatment for central lung cancer.
      ,
      • Westover K.D.
      • Seco J.
      • Adams J.A.
      • et al.
      Proton SBRT for Medically Inoperable Stage I NSCLC.
      ,
      • Bush D.A.
      • Cheek G.
      • Zaheer S.
      • et al.
      High-Dose Hypofractionated Proton Beam Radiation Therapy Is Safe and Effective for Central and Peripheral Early-Stage Non-Small Cell Lung Cancer: Results of a 12-Year Experience at Loma Linda University Medical Center.
      ,
      • Iwata H.
      • Demizu Y.
      • Fujii O.
      • et al.
      Long-Term Outcome of Proton Therapy and Carbon-Ion Therapy for Large (T2a–T2bN0M0) Non–Small-Cell Lung Cancer.
      ,
      • Hatayama Y.
      • Nakamura T.
      • Suzuki M.
      • et al.
      Clinical Outcomes and Prognostic Factors of High-Dose Proton Beam Therapy for Peripheral Stage I Non-Small-Cell Lung Cancer.
      ], and considered as an alternative to chest CT in four studies [
      • Nantavithya C.
      • Gomez D.R.
      • Wei X.
      • et al.
      Phase 2 Study of Stereotactic Body Radiation Therapy and Stereotactic Body Proton Therapy for High-Risk, Medically Inoperable, Early-Stage Non-Small Cell Lung Cancer.
      ,
      • Kharod S.M.
      • Nichols R.C.
      • Henderson R.H.
      • et al.
      Image-Guided Hypofractionated Proton Therapy in Early-Stage Non-Small Cell Lung Cancer: A Phase 2 Study.
      ,
      • Makita C.
      • Nakamura T.
      • Takada A.
      • et al.
      High-dose proton beam therapy for stage I non-small cell lung cancer: Clinical outcomes and prognostic factors.
      ,
      • Nakamura N.
      • Hotta K.
      • Zenda S.
      • et al.
      Hypofractionated proton beam therapy for centrally located lung cancer.
      ]; the information was not available in the two remaining works [
      • Shioyama Y.
      • Tokuuye K.
      • Okumura T.
      • et al.
      Clinical evaluation of proton radiotherapy for non–small-cell lung cancer.
      ,
      • Nihei K.
      • Ogino T.
      • Ishikura S.
      • et al.
      High-dose proton beam therapy for Stage I non–small-cell lung cancer.
      ].
      After a median follow-up of 30.5 months (IQR: 24.3–44.9), OS data were presented by all studies. Toxicities were assessed according to the Common Terminology Criteria for Adverse Events (CTCAE) in 13 cases, and by the Radiation Therapy Oncology Group (RTOG) scoring system in the remaining two [
      • Hata M.
      • Tokuuye K.
      • Kagei K.
      • et al.
      Hypofractionated High-Dose Proton Beam Therapy for Stage I Non–Small-Cell Lung Cancer: Preliminary Results of A Phase I/II Clinical Study.
      ,
      • Ono T.
      • Yabuuchi T.
      • Nakamura T.
      • et al.
      High dose hypofractionated proton beam therapy is a safe and feasible treatment for central lung cancer.
      ]. Reports on acute toxicity were present in 13/15 works: overall, treatments were optimally tolerated, with a total number of grade 3 events of nine (1%). Of these, six were dermatitis [
      • Makita C.
      • Nakamura T.
      • Takada A.
      • et al.
      High-dose proton beam therapy for stage I non-small cell lung cancer: Clinical outcomes and prognostic factors.
      ,
      • Iwata H.
      • Demizu Y.
      • Fujii O.
      • et al.
      Long-Term Outcome of Proton Therapy and Carbon-Ion Therapy for Large (T2a–T2bN0M0) Non–Small-Cell Lung Cancer.
      ] and the remaining were lung-related toxicities [
      • Shioyama Y.
      • Tokuuye K.
      • Okumura T.
      • et al.
      Clinical evaluation of proton radiotherapy for non–small-cell lung cancer.
      ,
      • Westover K.D.
      • Seco J.
      • Adams J.A.
      • et al.
      Proton SBRT for Medically Inoperable Stage I NSCLC.
      ,
      • Kharod S.M.
      • Nichols R.C.
      • Henderson R.H.
      • et al.
      Image-guided hypofractionated double-scattering proton therapy in the management of centrally-located early-stage non-small cell lung cancer.
      ]. Data on late treatment-related toxicity of grade ≥ 3 were provided by 14/15 studies, and encompassed the following: pneumonitis (5 cases) [
      • Makita C.
      • Nakamura T.
      • Takada A.
      • et al.
      High-dose proton beam therapy for stage I non-small cell lung cancer: Clinical outcomes and prognostic factors.
      ,
      • Nihei K.
      • Ogino T.
      • Ishikura S.
      • et al.
      High-dose proton beam therapy for Stage I non–small-cell lung cancer.
      ,
      • Westover K.D.
      • Seco J.
      • Adams J.A.
      • et al.
      Proton SBRT for Medically Inoperable Stage I NSCLC.
      ,
      • Gomez D.R.
      • Gillin M.
      • Liao Z.
      • et al.
      Phase 1 Study of Dose Escalation in Hypofractionated Proton Beam Therapy for Non-Small Cell Lung Cancer.
      ], hypoxia (2 cases) [
      • Kharod S.M.
      • Nichols R.C.
      • Henderson R.H.
      • et al.
      Image-guided hypofractionated double-scattering proton therapy in the management of centrally-located early-stage non-small cell lung cancer.
      ], bronchial stricture, dyspnea and skin fibrosis (1 case each) [
      • Nantavithya C.
      • Gomez D.R.
      • Wei X.
      • et al.
      Phase 2 Study of Stereotactic Body Radiation Therapy and Stereotactic Body Proton Therapy for High-Risk, Medically Inoperable, Early-Stage Non-Small Cell Lung Cancer.
      ,
      • Nakamura N.
      • Hotta K.
      • Zenda S.
      • et al.
      Hypofractionated proton beam therapy for centrally located lung cancer.
      ,
      • Gomez D.R.
      • Gillin M.
      • Liao Z.
      • et al.
      Phase 1 Study of Dose Escalation in Hypofractionated Proton Beam Therapy for Non-Small Cell Lung Cancer.
      ,
      • Kharod S.M.
      • Nichols R.C.
      • Henderson R.H.
      • et al.
      Image-guided hypofractionated double-scattering proton therapy in the management of centrally-located early-stage non-small cell lung cancer.
      ]. Additionally, Lee et al. [
      • Lee S.U.
      • Moon S.H.
      • Cho K.H.
      • et al.
      Ablative dose proton beam therapy for stage I and recurrent non-small cell lung carcinomas: Ablative dose PBT for NSCLC.
      ] reported one grade 5 respiratory failure due to the sudden exacerbation of a pre-existent symptomatic idiopathic pulmonary fibrosis 3 months after the completion of PBT. An overview of the main patients’, tumor and treatment characteristics of the included studies is provided in Table 1.
      Table 1Characteristics of the studies included in the qualitative synthesis.
      Author

      (year)
      Type of studyIncluded ptsPTS’ AGE
      Numbers in brackets should be intended as ranges, reported as provided by each study.
      MEDIAN TUMOR SIZE (cm)Fractionation SCHEME(s)Median BED (α/β = 10 Gy(RBE))USE OF IGRTMedian follow-up, months, (range)Oncological outcomesAcute toxicitiesLate toxicities
      Bush et al. (2013)¥,
      • Bush D.A.
      • Cheek G.
      • Zaheer S.
      • et al.
      High-Dose Hypofractionated Proton Beam Radiation Therapy Is Safe and Effective for Central and Peripheral Early-Stage Non-Small Cell Lung Cancer: Results of a 12-Year Experience at Loma Linda University Medical Center.
      Prospective111 pts with histologically proven T1-T2 NSCL73.2 (53–91)3.6 (1.1–9.0)51 Gy/10fr (29pts)

      60 Gy/10fr (56pts)

      70 Gy/10fr (26pts)
      96Yes (kilovoltage imaging)484-yrs OS 18% (51 Gy), 32% (60 Gy) and 51% (70 Gy)NoneRib fracture (4pts)
      Hata et al. (2007),
      • Hata M.
      • Tokuuye K.
      • Kagei K.
      • et al.
      Hypofractionated High-Dose Proton Beam Therapy for Stage I Non–Small-Cell Lung Cancer: Preliminary Results of A Phase I/II Clinical Study.
      Prospective21 pts with histologically proven stage I NSCLC74 (51–85)2.5 (1.0–4.2)50 Gy/10fr (3pts)

      60 Gy/10fr (18pts)
      96Yes (fluoroscopy)25

      (10–54)
      2-yrs OS 74%

      2-yrs CSS 86%

      2-yrs PFS 95%

      2-yrs DFS 79%
      G2 anemia (1pt)

      G2 pneumonitis (1pt)
      G2 subcutaneous induration (1pt)

      G2 myositis (1pt)
      Hatayama et al. (2016)¥,
      • Hatayama Y.
      • Nakamura T.
      • Suzuki M.
      • et al.
      Clinical Outcomes and Prognostic Factors of High-Dose Proton Beam Therapy for Peripheral Stage I Non-Small-Cell Lung Cancer.
      Retrospective50 pts with peripheral stage I NSCLC72.5 (54–87)NA66 Gy/10fr (50pts)109.56No22.8

      (5.6–60.1)
      3-yrs OS 87.9%

      3-yrs LC 95.7%

      3-yrs PFS 76.3%
      G2 pneumonitis (1pt)

      G3 dermatitis (3pts)
      G1-G2 rib fracture (15pts)
      Iwata et al. (2010)¥,
      • Iwata H.
      • Murakami M.
      • Demizu Y.
      • et al.
      High-dose proton therapy and carbon-ion therapy for stage I nonsmall cell lung cancer.
      Prospective80 pts with histologically-proven stage I NSCLC (57 pts treated with proton and 23 with carbon ion)76 (48–89)3.1 (1.0–7.0)80 Gy/10fr (20pts)

      60 Gy/10fr (37pts)
      96No35.5

      (18–66)
      3-yrs OS 90% (80 Gy), 61% (60 Gy)

      3-yrs LC 83% (80 Gy), 81% (60 Gy)
      G ≥ 2 dermatitis (13pts)G ≥ 2 pneumonitis (10pts)

      G2 rib fracture (18pts)

      G2 fibrosis (5pts)
      Iwata et al. (2013),
      • Iwata H.
      • Demizu Y.
      • Fujii O.
      • et al.
      Long-Term Outcome of Proton Therapy and Carbon-Ion Therapy for Large (T2a–T2bN0M0) Non–Small-Cell Lung Cancer.
      Retrospective70 pts with inoperable NSCLC (43pts treated with proton and 27 with carbon ion)75 (57–92)4.1 (3.1–7.0)80 Gy/20fr (14pts)

      60 Gy/10fr (20pts)

      66 Gy/10fr (8pts)

      70.2 Gy/26fr (1pt)
      96No51

      (24–103)
      4-yrs OS 58%

      4-yrs LC 75%

      4-yrs PFS 46%

      G2 dermatitis (10pts)

      G ≥ 3 dermatitis (5pts)
      G2 pneumonitis (10pts)

      Pneumothorax (2pts)

      G2 rib fracture (19pts)

      G2 fibrosis (5pts)

      Kanemoto et al. (2014)¥,
      • Kanemoto A.
      • Okumura T.
      • Ishikawa H.
      • et al.
      Outcomes and Prognostic Factors for Recurrence After High-Dose Proton Beam Therapy for Centrally and Peripherally Located Stage I Non–Small-Cell Lung Cancer.
      Retrospective74 pts with stage I NSCLC75 (51–86)2.2 (1.0–4.8)72.6 Gy/22fr (21pts)

      66 Gy/10 or 12fr (59pts)
      105.6NA31

      (7.3–104.3)
      3-yrs OS 76.7%

      3-yrs CSS 83%

      3-yrs PFS 58.6%

      3-yrs LC 63.9% (72,6Gy)

      88.4% (66 Gy)
      NoneNone
      Kharod et al., (2020)¥,
      • Kharod S.M.
      • Nichols R.C.
      • Henderson R.H.
      • et al.
      Image-Guided Hypofractionated Proton Therapy in Early-Stage Non-Small Cell Lung Cancer: A Phase 2 Study.
      Prospective23 pts with inoperable early-stage NSCLC74 (58–88)NA60 Gy/10fr96,00Yes (kilovoltage imaging)38.4 (2–110)

      3-yrs OS 81%

      5-yrs OS 50%

      3-yrs CSS 81%

      5-yrs CSS 71%

      3-yrs LC 90%
      G3 hypoxia (1pt)G3 hypoxia (1pt)

      G3 bronchial stricture (1pt)
      Lee et al. (2016),
      • Lee S.U.
      • Moon S.H.
      • Cho K.H.
      • et al.
      Ablative dose proton beam therapy for stage I and recurrent non-small cell lung carcinomas: Ablative dose PBT for NSCLC.
      Retrospective56 pts with stage I (42) and recurrent (13) NSCLC medically inoperable75 (47–89)2.5 (0.5–5.0)60 Gy/5fr (27pts)

      50 Gy/5fr (18pts)

      60 Gy/10fr (7pts)

      72 Gy/12fr (4pts)
      120Yes (Digital Imaging Position System)29

      (4–95)
      3-yrs OS 54.9%

      3-yrs LCR 85.4%

      G2 dermatitis (1pt)G2 pneumonitis (7pts)

      G5 (Exacerbation of idiopathic pulmonary fibrosis) (1pt)

      Mild atelectasis (7pts)

      Soft tissue fibrosis (4pts)

      Rib fracture (3pts)
      Makita et al. (2015)¥,
      • Makita C.
      • Nakamura T.
      • Takada A.
      • et al.
      High-dose proton beam therapy for stage I non-small cell lung cancer: Clinical outcomes and prognostic factors.
      Retrospective56 pts with stage I NSCLC77 (61–89)NA66 Gy/10fr (32pts)

      80 Gy/25fr (24pts)
      109.56NA33.7

      (4.6–57.5
      3-yrs OS 81.3%

      3-yrs LC 96%

      3-yrs PFS 73.4%
      G2 dermatitis (10pt)

      G3 dermatitis (1pt)
      G2 soft tissue damage (2pts)

      G2 rib fracture (10pts)

      G2 pneumonitis (9pts)

      G2 pericardial effusion (1pt)

      G3 pneumonitis (1pt)
      Nakamura et al. (2019),
      • Nakamura N.
      • Hotta K.
      • Zenda S.
      • et al.
      Hypofractionated proton beam therapy for centrally located lung cancer.
      Retrospective39 pts with centrally located cT1-2N0M0 lung cancer75 (48–88)NA88 Gy/20fr (2pts)

      80 Gy/20fr (24pts)

      66 Gy/10fr (8pts)

      75 Gy/25fr (2pts)

      60 Gy/10fr (1pt)

      70 Gy/20fr (1pt)

      60 Gy/20fr (1pt)
      116.8NA48

      (4–140)
      2-yrs PFS and OS were 86 and 100% for T1



      2-yrs PFS and OS 56% and 94% for T2
      G2 dermatitis (1pt)G2 pneumonitis (4pts)

      G3 dyspnea (1pt)
      Nantavithya et al. (2018)¥,
      • Nantavithya C.
      • Gomez D.R.
      • Wei X.
      • et al.
      Phase 2 Study of Stereotactic Body Radiation Therapy and Stereotactic Body Proton Therapy for High-Risk, Medically Inoperable, Early-Stage Non-Small Cell Lung Cancer.
      Prospective19 pts medically inoperable, early-stage

      NSCLC (10pts treated with SBPT, 9pts with SBRT)
      73.5 (53–88)1.950 Gy/4fr112.5Yes (kilovoltage imaging)32SBPT group

      3-yrs OS 90%

      3-yrs LC 90%

      3-yrs LCR 90%
      SBPT group

      G2 dyspnea (2pts)

      G2 Cough (1pt)
      SBPT group

      G2 dyspnea (2pts)

      G2 fatigue (1pt)

      G3 fibrosis (1pt)
      Nihei et al. (2006),
      • Nihei K.
      • Ogino T.
      • Ishikura S.
      • et al.
      High-dose proton beam therapy for Stage I non–small-cell lung cancer.
      Retrospective37 pts with histologically-proven stage I NSCL75 (63–87)NA70 Gy/20fr (3pts)

      80 Gy/20fr (17pts)

      88 Gy/20fr (16pts)

      94 Gy/20fr (1pt)
      112Yes (kilovoltage imaging)24

      (3–62)
      2-yrs OS 84%

      2-yrs LC 80%

      NoneG2 pulmonary toxicities (3pts)

      G3 pulmonary toxicities (3pts
      Ono et al. (2017)¥,
      • Ono T.
      • Yabuuchi T.
      • Nakamura T.
      • et al.
      High dose hypofractionated proton beam therapy is a safe and feasible treatment for central lung cancer.
      Retrospective20 pts with central lung cancer (stage I-III NSCLC)75 (63–90)3.9 (2.4–8.1)80 Gy/25fr105.6Yes (kilovoltage imaging)27.5

      (12–72)
      2-yrs OS 73.8%

      2-yrs LC 78.5%

      NoneG2 pneumonitis (2pts)

      G2 rib fracture (2pts)

      Shioyama et al. (2003),
      • Shioyama Y.
      • Tokuuye K.
      • Okumura T.
      • et al.
      Clinical evaluation of proton radiotherapy for non–small-cell lung cancer.
      Retrospective54 patients with inoperable NSCLC

      (stage I-IV NSCLC and 5 recurrences after surgery)
      74 (25–87)NAMedian: 3 Gy/fr and 76 Gy98.8Yes30

      (18–153)
      5-yrs OS 29%

      5-yrs CSS 47%

      5-yrs PFS 37%
      Lung toxicities

      G2 (3pts)

      G3 (1pt)



      Westover et al. (2012),
      • Westover K.D.
      • Seco J.
      • Adams J.A.
      • et al.
      Proton SBRT for Medically Inoperable Stage I NSCLC.
      Retrospective15 pts with medically inoperable stage

      I NSCLC
      78 (62–89)1.5 (1.0–3.1)Median: 14 Gy/fr and 45 Gy108Yes (Digital Imaging Position System, kilovoltage imaging)24.12-yrs OS 64%

      2-yrs LC 100%

      G2 dermatitis (1pt)G2 fatigue (1pt)

      G2 chest pain (1pt)

      G3 pneumonitis (1pt)
      Abbreviations: CSS: cancer-specific survival, fr: fraction, Gy: Gray, IGRT: image Guided Radiotherapy, LC: local control, NA: Not available, NSCLC: non-small cell lung cancer, OS: overall survival, PFS: progression-free survival, pts: patients, SBPT: stereotactic body proton therapy, SBRT: stereotactic body radiation therapy, yrs: years.
      N.B.) The symbol ¥ indicates studies included in the quantitative synthesis.
      * All fractionations and total doses are intended as Gy(RBE).
      ** Numbers in brackets should be intended as ranges, reported as provided by each study.
      Image guidance was mainly performed by kilovoltage imaging [
      • Nantavithya C.
      • Gomez D.R.
      • Wei X.
      • et al.
      Phase 2 Study of Stereotactic Body Radiation Therapy and Stereotactic Body Proton Therapy for High-Risk, Medically Inoperable, Early-Stage Non-Small Cell Lung Cancer.
      ,
      • Nihei K.
      • Ogino T.
      • Ishikura S.
      • et al.
      High-dose proton beam therapy for Stage I non–small-cell lung cancer.
      ,
      • Ono T.
      • Yabuuchi T.
      • Nakamura T.
      • et al.
      High dose hypofractionated proton beam therapy is a safe and feasible treatment for central lung cancer.
      ,
      • Westover K.D.
      • Seco J.
      • Adams J.A.
      • et al.
      Proton SBRT for Medically Inoperable Stage I NSCLC.
      ,
      • Bush D.A.
      • Cheek G.
      • Zaheer S.
      • et al.
      High-Dose Hypofractionated Proton Beam Radiation Therapy Is Safe and Effective for Central and Peripheral Early-Stage Non-Small Cell Lung Cancer: Results of a 12-Year Experience at Loma Linda University Medical Center.
      ,
      • Kharod S.M.
      • Nichols R.C.
      • Henderson R.H.
      • et al.
      Image-guided hypofractionated double-scattering proton therapy in the management of centrally-located early-stage non-small cell lung cancer.
      ]. Passively scattered beams were used in six studies [
      • Nantavithya C.
      • Gomez D.R.
      • Wei X.
      • et al.
      Phase 2 Study of Stereotactic Body Radiation Therapy and Stereotactic Body Proton Therapy for High-Risk, Medically Inoperable, Early-Stage Non-Small Cell Lung Cancer.
      ,
      • Lee S.U.
      • Moon S.H.
      • Cho K.H.
      • et al.
      Ablative dose proton beam therapy for stage I and recurrent non-small cell lung carcinomas: Ablative dose PBT for NSCLC.
      ,
      • Makita C.
      • Nakamura T.
      • Takada A.
      • et al.
      High-dose proton beam therapy for stage I non-small cell lung cancer: Clinical outcomes and prognostic factors.
      ,
      • Makita C.
      • Nakamura T.
      • Takada A.
      • et al.
      High-dose proton beam therapy for stage I non-small cell lung cancer: Clinical outcomes and prognostic factors.
      ,
      • Ono T.
      • Yabuuchi T.
      • Nakamura T.
      • et al.
      High dose hypofractionated proton beam therapy is a safe and feasible treatment for central lung cancer.
      ,
      • Westover K.D.
      • Seco J.
      • Adams J.A.
      • et al.
      Proton SBRT for Medically Inoperable Stage I NSCLC.
      ], while in the remaining the information could not be retrieved. Considering motion management, 11 studies used a respiratory gating system with treatment delivery in the expiratory phase [
      • Kanemoto A.
      • Okumura T.
      • Ishikawa H.
      • et al.
      Outcomes and Prognostic Factors for Recurrence After High-Dose Proton Beam Therapy for Centrally and Peripherally Located Stage I Non–Small-Cell Lung Cancer.
      ,
      • Lee S.U.
      • Moon S.H.
      • Cho K.H.
      • et al.
      Ablative dose proton beam therapy for stage I and recurrent non-small cell lung carcinomas: Ablative dose PBT for NSCLC.
      ,
      • Shioyama Y.
      • Tokuuye K.
      • Okumura T.
      • et al.
      Clinical evaluation of proton radiotherapy for non–small-cell lung cancer.
      ,
      • Hata M.
      • Tokuuye K.
      • Kagei K.
      • et al.
      Hypofractionated High-Dose Proton Beam Therapy for Stage I Non–Small-Cell Lung Cancer: Preliminary Results of A Phase I/II Clinical Study.
      ,
      • Iwata H.
      • Murakami M.
      • Demizu Y.
      • et al.
      High-dose proton therapy and carbon-ion therapy for stage I nonsmall cell lung cancer.
      ,
      • Makita C.
      • Nakamura T.
      • Takada A.
      • et al.
      High-dose proton beam therapy for stage I non-small cell lung cancer: Clinical outcomes and prognostic factors.
      ,
      • Nakamura N.
      • Hotta K.
      • Zenda S.
      • et al.
      Hypofractionated proton beam therapy for centrally located lung cancer.
      ,
      • Nihei K.
      • Ogino T.
      • Ishikura S.
      • et al.
      High-dose proton beam therapy for Stage I non–small-cell lung cancer.
      ,
      • Ono T.
      • Yabuuchi T.
      • Nakamura T.
      • et al.
      High dose hypofractionated proton beam therapy is a safe and feasible treatment for central lung cancer.
      ,
      • Iwata H.
      • Demizu Y.
      • Fujii O.
      • et al.
      Long-Term Outcome of Proton Therapy and Carbon-Ion Therapy for Large (T2a–T2bN0M0) Non–Small-Cell Lung Cancer.
      ,
      • Hatayama Y.
      • Nakamura T.
      • Suzuki M.
      • et al.
      Clinical Outcomes and Prognostic Factors of High-Dose Proton Beam Therapy for Peripheral Stage I Non-Small-Cell Lung Cancer.
      ]. None on the works considered the use of fiducials as mandatory, being their used considered as optional in two cases only [
      • Nantavithya C.
      • Gomez D.R.
      • Wei X.
      • et al.
      Phase 2 Study of Stereotactic Body Radiation Therapy and Stereotactic Body Proton Therapy for High-Risk, Medically Inoperable, Early-Stage Non-Small Cell Lung Cancer.
      ,
      • Kharod S.M.
      • Nichols R.C.
      • Henderson R.H.
      • et al.
      Image-guided hypofractionated double-scattering proton therapy in the management of centrally-located early-stage non-small cell lung cancer.
      ]. Nine works provided information on the GTV to CTV (Gross Tumor Volume and Clinical Target Volume, respectively) expansion, which was of 5 mm in most cases [
      • Iwata H.
      • Murakami M.
      • Demizu Y.
      • et al.
      High-dose proton therapy and carbon-ion therapy for stage I nonsmall cell lung cancer.
      ,
      • Nakamura N.
      • Hotta K.
      • Zenda S.
      • et al.
      Hypofractionated proton beam therapy for centrally located lung cancer.
      ,
      • Nihei K.
      • Ogino T.
      • Ishikura S.
      • et al.
      High-dose proton beam therapy for Stage I non–small-cell lung cancer.
      ,
      • Ono T.
      • Yabuuchi T.
      • Nakamura T.
      • et al.
      High dose hypofractionated proton beam therapy is a safe and feasible treatment for central lung cancer.
      ,
      • Westover K.D.
      • Seco J.
      • Adams J.A.
      • et al.
      Proton SBRT for Medically Inoperable Stage I NSCLC.
      ,
      • Bush D.A.
      • Cheek G.
      • Zaheer S.
      • et al.
      High-Dose Hypofractionated Proton Beam Radiation Therapy Is Safe and Effective for Central and Peripheral Early-Stage Non-Small Cell Lung Cancer: Results of a 12-Year Experience at Loma Linda University Medical Center.
      ,
      • Iwata H.
      • Demizu Y.
      • Fujii O.
      • et al.
      Long-Term Outcome of Proton Therapy and Carbon-Ion Therapy for Large (T2a–T2bN0M0) Non–Small-Cell Lung Cancer.
      ,
      • Gomez D.R.
      • Gillin M.
      • Liao Z.
      • et al.
      Phase 1 Study of Dose Escalation in Hypofractionated Proton Beam Therapy for Non-Small Cell Lung Cancer.
      ,
      • Hatayama Y.
      • Nakamura T.
      • Suzuki M.
      • et al.
      Clinical Outcomes and Prognostic Factors of High-Dose Proton Beam Therapy for Peripheral Stage I Non-Small-Cell Lung Cancer.
      ,
      • Kharod S.M.
      • Nichols R.C.
      • Henderson R.H.
      • et al.
      Image-guided hypofractionated double-scattering proton therapy in the management of centrally-located early-stage non-small cell lung cancer.
      ]. The most commonly accepted threshold for target coverage was 95% of the prescription dose to the 100% of the volume [
      • Kanemoto A.
      • Okumura T.
      • Ishikawa H.
      • et al.
      Outcomes and Prognostic Factors for Recurrence After High-Dose Proton Beam Therapy for Centrally and Peripherally Located Stage I Non–Small-Cell Lung Cancer.
      ,
      • Lee S.U.
      • Moon S.H.
      • Cho K.H.
      • et al.
      Ablative dose proton beam therapy for stage I and recurrent non-small cell lung carcinomas: Ablative dose PBT for NSCLC.
      ,
      • Westover K.D.
      • Seco J.
      • Adams J.A.
      • et al.
      Proton SBRT for Medically Inoperable Stage I NSCLC.
      ,
      • Bush D.A.
      • Cheek G.
      • Zaheer S.
      • et al.
      High-Dose Hypofractionated Proton Beam Radiation Therapy Is Safe and Effective for Central and Peripheral Early-Stage Non-Small Cell Lung Cancer: Results of a 12-Year Experience at Loma Linda University Medical Center.
      ], while the maximum accepted dose was 110% and 120% in the studies by Ono et al. [
      • Ono T.
      • Yabuuchi T.
      • Nakamura T.
      • et al.
      High dose hypofractionated proton beam therapy is a safe and feasible treatment for central lung cancer.
      ] and by Lee et al. [
      • Lee S.U.
      • Moon S.H.
      • Cho K.H.
      • et al.
      Ablative dose proton beam therapy for stage I and recurrent non-small cell lung carcinomas: Ablative dose PBT for NSCLC.
      ], respectively.

      Quantitative synthesis- meta-analysis

      Eight works were available for the quantitative synthesis [
      • Nantavithya C.
      • Gomez D.R.
      • Wei X.
      • et al.
      Phase 2 Study of Stereotactic Body Radiation Therapy and Stereotactic Body Proton Therapy for High-Risk, Medically Inoperable, Early-Stage Non-Small Cell Lung Cancer.
      ,
      • Kanemoto A.
      • Okumura T.
      • Ishikawa H.
      • et al.
      Outcomes and Prognostic Factors for Recurrence After High-Dose Proton Beam Therapy for Centrally and Peripherally Located Stage I Non–Small-Cell Lung Cancer.
      ,
      • Iwata H.
      • Murakami M.
      • Demizu Y.
      • et al.
      High-dose proton therapy and carbon-ion therapy for stage I nonsmall cell lung cancer.
      ,
      • Makita C.
      • Nakamura T.
      • Takada A.
      • et al.
      High-dose proton beam therapy for stage I non-small cell lung cancer: Clinical outcomes and prognostic factors.
      ,
      • Ono T.
      • Yabuuchi T.
      • Nakamura T.
      • et al.
      High dose hypofractionated proton beam therapy is a safe and feasible treatment for central lung cancer.
      ,
      • Bush D.A.
      • Cheek G.
      • Zaheer S.
      • et al.
      High-Dose Hypofractionated Proton Beam Radiation Therapy Is Safe and Effective for Central and Peripheral Early-Stage Non-Small Cell Lung Cancer: Results of a 12-Year Experience at Loma Linda University Medical Center.
      ,
      • Hatayama Y.
      • Nakamura T.
      • Suzuki M.
      • et al.
      Clinical Outcomes and Prognostic Factors of High-Dose Proton Beam Therapy for Peripheral Stage I Non-Small-Cell Lung Cancer.
      ,
      • Kharod S.M.
      • Nichols R.C.
      • Henderson R.H.
      • et al.
      Image-guided hypofractionated double-scattering proton therapy in the management of centrally-located early-stage non-small cell lung cancer.
      ]. Of these, half were prospective trials [
      • Nantavithya C.
      • Gomez D.R.
      • Wei X.
      • et al.
      Phase 2 Study of Stereotactic Body Radiation Therapy and Stereotactic Body Proton Therapy for High-Risk, Medically Inoperable, Early-Stage Non-Small Cell Lung Cancer.
      ,
      • Kharod S.M.
      • Nichols R.C.
      • Henderson R.H.
      • et al.
      Image-Guided Hypofractionated Proton Therapy in Early-Stage Non-Small Cell Lung Cancer: A Phase 2 Study.
      ,
      • Iwata H.
      • Murakami M.
      • Demizu Y.
      • et al.
      High-dose proton therapy and carbon-ion therapy for stage I nonsmall cell lung cancer.
      ,
      • Bush D.A.
      • Cheek G.
      • Zaheer S.
      • et al.
      High-Dose Hypofractionated Proton Beam Radiation Therapy Is Safe and Effective for Central and Peripheral Early-Stage Non-Small Cell Lung Cancer: Results of a 12-Year Experience at Loma Linda University Medical Center.
      ], and half were retrospective series [
      • Kanemoto A.
      • Okumura T.
      • Ishikawa H.
      • et al.
      Outcomes and Prognostic Factors for Recurrence After High-Dose Proton Beam Therapy for Centrally and Peripherally Located Stage I Non–Small-Cell Lung Cancer.
      ,
      • Iwata H.
      • Murakami M.
      • Demizu Y.
      • et al.
      High-dose proton therapy and carbon-ion therapy for stage I nonsmall cell lung cancer.
      ,
      • Makita C.
      • Nakamura T.
      • Takada A.
      • et al.
      High-dose proton beam therapy for stage I non-small cell lung cancer: Clinical outcomes and prognostic factors.
      ,
      • Ono T.
      • Yabuuchi T.
      • Nakamura T.
      • et al.
      High dose hypofractionated proton beam therapy is a safe and feasible treatment for central lung cancer.
      ,
      • Hatayama Y.
      • Nakamura T.
      • Suzuki M.
      • et al.
      Clinical Outcomes and Prognostic Factors of High-Dose Proton Beam Therapy for Peripheral Stage I Non-Small-Cell Lung Cancer.
      ]. Globally, data from 401 patients were incorporated in the analysis; median follow-up was 32.85 (IQR: 29.25–36.95) months.
      Assuming α/β = 10 Gy, prescription doses ranged from a median BED of 96.0 to 112.5 Gy(RBE), with 66 Gy(RBE)/10 fractions being the most common treatment schedule. Based on a median BED of 105.6 Gy(RBE), patients were stratified into two groups, above and below the median value. The most hypofractionated regimen was used by Nantavithya et al. [
      • Nantavithya C.
      • Gomez D.R.
      • Wei X.
      • et al.
      Phase 2 Study of Stereotactic Body Radiation Therapy and Stereotactic Body Proton Therapy for High-Risk, Medically Inoperable, Early-Stage Non-Small Cell Lung Cancer.
      ], who used a dose 50 Gy(RBE)/4 fractions with either protons or photons in a small cohort of prospectively enrolled, medically inoperable ES-NSCLC patients.
      All the oncological outcomes of interest could be analyzed: specifically, the most common endpoints of the included studies were OS and LC, which were both provided by seven studies, for a total number of 391 and 330 patients, respectively. Information on either acute or late toxicity of grade ≥ 2 was reported and available for analysis in all cases. All performed analyses are available in Supplementary Material 2.

      Overall survival (OS)

      A progressive reduction of survival probability over time was noticed in both groups (BED < 105.6 Gy(RBE) and ≥ 105.6 Gy(RBE)). Globally, OS was consistently superior in the group who had received higher BEDs, with the corresponding 2-, 3- and 4-year OS being 0.75 [95%, CI: 0.57–0.87], 0.64 [0.40–0.82] and 0.56 [0.34–0.76] for BED < 105.6 Gy(RBE) versus 0.86 [0.81–0.90], 0.83 [0.77–0.88] and 0.78 [0.64–0.88], for BED greater than 105.6 Gy(RBE), respectively. A high level of heterogeneity was observed at all the analyzed time points. Forrest plots with study-specific and summary proportions at 3-years are reported in Fig. 1, while Fig. 2 provides a visual representation of OS over time for both study groups.
      Figure thumbnail gr2
      Fig. 2Representation of overall survival (OS) trends stratified per BED ≥ 105.6 Gy(RBE) and BED < 105.6 Gy(RBE).

      Cause-specific survival (CSS)

      Estimates for the 2- and 4- year CSS could be performed based on three studies [
      • Kanemoto A.
      • Okumura T.
      • Ishikawa H.
      • et al.
      Outcomes and Prognostic Factors for Recurrence After High-Dose Proton Beam Therapy for Centrally and Peripherally Located Stage I Non–Small-Cell Lung Cancer.
      ,
      • Kharod S.M.
      • Nichols R.C.
      • Henderson R.H.
      • et al.
      Image-Guided Hypofractionated Proton Therapy in Early-Stage Non-Small Cell Lung Cancer: A Phase 2 Study.
      ,
      • Bush D.A.
      • Cheek G.
      • Zaheer S.
      • et al.
      High-Dose Hypofractionated Proton Beam Radiation Therapy Is Safe and Effective for Central and Peripheral Early-Stage Non-Small Cell Lung Cancer: Results of a 12-Year Experience at Loma Linda University Medical Center.
      ] and a total number of 147 patients. Additionally, results from the trial by Nantavithya et al. [
      • Nantavithya C.
      • Gomez D.R.
      • Wei X.
      • et al.
      Phase 2 Study of Stereotactic Body Radiation Therapy and Stereotactic Body Proton Therapy for High-Risk, Medically Inoperable, Early-Stage Non-Small Cell Lung Cancer.
      ] were incorporated into the 3-year CSS analysis, which therefore encompassed 157 patients. Despite fewer patients being available for the analysis, the superiority of a BED ≥ 105.6 Gy(RBE) was confirmed after a 2- and 3-years follow-up. Specifically, patients treated with higher doses showed a CSS of 0.95 [0.86–0.98] and 0.90 [0.81–0.94] at 2- and 3-years, respectively, versus a CSS of 0.89 [0.79–0.94] and 0.86 [0.76–0.92] of the group receiving a BED < 105.6 Gy(RBE). Such advantage was not confirmed at a 4-year follow-up.

      Progression-Free survival (PFS)

      Overall, data on the progression-free survival (PFS) at 2 years where provided by four studies; of these only one delivered a total prescription dose < 105.6 Gy(RBE) [
      • Iwata H.
      • Murakami M.
      • Demizu Y.
      • et al.
      High-dose proton therapy and carbon-ion therapy for stage I nonsmall cell lung cancer.
      ]. At 3 and 4 years, PFS was evaluated by five and four works, respectively. Better outcomes were consistently obtained in the higher dose subgroup, with a PFS of 0.75 [0.66–0.82], 0.71 [0.63–0.77] and 0.68 [0.57–0.77] after 2, 3 and 4-years since the completion of PBT, respectively. For comparison, PFS at the same time points was 0.58 [0.45–0.70], 0.52 [0.39–0.64], and 0.50 [0.37–0.63] in the cohort by Iwata et al. [
      • Iwata H.
      • Murakami M.
      • Demizu Y.
      • et al.
      High-dose proton therapy and carbon-ion therapy for stage I nonsmall cell lung cancer.
      ].

      Local control (LC)

      Three hundred thirty-three and 340 patients were available for the assessment of LC at 2-, 3-, and 4-years, respectively. Overall, excellent LC rates were achieved and maintained over time in both groups (namely, BED < or ≥ 105.6 Gy(RBE), α/β = 10 Gy). However, an advantage was noted at all time points when BEDs greater than 105.6 Gy(RBE) were delivered (LC: 0.93 [0.85–0.97], 0.91 [0.82–0.96] and 0.90 [0.75–0.97] versus LC: 0.85 [0.77–0.90], 0.83 [0.75–0.88] and 0.82 [0.74–0.88] for BEDs inferior to 105.6 Gy(RBE)). A visual representation of LC rates over time for both groups is provided by the Kaplan Meier curve in Fig. 3.
      Figure thumbnail gr3
      Fig. 3Representation of local control (LC) trends stratified per BED ≥ 105.6 Gy(RBE) and BED < 105.6 Gy(RBE).

      Acute and late toxicities

      Thirty-two acute toxicities of grade ≥ 2 were observed in 307 patients, with an overall incidence of 10%. Considering the 105.6 Gy(RBE) threshold, 14/32 events were observed in the lower-dose subgroup, while 18/32 were recorded in the higher-dose sub-group. In details, the meta-analysis of proportions (six studies, [
      • Nantavithya C.
      • Gomez D.R.
      • Wei X.
      • et al.
      Phase 2 Study of Stereotactic Body Radiation Therapy and Stereotactic Body Proton Therapy for High-Risk, Medically Inoperable, Early-Stage Non-Small Cell Lung Cancer.
      ,
      • Iwata H.
      • Murakami M.
      • Demizu Y.
      • et al.
      High-dose proton therapy and carbon-ion therapy for stage I nonsmall cell lung cancer.
      ,
      • Makita C.
      • Nakamura T.
      • Takada A.
      • et al.
      High-dose proton beam therapy for stage I non-small cell lung cancer: Clinical outcomes and prognostic factors.
      ,
      • Bush D.A.
      • Cheek G.
      • Zaheer S.
      • et al.
      High-Dose Hypofractionated Proton Beam Radiation Therapy Is Safe and Effective for Central and Peripheral Early-Stage Non-Small Cell Lung Cancer: Results of a 12-Year Experience at Loma Linda University Medical Center.
      ,
      • Hatayama Y.
      • Nakamura T.
      • Suzuki M.
      • et al.
      Clinical Outcomes and Prognostic Factors of High-Dose Proton Beam Therapy for Peripheral Stage I Non-Small-Cell Lung Cancer.
      ,
      • Kharod S.M.
      • Nichols R.C.
      • Henderson R.H.
      • et al.
      Image-guided hypofractionated double-scattering proton therapy in the management of centrally-located early-stage non-small cell lung cancer.
      ]) showed a comparable probability of developing toxicity (0.03 [0.00–0.34] for BED < 105.6 Gy(RBE) and 0.16 [0.09–0.26] for BED ≥ 105.6 Gy(RBE)), as shown in Fig. 4. A quantitative analysis could also be performed for acute dermatitis of grade ≥ 2: three studies were available [
      • Iwata H.
      • Murakami M.
      • Demizu Y.
      • et al.
      High-dose proton therapy and carbon-ion therapy for stage I nonsmall cell lung cancer.
      ,
      • Makita C.
      • Nakamura T.
      • Takada A.
      • et al.
      High-dose proton beam therapy for stage I non-small cell lung cancer: Clinical outcomes and prognostic factors.
      ,
      • Hatayama Y.
      • Nakamura T.
      • Suzuki M.
      • et al.
      Clinical Outcomes and Prognostic Factors of High-Dose Proton Beam Therapy for Peripheral Stage I Non-Small-Cell Lung Cancer.
      ], with a total number of 27 events/163 evaluable patients. A slight prevalence of events was noted in the group receiving BED < 105.6 Gy(RBE) (0.23 [0.14–0.35] versus 0.12 [0.05–0.26] in case the delivered total BED was ≥ 105.6 Gy(RBE). Acute grade 2 dyspnea was recorded in two cases [
      • Nantavithya C.
      • Gomez D.R.
      • Wei X.
      • et al.
      Phase 2 Study of Stereotactic Body Radiation Therapy and Stereotactic Body Proton Therapy for High-Risk, Medically Inoperable, Early-Stage Non-Small Cell Lung Cancer.
      ]; additionally grade 2 pneumonitis and cough occurred in one case, each [
      • Nantavithya C.
      • Gomez D.R.
      • Wei X.
      • et al.
      Phase 2 Study of Stereotactic Body Radiation Therapy and Stereotactic Body Proton Therapy for High-Risk, Medically Inoperable, Early-Stage Non-Small Cell Lung Cancer.
      ,
      • Hatayama Y.
      • Nakamura T.
      • Suzuki M.
      • et al.
      Clinical Outcomes and Prognostic Factors of High-Dose Proton Beam Therapy for Peripheral Stage I Non-Small-Cell Lung Cancer.
      ]. A single case of G3 toxicity was described (hypoxia, by Kharod et al.) [
      • Kharod S.M.
      • Nichols R.C.
      • Henderson R.H.
      • et al.
      Image-Guided Hypofractionated Proton Therapy in Early-Stage Non-Small Cell Lung Cancer: A Phase 2 Study.
      ].
      Figure thumbnail gr4
      Fig. 4Forrest plots with study-specific data and summary proportions for acute toxicities.
      Considering late side effects of grade ≥ 2, 87 events were described over a population of 327 (27%). Overall, the probability of any late event of grade ≥ 2 was almost three-times greater in the BED ≥ 105.6 Gy(RBE) subgroup (0.35 [0.28–0.44] vs 0.14 [0.02–0.52] with BED < 105.6 Gy(RBE)). Forrest plots with both study-specific and pooled proportions are displayed in Fig. 5. It was possible to realize a meta-analysis for both rib fractures (RFs) and pneumonitis. Specifically, RFs occurred in 49/294 evaluable patients: 22 and 27 events were recorded in the low and high dose subgroups, respectively, resulting in an estimate risk of RF of 0.12 [0.02–0.44] and 0.21 [0.13–0.31], respectively. Of all the reported events, 40 (82%) occurred in those treated for peripherally-located lesions (40/49, 82%), while the remaining nine were described for central lesions by Iwata et al., Makita et al., and Ono et al. (one, seven and two events, respectively) [
      • Iwata H.
      • Murakami M.
      • Demizu Y.
      • et al.
      High-dose proton therapy and carbon-ion therapy for stage I nonsmall cell lung cancer.
      ,
      • Makita C.
      • Nakamura T.
      • Takada A.
      • et al.
      High-dose proton beam therapy for stage I non-small cell lung cancer: Clinical outcomes and prognostic factors.
      ,
      • Ono T.
      • Yabuuchi T.
      • Nakamura T.
      • et al.
      High dose hypofractionated proton beam therapy is a safe and feasible treatment for central lung cancer.
      ]. Conversely, the 21 observed late pneumonitis of grade ≥ 2 were not associated with different total prescription doses in our study (BED < 105.6 Gy(RBE): 0.18 [0.10–0.30 vs 0.14 [0.08–0.24]. Rarer toxicities included G2 fibrosis (5 patients), G2 soft tissue damage (2 patients), G2 pericardial effusion (1 patient), G3 bronchial stricture (1 patient), and G3 hypoxia (1 patient).
      Figure thumbnail gr5
      Fig. 5Forrest plots with study-specific data and summary proportions for late toxicities.

      Discussion

      Results from our meta-analysis have shown that hypofractionated PBT is an actionable treatment option in patients with ES-NSCLC. In particular, the delivery of BED ≥ 105.6 Gy(RBE) is associated with improved oncological outcomes in terms of OS, CSS, PFS and LC. Notably, such results are maintained over the course of the follow-up, at any of the analyzed time points. With the sole exception of PFS, the low and high dose groups presented a roughly equal distribution all through the course of follow-up, which allowed to evaluate outcome data after 4-years post-PBT. However, the delivery of higher BEDs was associated with a higher risk of long-term toxicity, which suggests the need of a further refinement in the selection of potential PBT candidates. However, none of these toxicities was life-threatening, except for a grade 5 event occurred in one patient with known symptomatic idiopathic pulmonary fibrosis. Adequate motion and uncertainty management are warranted in this clinical setting, and widely implemented in the considered studies.
      Following the publication of the groundbreaking work by Blomgren et al. in 1995, hypofractionation with photons has progressively become a mainstay for curative-intent treatment of ES-NSCLC [
      • Blomgren H.
      • Lax I.
      • Näslund I.
      • et al.
      Stereotactic High Dose Fraction Radiation Therapy of Extracranial Tumors Using An Accelerator: Clinical experience of the first thirty-one patients.
      ]. Specifically, the advantage of extremely hypofractionated SBRT over conventionally-fractionated RT has been proven by several retrospective series [
      • Widder J.
      • Postmus D.
      • Ubbels J.F.
      • et al.
      Survival and quality of life after stereotactic or 3D-conformal radiotherapy for inoperable early-stage lung cancer.
      ,
      • Shirvani S.M.
      • Jiang J.
      • Chang J.Y.
      • et al.
      Comparative effectiveness of 5 treatment strategies for early-stage non-small cell lung cancer in the elderly.
      ,
      • Jeppesen S.S.
      • Schytte T.
      • Jensen H.R.
      • et al.
      Stereotactic body radiation therapy versus conventional radiation therapy in patients with early stage non-small cell lung cancer: an updated retrospective study on local failure and survival rates.
      ,
      • Chiang A.
      • Thibault I.
      • Warner A.
      • et al.
      A comparison between accelerated hypofractionation and stereotactic ablative radiotherapy (SABR) for early-stage non-small cell lung cancer (NSCLC): Results of a propensity score-matched analysis.
      ,
      • Haque W.
      • Verma V.
      • Polamraju P.
      • et al.
      Stereotactic body radiation therapy versus conventionally fractionated radiation therapy for early stage non-small cell lung cancer.
      ], one meta-analysis [
      • Grutters J.P.C.
      • Kessels A.G.H.
      • Pijls-Johannesma M.
      • et al.
      Comparison of the effectiveness of radiotherapy with photons, protons and carbon-ions for non-small cell lung cancer: a meta-analysis.
      ], and two randomized controlled trials [
      • Ball D.
      • Mai G.T.
      • Vinod S.
      • et al.
      Stereotactic ablative radiotherapy versus standard radiotherapy in stage 1 non-small-cell lung cancer (TROG 09.02 CHISEL): a phase 3, open-label, randomised controlled trial.
      ,
      • Nyman J.
      • Hallqvist A.
      • Lund J.-Å.
      • et al.
      SPACE – A randomized study of SBRT vs conventional fractionated radiotherapy in medically inoperable stage I NSCLC.
      ]. To date, this body of evidence has translated into the recommendation of international multidisciplinary guidelines (e.g. NCCN, ESMO), acknowledging the superiority of SBRT over standard fractionation in this subset of patients [

      NCCN- National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines)- Non-Small Cell Lung Cancer. Version 4.2021- March 3, 2021, https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf.

      ,

      Postmus PE, Kerr KM, Oudkerk M, et al. Early and locally advanced non-small-cell lung cancer (NSCLC): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Annals of Oncology 2017; 28: iv1–iv21.

      ]. Currently, the minimum acceptable BED for a curative-intent treatment in ES-NSCLC is 100 Gy, which is in line with the median delivered dose in the analyzed PBT population. While this work does not specifically address the issue of defining the role of SBPT as an alternative to the more established SBRT, it is worth mentioning that there is a strong unmet need for further evidence in the field. To the best of our knowledge, the only available study presenting a direct comparison these modalities has been published by Nantavithya et al. [
      • Nantavithya C.
      • Gomez D.R.
      • Wei X.
      • et al.
      Phase 2 Study of Stereotactic Body Radiation Therapy and Stereotactic Body Proton Therapy for High-Risk, Medically Inoperable, Early-Stage Non-Small Cell Lung Cancer.
      ]. The Authors designed a phase II randomized trial with parallel assignment with the primary endpoint of quantify the 2-year rate of severe SBRT- and SBPT-related toxicities, but the trial had to be terminated earlier due to poor accrual. Despite relevant selection biases prevent from any strong clinical conclusion (i.e. small sample size, worse patients’ performance status in the SBRT group), SBPT seemed to be associated with superior PFS and OS, and a comparable toxicity profile. Moreover, in few systematic reviews and meta-analyses, the presence of multiple confounding factors (e.g. selection bias, heterogeneity, majority of single-arm, observational trials for PBT) prevented to draw any reliable conclusion on the best treatment option in this clinical scenario [
      • Chi A.
      • Chen H.
      • Wen S.
      • et al.
      Comparison of particle beam therapy and stereotactic body radiotherapy for early stage non-small cell lung cancer: A systematic review and hypothesis-generating meta-analysis.
      ,
      • Georg D.
      • Hillbrand M.
      • Stock M.
      • et al.
      Can protons improve SBRT for lung lesions? Dosimetric considerations.
      ]. Predictably, this applies for both outcomes of benefit (e.g.: LC, OS) and outcomes of harm (e.g.: cardiac toxicity). However, Chi et al. hypothesize that lower cardiac and pulmonary doses of PBT may translate into a survival benefit, which could be relevant especially in case of older and comorbid populations [
      • Chi A.
      • Chen H.
      • Wen S.
      • et al.
      Comparison of particle beam therapy and stereotactic body radiotherapy for early stage non-small cell lung cancer: A systematic review and hypothesis-generating meta-analysis.
      ]. Arguably, these questions will progressively be addressed, and translated into clinical practice guidelines, in the upcoming years. As an example, the ongoing interventional trial LU03-NCT00875901, whose results are awaited by the end of 2023, will help clarifying the toxicity profile and the efficacy of hypofractionated PBT in the setting of both central and peripherally-located stage I NSCLCs [

      Chang JY. Stereotactic Body Radiotherapy (SBRT) Versus Stereotactic Body Proton Therapy (SBPT)- ClinicalTrials.gov Identifier: NCT01511081, https://www.clinicaltrials.gov/ct2/show/results/NCT01511081?term=proton+therapy&type=Intr&cond=Non+Small+Cell+Lung+Cancer&age=12&draw=2&rank=3 (accessed 31 October 2021).

      ].
      However, our systematic review clearly shows that hypofractionation has already been implemented into clinical practice, with half of the studies using extremely hypofractionated schemes [
      • Kanemoto A.
      • Okumura T.
      • Ishikawa H.
      • et al.
      Outcomes and Prognostic Factors for Recurrence After High-Dose Proton Beam Therapy for Centrally and Peripherally Located Stage I Non–Small-Cell Lung Cancer.
      ,
      • Lee S.U.
      • Moon S.H.
      • Cho K.H.
      • et al.
      Ablative dose proton beam therapy for stage I and recurrent non-small cell lung carcinomas: Ablative dose PBT for NSCLC.
      ,
      • Iwata H.
      • Murakami M.
      • Demizu Y.
      • et al.
      High-dose proton therapy and carbon-ion therapy for stage I nonsmall cell lung cancer.
      ,
      • Bush D.A.
      • Cheek G.
      • Zaheer S.
      • et al.
      High-Dose Hypofractionated Proton Beam Radiation Therapy Is Safe and Effective for Central and Peripheral Early-Stage Non-Small Cell Lung Cancer: Results of a 12-Year Experience at Loma Linda University Medical Center.
      ,
      • Hatayama Y.
      • Nakamura T.
      • Suzuki M.
      • et al.
      Clinical Outcomes and Prognostic Factors of High-Dose Proton Beam Therapy for Peripheral Stage I Non-Small-Cell Lung Cancer.
      ,
      • Kharod S.M.
      • Nichols R.C.
      • Henderson R.H.
      • et al.
      Image-guided hypofractionated double-scattering proton therapy in the management of centrally-located early-stage non-small cell lung cancer.
      ]. As no direct comparison between fractionation schedules could be performed, studies were stratified per the median value of BED (α/β = 10 Gy), upper and below the threshold of 105.6 Gy(RBE). As anticipated, not only BEDs greater than 105.6 Gy(RBE) allow for better oncological outcomes, but also do not lead to increased moderate-to-severe acute toxicity. Considering late toxicity, the meta-analysis showed a threefold absolute risk of developing any late toxicity of grade ≥ 2. However, CIs are quite broad (0.35 [0.28–0.44] vs 0.14 [0.02–0.52] with BED ≥ 105.6 Gy(RBE) and < 105.6, respectively), and the heterogeneity index (I2) is high, so no definitive conclusions can be drawn from this finding. Similar considerations can be done for the occurrence of RFs and radiation-induced pneumonitis, which represented the most common late adverse events, occurring in roughly 21% and 16% of patients, respectively. Overall, the risk of developing a RF in patients receiving PBT for NSCLC has not been extensively investigated so far. The most comprehensive report has been provided by Ishikawa et al., who analyzed the dosimetric parameters predictive of RF in a cohort of 52 early-stage NSCLC patients with predominantly peripherally-located lesions (41/52, 79%) [
      • Ishikawa Y.
      • Nakamura T.
      • Kato T.
      • et al.
      Dosemetric Parameters Predictive of Rib Fractures after Proton Beam Therapy for Early-Stage Lung Cancer.
      ]. Specifically, the authors identified that the incidence of a grade 2 event was significantly increased if a rib volume greater than 3.7 cm3 received more than 120 Gy(RBE), with an α/β = 3 Gy (p < 0.001), and a median time-to-event of 17 (range: 9–29) months. Further reports on other disease sites (mainly breast and liver malignancies) confirm that the development of RF is a relatively early toxicity of PBT, while providing partially contradictory evidence on clinical risk factors (namely, patients’ characteristics such as gender and age, and tumor-related parameters such as distance from the chest wall) [
      • Kanemoto A.
      • Mizumoto M.
      • Okumura T.
      • et al.
      Dose-volume histogram analysis for risk factors of radiation-induced rib fracture after hypofractionated proton beam therapy for hepatocellular carcinoma.
      ,
      • Yeung R.
      • Bowen S.R.
      • Chapman T.R.
      • et al.
      Chest wall toxicity after hypofractionated proton beam therapy for liver malignancies.
      ,
      • Wang C.-C.
      • McNamara A.L.
      • Shin J.
      • et al.
      End-of-Range Radiobiological Effect on Rib Fractures in Patients Receiving Proton Therapy for Breast Cancer.
      ]. Finally, considering all patients included in the systematic review, only one grade 5 event was recorded, and described by Lee et al. [
      • Lee S.U.
      • Moon S.H.
      • Cho K.H.
      • et al.
      Ablative dose proton beam therapy for stage I and recurrent non-small cell lung carcinomas: Ablative dose PBT for NSCLC.
      ]. The Authors describe a single case of a sudden respiratory failure three months after the end of PBT, which occurred in a patient with pre-existent symptomatic idiopathic pulmonary fibrosis.
      Therefore, if the general tolerability profile seems to be optimal for PBT, patients’ selection is crucial. As an example, SBRT data have shown that a higher toxicity risk exists for patients with interstitial lung fibrosis (ILD), an umbrella term used to group together a heterogenous group of disorders involving primarily the pulmonary interstitium, but also affect the architecture of the alveola and the airways, with progressive impairment of the respiratory function [
      • King T.E.
      • Pardo A.
      • Selman M.
      Idiopathic pulmonary fibrosis.
      ]. Moreover, as tumor location is the primary determinant of toxicity, caution should be taken when central and ultra-central lesions are treated, also considering the paucity of currently available data on PBT [
      • Andruska N.
      • Stowe H.B.
      • Crockett C.
      • et al.
      Stereotactic Radiation for Lung Cancer: A Practical Approach to Challenging Scenarios.
      ]. If these characteristics do not represent an absolute contraindication to RT, toxicity concerns including tracheoesophageal fistulas and bronchopulmonary hemorrhage, recommend maintaining the dose below 10 Gy/fr [
      • Guckenberger M.
      • Andratschke N.
      • Dieckmann K.
      • et al.
      ESTRO ACROP consensus guideline on implementation and practice of stereotactic body radiotherapy for peripherally located early stage non-small cell lung cancer.
      ,
      • Andruska N.
      • Stowe H.B.
      • Crockett C.
      • et al.
      Stereotactic Radiation for Lung Cancer: A Practical Approach to Challenging Scenarios.
      ,
      • Louie A.V.
      • Palma D.A.
      • Dahele M.
      • et al.
      Management of early-stage non-small cell lung cancer using stereotactic ablative radiotherapy: Controversies, insights, and changing horizons.
      ]. Data from our work show that the same indication has been observed for PBT, as well. Specifically, central lesions treated with an extremely hypofractionated schedule (namely, 6 Gy(RBE)/fr in 10 fractions) are described only by Kharod et al. [
      • Kharod S.M.
      • Nichols R.C.
      • Henderson R.H.
      • et al.
      Image-guided hypofractionated double-scattering proton therapy in the management of centrally-located early-stage non-small cell lung cancer.
      ]. Interestingly, while these lesions constituted the 60% of the study population, only one G3 case of bronchial stricture was observed among the 23 treated patients. Altogether, the relatively low rate of G2-G3 adverse events shown in the present work is consistent with prior knowledge demonstrating the dosimetric advantage of PBT over photon-based techniques, thanks to the delivery of less radiation dose to the thoracic healthy tissues (i.e. the heart, lungs, trachea, esophagus, and spinal cord) [
      • Register S.P.
      • Zhang X.
      • Mohan R.
      • et al.
      Proton Stereotactic Body Radiation Therapy for Clinically Challenging Cases of Centrally and Superiorly Located Stage I Non-Small-Cell Lung Cancer.
      ,
      • Chang J.Y.
      • Zhang X.
      • Wang X.
      • et al.
      Significant reduction of normal tissue dose by proton radiotherapy compared with three-dimensional conformal or intensity-modulated radiation therapy in Stage I or Stage III non–small-cell lung cancer.
      ,
      • van Baardwijk A.
      • Wanders S.
      • Boersma L.
      • et al.
      Mature Results of an Individualized Radiation Dose Prescription Study Based on Normal Tissue Constraints in Stages I to III Non–Small-Cell Lung Cancer.
      ,
      • Ribeiro C.O.
      • Visser S.
      • Korevaar E.W.
      • et al.
      Towards the clinical implementation of intensity-modulated proton therapy for thoracic indications with moderate motion: Robust optimised plan evaluation by means of patient and machine specific information.
      ]. For these reasons, PBT is particularly attractive in case of concomitant lung diseases, with a theorical dose escalation potential as high as 40%, as shown in a virtual clinical study by Zhang et al. [
      • Zhang X.
      • Li Y.
      • Pan X.
      • et al.
      Intensity-Modulated Proton Therapy Reduces the Dose to Normal Tissue Compared With Intensity-Modulated Radiation Therapy or Passive Scattering Proton Therapy and Enables Individualized Radical Radiotherapy for Extensive Stage IIIB Non-Small-Cell Lung Cancer: A Virtual Clinical Study.
      ], while its applicability in patients with (ultra)central lesions needs to be supported by a more solid base of evidence.
      Admittedly, to fully translate the dosimetric potentials of PBT into a clinically-relevant benefit, several issues need to be managed for adequate treatment planning and delivery, including but not limited to respiratory motion, set-up uncertainties, machine delivery imperfections, and computed tomography (CT) number conversions into proton stopping power [
      • Ribeiro C.O.
      • Visser S.
      • Korevaar E.W.
      • et al.
      Towards the clinical implementation of intensity-modulated proton therapy for thoracic indications with moderate motion: Robust optimised plan evaluation by means of patient and machine specific information.
      ,
      • Han Y.
      Current status of proton therapy techniques for lung cancer.
      ]. Considering the 15 studies included in our systematic review, a respiratory gating system was used to deliver the radiation dose in the expiratory phase of the breathing cycle [
      • Kanemoto A.
      • Okumura T.
      • Ishikawa H.
      • et al.
      Outcomes and Prognostic Factors for Recurrence After High-Dose Proton Beam Therapy for Centrally and Peripherally Located Stage I Non–Small-Cell Lung Cancer.
      ,
      • Lee S.U.
      • Moon S.H.
      • Cho K.H.
      • et al.
      Ablative dose proton beam therapy for stage I and recurrent non-small cell lung carcinomas: Ablative dose PBT for NSCLC.
      ,
      • Shioyama Y.
      • Tokuuye K.
      • Okumura T.
      • et al.
      Clinical evaluation of proton radiotherapy for non–small-cell lung cancer.
      ,
      • Hata M.
      • Tokuuye K.
      • Kagei K.
      • et al.
      Hypofractionated High-Dose Proton Beam Therapy for Stage I Non–Small-Cell Lung Cancer: Preliminary Results of A Phase I/II Clinical Study.
      ,
      • Iwata H.
      • Murakami M.
      • Demizu Y.
      • et al.
      High-dose proton therapy and carbon-ion therapy for stage I nonsmall cell lung cancer.
      ,
      • Makita C.
      • Nakamura T.
      • Takada A.
      • et al.
      High-dose proton beam therapy for stage I non-small cell lung cancer: Clinical outcomes and prognostic factors.
      ,
      • Nakamura N.
      • Hotta K.
      • Zenda S.
      • et al.
      Hypofractionated proton beam therapy for centrally located lung cancer.
      ,
      • Nihei K.
      • Ogino T.
      • Ishikura S.
      • et al.
      High-dose proton beam therapy for Stage I non–small-cell lung cancer.
      ,
      • Ono T.
      • Yabuuchi T.
      • Nakamura T.
      • et al.
      High dose hypofractionated proton beam therapy is a safe and feasible treatment for central lung cancer.
      ,
      • Iwata H.
      • Demizu Y.
      • Fujii O.
      • et al.
      Long-Term Outcome of Proton Therapy and Carbon-Ion Therapy for Large (T2a–T2bN0M0) Non–Small-Cell Lung Cancer.
      ,
      • Hatayama Y.
      • Nakamura T.
      • Suzuki M.
      • et al.
      Clinical Outcomes and Prognostic Factors of High-Dose Proton Beam Therapy for Peripheral Stage I Non-Small-Cell Lung Cancer.
      ]. A personalized immobilization device was used in most cases to further reduce inter- and intra-fractional motion. Additionally, uncertainties were managed in all cases by robust optimization methods, and by the widespread use in our cohort of a conservative GTV/PTV expansion of 5 mm [
      • Iwata H.
      • Murakami M.
      • Demizu Y.
      • et al.
      High-dose proton therapy and carbon-ion therapy for stage I nonsmall cell lung cancer.
      ,
      • Nakamura N.
      • Hotta K.
      • Zenda S.
      • et al.
      Hypofractionated proton beam therapy for centrally located lung cancer.
      ,
      • Nihei K.
      • Ogino T.
      • Ishikura S.
      • et al.
      High-dose proton beam therapy for Stage I non–small-cell lung cancer.
      ,
      • Ono T.
      • Yabuuchi T.
      • Nakamura T.
      • et al.
      High dose hypofractionated proton beam therapy is a safe and feasible treatment for central lung cancer.
      ,
      • Westover K.D.
      • Seco J.
      • Adams J.A.
      • et al.
      Proton SBRT for Medically Inoperable Stage I NSCLC.
      ,
      • Bush D.A.
      • Cheek G.
      • Zaheer S.
      • et al.
      High-Dose Hypofractionated Proton Beam Radiation Therapy Is Safe and Effective for Central and Peripheral Early-Stage Non-Small Cell Lung Cancer: Results of a 12-Year Experience at Loma Linda University Medical Center.
      ,
      • Iwata H.
      • Demizu Y.
      • Fujii O.
      • et al.
      Long-Term Outcome of Proton Therapy and Carbon-Ion Therapy for Large (T2a–T2bN0M0) Non–Small-Cell Lung Cancer.
      ,
      • Gomez D.R.
      • Gillin M.
      • Liao Z.
      • et al.
      Phase 1 Study of Dose Escalation in Hypofractionated Proton Beam Therapy for Non-Small Cell Lung Cancer.
      ,
      • Hatayama Y.
      • Nakamura T.
      • Suzuki M.
      • et al.
      Clinical Outcomes and Prognostic Factors of High-Dose Proton Beam Therapy for Peripheral Stage I Non-Small-Cell Lung Cancer.
      ,
      • Kharod S.M.
      • Nichols R.C.
      • Henderson R.H.
      • et al.
      Image-guided hypofractionated double-scattering proton therapy in the management of centrally-located early-stage non-small cell lung cancer.
      ]. This is in line with current recommendations, which prioritize target coverage, and underline the importance of considering that actual target motion may exceed the breathing pattern observed in the simulation 4D-CTs [
      • Paganetti H.
      Relating the proton relative biological effectiveness to tumor control and normal tissue complication probabilities assuming interpatient variability in α/β.
      ]. Overall, all considered studies show that multiple strategies need to be integrated to mitigate the technical challenges of PBT is NSCLC patients: such approach translates into an excellent therapeutic ratio, as confirmed by our meta-analysis.
      We are aware of the limitations of our meta-analysis. Firstly, only half of the studies included in the qualitative synthesis could be incorporated into the meta-analysis, which may have led to the loss of potentially relevant information. Notably, it was not possible to perform differentiated analyses according to lesion location ((ultra)central vs peripheral): data are scarce, and no granular detail was provided, which due to relatively small sample sizes and inhomogeneous definition of “central” lesions, especially in older studies [
      • Chang J.Y.
      • Bezjak A.
      • Mornex F.
      Stereotactic Ablative Radiotherapy for Centrally Located Early Stage Non–Small-Cell Lung Cancer: What We Have Learned.
      ]. Overall, studies were quite heterogenous: follow-ups modality are not always disclosed, and toxicity assessment may have been biased by inter-center variabilities. While these are common limitations in systematic reviews and meta-analyses, in our series all studies used standardized reporting, which was CTCAE in almost all cases. Moreover, we are not able to support the use any specific fractionation schedule: the heterogeneity in dose prescriptions among studies- albeit expected- could be managed only by calculating the BED. However, we the stratification into a “high” and “low” dose subgroup has allowed to achieve clinically-meaningful conclusions for both outcomes of benefit (i.e. OS, CSS, LC and PFS) and harm (acute and late PBT-related toxicities of grade ≥ 2). Also, the definition of PFS may slightly differ among the studies, which in theory could partially impair the meta-analysis for this specific outcome. As an example, Kanemoto et al. [
      • Kanemoto A.
      • Okumura T.
      • Ishikawa H.
      • et al.
      Outcomes and Prognostic Factors for Recurrence After High-Dose Proton Beam Therapy for Centrally and Peripherally Located Stage I Non–Small-Cell Lung Cancer.
      ], considered the sole rise in tumor biomarkers levels as a progression of disease, which is quite uncommon in the absence of any confirmative imaging examination. Finally, despite the follow-up time is line with other published metanalyses on ES-NSCLC [
      • Zhang R.
      • Kang J.
      • Ren S.
      • et al.
      Comparison of stereotactic body radiotherapy and radiofrequency ablation for early-stage non-small cell lung cancer: a systematic review and meta-analysis.
      ,
      • Viani G.A.
      • Gouveia A.G.
      • Yan M.
      • et al.
      Stereotactic body radiotherapy versus surgery for early-stage non-small cell lung cancer: an updated meta-analysis involving 29,511 patients included in comparative studies.
      ], it should be noted that the assessment of at least some long-term toxicities may have been impaired; also, selective outcome reporting may be present.
      While acknowledging the above-mentioned caveats, it should however be noted that almost three out of four patients included the meta-analysis were treated in the setting of prospective trials, which theoretically warrants a higher level of evidence and higher quality of collected data compared to retrospective series. Additionally, when considering the characteristics of the study population, it can be noted that these are representative of the features of PBT candidates in real life (e.g. comorbid, medically-inoperable patient, with a median age of 75 or older, central lesions); therefore, the risk of indirectness for our results is very low [

      The Grading of Recommendations Assessment, Development and Evaluation (GRADE) Working Group. GRADE Handbook- Introduction to GRADE Handbook, https://gdt.gradepro.org/app/handbook/handbook.html#h.w6r7mtvq3mjz (accessed 31 October 2021).

      ].

      Conclusion

      Overall, to the best of our knowledge, this is the first meta-analysis on hypofractionated PBT in NSCLC, and its results may be informative for treating physicians in the field. To date, the prescription of a BED of at least 105.6 Gy(RBE), considering an α/β ratio of 10 Gy, can be considered as both safe and effective provided that advanced techniques for uncertainty management (e.g. respiratory motion gating, robust optimization) are implemented. Further evidence-based knowledge is warranted on the choice of the best hypofractionated schemes, and to identify the optimal PBT candidates.

      CRediT authorship contribution statement

      Stefania Volpe: Conceptualization, Data Curation, Formal Analysis, Investigation, Methodology, Writing- original draft, Writing- review & editing. Gaia Piperno: Conceptualization, Supervision, Writing- original draft, Writing- review & editing. Francesca Colombo: Data Curation, Formal Analysis, Data acquisition, Investigation, Writing- original draft, Writing- review & editing. Annalisa Biffi: Formal Analysis, Methodology, Visualization, Writing- original draft, Writing- review & editing. Stefania Comi: Data acquisition, Writing- original draft, riting- review & editing. Federico Mastroleo: Data Curation, Data acquisition, Writing- original draft, Writing- review & editing. Anna Maria Camarda: Data Curation, Writing- original draft, Writing- original draft, Writing- original draft, Writing- review & editing. Alessia Casbarra: Visualization, Writing- original draft, Writing- review & editing. Federica Cattani: Investigation, Writing- review & editing. Giulia Corrao: Investigation, Writing- review & editing. Filippode Marinis: Writing- review & editing. Lorenzo. Spaggiari: Writing- review & editing. Matthias Guckenberger: Supervision, Writing- review & editing. Roberto Orecchia: Supervision, Writing- review & editing. Daniela Alterio: Conceptualization, Supervision, Writing- review & editing. Barbara Alicja Jereczek-Fossa: Conceptualization, Supervision.

      Funding

      The IEO IRCSS is partially supported by the Italian Ministry of Health (with “Ricerca Corrente” and “5x1000” funds), by Institutional grants from Accuray Inc, and by a research grant from IBA, Louvain-La-Neuve, Belgium. Stefania Volpe and Giulia Corrao were partially supported by a research fellowship from Accuray Inc. Stefania Volpe is a PhD student within the European School of Molecular Medicine (SEMM) in Milan, Italy.

      Declaration of Competing Interest

      The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

      Appendix A. Supplementary data

      The following are the Supplementary data to this article:

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