Advertisement

Incidence of Pneumonitis Among Limited Stage Small Cell Lung Cancer Patients Exposed to Concurrent Chemoradiation: A Systematic Literature Review and Meta-Analysis

Published:September 26, 2022DOI:https://doi.org/10.1016/j.cllc.2022.09.008

      Highlights

      • Pneumonitis risk was estimated in SCLC patients receiving concurrent chemoradiation.
      • Pooled risk of ≥ grade 3 pneumonitis ranged 3.28% to 6.34% in RCTs and other studies.
      • Pooled risk of fatal pneumonitis ranged 0.29% to 0.88% in RCTs and other studies.
      • Benchmark pneumonitis risks help understand the safety of novel therapeutic agents.

      Abstract

      Severe pneumonitis (≥ grade 3 by Common Terminology Criteria for Adverse Events [CTCAE]) is a toxicity associated with concurrent chemoradiation therapy (CCRT), which is the standard first-line treatment for patients with limited-stage small cell lung cancer (LS-SCLC).
      We summarize and quantify the risk of pneumonitis in LS-SCLC patients receiving first-line CCRT. A systematic literature review (SLR) and meta-analysis were performed in accordance with Cochrane and PRISMA guidelines. Electronic databases were searched to identify relevant randomized controlled trials (RCTs), observational studies, and non-randomized trials between 2014 to July 16, 2020. The primary outcome was incidence of pneumonitis. Thirteen studies were included in the SLR and 1539 pooled patients from 10 studies were included in the base-case meta-analysis. The pooled incidence of ≥ grade 3 pneumonitis was 3.28% (95% confidence interval [CI]: 1.52%-5.04%) in RCTs, and 6.34% (95% CI: 3.64%-9.04%) in non-RCTs. The pooled incidence risk of grade 5 (fatal) pneumonitis was 0.29% (95% CI: 0.00%-0.62%) in RCTs and 0.88% (95% CI: 0.02%-1.74%) in non-RCT. Results from sensitivity analyses were consistent with the base-case analysis. The results from this analysis show that the incidence of ≥ grade 3 pneumonitis in patients with LS-SCLC was 3.28% to 6.34%. The incidence of pneumonitis was higher in studies conducted in non-RCTs compared to RCTs. These results can be used to understand the safety, with regard to pneumonitis, of novel therapeutic agents when administered with CCRT to treat patients with LS-SCLC.
      To summarize and quantify the risk of pneumonitis in LS-SCLC patients receiving first-line CCRT, a systematic literature review (SLR) and meta-analysis were performed in accordance with Cochrane and PRISMA guidelines.

      Graphical abstract

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Clinical Lung Cancer
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • 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 Cancer J Clin. 2021; 71: 209-249
        • Siegel RL
        • Miller KD
        • Fuchs HE
        • Jemal A.
        Cancer statistics, 2021.
        CA Cancer J Clin. 2021; 71: 7-33
        • Basumallik N
        • Agarwal M.
        Small cell lung cancer.
        StatPearls. Treasure Island, FL2021
        • Wang S
        • Tang J
        • Sun T
        • et al.
        Survival changes in patients with small cell lung cancer and disparities between different sexes, socioeconomic statuses and ages.
        Sci Rep. 2017; 7 (1339-1339)
        • Farago AF
        • Keane FK.
        Current standards for clinical management of small cell lung cancer.
        Transl Lung Cancer Res. 2018; 7: 69-79
        • Wang S
        • Zimmermann S
        • Parikh K
        • Mansfield AS
        • Adjei AA.
        Current diagnosis and management of small-cell lung cancer.
        Mayo Clin Proc. 2019; 94: 1599-1622
        • Faivre-Finn C
        • Snee M
        • Ashcroft L
        • et al.
        Concurrent once-daily versus twice-daily chemoradiotherapy in patients with limited-stage small-cell lung cancer (CONVERT): an open-label, phase 3, randomised, superiority trial.
        Lancet Oncol. 2017; 18: 1116-1125
        • Bernhardt EB
        • Jalal SI.
        Small cell lung cancer.
        Cancer Treat Res. 2016; 170: 301-322
        • NCCN
        NCCN Clinical Practice Guidelines in Oncology - Small Lung Cell Cancer Version 3.2021.
        National Comprehensive Cancer Network, 2021
        • Pignon JP
        • Arriagada R
        • Ihde DC
        • et al.
        A meta-analysis of thoracic radiotherapy for small-cell lung cancer.
        N Engl J Med. 1992; 327: 1618-1624
        • Warde P
        • Payne D
        Does thoracic irradiation improve survival and local control in limited-stage small-cell carcinoma of the lung? A meta-analysis.
        J Clin Oncol. 1992; 10: 890-895
        • Ross HJ
        • Hu C
        • Higgins KA
        • et al.
        NRG Oncology/Alliance LU005: A phase II/III randomized clinical trial of chemoradiation versus chemoradiation plus atezolizumab in limited stage small cell lung cancer.
        J Clin Oncol. 2020; 38 (TPS9082-TPS9082)
        • Rimner A
        • Lai WVV
        • Califano R
        • et al.
        KEYLYNK-013: A phase 3 study of pembrolizumab in combination with concurrent chemoradiation therapy followed by pembrolizumab with or without olaparib versus concurrent chemoradiation therapy in patients with newly diagnosed limited-stage SCLC.
        J Clin Oncol. 2021; 39 (TPS8587-TPS8587)
        • Wong SK
        • Iams WT.
        Front line applications and future directions of immunotherapy in small-cell lung cancer.
        Cancers (Basel). 2021; 13: 506
        • Welsh JW
        • Heymach JV
        • Guo C
        • et al.
        Phase 1/2 trial of pembrolizumab and concurrent chemoradiation therapy for limited-stage sclc.
        J Thorac Oncol. 2020; 15: 1919-1927
      1. Higgins JPT, Thomas J, Chandler J, et al. Cochrane handbook for systematic reviews of interventions (version 6.0). Updated 2019; Available at: www.training.cochrane.org/handbook. Accessed: May 10, 2020.

        • Moher D
        • Liberati A
        • Tetzlaff J
        • Altman DG
        • Group P.
        Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement.
        PLoS Med. 2009; 6e1000097
        • Editors PLM.
        Best practice in systematic reviews: the importance of protocols and registration.
        PLoS Med. 2011; 8e1001009
      2. Zu K, Pierce C, Uyei J, et al. Incidence of pneumonitis among stage III unresectable non-small cell lung cancer patients exposed to chemoradiation: a systematic literature review and meta-analysis. PROSPERO 2020 CRD42020196104 Available at: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD420201961042020. Accessed: September 11, 2020.

        • Sterne JAC
        • Savović J
        • Page MJ
        • et al.
        RoB 2: a revised tool for assessing risk of bias in randomised trials.
        BMJ. 2019; 366: l4898
      3. Wells GA SB, O'Connell D, Peterson J, Welch V, Losos M, et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses

        • Higgins JP
        • Altman DG
        • Gotzsche PC
        • et al.
        The Cochrane Collaboration's tool for assessing risk of bias in randomised trials.
        BMJ. 2011; 343: d5928
        • Wang ZB
        • Ning FL
        • Wang XL
        • et al.
        Radiation dose is associated with prognosis of small cell lung cancer with superior vena cava syndrome.
        Int J Clin Exp Med. 2015; 8: 4263-4268
        • Xia B
        • Hong LZ
        • Cai XW
        • et al.
        Phase 2 study of accelerated hypofractionated thoracic radiation therapy and concurrent chemotherapy in patients with limited-stage small-cell lung cancer.
        Int J Radiat Oncol Biol Phys. 2015; 91: 517-523
        • Grønberg BH
        • Halvorsen TO
        • Fløtten Ø
        • et al.
        Randomized phase II trial comparing twice daily hyperfractionated with once daily hypofractionated thoracic radiotherapy in limited disease small cell lung cancer.
        Acta oncologica (Stockholm, Sweden). 2016; 55: 591-597
        • Hu X
        • Bao Y
        • Xu YJ
        • et al.
        Final report of a prospective randomized study on thoracic radiotherapy target volume for limited-stage small cell lung cancer with radiation dosimetric analyses.
        Cancer. 2020; 126: 840-849
        • Kubota K
        • Hida T
        • Ishikura S
        • et al.
        Etoposide and cisplatin versus irinotecan and cisplatin in patients with limited-stage small-cell lung cancer treated with etoposide and cisplatin plus concurrent accelerated hyperfractionated thoracic radiotherapy (JCOG0202): a randomised phase 3 study.
        Lancet Oncol. 2014; 15: 106-113
        • Chen XR
        • Liang JZ
        • Ma SX
        • et al.
        Consolidation chemotherapy improves progression-free survival in stage III small-cell lung cancer following concurrent chemoradiotherapy: a retrospective study.
        OncoTargets and therapy. 2016; 9: 5729-5736
        • Giuliani ME
        • Lindsay PE
        • Kwan JY
        • et al.
        Correlation of dosimetric and clinical factors with the development of esophagitis and radiation pneumonitis in patients with limited-stage small-cell lung carcinoma.
        Clin Lung Cancer. 2015; 16: 216-220
        • Morimoto M
        • Okishio K
        • Akira M
        • et al.
        Duration of twice-daily thoracic radiotherapy and time from the start of any treatment to the end of chest irradiation as significant predictors of outcomes in limited-disease small-cell lung cancer.
        Clin Lung Cancer. 2017; 18: e117-e127
        • Teng F
        • Yue J
        • Kong L
        • Yu J.
        The influence of response to initial chemotherapy on optimal timing of radiation therapy administration for limited-disease small cell lung cancer.
        Int J Radiat Oncol Biol Phys. 2014; 90: S613
        • Winther-Larsen A
        • Hoffmann L
        • Moeller DS
        • Khalil AA
        • Knap MM.
        Evaluation of factors associated with loco-regional failure and survival in limited disease small cell lung cancer patients treated with chemoradiotherapy.
        Acta oncologica (Stockholm, Sweden). 2015; 54: 1574-1581
        • Zhang J
        • Fan M
        • Liu D
        • et al.
        Hypo- or conventionally fractionated radiotherapy combined with chemotherapy in patients with limited stage small cell lung cancer.
        Radiation oncology (London, England). 2017; 12: 51
        • Yoshida H
        • Nagai H
        • Sakamori Y
        • et al.
        Phase II study of consolidation amrubicin after concurrent chemoradiotherapy in patients with limited-stage small-cell lung cancer.
        In Vivo. 2020; 34: 897-902
        • Cui P
        • Huang D
        • Wu Z
        • et al.
        Association of immune-related pneumonitis with the efficacy of PD-1/PD-L1 inhibitors in non-small cell lung cancer.
        Ther Adv Med Oncol. 2020; 121758835920922033
        • Herbst RS
        • Baas P
        • Kim DW
        • et al.
        Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial.
        Lancet. 2016; 387: 1540-1550
        • Nishino M
        • Chambers ES
        • Chong CR
        • et al.
        Anti–PD-1 inhibitor–related pneumonitis in non–small cell lung cancer.
        Cancer Immunol Res. 2016; 4: 289-293
        • Nishino M
        • Giobbie-Hurder A
        • Hatabu H
        • Ramaiya NH
        • Hodi FS.
        Incidence of programmed cell death 1 inhibitor–related pneumonitis in patients with advanced cancer: a systematic review and meta-analysis.
        JAMA Oncol. 2016; 2: 1607-1616
        • Pierce C
        • Kuang Y
        • Chang H-C
        • et al.
        Chemoradiation-induced pneumonitis in patients with unresectable stage III non-small cell lung cancer: a meta-analysis.
        J Clin Oncol. 2021; 39 (e20532-e20532)
        • Steuer CE
        • Behera M
        • Ernani V
        • et al.
        Comparison of concurrent use of thoracic radiation with either carboplatin-paclitaxel or cisplatin-etoposide for patients with stage III non-small-cell lung cancer: a systematic review.
        JAMA Oncol. 2017; 3: 1120-1129
        • Bogart JA
        • Wang X
        • Masters GA
        • et al.
        Short Communication: Interim toxicity analysis for patients with limited stage small cell lung cancer (LSCLC) treated on CALGB 30610 (Alliance) /RTOG 0538.
        Lung Cancer. 2021; 156: 68-71
        • Bogart JA
        • Wang XF
        • Masters GA
        • et al.
        Phase 3 comparison of high-dose once-daily (QD) thoracic radiotherapy (TRT) with standard twice-daily (BID) TRT in limited stage small cell lung cancer (LSCLC): CALGB 30610 (Alliance)/RTOG 0538.
        J Clin Oncol. 2021; 39 (8505-8505ASCO Presentation)