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Letter regarding “The clinical efficacy of low-dose whole-lung irradiation in moderate-to-severe COVID-19 pneumonia: RTMX-20 trial”

  • Author Footnotes
    1 Zheng Li and Yue Hu contributed equally to this work.
    Zheng Li
    Footnotes
    1 Zheng Li and Yue Hu contributed equally to this work.
    Affiliations
    Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, China

    Lanzhou Heavy Ion Hospital, Lanzhou, China
    Search for articles by this author
  • Author Footnotes
    1 Zheng Li and Yue Hu contributed equally to this work.
    Yue Hu
    Footnotes
    1 Zheng Li and Yue Hu contributed equally to this work.
    Affiliations
    Chengdu Women's and Children's Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
    Search for articles by this author
  • Qiang Li
    Correspondence
    Corresponding author at: Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, China.
    Affiliations
    Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, China

    Lanzhou Heavy Ion Hospital, Lanzhou, China
    Search for articles by this author
  • Author Footnotes
    1 Zheng Li and Yue Hu contributed equally to this work.
Published:November 23, 2022DOI:https://doi.org/10.1016/j.radonc.2022.11.009
      To the Editor
      Low-dose whole-lung irradiation (LDWLI), a novel potential therapy of coronavirus disease 2019 (COVID-19) pneumonia, is a readily available modern medical resource worldwide [
      • Kolahdouzan K.
      • Chavoshi M.
      • Bayani R.
      • Darzikolaee N.M.
      Low-dose whole lung irradiation for treatment of COVID-19 pneumonia: A systematic review and meta-analysis.
      ]. Many clinical trials have been conducted to investigate the efficacy of LDWLI in reducing the COVID-19-related mortality risk [
      • Kolahdouzan K.
      • Chavoshi M.
      • Bayani R.
      • Darzikolaee N.M.
      Low-dose whole lung irradiation for treatment of COVID-19 pneumonia: A systematic review and meta-analysis.
      ,
      • Ortiz C.S.
      • Hernández D.
      • Trujillo C.
      • Calderón D.
      • Esqueda P.
      • Calva F.
      • et al.
      The clinical efficacy of low-dose whole-lung irradiation in moderate-to-severe COVID-19 pneumonia: RTMX-20 trial.
      ,
      • Rodríguez-Tomàs E.
      • Acosta J.C.
      • Torres-Royo L.
      • De Febrer G.
      • Baiges-Gaya G.
      • Castañé H.
      • et al.
      Effect of low-dose radiotherapy on the circulating levels of paraoxonase-1-related variables and markers of inflammation in patients with COVID-19 pneumonia.
      ,
      • Saleh M.
      • Sharma K.
      • Shah J.
      • Karsan F.
      • Waweru A.
      • Musumbi M.
      • et al.
      A pilot phase Ib/II study of whole-lung low dose radiation therapy (LDRT) for the treatment of severe COVID-19 pneumonia: First experience from Africa.
      ,
      • Sanmamed N.
      • Alcantara P.
      • Gómez S.
      • Bustos A.
      • Cerezo E.
      • Gaztañaga M.
      • et al.
      Low-dose radiation therapy in the management of COVID-19 pneumonia (LOWRAD-Cov19). Final results of a prospective phase I-II trial.
      ,
      • Singh P.
      • Mandal A.
      • Singh D.
      • Kumar S.
      • Kumar A.
      • Rakesh A.
      • et al.
      Interim analysis of impact of adding low dose pulmonary radiotherapy to moderate COVID-19 pneumonia patients: IMpaCt-RT Study.
      ,
      • Magrini S.M.
      • Tomasini D.
      • Focà E.
      • Garrafa E.M.
      • Singh N.
      • Guerini A.E.
      • et al.
      Low-dose lung radiotherapy for COVID-19-related pneumonia: preliminary results of the Italian mono-institutional COLOR-19 trial.
      ]. As per our knowledge, the study published in the Green Journal by Ortiz et al. [
      • Ortiz C.S.
      • Hernández D.
      • Trujillo C.
      • Calderón D.
      • Esqueda P.
      • Calva F.
      • et al.
      The clinical efficacy of low-dose whole-lung irradiation in moderate-to-severe COVID-19 pneumonia: RTMX-20 trial.
      ] has the largest sample size among similar studies published to date [
      • Kolahdouzan K.
      • Chavoshi M.
      • Bayani R.
      • Darzikolaee N.M.
      Low-dose whole lung irradiation for treatment of COVID-19 pneumonia: A systematic review and meta-analysis.
      ,
      • Ortiz C.S.
      • Hernández D.
      • Trujillo C.
      • Calderón D.
      • Esqueda P.
      • Calva F.
      • et al.
      The clinical efficacy of low-dose whole-lung irradiation in moderate-to-severe COVID-19 pneumonia: RTMX-20 trial.
      ,
      • Rodríguez-Tomàs E.
      • Acosta J.C.
      • Torres-Royo L.
      • De Febrer G.
      • Baiges-Gaya G.
      • Castañé H.
      • et al.
      Effect of low-dose radiotherapy on the circulating levels of paraoxonase-1-related variables and markers of inflammation in patients with COVID-19 pneumonia.
      ,
      • Saleh M.
      • Sharma K.
      • Shah J.
      • Karsan F.
      • Waweru A.
      • Musumbi M.
      • et al.
      A pilot phase Ib/II study of whole-lung low dose radiation therapy (LDRT) for the treatment of severe COVID-19 pneumonia: First experience from Africa.
      ,
      • Sanmamed N.
      • Alcantara P.
      • Gómez S.
      • Bustos A.
      • Cerezo E.
      • Gaztañaga M.
      • et al.
      Low-dose radiation therapy in the management of COVID-19 pneumonia (LOWRAD-Cov19). Final results of a prospective phase I-II trial.
      ,
      • Singh P.
      • Mandal A.
      • Singh D.
      • Kumar S.
      • Kumar A.
      • Rakesh A.
      • et al.
      Interim analysis of impact of adding low dose pulmonary radiotherapy to moderate COVID-19 pneumonia patients: IMpaCt-RT Study.
      ,
      • Magrini S.M.
      • Tomasini D.
      • Focà E.
      • Garrafa E.M.
      • Singh N.
      • Guerini A.E.
      • et al.
      Low-dose lung radiotherapy for COVID-19-related pneumonia: preliminary results of the Italian mono-institutional COLOR-19 trial.
      ]. The authors conducted a prospective comparative cohort study to evaluate the clinical efficacy of LDWLI in moderate-to-severe COVID-19 pneumonia. We congratulate Ortiz et al. for their inspiring conclusions and for having the largest sample size in this research [
      • Kolahdouzan K.
      • Chavoshi M.
      • Bayani R.
      • Darzikolaee N.M.
      Low-dose whole lung irradiation for treatment of COVID-19 pneumonia: A systematic review and meta-analysis.
      ,
      • Ortiz C.S.
      • Hernández D.
      • Trujillo C.
      • Calderón D.
      • Esqueda P.
      • Calva F.
      • et al.
      The clinical efficacy of low-dose whole-lung irradiation in moderate-to-severe COVID-19 pneumonia: RTMX-20 trial.
      ,
      • Rodríguez-Tomàs E.
      • Acosta J.C.
      • Torres-Royo L.
      • De Febrer G.
      • Baiges-Gaya G.
      • Castañé H.
      • et al.
      Effect of low-dose radiotherapy on the circulating levels of paraoxonase-1-related variables and markers of inflammation in patients with COVID-19 pneumonia.
      ,
      • Saleh M.
      • Sharma K.
      • Shah J.
      • Karsan F.
      • Waweru A.
      • Musumbi M.
      • et al.
      A pilot phase Ib/II study of whole-lung low dose radiation therapy (LDRT) for the treatment of severe COVID-19 pneumonia: First experience from Africa.
      ,
      • Sanmamed N.
      • Alcantara P.
      • Gómez S.
      • Bustos A.
      • Cerezo E.
      • Gaztañaga M.
      • et al.
      Low-dose radiation therapy in the management of COVID-19 pneumonia (LOWRAD-Cov19). Final results of a prospective phase I-II trial.
      ,
      • Singh P.
      • Mandal A.
      • Singh D.
      • Kumar S.
      • Kumar A.
      • Rakesh A.
      • et al.
      Interim analysis of impact of adding low dose pulmonary radiotherapy to moderate COVID-19 pneumonia patients: IMpaCt-RT Study.
      ,
      • Magrini S.M.
      • Tomasini D.
      • Focà E.
      • Garrafa E.M.
      • Singh N.
      • Guerini A.E.
      • et al.
      Low-dose lung radiotherapy for COVID-19-related pneumonia: preliminary results of the Italian mono-institutional COLOR-19 trial.
      ]. However, some potential pitfalls should be addressed before we proceed with this evidence for clinical practice and research.
      First, there are some substantial discrepancies between the registered protocol (NCT04534790, clinicaltrials.gov) and the eventually reported article [
      • Ortiz C.S.
      • Hernández D.
      • Trujillo C.
      • Calderón D.
      • Esqueda P.
      • Calva F.
      • et al.
      The clinical efficacy of low-dose whole-lung irradiation in moderate-to-severe COVID-19 pneumonia: RTMX-20 trial.
      ,

      ClinicalTrials.gov Identifier: NCT04534790. Anti-inflammatory Effect of Low-Dose Whole-Lung Radiation for COVID-19 Pneumonia. https://clinicaltrials.gov/ct2/show/NCT04534790?id=NCT04534790&draw=2&rank=1 (Accessed September 1, 2022).

      ]. The study design and primary outcome measures (endpoints) in this article deviate substantially from those in the initially registered protocol (randomized trial with improvement in oxygen saturation as the primary outcome measure) [
      • Ortiz C.S.
      • Hernández D.
      • Trujillo C.
      • Calderón D.
      • Esqueda P.
      • Calva F.
      • et al.
      The clinical efficacy of low-dose whole-lung irradiation in moderate-to-severe COVID-19 pneumonia: RTMX-20 trial.
      ,

      ClinicalTrials.gov Identifier: NCT04534790. Anti-inflammatory Effect of Low-Dose Whole-Lung Radiation for COVID-19 Pneumonia. https://clinicaltrials.gov/ct2/show/NCT04534790?id=NCT04534790&draw=2&rank=1 (Accessed September 1, 2022).

      ]. Moreover, the authors wrote “with high suspicion of COVID-19 pneumonia without laboratory confirmation” in the Inclusion Criteria subsection of this paper [
      • Ortiz C.S.
      • Hernández D.
      • Trujillo C.
      • Calderón D.
      • Esqueda P.
      • Calva F.
      • et al.
      The clinical efficacy of low-dose whole-lung irradiation in moderate-to-severe COVID-19 pneumonia: RTMX-20 trial.
      ]. However, the corresponding item for this subsection is “Laboratory confirmation of SARS-CoV-2 infection” in the online registered protocol [

      ClinicalTrials.gov Identifier: NCT04534790. Anti-inflammatory Effect of Low-Dose Whole-Lung Radiation for COVID-19 Pneumonia. https://clinicaltrials.gov/ct2/show/NCT04534790?id=NCT04534790&draw=2&rank=1 (Accessed September 1, 2022).

      ].
      Second, the authors have reported in the first paragraph of the Results section that 59 patients were analyzed finally [
      • Ortiz C.S.
      • Hernández D.
      • Trujillo C.
      • Calderón D.
      • Esqueda P.
      • Calva F.
      • et al.
      The clinical efficacy of low-dose whole-lung irradiation in moderate-to-severe COVID-19 pneumonia: RTMX-20 trial.
      ]. However, 58 cases are shown in Table 1 [
      • Ortiz C.S.
      • Hernández D.
      • Trujillo C.
      • Calderón D.
      • Esqueda P.
      • Calva F.
      • et al.
      The clinical efficacy of low-dose whole-lung irradiation in moderate-to-severe COVID-19 pneumonia: RTMX-20 trial.
      ].
      Third, although the authors wrote “matched” and “In both groups, there was an equal distribution among the patients.” in the Study design subsection, there were significant differences between the radiotherapy group and control group with respect to the baseline data of obesity and image classification by COVID-19 Reporting and Data System (Table 1) [
      • Ortiz C.S.
      • Hernández D.
      • Trujillo C.
      • Calderón D.
      • Esqueda P.
      • Calva F.
      • et al.
      The clinical efficacy of low-dose whole-lung irradiation in moderate-to-severe COVID-19 pneumonia: RTMX-20 trial.
      ]. However, there was no corresponding analysis or appropriate remediation for the undeniable selection bias of the participants reflected in Table 1 [
      • Ortiz C.S.
      • Hernández D.
      • Trujillo C.
      • Calderón D.
      • Esqueda P.
      • Calva F.
      • et al.
      The clinical efficacy of low-dose whole-lung irradiation in moderate-to-severe COVID-19 pneumonia: RTMX-20 trial.
      ].
      Fourth, the survival curves in Figure 1 differed substantially from the descriptive report of mortality and survival in the second paragraph of the Results section [
      • Kolahdouzan K.
      • Chavoshi M.
      • Bayani R.
      • Darzikolaee N.M.
      Low-dose whole lung irradiation for treatment of COVID-19 pneumonia: A systematic review and meta-analysis.
      ,
      • Ortiz C.S.
      • Hernández D.
      • Trujillo C.
      • Calderón D.
      • Esqueda P.
      • Calva F.
      • et al.
      The clinical efficacy of low-dose whole-lung irradiation in moderate-to-severe COVID-19 pneumonia: RTMX-20 trial.
      ].
      Fifth, it would be difficult for the readers to understand the contrastive groups in the sentence, “When comorbidities were analysed, we did not find any difference in survival between patients treated with radiotherapy and patients with hypertension (P 0.8), diabetes (P 1.09) or obesity (P 0.6).” in the third paragraph of the Results section [
      • Ortiz C.S.
      • Hernández D.
      • Trujillo C.
      • Calderón D.
      • Esqueda P.
      • Calva F.
      • et al.
      The clinical efficacy of low-dose whole-lung irradiation in moderate-to-severe COVID-19 pneumonia: RTMX-20 trial.
      ]. Furthermore, it is not clear which is the radiotherapy group in the sentence, “none of the moderate cases in the control group required OTI, while 45% of the control group required OTI.” in the fourth paragraph of the Results section [
      • Ortiz C.S.
      • Hernández D.
      • Trujillo C.
      • Calderón D.
      • Esqueda P.
      • Calva F.
      • et al.
      The clinical efficacy of low-dose whole-lung irradiation in moderate-to-severe COVID-19 pneumonia: RTMX-20 trial.
      ]. The authors should improve the accuracy of the results interpretation and reporting.
      This study by Ortiz et al. has contributed greatly to this controversial subject [
      • Ortiz C.S.
      • Hernández D.
      • Trujillo C.
      • Calderón D.
      • Esqueda P.
      • Calva F.
      • et al.
      The clinical efficacy of low-dose whole-lung irradiation in moderate-to-severe COVID-19 pneumonia: RTMX-20 trial.
      ,
      • Hanna C.R.
      • Robb K.A.
      • Blyth K.G.
      • Jones R.J.
      • Chalmers A.J.
      Clinician attitudes to using low-dose radiation therapy to treat COVID-19 lung disease.
      ]. However, addressing the aforementioned flaws is necessary to further enhance the value of this cohort study and promote wide citations of the article.

      Funding

      This work was jointly supported by the Medical Science and Technology Project of Sichuan Provincial Health Commission (Grant No. 21PJ135), and the National Natural Science Foundation of China (Grant No. 11875299).

      Conflict of Interest

      The authors declare no conflicts of interest.

      Appendix A. Supplementary material

      The following are the Supplementary data to this article:

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        • Chalmers A.J.
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