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Tomotherapy for cranio-spinal irradiation

  • Andrada Turcas
    Correspondence
    Corresponding author at: Avenue E Mounier 83/1, 1200 Brussels, Belgium.
    Affiliations
    The European Society for Paediatric Oncology (SIOPE), Brussels, Belgium

    The European Organization for Research and Treatment of Cancer (EORTC) Headquarters, Brussels, Belgium

    Radiotherapy Department, The Oncology Institute “Prof. Dr. Ion Chiricuta”, Cluj-Napoca, Romania

    Oncology Department, University of Medicine and Pharmacy “Iuliu-Hatieganu”, Cluj-Napoca, Romania
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  • Sarah M. Kelly
    Affiliations
    The European Society for Paediatric Oncology (SIOPE), Brussels, Belgium

    The European Organization for Research and Treatment of Cancer (EORTC) Headquarters, Brussels, Belgium
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  • Enrico Clementel
    Affiliations
    The European Organization for Research and Treatment of Cancer (EORTC) Headquarters, Brussels, Belgium
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  • Dana Cernea
    Affiliations
    Radiotherapy Department, The Oncology Institute “Prof. Dr. Ion Chiricuta”, Cluj-Napoca, Romania
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Open AccessPublished:November 10, 2022DOI:https://doi.org/10.1016/j.ctro.2022.11.003

      Highlights

      • Tomotherapy is safe and effective for cranio-spinal irradiation, both in paediatric patients and in adults, with similar disease-specific outcomes and toxicities as other techniques such as 3DCRT or IMRT/VMAT.
      • Tomotherapy offers several technical advantages when compared to other radiotherapy techniques such as higher target conformity and better dose homogeneity.
      • Helical Tomotherapy provides good organ-at-risk sparing for several structures, especially the vertebrae, parotids, and optic system.
      • Reported treatment time/ beam-on-time is longer with helical Tomotherapy compared to other techniques.

      Abstract

      Tomotherapy is a method of delivering rotational IMRT offering various advantages, notably for complex and large targets such as the cranio-spinal axis. This systematic literature review reports on main clinical outcomes and toxicities in patients with various cancer types that received whole craniospinal axis irradiation (CSI) using Tomotherapy and offers a comprehensive comparison between Tomotherapy and other radiotherapy delivery techniques. Databases including PubMed, PubMed Central, Embase, and Cochrane were searched using the keywords “tomotherapy” AND “craniospinal”. Fifty-six papers were included in the review. Patient population was adult in 9 papers, paediatric in 26 papers and mixed in 14 papers. Patients treated with helical Tomotherapy had similar disease-specific clinical outcomes and toxicities as patients treated using other techniques. Compared to any other technique, Tomotherapy provides better target coverage, homogeneity, and conformity in 23, 34 and 22 reports. Tomotherapy showed better organ-at-risk sparing for the thyroid, parotids, cochlea, eyes, heart and esophagus. Beam-On-Time (BOT) was reported to be longer for Tomotherapy in most studies (Median BOT: HT = 11 min, VMAT = 5.49 min, 3DCRT = 1.46 min). In conclusion, Tomotherapy offers good cranio-spinal axis coverage with improved homogeneity and conformity compared to other techniques, but with a considerably longer treatment time. Clinical outcome and toxicities suggest using Tomotherapy for CSI is efficient and safe.

      Introduction

      Tomotherapy is one potential modality used to deliver highly conformal, image-guided, rotational intensity-modulated radiotherapy (RT), using an integrated unit composed of a LINAC mounted on a circular CT gantry. The technique uses a fan-shaped 6MV beam that delivers radiation in a helical pattern using a binary multi-leaf collimator while the couch is advanced through the circular gantry[

      Mackie TR, Balog J, Ruchala K, Shepard D, Aldridge S, Fitchard E, et al. Tomotherapy. 1999.

      ,
      • Welsh J.S.
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      Clinical implementation of adaptive helical tomotherapy: A unique approach to image-guided intensity modulated radiotherapy.
      ,
      • Mackie T.R.
      History of tomotherapy.
      ]. This technique offers several advantages for treating complex targets with high conformity and homogeneity, supplemented by the ability to treat large volumes without requiring multiple isocenters or multiple abutting fields.
      One of the most challenging techniques that involves large, complex targets is whole cranio-spinal axis irradiation (CSI). CSI is mainly indicated for patients diagnosed with CNS tumors, such as Medulloblastoma, Ependymoma, ATRTs (Atypical Teratoid Rhabdoid Tumor), and Germinoma, which mostly occur in the paediatric population, underlining the importance of a highly conformal, efficient, and comfortable treatment.
      Conventional techniques[
      • Jia-Mahasap B.
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      • Onchan W.
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      Dosimetric comparison of helical tomotherapy using different techniques, simultaneous integrated boost and sequential boost for craniospinal irradiation: A single institution experience.
      ,
      • Kunos C.A.
      • Dobbins D.C.
      • Kulasekere R.
      • Latimer B.
      • Kinsella T.J.
      Comparison of helical tomotherapy versus conventional radiation to deliver craniospinal radiation [Internet].
      ,
      • Gupta T.
      • Nair V.
      • Phurailatpam R.
      • Jalali R.
      • Sarin R.
      Hyperfractionated craniospinal re-irradiation for recurrent/progressive disseminated medulloblastoma using image-guided radiotherapy: leveraging radiobiology with technology.
      ,

      Mascarin M, Drigo A, Dassie A, Gigante M, Franchin G, Sartor G, et al. Optimizing craniospinal radiotherapy delivery in a pediatric patient affected by supratentorial PNET: A case report (Tumori (2010), 96 (316-321)) [Internet]. Vol. 96, Tumori. 2010. Available from: www.tumorionline.it.

      ] and the more modern 3DCRT, IMRT and VMAT use multiple abutting fields or arcs with multiple isocentres. The most used approach is having one cranial and one or two spinal isocentres with 2 lateral opposed fields for whole brain irradiation and 1 or 2 posterior spinal fields for spinal irradiation [

      Mascarin M, Drigo A, Dassie A, Gigante M, Franchin G, Sartor G, et al. Optimizing craniospinal radiotherapy delivery in a pediatric patient affected by supratentorial PNET: A case report (Tumori (2010), 96 (316-321)) [Internet]. Vol. 96, Tumori. 2010. Available from: www.tumorionline.it.

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      Herdian F, Lestari AASA, Jayalie VF, Handoko, Wibowo WE, Djakaria M, et al. Analysis of dosimetric parameter on craniospinal irradiation with helical tomotherapy (HT), 3D conformal radiotherapy (3DCRT), and intensity modulated radiotherapy (IMRT). Vol. 14, Onkologia i Radioterapia. 2020.

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      • Myers P.A.
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      ,

      Patel S, Drodge S, Jacques A, Warkentin H, Powell K, Chafe S. A comparative planning analysis and integral dose of volumetric modulated arc therapy, helical tomotherapy, and three-dimensional conformal craniospinal irradiation for pediatric medulloblastoma. In: Journal of Medical Imaging and Radiation Sciences. Elsevier Inc.; 2015. p. 134–40.

      ,
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      ] or combining 2–3 full and/or partial arcs if using VMAT[
      • Myers P.A.
      • Mavroidis P.
      • Komisopoulos G.
      • Papanikolaou N.
      • Stathakis S.
      Pediatric Cranio-spinal Axis Irradiation: Comparison of Radiation-induced Secondary Malignancy Estimations Based on Three Methods of Analysis for Three Different Treatment Modalities.
      ,

      Patel S, Drodge S, Jacques A, Warkentin H, Powell K, Chafe S. A comparative planning analysis and integral dose of volumetric modulated arc therapy, helical tomotherapy, and three-dimensional conformal craniospinal irradiation for pediatric medulloblastoma. In: Journal of Medical Imaging and Radiation Sciences. Elsevier Inc.; 2015. p. 134–40.

      ,
      • Myers P.A.
      • Mavroidis P.
      • Papanikolaou N.
      • Stathakis S.
      Comparing conformal, arc radiotherapy and helical tomotherapy in craniospinal irradiation planning.
      ,
      • Goswami B.
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      • Yadav S.
      • Kumar S.
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      • Manocha S.
      • et al.
      Dosimetric comparison of integral dose for different techniques of craniospinal irradiation.
      ,
      • Zongwen S.
      • Shuangyan Y.
      • Fenglei D.
      • Xiaolong C.
      • Qinglin L.
      • Mengyuan C.
      • et al.
      Radiotherapy for adult medulloblastoma: Evaluation of helical tomotherapy, volumetric intensity modulated arc therapy, and three-dimensional conformal radiotherapy and the results of helical tomotherapy therapy.
      ,
      • Sakthivel V.
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      • Boopathy R.
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      Second malignant neoplasm risk after craniospinal irradiation in X-ray-based techniques compared to proton therapy.
      ,
      • Zheng J.
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      ]. These lead to field junctions in which gap and overlaps may create areas of dose inhomogeneity including underdosage or hotspots. Underdosing the target volume may compromise outcome and having significantly higher dose in some regions might lead to severe toxicities, especially with the spine being a serial organ-at-risk. Therefore, dose homogeneity is essential in having the intended outcome. Using helical Tomotherapy (HT) is much simpler in terms of planning, solving the issue of multiple field combinations, collimation, extending skin-surface distance (SSD) [
      • Seravalli E.
      • Bosman M.
      • Lassen-Ramshad Y.
      • Vestergaard A.
      • Oldenburger F.
      • Visser J.
      • et al.
      Dosimetric comparison of five different techniques for craniospinal irradiation across 15 European centers: analysis on behalf of the SIOP-E-BTG (radiotherapy working group)*.
      ] or using Electrons for certain spinal segments [
      • De Saint-Hubert M.
      • Verellen D.
      • Poels K.
      • Crijns W.
      • Magliona F.
      • Depuydt T.
      • et al.
      Out-of-field doses from pediatric craniospinal irradiations using 3D-CRT, IMRT, helical tomotherapy and electron-based therapy.
      ,
      • Harron E.
      • Lewis J.
      Bowel sparing in pediatric cranio-spinal radiotherapy: A comparison of combined electron and photon and helical TomoTherapy techniques to a standard photon method.
      ]. The Tomotherapy unit delivers a continuous, helical-shaped beam, using a single isocentre, no field junctions and no gaps or overlaps within the entire irradiated volume. This translates to a highly homogenous dose distribution, thus increasing the chances of disease control and lowering the toxicity risk. Moreover, Tomotherapy offers the possibility to perform cranio-spinal irradiation with the patient laying supine, thus facilitating anesthesia when necessary. However, the long treatment time and the relatively large volumes that receive a low dose raise some concerns about its safety and feasibility in clinical practice.
      This systematic literature review reports on several aspects of craniospinal irradiation performed with helical Tomotherapy, including clinical outcome, toxicities, and technical issues. We assessed the advantages and disadvantages of this technique and compared it to others such as 3DCRT, IMRT/VMAT and PBT. The aim of this paper is to offer a comprehensive overview and facilitate clinical decision making in practice, especially when a radiotherapy department has several techniques available.

      Methods

      Search strategy and inclusion criteria

      We carried out a search in several databases including PubMed, PubMed Central, Embase, and Cochrane (last search date- 27th of November 2021). The terms used were “tomotherapy” AND “craniospinal”. No automatic tools or filters were used. The papers were screened and selected as shown in Fig. 1 [

      Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ [Internet]. 2021 Mar 29 [cited 2022 Jun 14];372. Available from: https://pubmed.ncbi.nlm.nih.gov/33782057/.

      ].
      Figure thumbnail gr1
      Fig. 1PRISMA Flow Diagram
      [

      Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ [Internet]. 2021 Mar 29 [cited 2022 Jun 14];372. Available from: https://pubmed.ncbi.nlm.nih.gov/33782057/.

      ]
      .
      Inclusion criteria: All papers that reported on craniospinal irradiation planned or/and delivered using Tomotherapy, including case reports, series of clinical cases/patient cohorts, in-silico (dosimetric) studies, and reports on technique feasibility were included in the review. In total, 56 papers met the inclusion criteria.
      Exclusion criteria: We excluded other reviews and meta-analysis, conference abstracts, letters and editorials, book chapters, guidelines, and papers in languages other than English. Also, we excluded papers that only reported on either just Tomotherapy or just CSI and the ones that reported on multiple techniques, without distinguishing between Tomotherapy and others.

      Data extraction and analysis

      We extracted data using predefined tables in Microsoft Excel. The following data were extracted: patient number and characteristic, diagnosis, treatment (including RT dose prescription), outcome (OS = Overall Survival, PFS = Progression Free Survival, DFS = Disease Free Survival, Relapse Rate), toxicities, homogeneity and conformity indices (HI, CI), beam-on- time (BOT), planning parameters (Pitch, Modulation Factor = MF, Beam width), and dosimetric data for structures reported in each study.
      Units were standardized as follows: when more than one dose prescription was used, we mentioned the dose range (minimum–maximum); temporal data (follow-up period, survival parameters) was converted into months and beam-on-time into minutes; if individual results were reported for each patient, a mean/average or median value (depending on the distribution of the data) was calculated and included in the analysis.
      For the dosimetric comparison studies, to determine if helical Tomotherapy offered any advantage, we used the following rules:
      • -
        When the study mentioned a threshold, we used the study’s criteria to adjudicate (p < 0.05 with statistical difference, 1 or 5 Gy difference, etc.)
      • -
        When no rule was mentioned by the authors, we considered that HT was better than other techniques if the HT/Other techniques ratio is < 0.9, same if the ratio is 0.9–1.1 and worse if HT/Other technique > 1.1. The ratio was calculated by dividing the reported doses –Dmean for parallel-like organs-at-risk (OARs) and Dmax for serial-like OARs.

      Results

      Fifty-six papers were included in the review (Fig. 1). Eleven [
      • Gupta T.
      • Nair V.
      • Phurailatpam R.
      • Jalali R.
      • Sarin R.
      Hyperfractionated craniospinal re-irradiation for recurrent/progressive disseminated medulloblastoma using image-guided radiotherapy: leveraging radiobiology with technology.
      ,
      • Schiopu S.R.I.
      • Habl G.
      • Haefner M.
      • Katayama S.
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      • Debus J.
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      Helical tomotherapy in patients with leptomeningeal metastases.
      ,
      • Gupta T.
      • Zade B.
      • Upasani M.
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      • Phurailatpam R.
      • Kurkure P.
      • et al.
      Helical tomotherapy-based craniospinal irradiation: mature outcomes of a prospective feasibility study.
      ,
      • Peñagarícano J.
      • Moros E.
      • Corry P.
      • Saylors R.
      • Ratanatharathorn V.
      Pediatric Craniospinal Axis Irradiation With Helical Tomotherapy: Patient Outcome and Lack of Acute Pulmonary Toxicity.
      ,
      • Lopez Guerra J.L.
      • Marrone I.
      • Jaen J.
      • Bruna M.
      • Sole C.
      • Sanchez-Reyes A.
      • et al.
      Outcome and toxicity using helical tomotherapy for craniospinal irradiation in pediatric medulloblastoma.
      ,
      • Qu B.
      • Du L.
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      • Yu W.
      • Cai B.
      • Xu S.
      • et al.
      Clinical analysis of intracranial germinoma’s craniospinal irradiation using helical tomotherapy.
      ,
      • Öztunali A.
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      • Channaoui M.
      • Haverkamp U.
      • Grauer O.
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      Toxicity reduction after craniospinal irradiation via helical tomotherapy in patients with medulloblastoma: A unicentric retrospective analysis.
      ,
      • El Shafie R.A.
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      Outcome and prognostic factors following palliative craniospinal irradiation for leptomeningeal carcinomatosis.
      ,
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      Assessment of three-dimensional set-up errors using megavoltage computed tomography (MVCT) during image-guided intensity-modulated radiation therapy (IMRT) for craniospinal irradiation (CSI) on helical tomotherapy (HT).
      ,
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      Glioneuronal tumor with neuropil-like islands of the spinal cord with diffuse leptomeningeal neuraxis dissemination.
      ,

      Gaito S, Malagoli M, Depenni R, Pavesi G, Bruni A. Pineoblastoma in Adults: A Rare Case Successfully Treated with Multimodal Approach Including Craniospinal Irradiation Using Helical Tomotherapy. Cureus. 2019 Oct 7;.

      ] reported on the outcome of patients receiving HT-CSI and 15 on toxicities [
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      ,
      • Gupta T.
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      Hyperfractionated craniospinal re-irradiation for recurrent/progressive disseminated medulloblastoma using image-guided radiotherapy: leveraging radiobiology with technology.
      ,

      Gaito S, Malagoli M, Depenni R, Pavesi G, Bruni A. Pineoblastoma in Adults: A Rare Case Successfully Treated with Multimodal Approach Including Craniospinal Irradiation Using Helical Tomotherapy. Cureus. 2019 Oct 7;.

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      • Gupta T.
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      Helical tomotherapy-based craniospinal irradiation: mature outcomes of a prospective feasibility study.
      ,
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      Sugie C, Shibamoto Y, Ayakawa S, Mimura M, Komai K, Ishii M, et al. Craniospinal irradiation using helical tomotherapy: Evaluation of acute toxicity and dose distribution. Technol Cancer Res Treat [Internet]. 2011;10(2):187–95. Available from: www.tcrt.org.

      ,
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      Helical tomotherapy for craniospinal radiation.
      ,
      • Zongwen S.
      • Shuangyan Y.
      • Fenglei D.
      • Xiaolong C.
      • Qinglin L.
      • Mengyuan C.
      • et al.
      Radiotherapy for adult medulloblastoma: Evaluation of helical tomotherapy, volumetric intensity modulated arc therapy, and three-dimensional conformal radiotherapy and the results of helical tomotherapy therapy.
      ,
      • Lee J.
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      Practical aspects of the application of helical tomotherapy for craniospinal irradiation.
      ,
      • Schiopu S.R.I.
      • Habl G.
      • Haefner M.
      • Katayama S.
      • Herfarth K.
      • Debus J.
      • et al.
      Helical tomotherapy in patients with leptomeningeal metastases.
      ,
      • Peñagarícano J.
      • Moros E.
      • Corry P.
      • Saylors R.
      • Ratanatharathorn V.
      Pediatric Craniospinal Axis Irradiation With Helical Tomotherapy: Patient Outcome and Lack of Acute Pulmonary Toxicity.
      ,
      • Lopez Guerra J.L.
      • Marrone I.
      • Jaen J.
      • Bruna M.
      • Sole C.
      • Sanchez-Reyes A.
      • et al.
      Outcome and toxicity using helical tomotherapy for craniospinal irradiation in pediatric medulloblastoma.
      ,
      • Qu B.
      • Du L.
      • Huang Y.
      • Yu W.
      • Cai B.
      • Xu S.
      • et al.
      Clinical analysis of intracranial germinoma’s craniospinal irradiation using helical tomotherapy.
      ,
      • Öztunali A.
      • Elsayad K.
      • Scobioala S.
      • Channaoui M.
      • Haverkamp U.
      • Grauer O.
      • et al.
      Toxicity reduction after craniospinal irradiation via helical tomotherapy in patients with medulloblastoma: A unicentric retrospective analysis.
      ,
      • El Shafie R.A.
      • Böhm K.
      • Weber D.
      • Lang K.
      • Schlaich F.
      • Adeberg S.
      • et al.
      Outcome and prognostic factors following palliative craniospinal irradiation for leptomeningeal carcinomatosis.
      ,
      • Ruppert B.
      • Welsh C.T.
      • Hannah J.
      • Giglio P.
      • Rumboldt Z.
      • Johnson I.
      • et al.
      Glioneuronal tumor with neuropil-like islands of the spinal cord with diffuse leptomeningeal neuraxis dissemination.
      ]. Thirty-eight studies performed a dosimetric comparison between Helical Tomotherapy and other techniques (conventional RT [
      • Jia-Mahasap B.
      • Chitapanarux I.
      • Tharavichitkul E.
      • Chakrabandhu S.
      • Klunklin P.
      • Onchan W.
      • et al.
      Dosimetric comparison of helical tomotherapy using different techniques, simultaneous integrated boost and sequential boost for craniospinal irradiation: A single institution experience.
      ,
      • Kunos C.A.
      • Dobbins D.C.
      • Kulasekere R.
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      ,
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      ,
      • Thondykandy B.
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      • Laskar S.
      • Mahantshetty U.
      • et al.
      Setup error analysis in helical tomotherapy based image-guided radiation therapy treatments.
      ,
      • Novak J.
      • Du D.
      • Shinde A.
      • Li R.
      • Amini A.
      • Chen Y.J.
      • et al.
      Setup Accuracy in Craniospinal Irradiation: Implications for Planning Treatment Volume Margins.
      ,
      • Sterzing F.
      • Schubert K.
      • Sroka-Perez G.
      • Kalz J.
      • Debus J.
      • Herfarth K.
      Helical tomotherapy: Experiences of the first 150 patients in Heidelberg.
      ], 26 studies only paediatric patients [
      • Kunos C.A.
      • Dobbins D.C.
      • Kulasekere R.
      • Latimer B.
      • Kinsella T.J.
      Comparison of helical tomotherapy versus conventional radiation to deliver craniospinal radiation [Internet].
      ,
      • Gupta T.
      • Nair V.
      • Phurailatpam R.
      • Jalali R.
      • Sarin R.
      Hyperfractionated craniospinal re-irradiation for recurrent/progressive disseminated medulloblastoma using image-guided radiotherapy: leveraging radiobiology with technology.
      ,
      • Sharma S.D.
      • Gupta T.
      • Jalali R.
      • Master Z.
      • Phurailatpam R.D.
      • Sarin R.
      High-precision radiotherapy for craniospinal irradiation: Evaluation of three-dimensional conformal radiotherapy, intensity-modulated radiation therapy and helical TomoTherapy.
      ,
      • Rene N.J.
      • Brodeur M.
      • Parker W.
      • Roberge D.
      • Freeman C.
      A comparison of optic nerve dosimetry in craniospinal radiotherapy planned and treated with conventional and intensity modulated techniques.
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      • Seravalli E.
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      Dosimetric comparison of five different techniques for craniospinal irradiation across 15 European centers: analysis on behalf of the SIOP-E-BTG (radiotherapy working group)*.
      ,
      • Holmes J.A.
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      • Shuryak I.
      • Wilson A.K.
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      • et al.
      Estimating the excess lifetime risk of radiation induced secondary malignancy (SMN) in pediatric patients treated with craniospinal irradiation (CSI): Conventional radiation therapy versus helical intensity modulated radiation therapy.
      ,
      • Peñagarícano J.A.
      • Papanikolaou N.
      • Yan Y.
      • Youssef E.
      • Ratanatharathorn V.
      Feasibility of cranio-spinal axis radiation with the Hi-Art tomotherapy system.
      ,
      • Myers P.A.
      • Mavroidis P.
      • Papanikolaou N.
      • Stathakis S.
      Comparing conformal, arc radiotherapy and helical tomotherapy in craniospinal irradiation planning.
      ,
      • Mavroidis P.
      • Ferreira B.C.
      • Shi C.
      • Delichas M.G.
      • Lind B.K.
      • Papanikolaou N.
      Comparison of the helical tomotherapy and MLC-based IMRT radiation modalities in treating brain and cranio-spinal tumors.
      ,
      • Sakthivel V.
      • Ganesh K.M.
      • McKenzie C.
      • Boopathy R.
      • Selvaraj J.
      Second malignant neoplasm risk after craniospinal irradiation in X-ray-based techniques compared to proton therapy.
      ,
      • Zheng J.
      • Aljabab S.
      • Lacasse P.
      • Bahm J.
      • Lekx-Toniolo K.
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      Functional cranio-spinal irradiation: A hippocampal and hypothalamic-pituitary axis sparing radiation technique using two IMRT modalities.
      ,
      • Harron E.
      • Lewis J.
      Bowel sparing in pediatric cranio-spinal radiotherapy: A comparison of combined electron and photon and helical TomoTherapy techniques to a standard photon method.
      ,

      Mascarin M, Drigo A, Dassie A, Gigante M, Franchin G, Sartor G, et al. Optimizing craniospinal radiotherapy delivery in a pediatric patient affected by supratentorial PNET: A case report (Tumori (2010), 96 (316-321)) [Internet]. Vol. 96, Tumori. 2010. Available from: www.tumorionline.it.

      ,
      • Lopez Guerra J.L.
      • Marrone I.
      • Jaen J.
      • Bruna M.
      • Sole C.
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      • et al.
      Outcome and toxicity using helical tomotherapy for craniospinal irradiation in pediatric medulloblastoma.
      ,
      • Mesbah L.
      • Matute R.
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      Helical tomotherapy in the treatment of pediatric malignancies: A preliminary report of feasibility and acute toxicity.
      ,
      • Bauman G.
      • Yartsev S.
      • Coad T.
      • Fisher B.
      • Kron T.
      Helical tomotherapy for craniospinal radiation.
      ,
      • Tang Z.
      • Zou X.
      • Luo Q.
      • Wang Y.
      • Jin F.
      The Risk of Radiogenic Second Cancer Based on Differential DVH: Central Nervous System Malignant Tumor in Children.
      ,
      • Peñagarícano J.A.
      • Yan Y.
      • Corry P.
      • Moros E.
      • Ratanatharathorn V.
      Retrospective evaluation of pediatric cranio-spinal axis irradiation plans with the Hi-ART tomotherapy system.
      ,
      • Myers P.A.
      • Mavroidis P.
      • Komisopoulos G.
      • Papanikolaou N.
      • Stathakis S.
      Pediatric Cranio-spinal Axis Irradiation: Comparison of Radiation-induced Secondary Malignancy Estimations Based on Three Methods of Analysis for Three Different Treatment Modalities.
      ,
      • Barra S.
      • Gusinu M.
      • Timon G.
      • Giannelli F.
      • Vidano G.
      • Garrè M.L.
      • et al.
      Pediatric craniospinal irradiation with conventional technique or helical tomotherapy: Impact of age and body volume on integral dose.
      ,
      • Hong J.Y.
      • Kim G.W.
      • Kim C.U.
      • Cheon G.S.
      • Son S.H.
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      • et al.
      Supine linac treatment versus tomotherapy in craniospinal irradiation: Planning comparison and dosimetric evaluation.
      ,
      • Langner U.W.
      • Molloy J.A.
      • Gleason J.F.
      • Feddock J.M.
      A feasibility study using tomodirect for craniospinal irradiation.
      ,
      • Yoon M.
      • Shin D.H.
      • Kim J.
      • Kim J.W.
      • Kim D.W.
      • Park S.Y.
      • et al.
      Craniospinal irradiation techniques: A dosimetric comparison of proton beams with standard and advanced photon radiotherapy.
      ,
      • De Saint-Hubert M.
      • Verellen D.
      • Poels K.
      • Crijns W.
      • Magliona F.
      • Depuydt T.
      • et al.
      Out-of-field doses from pediatric craniospinal irradiations using 3D-CRT, IMRT, helical tomotherapy and electron-based therapy.
      ,

      Patel S, Drodge S, Jacques A, Warkentin H, Powell K, Chafe S. A comparative planning analysis and integral dose of volumetric modulated arc therapy, helical tomotherapy, and three-dimensional conformal craniospinal irradiation for pediatric medulloblastoma. In: Journal of Medical Imaging and Radiation Sciences. Elsevier Inc.; 2015. p. 134–40.

      ], 14 both adult and paediatric population[
      • Jia-Mahasap B.
      • Chitapanarux I.
      • Tharavichitkul E.
      • Chakrabandhu S.
      • Klunklin P.
      • Onchan W.
      • et al.
      Dosimetric comparison of helical tomotherapy using different techniques, simultaneous integrated boost and sequential boost for craniospinal irradiation: A single institution experience.
      ,

      Herdian F, Lestari AASA, Jayalie VF, Handoko, Wibowo WE, Djakaria M, et al. Analysis of dosimetric parameter on craniospinal irradiation with helical tomotherapy (HT), 3D conformal radiotherapy (3DCRT), and intensity modulated radiotherapy (IMRT). Vol. 14, Onkologia i Radioterapia. 2020.

      ,
      • Lee J.
      • Kim E.
      • Kim N.
      • Byun H.K.
      • Suh C.O.
      • Chung Y.
      • et al.
      Practical aspects of the application of helical tomotherapy for craniospinal irradiation.
      ,
      • Noble D.J.
      • Ajithkumar T.
      • Lambert J.
      • Gleeson I.
      • Williams M.V.
      • Jefferies S.J.
      Highly Conformal Craniospinal Radiotherapy Techniques Can Underdose the Cranial Clinical Target Volume if Leptomeningeal Extension through Skull Base Exit Foramina is not Contoured.
      ,
      • Sun Y.
      • Liu G.
      • Chen W.
      • Chen T.
      • Liu P.
      • Zeng Q.
      • et al.
      Dosimetric comparisons of craniospinal axis irradiation using helical tomotherapy, volume-modulated arc therapy and intensity-modulated radiotherapy for medulloblastoma.
      ,
      • Al-Wassia R.
      • Bahig H.
      • Poon E.
      • Parker W.
      • Freeman C.
      Daily setup uncertainty analysis for craniospinal irradiation using helical tomotherapy.
      ,
      • Tsang S.W.S.
      • Collins M.
      • Wong J.T.L.
      • Chiu G.
      A dosimetric comparison of craniospinal irradiation using TomoDirect radiotherapy, TomoHelical radiotherapy and 3D conventional radiotherapy.
      ,
      • Peñagarícano J.
      • Moros E.
      • Corry P.
      • Saylors R.
      • Ratanatharathorn V.
      Pediatric Craniospinal Axis Irradiation With Helical Tomotherapy: Patient Outcome and Lack of Acute Pulmonary Toxicity.
      ,
      • Qu B.
      • Du L.
      • Huang Y.
      • Yu W.
      • Cai B.
      • Xu S.
      • et al.
      Clinical analysis of intracranial germinoma’s craniospinal irradiation using helical tomotherapy.
      ,
      • Öztunali A.
      • Elsayad K.
      • Scobioala S.
      • Channaoui M.
      • Haverkamp U.
      • Grauer O.
      • et al.
      Toxicity reduction after craniospinal irradiation via helical tomotherapy in patients with medulloblastoma: A unicentric retrospective analysis.
      ,
      • Gupta T.
      • Upasani M.
      • Master Z.
      • Patil A.
      • Phurailatpam R.
      • Nojin S.
      • et al.
      Assessment of three-dimensional set-up errors using megavoltage computed tomography (MVCT) during image-guided intensity-modulated radiation therapy (IMRT) for craniospinal irradiation (CSI) on helical tomotherapy (HT).
      ,
      • Gupta T.
      • Zade B.
      • Upasani M.
      • Master Z.
      • Phurailatpam R.
      • Kurkure P.
      • et al.
      Helical tomotherapy-based craniospinal irradiation: mature outcomes of a prospective feasibility study.
      ,
      • Schiopu S.R.I.
      • Habl G.
      • Häfner M.
      • Katayama S.
      • Herfarth K.
      • Debus J.
      • et al.
      Craniospinal irradiation using helical tomotherapy for central nervous system tumors.
      ,

      Sugie C, Shibamoto Y, Ayakawa S, Mimura M, Komai K, Ishii M, et al. Craniospinal irradiation using helical tomotherapy: Evaluation of acute toxicity and dose distribution. Technol Cancer Res Treat [Internet]. 2011;10(2):187–95. Available from: www.tcrt.org.

      ], and 7 papers did not report on patient age [
      • Peñagarícano J.A.
      • Papanikolaou N.
      • Yan Y.
      • Youssef E.
      • Ratanatharathorn V.
      Feasibility of cranio-spinal axis radiation with the Hi-Art tomotherapy system.
      ,
      • Goswami B.
      • Jain R.K.
      • Yadav S.
      • Kumar S.
      • Oommen S.
      • Manocha S.
      • et al.
      Dosimetric comparison of integral dose for different techniques of craniospinal irradiation.
      ,
      • El Shafie R.A.
      • Böhm K.
      • Weber D.
      • Lang K.
      • Schlaich F.
      • Adeberg S.
      • et al.
      Outcome and prognostic factors following palliative craniospinal irradiation for leptomeningeal carcinomatosis.
      ,
      • Parker W.
      • Brodeur M.
      • Roberge D.
      • Freeman C.
      Standard and Nonstandard Craniospinal Radiotherapy Using Helical TomoTherapy.
      ,
      • Zhang X.
      • Penagaricano J.
      • Han E.Y.
      • Morrill S.
      • Hardee M.
      • Liang X.
      • et al.
      Dosimetric comparison of craniospinal irradiation using different tomotherapy techniques.
      ,
      • Shi C.
      • Peñagarícano J.
      • Papanikolaou N.
      Comparison of IMRT Treatment Plans Between Linac and Helical Tomotherapy Based on Integral Dose and Inhomogeneity Index.
      ,
      • Kraus K.M.
      • Kampfer S.
      • Wilkens J.J.
      • Schüttrumpf L.
      • Combs S.E.
      Helical tomotherapy: Comparison of Hi-ART and Radixact clinical patient treatments at the Technical University of Munich.
      ].

      Technical aspects

      Simulation and planning

      Most papers reported on using both a head or head-and-neck thermoplastic masks and body vacuum cradles, cushions, or body thermoplastic masks for patient immobilization. The simulation CT was mostly performed with 3 mm or 5 mm thick slices (12 and 18 papers respectively). Out of the 56 papers, only 9 reported on using sedation, anaesthesia, or both. Eighteen authors mentioned using co-registered CT and MRI for treatment planning. Intra-venous contrast use during the planning CT was reported in 4 publications.

      Treatment planning system and contouring

      The most used planning system was TomoTherapy®, followed by the newer Radixact™ system which was reported by 3 authors[
      • Kraus K.M.
      • Kampfer S.
      • Wilkens J.J.
      • Schüttrumpf L.
      • Combs S.E.
      Helical tomotherapy: Comparison of Hi-ART and Radixact clinical patient treatments at the Technical University of Munich.
      ,
      • Goswami B.
      • Jain R.K.
      • Yadav S.
      • Kumar S.
      • Oommen S.
      • Manocha S.
      • et al.
      Dosimetric comparison of integral dose for different techniques of craniospinal irradiation.
      ,
      • Lee J.
      • Kim E.
      • Kim N.
      • Byun H.K.
      • Suh C.O.
      • Chung Y.
      • et al.
      Practical aspects of the application of helical tomotherapy for craniospinal irradiation.
      ]. 12 authors reported on using the same system for contouring as for planning (i.e., Tomotherapy station), 20 reported using other contouring software (9 Pinnacle/Philips, 6 Eclipse/Varian) and 24 authors did not mention this aspect.

      Pitch, modulation factor, beam width

      The most used pitches were 0.287 (16 reports), 0.43 (10 reports) and 0.3 (8 reports). A beam width of 5 cm was most frequently chosen (25 reports), followed by 2.5 cm (17 reports). The majority of the plans were developed using a low modulation factor (1.5–2 reported 17 times). The lowest modulation factor (MF) used was 1.5, the highest was 3, with a median of 2.3. The most used fan beam width was 5 cm (29 reports). Using a higher modulation factor and a narrower beam increases beam-on time. Average BOT when using a 2.5 cm beam was 21.2 min, 12.11 min with a 5 cm beam, 11.84 min with a MF of 2 and 15.13 with a MF > 2. [
      • Zhang X.
      • Penagaricano J.
      • Han E.Y.
      • Morrill S.
      • Hardee M.
      • Liang X.
      • et al.
      Dosimetric comparison of craniospinal irradiation using different tomotherapy techniques.
      ,
      • Peñagarícano J.A.
      • Yan Y.
      • Corry P.
      • Moros E.
      • Ratanatharathorn V.
      Retrospective evaluation of pediatric cranio-spinal axis irradiation plans with the Hi-ART tomotherapy system.
      ,
      • Sterzing F.
      • Schubert K.
      • Sroka-Perez G.
      • Kalz J.
      • Debus J.
      • Herfarth K.
      Helical tomotherapy: Experiences of the first 150 patients in Heidelberg.
      ].

      Setup accuracy

      Six papers looked at setup accuracy when using Tomotherapy for CSI. Inter-fractional or intra-fractional motion were recorded for 169 patients, encompassing>2722 fractions. The maximum setup error was 15 mm in the antero-posterior direction. [
      • Al-Wassia R.
      • Bahig H.
      • Poon E.
      • Parker W.
      • Freeman C.
      Daily setup uncertainty analysis for craniospinal irradiation using helical tomotherapy.
      ,
      • Novak J.
      • Du D.
      • Shinde A.
      • Li R.
      • Amini A.
      • Chen Y.J.
      • et al.
      Setup Accuracy in Craniospinal Irradiation: Implications for Planning Treatment Volume Margins.
      ] Four authors[
      • Lee J.
      • Kim E.
      • Kim N.
      • Byun H.K.
      • Suh C.O.
      • Chung Y.
      • et al.
      Practical aspects of the application of helical tomotherapy for craniospinal irradiation.
      ,
      • Al-Wassia R.
      • Bahig H.
      • Poon E.
      • Parker W.
      • Freeman C.
      Daily setup uncertainty analysis for craniospinal irradiation using helical tomotherapy.
      ,
      • Gupta T.
      • Upasani M.
      • Master Z.
      • Patil A.
      • Phurailatpam R.
      • Nojin S.
      • et al.
      Assessment of three-dimensional set-up errors using megavoltage computed tomography (MVCT) during image-guided intensity-modulated radiation therapy (IMRT) for craniospinal irradiation (CSI) on helical tomotherapy (HT).
      ,
      • Novak J.
      • Du D.
      • Shinde A.
      • Li R.
      • Amini A.
      • Chen Y.J.
      • et al.
      Setup Accuracy in Craniospinal Irradiation: Implications for Planning Treatment Volume Margins.
      ] reported that the PTV margin used contains the setup error recorded and only one[
      • Thondykandy B.
      • Swamidas J.
      • Agarwal J.
      • Gupta T.
      • Laskar S.
      • Mahantshetty U.
      • et al.
      Setup error analysis in helical tomotherapy based image-guided radiation therapy treatments.
      ] reported the opposite. (Supplementary material- Table 3).

      Tomotherapy compared to other techniques

      Target coverage, Homogeneity, Conformity, Beam-on-time

      Median Homogeneity Index (HI) for HT was 0.07, ranging from 0.04 to 0.17. The median Conformity Index (CI) was 0.92, ranging 0.59 to 1.34. Compared to other techniques (Photon 3DCRT, IMRT, VMAT and PBT), HT showed better coverage, homogeneity, and conformity in 41 %, 75 %, and 63 % of the reports (Fig. 2). The average beam-on time for HT was 13.54 min and the median 12.02 min, with a minimum of 6 min and a maximum of 30 min. Fig. 3 shows the BOT reported for different techniques.
      Figure thumbnail gr2
      Fig. 2Target coverage, HI = homogeneity index and CI = conformity index for Helical Tomotherapy compared to other techniques.
      Figure thumbnail gr3
      Fig. 3Comparison of the Beam-On-Time (BOT) in minutes for cranio-spinal irradiation using different techniques; IMRT = Intensity-Modulated Radiotherapy, VMAT = Volumetric Modulated Arc Therapy, 3DCRT- Three-Dimensional Conformal Radiotherapy.

      Organs-at-risk dosimetry

      The integral dose delivered to the total body, the so-called “dose bath” was reported to be higher with Tomotherapy in 18 papers, the same as with other techniques in 12 papers and lower in only 3 reports. Papers (n = 4) reporting on the vertebrae showed better sparing [
      • Kunos C.A.
      • Dobbins D.C.
      • Kulasekere R.
      • Latimer B.
      • Kinsella T.J.
      Comparison of helical tomotherapy versus conventional radiation to deliver craniospinal radiation [Internet].
      ] and homogeneity [
      • Holmes J.A.
      • Chera B.S.
      • Brenner D.J.
      • Shuryak I.
      • Wilson A.K.
      • Lehman-Davis M.
      • et al.
      Estimating the excess lifetime risk of radiation induced secondary malignancy (SMN) in pediatric patients treated with craniospinal irradiation (CSI): Conventional radiation therapy versus helical intensity modulated radiation therapy.
      ,

      Sugie C, Shibamoto Y, Ayakawa S, Mimura M, Komai K, Ishii M, et al. Craniospinal irradiation using helical tomotherapy: Evaluation of acute toxicity and dose distribution. Technol Cancer Res Treat [Internet]. 2011;10(2):187–95. Available from: www.tcrt.org.

      ,
      • Bauman G.
      • Yartsev S.
      • Coad T.
      • Fisher B.
      • Kron T.
      Helical tomotherapy for craniospinal radiation.
      ] with Tomotherapy compared to other techniques. The heart, optic nerves, eyes, cochlea, parotid, and thyroid gland were better spared using Helical Tomotherapy. All reports showed Tomotherapy to be the least effective in breast sparing. When compared to PBT, HT offered similar target coverage (3/4) and conformity (3/3), but worse OAR sparing, except for 1 report in which the parotid was better spared with HT. Similar results were reported when the Integral Dose to OARs was compared between techniques[

      Mascarin M, Drigo A, Dassie A, Gigante M, Franchin G, Sartor G, et al. Optimizing craniospinal radiotherapy delivery in a pediatric patient affected by supratentorial PNET: A case report (Tumori (2010), 96 (316-321)) [Internet]. Vol. 96, Tumori. 2010. Available from: www.tumorionline.it.

      ,
      • Barra S.
      • Gusinu M.
      • Timon G.
      • Giannelli F.
      • Vidano G.
      • Garrè M.L.
      • et al.
      Pediatric craniospinal irradiation with conventional technique or helical tomotherapy: Impact of age and body volume on integral dose.
      ,
      • De Saint-Hubert M.
      • Verellen D.
      • Poels K.
      • Crijns W.
      • Magliona F.
      • Depuydt T.
      • et al.
      Out-of-field doses from pediatric craniospinal irradiations using 3D-CRT, IMRT, helical tomotherapy and electron-based therapy.
      ,
      • Sharma S.D.
      • Gupta T.
      • Jalali R.
      • Master Z.
      • Phurailatpam R.D.
      • Sarin R.
      High-precision radiotherapy for craniospinal irradiation: Evaluation of three-dimensional conformal radiotherapy, intensity-modulated radiation therapy and helical TomoTherapy.
      ,
      • Peñagarícano J.A.
      • Papanikolaou N.
      • Yan Y.
      • Youssef E.
      • Ratanatharathorn V.
      Feasibility of cranio-spinal axis radiation with the Hi-Art tomotherapy system.
      ,
      • Goswami B.
      • Jain R.K.
      • Yadav S.
      • Kumar S.
      • Oommen S.
      • Manocha S.
      • et al.
      Dosimetric comparison of integral dose for different techniques of craniospinal irradiation.
      ,
      • Tsang S.W.S.
      • Collins M.
      • Wong J.T.L.
      • Chiu G.
      A dosimetric comparison of craniospinal irradiation using TomoDirect radiotherapy, TomoHelical radiotherapy and 3D conventional radiotherapy.
      ,
      • Shi C.
      • Peñagarícano J.
      • Papanikolaou N.
      Comparison of IMRT Treatment Plans Between Linac and Helical Tomotherapy Based on Integral Dose and Inhomogeneity Index.
      ]. Fig. 4 illustrates the dosimetric performance comparison of Tomotherapy against other techniques.
      Figure thumbnail gr4
      Fig. 4Proportion of the total number of papers reporting a better, worse, or equivalent sparing capacity of helical Tomotherapy for each OAR, when compared to other techniques (3DCRT, IMRT, VMAT, PBT).
      Five studies [
      • Myers P.A.
      • Mavroidis P.
      • Komisopoulos G.
      • Papanikolaou N.
      • Stathakis S.
      Pediatric Cranio-spinal Axis Irradiation: Comparison of Radiation-induced Secondary Malignancy Estimations Based on Three Methods of Analysis for Three Different Treatment Modalities.
      ,
      • Yoon M.
      • Shin D.H.
      • Kim J.
      • Kim J.W.
      • Kim D.W.
      • Park S.Y.
      • et al.
      Craniospinal irradiation techniques: A dosimetric comparison of proton beams with standard and advanced photon radiotherapy.
      ,
      • Holmes J.A.
      • Chera B.S.
      • Brenner D.J.
      • Shuryak I.
      • Wilson A.K.
      • Lehman-Davis M.
      • et al.
      Estimating the excess lifetime risk of radiation induced secondary malignancy (SMN) in pediatric patients treated with craniospinal irradiation (CSI): Conventional radiation therapy versus helical intensity modulated radiation therapy.
      ,
      • Sakthivel V.
      • Ganesh K.M.
      • McKenzie C.
      • Boopathy R.
      • Selvaraj J.
      Second malignant neoplasm risk after craniospinal irradiation in X-ray-based techniques compared to proton therapy.
      ,
      • Tang Z.
      • Zou X.
      • Luo Q.
      • Wang Y.
      • Jin F.
      The Risk of Radiogenic Second Cancer Based on Differential DVH: Central Nervous System Malignant Tumor in Children.
      ] focused on SMN risk estimation following CSI in paediatric patients. PBT had the lowest estimated risk when compared to any other photon technique. HT and IMRT/VMAT showed similar SMN risk but when compared with 3DCRT, results were inconsistent, with the same papers reporting both higher and lower risk for HT depending on the calculation algorithm used.

      Toxicities

      Several authors reported less, or similar acute toxicities compared to existing data from the literature. The most frequent acute adverse effects reported were cytopenia, nausea/vomiting, fatigue, and alopecia. Tomotherapy was considered to be well tolerated with low and acceptable rates of severe toxicity by most of the authors, with 6 reporting a total number of 41 patients who interrupted treatment, mainly due to haematological toxicity. Reported late effects were neuro-cognitive impairment, chronic fatigue, hormonal imbalance, and hearing disorders. There were two cases of second malignancies reported in the HT groups. [
      • Schiopu S.R.I.
      • Habl G.
      • Häfner M.
      • Katayama S.
      • Herfarth K.
      • Debus J.
      • et al.
      Craniospinal irradiation using helical tomotherapy for central nervous system tumors.
      ,
      • Öztunali A.
      • Elsayad K.
      • Scobioala S.
      • Channaoui M.
      • Haverkamp U.
      • Grauer O.
      • et al.
      Toxicity reduction after craniospinal irradiation via helical tomotherapy in patients with medulloblastoma: A unicentric retrospective analysis.
      ] Table 1 offers more details on the toxicities reported in the selected papers.
      Table 1Reported toxicities.
      PublicationTotal no. of patientsHT-CSI (n)Paediatric/AdultDiseaseDose/CSI (Gy)D/fr (Gy)ChTTop 3 Acute ToxicitiesTop 3 Late ToxicitiesGreatest toxicity levelSMN/HT (n)Comments
      Guerra et al., 20141919PaediatricMBL23.4–391.3–1.8YesCytopenia



      Nausea/Vomiting

      Skin toxicity
      No ≥ G2 toxicitiesG3
      Mesbah et al., 20116623PaediatricMBL



      Other
      23.4–361.8YesCytopenia

      Skin



      GI
      G4
      Kunos et al., 200844PaediatricMBL23.41.8YesCytopenia
      Gupta et al., 201211PaediatricMBL



      LMM
      30–361–1.2YesHematologicG20No treatment interruption
      Schiopu et al., 20174545Paediatric + AdultMBL



      ICG

      EPD

      PNET

      Other
      16.2–401–1.6YesCytopenia



      Nausea/Vomiting

      Alopecia
      Learning&memory deficits



      Headaches/ Dizziness

      Fatigue
      G411 patient died during RT



      1 patient interrupted the treatment
      Peñagarícano et al., 20091818Paediatric + AdultMBL



      PBL

      ICG

      Other
      15–401.5–2YesWeight loss



      Nausea/Vomiting

      Esophagitis
      G3No symptomatic Acute Radiation Pneumonitis
      Qu et al., 20142323Paediatric + AdultICG27–361.5–2YesAlopecia



      Cytopenia

      Nausea/Vomiting
      Growth retardation



      Hormonal inbalance
      G41 patient abandoned treatment - G3 Low GI toxicities
      Öztunali et al., 20214619Paediatric + AdultMBL23.4–401–2YesFatigue



      Skin reactions

      Nausea/Vomiting
      Skin reactions



      Upper GI

      Hearing loss
      G415 SMN (1 in HT group,4 in 3DCRT group)



      No treatment related death/no interruptions
      Lee et al., 20218383Paediatric + AdultICG



      GBM
      1.2–31.2–3YesWeight loss



      Nausea

      Hematologic
      Treatment interrupted due to thrombocytopenia in 28 patients (33.7 %)
      Gupta et al., 20152020Paediatric + AdultMBL



      ICG
      25–401.67YesHematologic



      Nausea/Vomiting

      Skin toxicity
      Hormonal imbalance



      Growth impairment

      Hearing loss
      G40No symptomatic Pneumonitis
      Sugie et al., 20111212Paediatric + AdultICG



      MBL

      ATRT

      PNET
      23.4–401.6–1.8YesHematologic



      Anorexia

      Alopecia
      G4All patients completed without interruptions



      No > G2 Pneumonitis
      Schiopu et al., 20191515AdultLMM18–39.61.6–1.8YesCytopenia



      Taste disorder/Xerostomia

      Alopecia
      G51/3 of the patients didn't complete treatment
      Petersson et al., 2014*208AdultYesHematologicG3Only hematologic toxicities assessed
      Bandurska-Luque et al.,201533AdultPNET



      MBL
      25.5–35.31.6–1.6YesNausea



      Skin

      Hematologic
      G3No treatment interruption
      Zong-Wen et al, 201855AdultMBL30.6–371.8YesHeadache/dizziness



      Nausea/Vomiting

      Hematologic
      Menstrual disordersG31 patient didn't complete the treatment
      Gaito et al., 201911AdultPBL362YesNausea



      Fatigue

      Hematologic
      TinnitusG20
      El Shafie et al., 20192520Not reportedLMM14.4–361.6–3YesFatigue



      Nausea/Vomiting

      Cytopenia
      G35 patients discontinued treatment due to tumour-associated clinical deterioration
      Reported acute and late toxicities, including second malignancies. HT-CSI = Helical Tomotherapy Cranio-Spinal Irradiation, D/fr = Dose per fraction, Gy = Gray, ChT = Chemotherapy, SMN = Second Malignancy, GBM = Glioblastoma, ATRT = Atypical Teratoid Rhabdoid Tumor, PNET = Primitive Neuroectodermal Tumor, MBL = Medulloblastoma, LMM = Leptomeningeal Metastasis, ICG = Intracranial Germ Cell Tumor, PBL = Pineoblastoma, EPD = Ependimoma, N/A = Not Applicable.
      * The “Supplementary Appendix” that reportedly contains more data regarding the included patients could not be retrieved.

      Clinical outcome

      Clinical outcome for patients that underwent cranio-spinal irradiation with Tomotherapy aligns with the literature data of patients treated for the same disease using other radiotherapy techniques. The most frequent cancer types that required CSI were medulloblastoma, ependymoma, intracranial germ cell tumours in children and medulloblastoma and leptomeningeal metastasis in adults. Table 2 summarizes all the information on survival and relapses reported in the selected papers.
      Table 2Reported clinical outcomes.
      ReportTotal no. of patientsHT-CSI (n)Patient categoryDiagnosisReported OutcomeValueRelapse
      Gupta et al., 201211PaediatricMBL



      LMM
      PFS18mo
      Guerra et al., 20141919PaediatricMBL2y DFS



      3y OS
      70 %



      68 %
      Qu et al., 20142323Paediatric + AdultICG3y RFS



      DFS

      3y OS
      95.2 %



      100 %

      91.3 %
      Öztunali et al., 20214619Paediatric + AdultMBL5y OS



      Median TTP
      88 %



      16 mo
      16 % HT (n = 3)



      11 % 3DCRT (n = 3)
      Peñagarícano et al., 20091818Paediatric + AdultMBL



      PBL

      ICG

      OS



      DFS

      Cause-specific survival
      89 %



      78 %

      89 %
      None- cribriform plate
      Gupta et al., 20162020Paediatric + AdultMBL



      ICG
      Median time to progression



      5y PFS

      5y OS
      20mo





      50 %



      55 %
      Schiopu et al., 20174545Paediatric + AdultMBL



      ICG

      EPD
      3y OS



      5y OS

      Median OS
      80 %



      70 %

      23.5 mo
      24.40 %
      Gaito et al., 201911AdultPBLDSF36moNone
      Ruppert et al., 201111AdultGlioneuronal tu.



      LMM
      PFS6mo
      Schiopu et al., 20191515AdultLMM6mo OS



      1y OS

      RFS

      Median OS
      30 %



      20 %

      1mo

      3mo
      El Shafie et al., 20192520Not reportedLMMMedian OS19.3 weeks
      Total no. of patients = total number of patients in the report; Patients receiving HT-CSI = total number of patients that were treated using helical tomotherapy, excluding those receiving CSI with other techniques; HT-CSI = Helical Tomotherapy, CSI = Cranio-spinal Irradiation, MBL = Medulloblastoma, ICG = Intracranial Germinoma, EPD = Ependymoma, PBL = Pineoblasotma, LMM = Leptomeningeal Metastasis, Tu = Tumor, OS = Overall Survival, DFS = Disease-Free Survival, PFS = Progression-free survival, mo = months, 3DCRT = 3D conformal radiotherapy.

      Discussions

      Craniospinal irradiation is a complex treatment that is associated with several technical challenges. The target volume is large (long) and has a complex, irregular shape with almost all Normal tissues at risk of incidental irradiation, as the volume extends from the vertex all the way to the cauda equina. It is mostly used in paediatric patients, a population highly susceptible to toxicities, both acute and late, including second malignancies. Having a conformal dose distribution is necessary in order to spare healthy tissue and organs-at-risk. CSI is also an option for adults diagnosed with leptomeningeal metastasis and other cancers that disseminate via the CSF (Cranio-spinal fluid) and could metastasise anywhere in the cranio-spinal axis.
      Using helical Tomotherapy for cranio-spinal irradiation in a variety of cancers (both primary tumours and metastases) was similarly efficient in terms of local control, survival, symptom relief, and relapse as other radiotherapy techniques. It proved to ensure good target coverage with great conformity and showed superiority to other techniques in sparing several OARs, such as the eyes, thyroid, bladder, cochlea, and ovaries. On the other hand, it seemed less performant than other techniques in terms of breast, spleen, optic chiasm, lung, skin, and uterus dosimetry. Vertebral irradiation in pre-pubertal patients, especially when inhomogeneous, could lead to spinal growth defects and deformities such as scoliosis. Thus, if sparing them is not feasible, the vertebrae should be homogenously covered, as recommended by Hoeben et. al, 2019[
      • Hoeben B.A.
      • Carrie C.
      • Timmermann B.
      • Mandeville H.C.
      • Gandola L.
      • Dieckmann K.
      • et al.
      Management of vertebral radiotherapy dose in paediatric patients with cancer: consensus recommendations from the SIOPE radiotherapy working group.
      ]. The included reports indicate a more homogenous irradiation of the vertebrae using HT. However, despite proving better HI and CI in most reports, the clinical outcomes and toxicity rates were similar to literature reports on other techniques and mostly relate to hematologic toxicities due to irradiation of large volumes of the hematogenous bone marrow. One concern, especially in children, is the large volume of healthy tissue irradiated with low doses, the so-called “dose bath”, which may cause second malignancies and was reported to be higher when using Tomotherapy. Two cases of second malignancies were reported in the HT cohort (vs 4 in the 3DCRT cohort), the number being too low to draw any conclusions on whether the incidence is higher in this group. SMN risk estimation studies suggest that HT has similar risk as IMRT/VMAT, but when compared to 3DCRT results are inconclusive, emphasising the need for further investigation in this area.
      Regarding simulation and treatment delivery, one advantage of using HT for CSI is having the patient lay in a comfortable supine position without the need of moving them during the treatment (single isocentre) and facilitating a smoother process for anaesthesia and/or sedation when needed, as opposed to standard techniques which require prone positioning and several field junctions. Patient positioning is simple and reproducible, further supported by daily IGRT using the built-in MVCT increases treatment precision.
      However, despite the convenient treatment planning and dosimetric benefits, Tomotherapy comes with a significantly longer beam-on-time, and this might be limiting for patients with poor compliance, low performance status or experiencing pain, or those who need anaesthesia or sedation during radiotherapy. However, this could be mitigated by employing several strategies such as projecting movies on the tube ceiling, thus increasing compliance, especially in children. Most authors reported on using a low modulation factor and a large beam width in order to keep the beam-on-time to a reasonable value while keeping a good target conformity, as BOT increases with higher MF and narrower beams.

      Limitations

      While offering a comprehensive overview of craniospinal irradiation using Helical Tomotherapy, this study also has several limitations. Due to the large heterogeneity in data reporting (dose prescriptions vary between 18 and 40 Gy, both median and mean values were reported for Dmax, Dmean, and various other Dose-Volume parameters), only a descriptive analysis was possible, without applying any statistical tests.
      Some long-term toxicities such as cognitive impairment and endocrine disfunction are reported, but dosimetric data regarding the hippocampus, cerebellum, hypothalamic-pituitary axis and other brain structures involved in these functions are scarce. In terms of clinical outcomes, a direct comparison between age groups or techniques could not be performed due to data heterogeneity and lack of discrimination between such groups when reporting. Some of the issues could be overcome by a more standardized and harmonized reporting in future radiotherapy publications.

      Conclusions

      In conclusion, Tomotherapy is a convenient and efficient method for cranio-spinal irradiation both in adults and in paediatric patient, for several disease types. It offers clear dosimetric advantages, good target coverage with high homogeneity and conformity and OAR sparing. However, the long treatment times and potential risk of second malignancies are aspects that might be less appealing, especially for the paediatric population. The choice to use this technique over another should be made on a case-by-case basis, taking into consideration both technical and clinical feasibility and relevance.

      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.

      Acknowledgments

      The work of Andrada Turcas and Sarah Kelly as fellows at EORTC Headquarters are funded thanks to the generosity of Fondatioun Kriibskrank Kanner, Luxembourg (SIOP Europe Grant).

      Appendix A. Supplementary data

      The following are the Supplementary data to this article:

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