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Point-A vs. volume-based brachytherapy for the treatment of cervix cancer: A meta-analysis

  • Varsha Hande
    Affiliations
    Department of Radiation Oncology, Advanced Centre for Treatment Research and Education in Cancer, Tata Memorial Centre, Homi Bhabha National Institute, Navi Mumbai, India

    Applied Radiation Biology and Radiotherapy Section, Division of Human Health, International Atomic Energy Agency, Vienna, Austria
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  • Author Footnotes
    1 Equal contribution.
    Supriya Chopra
    Correspondence
    Corresponding authors at: ACTREC, Tata Memorial Centre, Mumbai, India (S. Chopra). Applied Radiation Biology and Radiotherapy Section, Division of Human Health, Department of Nuclear Sciences & Applications, International Atomic Energy Agency, Vienna, Austria (J.A.P. Rubio).
    Footnotes
    1 Equal contribution.
    Affiliations
    Department of Radiation Oncology, Advanced Centre for Treatment Research and Education in Cancer, Tata Memorial Centre, Homi Bhabha National Institute, Navi Mumbai, India
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  • Babusha Kalra
    Affiliations
    Department of Radiation Oncology, Advanced Centre for Treatment Research and Education in Cancer, Tata Memorial Centre, Homi Bhabha National Institute, Navi Mumbai, India
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  • May Abdel-Wahab
    Affiliations
    Applied Radiation Biology and Radiotherapy Section, Division of Human Health, International Atomic Energy Agency, Vienna, Austria
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  • Sadhana Kannan
    Affiliations
    Department of Epidemiology and Clinical Trials Unit, Advanced Centre for Treatment Research and Education in Cancer, Tata Memorial Centre, Homi Bhaba National Institute, Navi Mumbai, India
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  • Kari Tanderup
    Affiliations
    Department of Oncology, Aarhus University Hospital, Denmark
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  • Surbhi Grover
    Affiliations
    Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States

    Botswana-UPenn Partnership, Gaborone, Botswana
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  • Eduardo Zubizarreta
    Affiliations
    Applied Radiation Biology and Radiotherapy Section, Division of Human Health, International Atomic Energy Agency, Vienna, Austria
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  • Author Footnotes
    1 Equal contribution.
    Jose Alfredo Polo Rubio
    Correspondence
    Corresponding authors at: ACTREC, Tata Memorial Centre, Mumbai, India (S. Chopra). Applied Radiation Biology and Radiotherapy Section, Division of Human Health, Department of Nuclear Sciences & Applications, International Atomic Energy Agency, Vienna, Austria (J.A.P. Rubio).
    Footnotes
    1 Equal contribution.
    Affiliations
    Applied Radiation Biology and Radiotherapy Section, Division of Human Health, International Atomic Energy Agency, Vienna, Austria
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  • Author Footnotes
    1 Equal contribution.

      Highlights

      • No trials to support transition to image-based brachytherapy in cervix cancer.
      • Study analyses available evidence comparing point-A and image-based brachytherapy.
      • Image-based brachytherapy showed superior DFS and LC.
      • No difference in OS or late-stage GU or GI toxicity.

      Abstract

      Background & Purpose

      To report disease-free survival (DFS) for volume-based and point-A based brachytherapy (BT) in locally advanced cervical cancer.

      Materials & Methods

      We conducted a meta-analysis of studies assessing the effects of point-A and volume-based brachytherapy on 3-year DFS. Studies including stage I-IVA cervical cancer patients were included if standard treatment of concomitant chemo-radiotherapy and high-dose- or pulsed dose rate BT was delivered. The primary outcome was 3-year DFS, and secondary outcomes were 3-year local control (LC), 3-year overall survival (OS) and late toxicity. A random-effects subgroup meta-analysis was done.

      Results

      In total, 5499 studies were screened, of which 24 studies with 5488 patients were eligible. There was significant heterogeneity among point-A studies (1538 patients) (I2 = 82%, p < 0.05) relative to volume-based studies (3950 patients) (I2 = 58, p = 0.01). The 3-year DFS for point-A and volume-based studies were 67% (95% CI 60%-73%) and 79% (95% CI 76%-82%) respectively (p = 0.001). Three-year LC for point-A and volume-based studies were 86% (95% CI 81%-90%) and 92% (91%-94%) respectively (p = 0.01). The difference in 3-year OS (72% vs. 79%, p = 0.12) was not statistically significant. The proportion of prospectively enrolled patients was 23% for point-A studies and 33% for volume-based studies. There was no difference in late grade 3 or higher gastrointestinal (3% vs. 4%, p = 0.76) genitourinary toxicities (3% vs. 3% p = 0.45) between the two groups.

      Conclusion

      Volume-based BT results in superior 3-year DFS and 3-year LC. In the absence of randomized trials, this meta-analysis provides the best evidence regarding transition to 3D planning.

      Keywords

      Cervical cancer represents a significant global health burden, particularly in low- and middle-income countries (LMICs), despite availability of prevention and treatment strategies [
      • Sung H.
      • Ferlay J.
      • Siegel R.L.
      • Laversanne M.
      • Soerjomataram I.
      • Jemal A.
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      Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.
      ]. Radiotherapy plays an essential role in controlling cervical cancer and the current standard of care for treatment of locally advanced tumours is external beam radiotherapy (EBRT) with concurrent chemotherapy and brachytherapy (BT) [

      E.L. Trimble D. Gius L.C. Harlan Impact of NCI Clinical Announcement upon use of chemoradiation for women with cervical cancer Journal of Clinical Oncology. 25 18_suppl 2007 5537 5537.

      ,
      • Pötter R.
      • Tanderup K.
      • Schmid M.P.
      • Jürgenliemk-Schulz I.
      • Haie-Meder C.
      • Fokdal L.U.
      • et al.
      MRI-guided adaptive brachytherapy in locally advanced cervical cancer (EMBRACE-I): a multicentre prospective cohort study.
      ]. Since emergence of evidence on concurrent chemo-radiation, further improvement in local control (LC) and disease-free survival (DFS) for cervical cancer has hinged on radiation dose escalation through advances in BT, specifically through development of Image-Guided Brachytherapy (IGBT) [
      • Pötter R.
      • Dimopoulos J.
      • Georg P.
      • Lang S.
      • Waldhäusl C.
      • Wachter-Gerstner N.
      • et al.
      Clinical impact of MRI assisted dose volume adaptation and dose escalation in brachytherapy of locally advanced cervix cancer.
      ]. The IGBT paradigm is based on integration of Magnetic Resonance Imaging (MRI) for accurate target identification and dose prescription to high-risk clinical target volume; and advanced intracavitary (IC) and interstitial (IS) techniques to facilitate dose escalation for bulky tumours or for poor response to chemo-radiation [
      • Pötter R.
      • Georg P.
      • Dimopoulos J.C.A.
      • Grimm M.
      • Berger D.
      • Nesvacil N.
      • et al.
      Clinical outcome of protocol based image (MRI) guided adaptive brachytherapy combined with 3D conformal radiotherapy with or without chemotherapy in patients with locally advanced cervical cancer.
      ,
      • Tiwari R.
      • Narayanan G.S.
      • Jayakumar V.
      • Narayanan S.
      • Vishwanathan B.
      • Mandal S.K.
      • et al.
      The promise of image-guided brachytherapy of better clinical outcomes in treatment of cervical cancer: Does it deliver? An Indian scenario.
      ]. Using these approaches, three-year LC of >85% was reported in mono-institutional series [
      • Mahantshetty U.
      • Krishnatry R.
      • Hande V.
      • Jamema S.
      • Ghadi Y.
      • Engineer R.
      • et al.
      Magnetic resonance image guided adaptive brachytherapy in locally advanced cervical cancer: an experience from a tertiary cancer center in a low and middle income countries setting.
      ,
      • Lindegaard J.C.
      • Fokdal L.U.
      • Nielsen S.K.
      • Juul-Christensen J.
      • Tanderup K.
      MRI-guided adaptive radiotherapy in locally advanced cervical cancer from a Nordic perspective.
      ,
      • Kawashima A.
      • Isohashi F.
      • Mabuchi S.
      • Sawada K.
      • Ueda Y.
      • Kobayashi E.
      • et al.
      A 3-year follow-up study of radiotherapy using computed tomography-based image-guided brachytherapy for cervical cancer.
      ]. Integration of advanced imaging and applicators for BT also facilitated dose reductions to organs at risk (OARs), improving therapeutic ratio [
      • Pötter R.
      • Dimopoulos J.
      • Georg P.
      • Lang S.
      • Waldhäusl C.
      • Wachter-Gerstner N.
      • et al.
      Clinical impact of MRI assisted dose volume adaptation and dose escalation in brachytherapy of locally advanced cervix cancer.
      ,
      • Horeweg N.
      • Creutzberg C.L.
      • Rijkmans E.C.
      • Laman M.S.
      • Velema L.A.
      • Coen V.L.M.A.
      • et al.
      Efficacy and toxicity of chemoradiation with image-guided adaptive brachytherapy for locally advanced cervical cancer.
      ]. Based on these advances and publication of the International Commission of Radiation Units (ICRU) 89, rapid IGBT adoption recommendations were undertaken across guidelines [
      • GEC-ESTRO
      ICRU Report 89.
      ,
      • Cibula D.
      • Potter R.
      • Rosaria-Raspollini M.
      ESGO-ESTRO-ESP guidelines for the management of patients with cervical cancer: 2018.
      ,
      • Chino J.
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      • Beriwal S.
      • Bradfield L.
      • Erickson B.A.
      • Fields E.C.
      • et al.
      Radiation therapy for cervical cancer: executive summary of an ASTRO clinical practice guideline.
      ,
      • Chopra S.J.
      • Mathew A.
      • Maheshwari A.
      • Bhatla N.
      • Singh S.
      • Rai B.
      • et al.
      National cancer grid of india consensus guidelines on the management of cervical cancer.
      ]. Recently, a multi-centric prospective cohort study reported 5-year LC of 92% (95% CI 90%-93%) and 5-year DFS of 68% (95% CI 65%-70%) [
      • Pötter R.
      • Tanderup K.
      • Schmid M.P.
      • Jürgenliemk-Schulz I.
      • Haie-Meder C.
      • Fokdal L.U.
      • et al.
      MRI-guided adaptive brachytherapy in locally advanced cervical cancer (EMBRACE-I): a multicentre prospective cohort study.
      ]. A meta-analysis reported superior overall survival [HR 0.78 (95%CI 0.62–0.98)] and pelvic disease-free survival [HR of 0.75 (95%CI 0.62–0.90)], with lower toxicities for IGBT, compared to point-A BT [
      • Suzumura E.A.
      • Gama L.M.
      • Jahn B.
      • Campolina A.G.
      • Carvalho H.d.A.
      • de Soárez P.C.
      Effects of 3D image-guided brachytherapy compared to 2D conventional brachytherapy on clinical outcomes in patients with cervical cancer: A systematic review and meta-analyses.
      ].
      Although IGBT transition has been recommended across guidelines, available supporting evidence are largely prospective studies with no comparator arms. There is only one ongoing phase III trial of point-A vs. volume-based BT [

      Mahantshetty U. Image Based Brachytherapy in Locally Advanced Cervical Cancers - a Randomized Controlled Trial. Mumbai, India: https://ClinicalTrials.gov/show/NCT03005743; 2016.

      ]. Transition requires modification of workflows, access to scanners, specialized equipment (MR compatible applicators) and highly skilled staff [

      INTERNATIONAL ATOMIC ENERGY AGENCY, Implementation of High Dose Rate Brachytherapy in Limited Resource Settings. Human Health Series No. 30 2015.

      ,

      INTERNATIONAL ATOMIC ENERGY AGENCY, Transition from 2D brachytherapy to 3D HDR brachytherapy. Vienna: International Atomic Energy Agency; 2015. IAEA Human Health Reports No. 12.

      ]. Introduction of such treatment modalities requiring specialized equipment and incurring significant costs require detailed evaluations of effectiveness and affordability, especially since high incidence occurs in LMICs, where access to technology and MRI scanners is limited (e.g., 27–37 MRI units per million population in high-income countries compared to 0.24–2.6 units in LMICs) [

      Zubizarreta E. Global Availability of brachytherapy minimizing disparity in cervical cancer cure through improved access to care, 2018.

      ,
      • Hricak H.
      • Abdel-Wahab M.
      • Atun R.
      • Lette M.M.
      • Paez D.
      • Brink J.A.
      • et al.
      Medical imaging and nuclear medicine: a Lancet Oncology Commission.
      ]. This led to significant efforts by healthcare organisations to support research on radiotherapy resource allocation [

      INTERNATIONAL ATOMIC ENERGY AGENCY, Implementation of High Dose Rate Brachytherapy in Limited Resource Settings. Human Health Series No. 30 2015.

      ,

      INTERNATIONAL ATOMIC ENERGY AGENCY, Transition from 2D brachytherapy to 3D HDR brachytherapy. Vienna: International Atomic Energy Agency; 2015. IAEA Human Health Reports No. 12.

      ,
      • Abdel-Wahab M.
      • Fidarova E.
      • Polo A.
      Global access to radiotherapy in low- and middle-income countries.
      ,
      • Agency I.A.E.
      Management of cervical cancer: strategies for limited-resource centres - a guide for radiation oncologists.
      ,
      • Abdel-Wahab M.
      • Grover S.
      • Zubizarreta E.H.
      • Polo Rubio J.A.
      Addressing the burden of cervical cancer through IAEA global brachytherapy initiatives.
      ]. The founding of the UN Joint Global Programme on Cervical Cancer Prevention and Control [

      World Health Organisation (2016) UN Joint Global Programme on Cervical Cancer Prevention and Control [Internet], UN Task Force. Available from: https://www.who.int/ncds/un-task-force/un-joint-action-cervical-cancer-leaflet.pdf

      ] and the adoption of the cervical cancer elimination strategy during the 73rd World Health Assembly in October 2020 [

      World Health Organization, Global strategy to accelerate the elimination of cervical cancer as a public health problem. Geneva; 2020. Licence: CC BY-NC-SA 3.0 IGO.

      ] add demands to find evidence-based policy recommendations to improve outcomes.
      The present meta-analysis was undertaken to pool available contemporary evidence and evaluate if management of locally advanced cervical cancers with IGBT improves outcomes.

      Methods

      Literature search for this study was performed in accordance to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) [
      • Page M.J.
      • McKenzie J.E.
      • Bossuyt P.M.
      • Boutron I.
      • Hoffmann T.C.
      • Mulrow C.D.
      • et al.
      The PRISMA 2020 statement: an updated guideline for reporting systematic reviews.
      ] statement, along with hand searches of reference sections of included studies.

      Search strategy

      PubMed/Medline, ScienceDirect, Web of Science, and Cochrane Reviews were searched in February 2019 and updated in April 2021 by the lead author (VH). A second search was done independently in February 2020 by another reviewer (BK). Search terms are provided in Supplementary Table A1. The search was restricted to studies published in English. Titles and abstracts were reviewed, and studies fulfilling selection criteria were included. Full texts were reviewed by three independent reviewers (VH, SC, BK), and discrepancies were discussed and resolved. All selected studies were included in the meta-analysis.

      Article eligibility characteristics

      Cohort, cross-sectional and clinical trial study designs (Phase II-III) published after 2000 (chemoradiation era) were included. Studies must have reported 3- or 5-year outcomes, with minimum 2-year follow-up. Required sample size was 50. However, articles with multiple patient group were included even if individual groups had n < 50. The following study designs were excluded: qualitative studies, reviews, abstracts, commentaries, and case reports. Studies not reporting EBRT, BT techniques or dose to point-A/ high-risk clinical target volumes were excluded.

      Study population eligibility characteristics

      Study samples of cervix carcinoma patients with squamous, adenocarcinoma or adeno-squamous histology were included. Other histologies (clear cell carcinoma, neuroendocrine cervix tumours, cervical sarcomas) were excluded. Studies of patients with human immunodeficiency virus infections were excluded.

      Treatment eligibility characteristics

      Treatment criteria for inclusion was optimal platinum-based chemo-radiotherapy and either high-dose rate (HDR) or pulsed-dose rate (PDR) BT. Treatments without chemotherapy, involving adjuvant chemotherapy or surgery were ineligible. Acceptable dose prescription modalities were point-A based (X-ray based or CT-based) or volume-based (3D CT-based or 3D MRI-based) BT.

      Outcome measures

      The primary outcome was DFS at three years (3yDFS). The secondary outcomes were LC at three years (3yLC), OS at three years (3yOS) and late grade 3 or grade 4 gastrointestinal and genitourinary toxicity. Outcomes should have been reported according to prescription type (point-A or volume-based), and as percentage or proportion of total sample. Results must have been reported by stage or as an aggregate of all stages combined.

      Data analysis

      Risk of bias assessment

      Methodological Index for Non-Randomized Studies (MINORS) [
      • Slim K.
      • Nini E.
      • Forestier D.
      • Kwiatkowski F.
      • Panis Y.
      • Chipponi J.
      Methodological index for non-randomized studies (minors): development and validation of a new instrument.
      ] was used for quality assessment of included studies. Studies were assessed for robustness of aims, patient inclusion criteria, data collection methods, endpoint evaluation, time and loss to follow-up and appropriateness of sample size. The following additional criteria were evaluated if studies were comparative: adequacy of the control group, comparison period, baseline characteristics and statistical analyses.

      Data extraction

      The following was extracted from included studies: publication details (author, publication year, country, study design, study population, sample size – overall, by stage), treatment details (EBRT dose, BT dose, BT technique [IC or IC-IS], BT dose prescription technique [point-A or volume-based], imaging modality used [X-Ray, CT or MRI], chemotherapy agents and schedule, tumour histology, nodal staging [pelvic or para-aortic]) and outcomes (3 year LC, DFS, OS, toxicity). For each study, RT cumulative dose (EBRT and BT) was calculated using data accumulation formulae to determine equivalent dose in 2 Gy (EQD2) [

      EMBRACE Collaborative Group. Physical-Biological Documentation of Gynaecological HDR BT 2017.

      ]. While final meta-analysis included all studies, additional sub-analysis was performed with studies administering EQD2 doses of at least 80 Gy (to point A or HRCTV).
      LC was defined across all studies as the proportion of patients who did not have local or primary relapse at three years from date from inclusion. Heterogeneity for DFS definition was noted across studies (Supplementary Table A2). For this meta-analysis, DFS definition used by most studies (proportion of patients from date of inclusion to date of disease relapse, censoring, last follow up or final analysis in case patient did not relapse) was chosen. DFS outcome was corrected by excluding “death due to other causes” and verified by contacting primary authors [
      • Pötter R.
      • Georg P.
      • Dimopoulos J.C.A.
      • Grimm M.
      • Berger D.
      • Nesvacil N.
      • et al.
      Clinical outcome of protocol based image (MRI) guided adaptive brachytherapy combined with 3D conformal radiotherapy with or without chemotherapy in patients with locally advanced cervical cancer.
      ,
      • Horeweg N.
      • Creutzberg C.L.
      • Rijkmans E.C.
      • Laman M.S.
      • Velema L.A.
      • Coen V.L.M.A.
      • et al.
      Efficacy and toxicity of chemoradiation with image-guided adaptive brachytherapy for locally advanced cervical cancer.
      ]. OS was defined as the proportion of patients alive three years after treatment. Late toxicity was defined as toxicity that persisted or appeared 90 days after treatment completion. It was reported as the proportion of patients with late-stage grade 3 and/or grade 4 gastrointestinal or genitourinary toxicity.

      Statistical methods

      Three-year DFS, LC, OS, and toxicity were noted for each study. If only 5-year outcomes were reported, 3-year outcomes were extrapolated from survival curves. All outcomes were treated as percentages (binary data). Data was input as proportions (numerator) and sample size (denominator). Total events were calculated from these proportions. Studies were classified according to BT prescription technique (point-A and volume-based) and subgroup meta-analysis was performed.
      A random-effects model was used to obtain combined effect sizes and to account for heterogeneity. Confidence intervals were calculated using exact binomial and score tests. Weighting was done using the inverse variance method. Forest plots were constructed according to BT prescription subgroups. Differences in subgroup outcomes were verified through regression analysis. Between-study variation was determined by the I2 value. Funnel plots were constructed to depict publication bias. Sensitivity analysis was done for all outcomes to observe effects of each study on subgroup effect size (Supplementary Figure A1). P-values < 0.05 were considered statistically significant. All analyses were performed using STATA version 14 [
      • StataCorp.
      Stata statistical software: Release 14.
      ].

      Results

      The literature search identified 5322 studies. From these, 343 full-text studies were selected for review, and 319 were excluded (Supplementary Table A3). Thus, 24 studies [
      • Pötter R.
      • Tanderup K.
      • Schmid M.P.
      • Jürgenliemk-Schulz I.
      • Haie-Meder C.
      • Fokdal L.U.
      • et al.
      MRI-guided adaptive brachytherapy in locally advanced cervical cancer (EMBRACE-I): a multicentre prospective cohort study.
      ,
      • Pötter R.
      • Georg P.
      • Dimopoulos J.C.A.
      • Grimm M.
      • Berger D.
      • Nesvacil N.
      • et al.
      Clinical outcome of protocol based image (MRI) guided adaptive brachytherapy combined with 3D conformal radiotherapy with or without chemotherapy in patients with locally advanced cervical cancer.
      ,
      • Tiwari R.
      • Narayanan G.S.
      • Jayakumar V.
      • Narayanan S.
      • Vishwanathan B.
      • Mandal S.K.
      • et al.
      The promise of image-guided brachytherapy of better clinical outcomes in treatment of cervical cancer: Does it deliver? An Indian scenario.
      ,
      • Lindegaard J.C.
      • Fokdal L.U.
      • Nielsen S.K.
      • Juul-Christensen J.
      • Tanderup K.
      MRI-guided adaptive radiotherapy in locally advanced cervical cancer from a Nordic perspective.
      ,
      • Kawashima A.
      • Isohashi F.
      • Mabuchi S.
      • Sawada K.
      • Ueda Y.
      • Kobayashi E.
      • et al.
      A 3-year follow-up study of radiotherapy using computed tomography-based image-guided brachytherapy for cervical cancer.
      ,
      • Horeweg N.
      • Creutzberg C.L.
      • Rijkmans E.C.
      • Laman M.S.
      • Velema L.A.
      • Coen V.L.M.A.
      • et al.
      Efficacy and toxicity of chemoradiation with image-guided adaptive brachytherapy for locally advanced cervical cancer.
      ,
      • Chatani M.
      • Tsuboi K.
      • Yagi M.
      • Fujiwara K.
      • Tachimoto R.
      Radiation therapy for carcinoma of the uterine cervix: comparison of two brachytherapy schedules.
      ,
      • Derks K.
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      • Haaren P.V.
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      Impact of brachytherapy technique (2D versus 3D) on outcome following radiotherapy of cervical cancer.
      ,
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      • Ghoshal S.
      Toxicity and clinical outcomes with definitive three-dimensional conformal radiotherapy (3DCRT) and concurrent cisplatin chemotherapy in locally advanced cervical carcinoma.
      ,
      • Gill B.S.
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      • Edwards R.P.
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      MRI-guided high-dose-rate intracavitary brachytherapy for treatment of cervical cancer: the University of Pittsburgh experience.
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      • Hammond A.
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      An early report on outcomes from computed tomographic-based high-dose-rate brachytherapy for locally advanced cervix cancer: A single institution experience.
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      Single-institution experience in 3D MRI-based brachytherapy for cervical cancer for 239 women: can dose overcome poor response?.
      ,
      • Kang H.-C.
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      3D CT-based high-dose-rate brachytherapy for cervical cancer: clinical impact on late rectal bleeding and local control.
      ,
      • Kim Y.-J.
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      • Jeong J.
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      Magnetic resonance image-guided brachytherapy for cervical cancer : Prognostic factors for survival.
      ,
      • Koh V.
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      Feasibility study of toxicity outcomes using GEC-ESTRO contouring guidelines on CT based instead of MRI-based planning in locally advanced cervical cancer patients.
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      Standard chemoradiation and conventional brachytherapy for locally advanced cervical cancer: is it still applicable in the era of magnetic resonance-based brachytherapy?.
      ,
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      CT based three dimensional dose-volume evaluations for high-dose rate intracavitary brachytherapy for cervical cancer.
      ,
      • Parker K.
      • Gallop-Evans E.
      • Hanna L.
      • Adams M.
      Five years' experience treating locally advanced cervical cancer with concurrent chemoradiotherapy and high-dose-rate brachytherapy: results from a single institution.
      ,
      • Rakhsha A.
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      Evaluation of survival and treatment toxicity with high-dose-rate brachytherapy with cobalt 60 in carcinoma of cervix.
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      Long term experience with 3D image guided brachytherapy and clinical outcome in cervical cancer patients.
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      ,
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      The effects of two HDR brachytherapy schedules in locally advanced cervical cancer treated with concurrent chemoradiation: a study from Chiang Mai, Thailand.
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      • Zolciak-Siwinska A.
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      • Dabkowski M.
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      ] were included. Samples from three studies [
      • Chatani M.
      • Tsuboi K.
      • Yagi M.
      • Fujiwara K.
      • Tachimoto R.
      Radiation therapy for carcinoma of the uterine cervix: comparison of two brachytherapy schedules.
      ,
      • Derks K.
      • Steenhuijsen J.L.G.
      • Berg H.A.V.D.
      • Houterman S.
      • Cnossen J.
      • Haaren P.V.
      • et al.
      Impact of brachytherapy technique (2D versus 3D) on outcome following radiotherapy of cervical cancer.
      ,
      • Tharavichitkul E.
      • Klunkin P.
      • Lorvidhaya V.
      • Sukthomya V.
      • Chakrabhandu S.
      • Pukanhaphan N.
      • et al.
      The effects of two HDR brachytherapy schedules in locally advanced cervical cancer treated with concurrent chemoradiation: a study from Chiang Mai, Thailand.
      ] were analysed as separate groups according to prescription types (point-A cohort and volume-based cohort), leading to 27 studies with 5488 patients (Fig. 1). Demographic characteristics of included studies are listed in Table 1. Eleven studies (1538 patients) were point-A based [
      • Chatani M.
      • Tsuboi K.
      • Yagi M.
      • Fujiwara K.
      • Tachimoto R.
      Radiation therapy for carcinoma of the uterine cervix: comparison of two brachytherapy schedules.
      ,
      • Derks K.
      • Steenhuijsen J.L.G.
      • Berg H.A.V.D.
      • Houterman S.
      • Cnossen J.
      • Haaren P.V.
      • et al.
      Impact of brachytherapy technique (2D versus 3D) on outcome following radiotherapy of cervical cancer.
      ,
      • Dracham C.B.
      • Mahajan R.
      • Rai B.
      • Elangovan A.
      • Bhattacharya T.
      • Ghoshal S.
      Toxicity and clinical outcomes with definitive three-dimensional conformal radiotherapy (3DCRT) and concurrent cisplatin chemotherapy in locally advanced cervical carcinoma.
      ,
      • Hallock A.
      • Surry K.
      • Batchelar D.
      • VanderSpek L.
      • Yuen J.
      • Hammond A.
      • et al.
      An early report on outcomes from computed tomographic-based high-dose-rate brachytherapy for locally advanced cervix cancer: A single institution experience.
      ,
      • Mittal P.
      • Chopra S.
      • Pant S.
      • Mahantshetty U.
      • Engineer R.
      • Ghosh J.
      • et al.
      Standard chemoradiation and conventional brachytherapy for locally advanced cervical cancer: is it still applicable in the era of magnetic resonance-based brachytherapy?.
      ,
      • Parker K.
      • Gallop-Evans E.
      • Hanna L.
      • Adams M.
      Five years' experience treating locally advanced cervical cancer with concurrent chemoradiotherapy and high-dose-rate brachytherapy: results from a single institution.
      ,
      • Rakhsha A.
      • Yousefi Kashi A.S.
      • Hoseini S.M.
      Evaluation of survival and treatment toxicity with high-dose-rate brachytherapy with cobalt 60 in carcinoma of cervix.
      ,
      • Tharavichitkul E.
      • Klunkin P.
      • Lorvidhaya V.
      • Sukthomya V.
      • Chakrabhandu S.
      • Pukanhaphan N.
      • et al.
      The effects of two HDR brachytherapy schedules in locally advanced cervical cancer treated with concurrent chemoradiation: a study from Chiang Mai, Thailand.
      ,
      • Wang W.
      • Hou X.
      • Yan J.
      • Shen J.
      • Lian X.
      • Sun S.
      • et al.
      Outcome and toxicity of radical radiotherapy or concurrent Chemoradiotherapy for elderly cervical cancer women.
      ] and 16 studies (3950 patients) were volume-based [
      • Pötter R.
      • Tanderup K.
      • Schmid M.P.
      • Jürgenliemk-Schulz I.
      • Haie-Meder C.
      • Fokdal L.U.
      • et al.
      MRI-guided adaptive brachytherapy in locally advanced cervical cancer (EMBRACE-I): a multicentre prospective cohort study.
      ,
      • Pötter R.
      • Georg P.
      • Dimopoulos J.C.A.
      • Grimm M.
      • Berger D.
      • Nesvacil N.
      • et al.
      Clinical outcome of protocol based image (MRI) guided adaptive brachytherapy combined with 3D conformal radiotherapy with or without chemotherapy in patients with locally advanced cervical cancer.
      ,
      • Tiwari R.
      • Narayanan G.S.
      • Jayakumar V.
      • Narayanan S.
      • Vishwanathan B.
      • Mandal S.K.
      • et al.
      The promise of image-guided brachytherapy of better clinical outcomes in treatment of cervical cancer: Does it deliver? An Indian scenario.
      ,
      • Lindegaard J.C.
      • Fokdal L.U.
      • Nielsen S.K.
      • Juul-Christensen J.
      • Tanderup K.
      MRI-guided adaptive radiotherapy in locally advanced cervical cancer from a Nordic perspective.
      ,
      • Kawashima A.
      • Isohashi F.
      • Mabuchi S.
      • Sawada K.
      • Ueda Y.
      • Kobayashi E.
      • et al.
      A 3-year follow-up study of radiotherapy using computed tomography-based image-guided brachytherapy for cervical cancer.
      ,
      • Horeweg N.
      • Creutzberg C.L.
      • Rijkmans E.C.
      • Laman M.S.
      • Velema L.A.
      • Coen V.L.M.A.
      • et al.
      Efficacy and toxicity of chemoradiation with image-guided adaptive brachytherapy for locally advanced cervical cancer.
      ,
      • Derks K.
      • Steenhuijsen J.L.G.
      • Berg H.A.V.D.
      • Houterman S.
      • Cnossen J.
      • Haaren P.V.
      • et al.
      Impact of brachytherapy technique (2D versus 3D) on outcome following radiotherapy of cervical cancer.
      ,
      • Gill B.S.
      • Kim H.
      • Houser C.J.
      • Kelley J.L.
      • Sukumvanich P.
      • Edwards R.P.
      • et al.
      MRI-guided high-dose-rate intracavitary brachytherapy for treatment of cervical cancer: the University of Pittsburgh experience.
      ,
      • Horne Z.D.
      • Karukonda P.
      • Kalash R.
      • Edwards R.P.
      • Kelley J.L.
      • Comerci J.T.
      • et al.
      Single-institution experience in 3D MRI-based brachytherapy for cervical cancer for 239 women: can dose overcome poor response?.
      ,
      • Kang H.-C.
      • Shin K.H.
      • Park S.-Y.
      • Kim J.-Y.
      3D CT-based high-dose-rate brachytherapy for cervical cancer: clinical impact on late rectal bleeding and local control.
      ,
      • Kim Y.-J.
      • Kim J.-Y.
      • Kim Y.
      • Lim Y.K.
      • Jeong J.
      • Jeong C.
      • et al.
      Magnetic resonance image-guided brachytherapy for cervical cancer : Prognostic factors for survival.
      ,
      • Koh V.
      • Choo B.A.
      • Lee K.M.
      • Tan T.H.
      • Low J.H.J.
      • Ng S.Y.J.
      • et al.
      Feasibility study of toxicity outcomes using GEC-ESTRO contouring guidelines on CT based instead of MRI-based planning in locally advanced cervical cancer patients.
      ,
      • Sturdza A.
      • Pötter R.
      • Fokdal L.U.
      • Haie-Meder C.
      • Tan L.T.
      • Mazeron R.
      • et al.
      Image guided brachytherapy in locally advanced cervical cancer: Improved pelvic control and survival in RetroEMBRACE, a multicenter cohort study.
      ,
      • Zolciak-Siwinska A.
      • Gruszczynska E.
      • Bijok M.
      • Jonska-Gmyrek J.
      • Dabkowski M.
      • Staniaszek J.
      • et al.
      Computed tomography-planned high-dose-rate brachytherapy for treating uterine cervical cancer.
      ]. Point-A studies were published from 2009 to 2018, and volume-based studies were published between 2010 and 2021. Median accrual period for point-A patients was 2004 – 2009, and for volume-based patients, it was 2008 – 2011. Twenty-five studies were retrospective cohorts, and 2 reported prospective cohorts (Potter 2021 [
      • Pötter R.
      • Tanderup K.
      • Schmid M.P.
      • Jürgenliemk-Schulz I.
      • Haie-Meder C.
      • Fokdal L.U.
      • et al.
      MRI-guided adaptive brachytherapy in locally advanced cervical cancer (EMBRACE-I): a multicentre prospective cohort study.
      ] and Tharavichitkul [
      • Tharavichitkul E.
      • Klunkin P.
      • Lorvidhaya V.
      • Sukthomya V.
      • Chakrabhandu S.
      • Pukanhaphan N.
      • et al.
      The effects of two HDR brachytherapy schedules in locally advanced cervical cancer treated with concurrent chemoradiation: a study from Chiang Mai, Thailand.
      ]). The proportion of prospectively enrolled patients was 23% for point-A studies and 33% for volume-based studies. Three studies [
      • Chatani M.
      • Tsuboi K.
      • Yagi M.
      • Fujiwara K.
      • Tachimoto R.
      Radiation therapy for carcinoma of the uterine cervix: comparison of two brachytherapy schedules.
      ,
      • Derks K.
      • Steenhuijsen J.L.G.
      • Berg H.A.V.D.
      • Houterman S.
      • Cnossen J.
      • Haaren P.V.
      • et al.
      Impact of brachytherapy technique (2D versus 3D) on outcome following radiotherapy of cervical cancer.
      ,
      • Tharavichitkul E.
      • Klunkin P.
      • Lorvidhaya V.
      • Sukthomya V.
      • Chakrabhandu S.
      • Pukanhaphan N.
      • et al.
      The effects of two HDR brachytherapy schedules in locally advanced cervical cancer treated with concurrent chemoradiation: a study from Chiang Mai, Thailand.
      ] had comparative arms; 2 studies compared fractionation schedules [
      • Chatani M.
      • Tsuboi K.
      • Yagi M.
      • Fujiwara K.
      • Tachimoto R.
      Radiation therapy for carcinoma of the uterine cervix: comparison of two brachytherapy schedules.
      ,
      • Tharavichitkul E.
      • Klunkin P.
      • Lorvidhaya V.
      • Sukthomya V.
      • Chakrabhandu S.
      • Pukanhaphan N.
      • et al.
      The effects of two HDR brachytherapy schedules in locally advanced cervical cancer treated with concurrent chemoradiation: a study from Chiang Mai, Thailand.
      ] and 1 [
      • Derks K.
      • Steenhuijsen J.L.G.
      • Berg H.A.V.D.
      • Houterman S.
      • Cnossen J.
      • Haaren P.V.
      • et al.
      Impact of brachytherapy technique (2D versus 3D) on outcome following radiotherapy of cervical cancer.
      ] compared patients with and without MRI guidance during BT. Treatment characteristics are summarized in Table 2. Mean EBRT dose was 47 Gy (range 42 Gy – 52 Gy). Twenty-five studies used cisplatin-based chemotherapy, one used carboplatin, and one did not report chemotherapy details. Following was the distribution of imaging modalities used for BT planning: X-ray (7 studies), CT (6 studies), MR (5 studies), CT and X-ray (1 study), CT and MR (8 studies). Mean cumulative EQD2 dose was 80 Gy (74 Gy − 89 Gy) to point-A for point-A studies and 83.3 Gy (64 Gy − 93 Gy) to CTVHR D90 for volume-based studies. Risk of bias in the included studies was low to moderate (supplementary Table A4). The results of individual study outcomes are provided in Table 2.
      Figure thumbnail gr1
      Fig. 1PRISMA Flow diagram: Study search and selection processes.
      Table 1Demographic characteristics of included studies.
      StudyCountryAccrual PeriodStudy TypeNo. of GroupsType of BTnF/U#
      Chatani 2014 (Group A)Japan1998–2009Retrospective2Point A9836–84
      Chatani 2014 (Group B)Japan1998–2009RetrospectivePoint A12036–84
      Derks 2018 (Group 2D)Netherlands1997–2009Retrospective2Point A3544 (6–166)
      Derks 2018 (Group 3D)Netherlands2009–2016RetrospectiveVolume-based9135 (5–97)
      Dracham 2018India2013–2015Retrospective1Point A21037 (19–54)
      Gill 2015USA2007–2013Retrospective1Volume-based12824.4 (2.1–77.2)
      Hallock 2011Canada2004–2008Retrospective1Point A5722.6 (2.5–54.1)
      Horeweg 2019Netherlands2008–2016Retrospective1Volume-based15556.7 (27.8–79.3)
      Horne 2018USA2007–2018Retrospective1Volume-based23928.6 (12.7–53.8)
      Kang 2010Korea2001–2005Retrospective1Volume-based9741 (8–60)
      Kawashima 2019Japan2012–2015Retrospective1Volume-based8436 (2–62)
      Kim 2018Germany2008–2013Retrospective1Volume-based12844 (6–78)
      Koh 2017Singapore2008–2014Retrospective1Volume-based9529 (6–76)
      Lindegaard 2013Denmark2005–2011Retrospective1Volume-based14036 (6–78)
      Mittal 2018India2014–2015Retrospective1Point A33928 (4–45)
      Murakami 2014Japan2008–2010Retrospective1Volume-based5139.2 (24.3–52.0)
      Parker 2009UK1999–2004Retrospective1Point A9226
      Potter 2011Austria2001–2008Retrospective1Volume-based15642
      Potter 2021*2008–2015Prospective1Volume-based131851 (20–64)
      Rakhsha 2015Iran2008–2015Retrospective1Point A15438 (6–60)
      Ribeiro 2016Belgium2002–2012Retrospective1Volume-based17037 (2–136)
      Sturdza 2016*1998–2013Retrospective1Volume-based73147 (2–169)
      Tharavichitkul 2012 (Group A)Thailand2004–2006Prospective2Point A17235
      Tharavichitkul 2012 (Group B)Thailand2004–2006ProspectivePoint A18835
      Tiwari 2018India2014–2017Retrospective1Volume-based15126 (9–41)
      Wang 2017China2006–2014Retrospective1Point A7332.4 (4.8–118.8)
      Zolciak-Siwinska 2016Poland2010–2011Retrospective1Volume-based21652 (37–63)
      *multicentric accrual.
      Table 2Patient and treatment characteristics of included studies.
      Treatment detailsReported results
      StudyStageEBRT (Gy)ImagingBT TechniqueEQD2 (Gy)OTT (days) Median (range)Squamous, Adeno (%)Node+ (%)3yLC (%)3yDFS (%)3yOS (%)Toxicity Scoring SystemGI Toxicity (%)GU Toxicity (%)
      Point A Studies
      Chatani Group A 2014IB-IV42X-rayIC80.0NR89, 11NR86NR70.5NCI-CTCAE1.11.1
      Chatani Group B 2014IB-IV52X-rayIC77.0NR89, 11NR93NR75.5NCI-CTCAE1.7NR
      Derks 2D 2018IB-IVA45CT/MRIC74.04789, 112984NR57CTCAE 4.011.45.7
      Dracham 2018II-III46CTIC74.5NR93, 72290.580.984.2CTCAE 3.04.20.9
      Hallock 2011IB-IIIB45CTIC82.9NR74, 1816836286NRNRNR
      Mittal 2018IB-IVA45X-ray, CTIC*84.063 (61–72)93, 52389.571.976.2NR4.7NR
      Parker 2009IB1-IVA45X-rayIC76.361 (45–94)79, 173970NR70NCI-CTCAE 3.0NR4
      Rakhsha 2015I-IVA50X-rayIC80.0NR89, 834NR5659.3RTOG3.95.2
      Tharavichitkul Group A 2012IIB-IVA50X-rayIC81.04983, 14NRNR63.4NRRTOG/EORTC3.51.1
      Tharavichitkul Group B 2012IIB-IVA50X-rayIC82.04972, 17NRNR63.8NRRTOG/EORTC2.7NR
      Wang 2017I-IVA50.4CTIC89.050 (26–87)93, 51579.566.564.9CTCAE 3.04.12.7
      Volume-based studies
      Horne 2018IB1-IVANRMRIC-IS83.751 (49–55)81, 194988NR71NCI-CTCAE8.83.3
      Derks 3D 2018IB-IVA45CT/MRIC-IS85.04786, 144791.681.8NRNR0.8NR
      Gill 2015IB1-IVA45CT, MRIC-IS83.050 (43–78)83, 164390.48074.8CTCAE 3.03.60.8
      Horeweg 2019IB-IVA45MRIC-IS83.842 (41–45.5)81, 145693.579.885.5NRNRNR
      Kang 2010IB-IVB45CT/MRIC81.857 (46–91)90,7649780NRRTOG/EORTC2NR
      Kawashima 2019IB1-IVA50CTIC73.4NR85, 1533898194CTCAE 4.05.5NR
      Kim 2018IB1-IVB45MRIC90.456 (43–94)82, 962948289RTOG/EORTC3.1NR
      Koh 2017IB-IVA51CTIC80.0NR82, 11NR94.876.869.7CTCAE 3.0112
      Lindegaard 2013IB-IVA46MR/CTIC-IS91.047 (36–70)83, 125091NR79CTCAE 3.0/ RTOG31
      Murakami 2014IB-IVA50CT MRIC-IS64.042 (36–67)94, 62291.785.382.4NRNRNR
      Potter 2011IA-IVA45MRIC-IS93.04886, 962957568LENT SOMA85
      Potter 2021IB-IVA50CT/MRIC-IS89.046 (42–50)82, 1452927281LENT SOMA7.66.5
      Ribeiro 2016IB1-IVB45MR, CTIC-IS85.053.6 (41–65)82, 115496NR73CTCAE 4.0211
      Sturdza 2016IB-IVA46MR, CTIC-IS83.0NR85, 94091NR74CTCAE 3.06.54.5
      Tiwari 2018IIB-IIIB45MRI/CTIC-IS79.048 (33–76)94, 55088.782.2NRCTCAE 3.01.91.9
      Zolciak-Siwinska 2016IB-IVA45CTIC88.0NR92, 523NR75NRLENT SOMA4.23.3
      *5% IC-IS.
      #in months, median (minimum – maximum).

      Disease-Free survival

      Nineteen studies (4011 patients) reported a 3yDFS of 75% (95% CI 72%-78%). Seven were point-A studies (1193 patients) and 12 (2818 patients) were volume-based. Point-A 3yDFS was 68% (95% CI 61%-74%) and volume-based 3yDFS was 79% (95% CI 76%-82%) (Fig. 2), p = 0.001. Point A heterogeneity was I2 = 82%, p < 0.05 and volume-based heterogeneity was lower (I2 = 58%, p = 0.01). Between-group heterogeneity was considerable (I2 = 77%, p < 0.01).
      Figure thumbnail gr2
      Fig. 23yDFS Forest Plot: Forest Plot showing 3-year disease-free survival between point-A studies and volume-based studies. I2: Heterogeneity ES = Estimate Size 95% CI = 95% Confidence Interval.
      A sub-analysis comparing 3yDFS for 15 studies (3515 patients) administering minimal EQD2 of 80 Gy (to point A or HRCTV was done. Overall 3yDFS was 73% (95% CI 69% − 76%). Six point A (983 patients) and 9 volume-based studies (2532 patients) reported 3yDFS of 64% (95% CI 59% − 70%). and 77% (95% CI 74% − 80%) respectively. This 13% difference was significant (p < 0.001). Within-group heterogeneity was similar among both groups (I2 = 64%, p = 0.02) and (I2 = 60%, p = 0.01). Between-group heterogeneity was higher (I2 = 78%, p < 0.05). (Supplementary Figure A2).

      Local control

      Twenty-four studies (4974 patients) reported 91% (95% CI 89%-92%) 3yLC. Eight point-A studies (1024 patients) 16 volume-based studies (3950 patients) reported 3yLC of 86% (95% CI 81%-90%) and 92% (91%-94%) respectively (Fig. 3), p = 0.01. Heterogeneity was higher for point-A studies (I2 = 75%, p < 0.05) compared to volume-based (I2 = 47%, p = 0.02). Between group heterogeneity was substantial (I2 = 67%, p < 0.05).
      Figure thumbnail gr3
      Fig. 33yLC Forest Plot: Forest Plot showing 3-year local control between point-A studies and volume-based studies I2: Heterogeneity ES = Estimate Size 95% CI = 95% Confidence Interval.
      The sub-analysis of 16 studies (4015 patients) prescribing EQD2 ≥ 80 Gy reported 92% (95% CI 90% − 93%) 3yLC. Four point-A studies (567 patients) and 12 volume-based studies (3448 patients) reported 3yLC of 86% (95% CI 81% − 90%) and 93% (95% CI 92% − 94%) respectively, for which the 7% difference was significant (p = 0.005). Within-group heterogeneity was 45% for both subgroups (p = 0.14, p = 0.04). Between-group heterogeneity was 61% (p < 0.05). (Supplementary Figure A3).

      Overall survival

      Twenty-one studies (4536 patients) reported 3yOS of 76% (95% CI 73% − 80%). Nine point-A (1178 patients) and 12 volume-based (3358 patients) had 3yOS of 72% (95% CI 66–79%) and 79% (95% CI 75%-83%) respectively (Fig. 4), p = 0.125. Heterogeneity was high both within subgroups (I2 = 83%, p < 0.05, (I2 = 87%, p < 0.05) and overall (I2 = 86%, p < 0.05).
      Figure thumbnail gr4
      Fig. 43yOS Forest Plot: Forest Plot showing 3-year overall survival between point-A studies and volume-based studies I2: Heterogeneity ES = Estimate Size 95% CI = 95% Confidence Interval.
      EQD2 ≥ 80 Gy sub-analysis included 15 studies (3932 patients) reporting 3yOS of 75% (95% CI 72% − 79%). Five point-A (721 patients) and 10 volume-based studies (3211 patients) reported 3yOS of 71% (95% CI 63% − 80%) and 77% (95% CI 73% − 81%) respectively, where the difference was not significant (p = 0.255). High heterogeneity was present both within groups (I2 = 84%, p < 0.05, I2 = 83%, p < 0.05) and overall (I2 = 85%, p < 0.05). (Supplementary Figure A4).

      Gastrointestinal toxicity

      Twenty-three studies (5050 patients) reported late-stage grade 3 /4 gastrointestinal toxicity of 3% (95% CI 3% − 4%). Nine point-A (1389 patients) and 14 volume-based results (3661 patients) showed gastrointestinal toxicity of 3% (95% CI 2% − 4%) and 4% (95% CI 2% − 5%) respectively (Supplementary Figure A5), p = 0.765. Point-A heterogeneity was lower (I2 = 23%, p = 0.24) than volume-based heterogeneity (I2 = 78%, p < 0.05). Overall heterogeneity was I2 = 69%, p < 0.05.

      Genitourinary toxicity

      Seventeen studies (4074 patients) reported late-stage grade 3/4 genitourinary toxicity of 3% (95% CI 2% − 4%). Seven point-A (850 patients) and 10 volume-based studies (3224 patients) reported genitourinary toxicity of 2% (95% CI 1% − 3%) and 3% (95% CI 2% − 5%) for respectively (Supplementary Figure A6), p = 0.455. Point-A heterogeneity was moderate (I2 = 45%, p = 0.09) compared to volume-based studies (I2 = 82%, p < 0.05). Overall heterogeneity was considerable (I2 = 77%, p < 0.05).
      Funnel plots (Supplementary Figure A7), secondary analysis of point-A versus MRI-based studies (Supplementary Figures A8, A9, A10) and stage-wise results (Supplementary Table A5) are provided as supplementary material.

      Discussion

      Though IGBT confers excellent results [
      • Pötter R.
      • Tanderup K.
      • Schmid M.P.
      • Jürgenliemk-Schulz I.
      • Haie-Meder C.
      • Fokdal L.U.
      • et al.
      MRI-guided adaptive brachytherapy in locally advanced cervical cancer (EMBRACE-I): a multicentre prospective cohort study.
      ,
      • Suzumura E.A.
      • Gama L.M.
      • Jahn B.
      • Campolina A.G.
      • Carvalho H.d.A.
      • de Soárez P.C.
      Effects of 3D image-guided brachytherapy compared to 2D conventional brachytherapy on clinical outcomes in patients with cervical cancer: A systematic review and meta-analyses.
      ,
      • Kim Y.J.
      • Kang H.-C.
      • Kim Y.S.
      Impact of intracavitary brachytherapy technique (2D versus 3D) on outcomes of cervical cancer: a systematic review and meta-analysis.
      ], there is only one ongoing randomized trial comparing point-A and volume-based BT outcomes [

      Mahantshetty U. Image Based Brachytherapy in Locally Advanced Cervical Cancers - a Randomized Controlled Trial. Mumbai, India: https://ClinicalTrials.gov/show/NCT03005743; 2016.

      ]. It is unlikely that level 1 evidence supporting IGBT will be accessible soon. Thus, synthesis of available evidence in the form of a meta-analysis may provide the best attestation supporting IGBT implementation in real world.
      Kim et al. [
      • Kim Y.J.
      • Kang H.-C.
      • Kim Y.S.
      Impact of intracavitary brachytherapy technique (2D versus 3D) on outcomes of cervical cancer: a systematic review and meta-analysis.
      ] conducted a meta-analysis of six cervix cancer studies assessing whether 3D-BT reduces toxicity and improves survival, compared to 2D-BT. Lower toxicity (HR 0.54, 95% CI 0.37–0.77), improved loco-regional recurrence-free survival (HR 0.61, 95% CI 0.40–0.93) and progression-free survival (HR 0.75, 95% CI 0.59–0.96) were reported for 3D-BT. Improvement in OS was not demonstrable. Suzumura et al. [
      • Suzumura E.A.
      • Gama L.M.
      • Jahn B.
      • Campolina A.G.
      • Carvalho H.d.A.
      • de Soárez P.C.
      Effects of 3D image-guided brachytherapy compared to 2D conventional brachytherapy on clinical outcomes in patients with cervical cancer: A systematic review and meta-analyses.
      ] conducted a meta-analysis with twenty studies demonstrating superior OS (HR 0.78, 95% CI 0.62–0.98), LC (HR 0.77, 95% CI 0.59–0.99), pelvic disease-free survival (HR 0.75, 95% CI 0.62–0.90), and lower grade 3–4 overall [9% lower, 95% CI 6% − 11%) and gastrointestinal toxicities (5% lower, 95% CI 2% − 8%) for 3D-BT. Metastasis-free survival and genitourinary toxicity demonstrated no differences.
      The present meta-analysis examines cervix cancer patients treated with point-A versus volume-based BT and demonstrates improvements in 3yLC (6%) and 3yDFS (12%), favouring IGBT. Superior LC in IGBT was previously demonstrated [
      • Horne Z.D.
      • Karukonda P.
      • Kalash R.
      • Edwards R.P.
      • Kelley J.L.
      • Comerci J.T.
      • et al.
      Single-institution experience in 3D MRI-based brachytherapy for cervical cancer for 239 women: can dose overcome poor response?.
      ,
      • Ribeiro I.
      • Janssen H.
      • De Brabandere M.
      • Nulens A.n.
      • De Bal D.
      • Vergote I.
      • et al.
      Long term experience with 3D image guided brachytherapy and clinical outcome in cervical cancer patients.
      ] as IGBT and IC/IS allow for escalation of target doses [
      • Pötter R.
      • Dimopoulos J.
      • Georg P.
      • Lang S.
      • Waldhäusl C.
      • Wachter-Gerstner N.
      • et al.
      Clinical impact of MRI assisted dose volume adaptation and dose escalation in brachytherapy of locally advanced cervix cancer.
      ,
      • Horne Z.D.
      • Karukonda P.
      • Kalash R.
      • Edwards R.P.
      • Kelley J.L.
      • Comerci J.T.
      • et al.
      Single-institution experience in 3D MRI-based brachytherapy for cervical cancer for 239 women: can dose overcome poor response?.
      ,
      • Tanderup K.
      • Nielsen S.K.
      • Nyvang G.-B.
      • Pedersen E.M.
      • Røhl L.
      • Aagaard T.
      • et al.
      From point A to the sculpted pear: MR image guidance significantly improves tumour dose and sparing of organs at risk in brachytherapy of cervical cancer.
      ]. While a consistent improvement in outcomes is reported in overall cohort or when limited to patients receiving optimal radiation doses, a lower LC benefit compared to DFS can be attributed to separate cohorts reporting each outcome. Alternatively, reduced pelvic nodal failure due to differences in adoption of diagnostic imaging between point-A and volume groups could be responsible. Improved pelvic control rates could have contributed to improved extra-pelvic disease control. Our meta-analysis differs from previous studies through its strict inclusion criteria, applied to reproduce the reality of clinical practice and allow for precise reflection of the differences in outcomes between subgroups.
      Our analysis shows small and non-significant differences in toxicities between subgroups. While there was no statistical difference, the slight excess in toxicity from IGBT studies [
      • Kawashima A.
      • Isohashi F.
      • Mabuchi S.
      • Sawada K.
      • Ueda Y.
      • Kobayashi E.
      • et al.
      A 3-year follow-up study of radiotherapy using computed tomography-based image-guided brachytherapy for cervical cancer.
      ] may be attributed to rigorous toxicity reporting, and not necessarily from increased symptoms. Furthermore, larger irradiated volumes (e.g., in poor responders) could have contributed to toxicity. The proportion of patients with prospective morbidity assessment is higher in the volume-based group, which can lead to higher reported incidence, as compared to retrospective assessment [
      • Chopra S.
      • Gupta S.
      • Kannan S.
      • Dora T.
      • Engineer R.
      • Mangaj A.
      • et al.
      Late toxicity after adjuvant conventional radiation versus image-guided intensity-modulated radiotherapy for cervical cancer (PARCER): A randomized controlled trial.
      ]. Therefore, it should be interpreted favourably that the incidence of morbidity in the volume-based group is not significantly higher than the point-A group. A decrease in morbidity after IGBT introduction was reported in several mono-institutional cohorts [
      • Pötter R.
      • Dimopoulos J.
      • Georg P.
      • Lang S.
      • Waldhäusl C.
      • Wachter-Gerstner N.
      • et al.
      Clinical impact of MRI assisted dose volume adaptation and dose escalation in brachytherapy of locally advanced cervix cancer.
      ,
      • Tiwari R.
      • Narayanan G.S.
      • Jayakumar V.
      • Narayanan S.
      • Vishwanathan B.
      • Mandal S.K.
      • et al.
      The promise of image-guided brachytherapy of better clinical outcomes in treatment of cervical cancer: Does it deliver? An Indian scenario.
      ,
      • Lindegaard J.C.
      • Fokdal L.U.
      • Nielsen S.K.
      • Juul-Christensen J.
      • Tanderup K.
      MRI-guided adaptive radiotherapy in locally advanced cervical cancer from a Nordic perspective.
      ,
      • Horne Z.D.
      • Karukonda P.
      • Kalash R.
      • Edwards R.P.
      • Kelley J.L.
      • Comerci J.T.
      • et al.
      Single-institution experience in 3D MRI-based brachytherapy for cervical cancer for 239 women: can dose overcome poor response?.
      ,
      • Ribeiro I.
      • Janssen H.
      • De Brabandere M.
      • Nulens A.n.
      • De Bal D.
      • Vergote I.
      • et al.
      Long term experience with 3D image guided brachytherapy and clinical outcome in cervical cancer patients.
      ] and may be likely when targets are not large. This is expected since average doses to OARs and irradiated volumes [
      • Pötter R.
      • Dimopoulos J.
      • Georg P.
      • Lang S.
      • Waldhäusl C.
      • Wachter-Gerstner N.
      • et al.
      Clinical impact of MRI assisted dose volume adaptation and dose escalation in brachytherapy of locally advanced cervix cancer.
      ,
      • Gill B.S.
      • Kim H.
      • Houser C.J.
      • Kelley J.L.
      • Sukumvanich P.
      • Edwards R.P.
      • et al.
      MRI-guided high-dose-rate intracavitary brachytherapy for treatment of cervical cancer: the University of Pittsburgh experience.
      ,
      • Tanderup K.
      • Nielsen S.K.
      • Nyvang G.-B.
      • Pedersen E.M.
      • Røhl L.
      • Aagaard T.
      • et al.
      From point A to the sculpted pear: MR image guidance significantly improves tumour dose and sparing of organs at risk in brachytherapy of cervical cancer.
      ] significantly decrease for most patients who responded well to chemoradiation.
      While this meta-analysis generates structured evidence, there are limitations. Firstly, included studies demonstrated some heterogeneity. Although this can be explained by differences in populations, methods, BT techniques and follow-up, effect size was affected. Secondly, we observed disparity in DFS definitions. We considered “any relapse” as DFS definition, but recent (especially IGBT) studies included “death due to other causes” within this definition. This bias was corrected by including the definition used by most studies. Authors of disparate studies were contacted, and corrected DFS values were obtained. Thirdly, stage-wise analysis was not feasible due to inadequate samples and non-reporting of stage-wise outcomes by individual studies. Furthermore, there will continue to be a population of good responders where point-A based approach may provide equivalent outcomes [
      • Gupta A.
      • Dey T.
      • Rai B.
      • Oinam A.S.
      • Gy S.
      • Ghoshal S.
      Point-based brachytherapy in cervical cancer with limited residual disease: A low-and middle-income country experience in the era of magnetic resonance-guided adaptive brachytherapy.
      ].
      Based on our results, results of other meta-analyses, and multiple guidelines (ASTRO [
      • Chino J.
      • Annunziata C.M.
      • Beriwal S.
      • Bradfield L.
      • Erickson B.A.
      • Fields E.C.
      • et al.
      Radiation therapy for cervical cancer: executive summary of an ASTRO clinical practice guideline.
      ], ESGO-ESTRO [
      • Cibula D.
      • Potter R.
      • Rosaria-Raspollini M.
      ESGO-ESTRO-ESP guidelines for the management of patients with cervical cancer: 2018.
      ], National Cancer Grid of India [
      • Chopra S.J.
      • Mathew A.
      • Maheshwari A.
      • Bhatla N.
      • Singh S.
      • Rai B.
      • et al.
      National cancer grid of india consensus guidelines on the management of cervical cancer.
      ]), transition to IGBT from X-ray-based BT is advisable and renders superior outcomes. Volume-based BT improves LC and DFS, with no increase in late toxicity, and should be considered as preferred treatment for locally advanced cervical cancer. Nonetheless, this transition incurs additional costs, resources, training, and personnel [

      INTERNATIONAL ATOMIC ENERGY AGENCY, Transition from 2D brachytherapy to 3D HDR brachytherapy. Vienna: International Atomic Energy Agency; 2015. IAEA Human Health Reports No. 12.

      ]. Robust economic evaluation is needed to aid financial comprehension of this transition [
      • Chakraborty S.
      • Mahantshetty U.
      • Chopra S.
      • Lewis S.
      • Hande V.
      • Gudi S.
      • et al.
      Income generated by women treated with magnetic resonance imaging-based brachytherapy: A simulation study evaluating the macroeconomic benefits of implementing a high-end technology in a public sector healthcare setting.
      ,
      • Kim H.
      • Rajagopalan M.S.
      • Beriwal S.
      • Huq M.S.
      • Smith K.J.
      Cost-effectiveness analysis of 3D image-guided brachytherapy compared with 2D brachytherapy in the treatment of locally advanced cervical cancer.
      ]. While studies have demonstrated IGBT cost-efficiency, these are mono-institutional, historical data comparisons, or cost recovery models [
      • Horne Z.D.
      • Karukonda P.
      • Kalash R.
      • Edwards R.P.
      • Kelley J.L.
      • Comerci J.T.
      • et al.
      Single-institution experience in 3D MRI-based brachytherapy for cervical cancer for 239 women: can dose overcome poor response?.
      ,
      • Kang H.-C.
      • Shin K.H.
      • Park S.-Y.
      • Kim J.-Y.
      3D CT-based high-dose-rate brachytherapy for cervical cancer: clinical impact on late rectal bleeding and local control.
      ]. Linkage with implementation programmes is crucial for wide-spread adoption of IGBT.

      Conclusion

      These results can be used to inform healthcare systems of the incremental benefits of IGBT for treatment of cervical cancer; and for international development agencies in designing appropriate technical assistance to countries in need.

      Disclaimer

      Views expressed in this article are authors’ own and not an official position of any institution or funder.

      Conflicts of interest statement

      None.

      Source of support

      Professor Chopra acknowledges grant support from IAEA through Coordinated Research Project no. E33042 for this research.

      Data sharing statement

      This is not an IPD based meta-analysis; however, information on data handling over and above included in methodology can be obtained by contacting corresponding authors.

      Acknowledgements

      None.

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