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Comparison of global treatment guidelines for locally advanced cervical cancer to optimize best care practices: A systematic and scoping review

Open AccessPublished:September 09, 2022DOI:https://doi.org/10.1016/j.ygyno.2022.08.013

      Highlights

      • We identified 46 global diagnostic imaging and treatment recommendations for locally advanced cervical cancer (LACC).
      • Chest X-ray, CT, MRI, and/or PET-CT were recommended by most guidelines for diagnosis or staging.
      • Concurrent chemoradiotherapy was the consensus recommendation for stage IIB-IVA LACC.
      • Treatment recommendations varied for early-stage LACC and neoadjuvant/adjuvant therapies varied.
      • Differences between guidelines may be due to varying staging criteria and/or resource availability between countries.

      Abstract

      Background

      Survival outcomes for cervical cancer differ between countries and world regions. Locally advanced cervical cancer (LACC) is associated with poorer outcomes than early-stage disease. Country-specific variations in diagnostic and treatment recommendations might contribute to differences in LACC outcomes among countries.

      Objective

      We compared international and country-specific guidelines for LACC diagnostic imaging and treatment recommendations.

      Methods

      A systematic literature review and targeted search were used to identify cervical cancer treatment guidelines published between January 1999—August 2021. Guidelines were identified via literature databases, health technology assessment databases, disease-specific websites, and health organization websites. The targeted search included guidelines from countries in regions known to have high cervical cancer prevalence or mortality. Non-English guidelines were translated by native speakers or online translation services.

      Results

      Forty-six guidelines from 31 countries, regions, and international organizations were compared (41/46 using staging criteria, 27 of which used 2009 FIGO). Most guidelines recommended imaging tests for diagnosis and staging. Chest X-ray, intravenous pyelogram, CT, and MRI were commonly recommended for diagnosis and staging while MRI and PET-CT were recommended for the assessment of lymph node status and distant metastases, with a preference for PET-CT over MRI. There was global consensus for cisplatin-based concurrent chemoradiation as primary treatment for stages IIB to IVA, with few exceptions. Treatment recommendations for stages IB2 to IIA2 varied. Most guidelines agreed on adjuvant concurrent chemoradiation after radical hysterectomy when there is a high recurrence risk, and adjuvant radiotherapy when there is an intermediate recurrence risk. Recommendations for other adjuvant and neoadjuvant therapies varied among the guidelines.

      Conclusions

      Differences among treatment guidelines by LACC stage might be influenced by staging criteria used, resource availability, and prevention program effectiveness. Addressing these areas may unify guidelines and improve global outcomes. Review and update of guidelines will be important as novel LACC therapies become available.

      Keywords

      1. Introduction

      Globally in 2020, cervical cancer was the 4th most common cancer and had the 4th highest cancer mortality in women [
      • Sung H.
      • Ferlay J.
      • Siegel R.L.
      • Laversanne M.
      • Soerjomataram I.
      • Jemal A.
      • Bray F.
      Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.
      ]. In certain areas of the world, such as Sub-Saharan Africa, South America, and South-East Asia, cervical cancer is the most commonly diagnosed cancer and the leading cause of cancer death [
      • Sung H.
      • Ferlay J.
      • Siegel R.L.
      • Laversanne M.
      • Soerjomataram I.
      • Jemal A.
      • Bray F.
      Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.
      ]. Between countries, cervical cancer burden, access to optimal treatments, and diagnostic methods vary. Additionally, differences in mortality and incidence may occur regionally within countries and this is associated with health inequality [
      • Robin T.P.
      • Amini A.
      • Schefter T.E.
      • Behbakht K.
      • Fisher C.M.
      Disparities in standard of care treatment and associated survival decrement in patients with locally advanced cervical cancer.
      ,
      • Uppal S.
      • Del Carmen M.G.
      • Rice L.W.
      • Reynolds R.K.
      • Jolly S.
      • Bregar A.
      • Abdelsattar Z.M.
      • Rauh-Hain J.A.
      Variation in care in concurrent chemotherapy administration during radiation for locally advanced cervical cancer.
      ]. Cervical cancer is considered a preventable disease because of both screening and human papillomavirus (HPV) vaccination [
      • World Health Organization
      Comprehensive Cervical Cancer Control: A Guide to Essential Practice.
      ]. However, lack of funding for these preventive strategies and poor adherence to these programs in some regions may lead to delayed diagnosis and poorer outcomes. These issues are well recognized as barriers to optimal treatment outcomes for cervical cancer patients. Examining these differences more closely may help us to understand the most effective treatments for patients under particular circumstances, as well as explain why disparities in cervical cancer survival exist between countries.
      The prognosis of locally advanced cervical cancer (LACC) is dependent on disease stage. Patients with stage III/IV LACC have poor prognosis, despite treatment with concurrent chemoradiation (cCRT), which has been the standard of care since 1999 [
      • Cancer Network
      NCI Urges Chemo-RT Combination for Invasive Cervical Cancer.
      ,
      • McNeil C.
      New standard of care for cervical cancer sets stage for next questions.
      ,
      • Potter R.
      • Tanderup K.
      • Schmid M.P.
      • Jurgenliemk-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.
      ,
      • Shrivastava S.
      • Mahantshetty U.
      • Engineer R.
      • Chopra S.
      • Hawaldar R.
      • Hande V.
      • et al.
      Cisplatin chemoradiotherapy vs radiotherapy in FIGO stage IIIB squamous cell carcinoma of the uterine cervix: a randomized clinical trial.
      ]. For stages IB2 to IIA2, many countries recommend hysterectomy as primary treatment; thus, treatment selection for cervical cancer depends on accurately diagnosing and staging the disease. A recent update to the international standard for staging (International Federation of Gynecology and Obstetrics, FIGO 2018) reclassified patients with early-stage cervical cancer IA to IB1 with lymph node involvement as having LACC [
      • Bhatla N.
      • Aoki D.
      • Sharma D.N.
      • Sankaranarayanan R.
      Cancer of the cervix uteri.
      ,
      • Pecorelli S.
      Revised FIGO staging for carcinoma of the vulva, cervix, and endometrium.
      ].
      The objective of this systematic and scoping review was to gain a global picture of LACC clinical practice guidelines related to recommended diagnostic imaging methods and treatments.

      2. Methods

      Our systematic and scoping review [
      • Munn Z.
      • Peters M.D.J.
      • Stern C.
      • Tufanaru C.
      • McArthur A.
      • Aromataris E.
      Systematic review or scoping review? Guidance for authors when choosing between a systematic or scoping review approach.
      ] utilized 2 search methods to identify regional cervical cancer treatment guidelines: a systematic literature review (SLR), followed by a targeted search to address gaps in geographic coverage. In the SLR, cervical cancer treatment guidelines were identified through a search of literature databases, health technology assessment databases, disease-specific websites, health organization websites (eg, the World Health Organization [WHO]), and through a general internet search (January 1999 to August 2021) (Fig. 1 and Table S1).
      The search start date was selected as January 1999, the year cCRT became the standard of care for LACC [
      • Cancer Network
      NCI Urges Chemo-RT Combination for Invasive Cervical Cancer.
      ,
      • McNeil C.
      New standard of care for cervical cancer sets stage for next questions.
      ]. LACC was defined as FIGO 2009 or FIGO 2018 stage IB2 to IVA cervical cancer [
      • Bhatla N.
      • Aoki D.
      • Sharma D.N.
      • Sankaranarayanan R.
      Cancer of the cervix uteri.
      ,
      • Pecorelli S.
      Revised FIGO staging for carcinoma of the vulva, cervix, and endometrium.
      ]. Included publications and guidelines represented the most recent versions, discussed the treatment of cervical cancer by stage of disease, and were published in English. Excluded publications focused on cervical cancer screening or prevention. PRISMA guidelines were followed for the SLR portion of the search (Fig. 1) [
      • 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.
      ]. Two independent reviewers determined the potential for inclusion for each article, with a third reviewer resolving any discrepancies.
      The targeted search included non-English guidelines recommended by the authors or guidelines from countries in regions of the world known to have high cervical cancer prevalence or mortality (Fig. 1) [
      • Sung H.
      • Ferlay J.
      • Siegel R.L.
      • Laversanne M.
      • Soerjomataram I.
      • Jemal A.
      • Bray F.
      Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.
      ]. Non-English guidelines were translated by native speakers or through online translation services. An English-language German guideline from 2009 (S2K) [
      • Beckmann M.W.
      • Mallmann P.
      • Uterus Commission of the Gynecological Oncology Working Group
      Interdisciplinary S2k guideline on the diagnosis and treatment of cervical carcinoma.
      ] initially identified in the SLR was removed and replaced with a non-English version updated in 2021 (S3) [
      S3-leitlinie diagnostik, therapie und nachsorge der patientin mit zervixkarzinom [S3 Guideline Diagnostics, Therapy and Aftercare of Patients With Cervical Cancer].
      ].
      Diagnostic imaging and treatment recommendations were extracted for stage IB2 to IVA disease. For certain analyses, guidelines were grouped by United Nations geographic regions [
      • United Nations Statistics Division
      ].
      A geographic gap was identified by the authors regarding countries in the Eastern Europe/Baltic region, and upon investigation and discussion, it was found that Lithuania and Latvia do not have country-specific guidelines; instead, each major hospital that treats cervical cancer develops its protocols based on international treatment guidelines such as European Society for Medical Oncology (ESMO) and National Comprehensive Cancer Network (NCCN) (personal communication, emails from Inge Lege [March 1, 2022, regarding Lithuania] and Edite Vitola [December 10, 2021, regarding Latvia]).

      3. Results

      3.1 Included studies

      A total of 46 cervical cancer treatment guidelines were identified (Fig. 1, Fig. 2, and Table S2). Most were last updated between 2016 and 2021 (33/46 [72%]), with the oldest guideline developed in 2010 (Fig. 2A). The 46 included guidelines represent 3 global health organizations, 5 pan-European organizations, 1 continental subregion, and 22 individual countries across 6 geographic regions (Fig. 2B, Fig. 3).
      Fig. 2
      Fig. 2Included treatment guidelines by date of last update (A) and geographic region (B).
      aGeographic regions were defined by the United Nations [
      • United Nations Statistics Division
      ].
      ABS, American Brachytherapy Society; ACR, American College of Radiology; AHS, Alberta Health Services; AIOM, Italian Association of Medical Oncology; ARNU, All-Russian National Union; ASCO, American Society of Clinical Oncology; ASTRO, American Society for Radiation Oncology; BCCA, British Columbia Cancer Agency; BGCS, British Gynaecological Cancer Society; CCO, Cancer Care Ontario; CCPS, Cervical Cancer Prevention Singapore; CSS, CervicalScreen Singapore; ESGO, European Society of Gynaecological Oncology; ESMO, European Society for Medical Oncology; ESP, European Society of Pathology; ESTRO, European Society for Radiotherapy and Oncology; ESUR, European Society of Urogenital Radiology; FIGO, International Federation of Gynecology and Obstetrics; HAS, Haute Autorité de Santé; IAEA, International Atomic Energy Agency; ICMR, Indian Council of Medical Research; INC, Indian National Conference; JSGO, Japan Society of Gynecologic Oncology; KSGO, Korean Society of Gynecologic Oncology; MHB, Ministry of Health Belize; MHFW, Ministry of Health & Family Welfare, India; MHM, Ministry of Health Malaysia; MHSW, Ministry of Health and Social Welfare; MPHS/MMS, Ministry of Public Health and Sanitation and Ministry of Medical Services; NCCN, National Comprehensive Cancer Network; NCGI, National Cancer Grid of India; NCI, National Cancer Institute; NCIS, National University Cancer Institute, Singapore; NHC-PRC, National Health Commission of the People's Republic of China; NHS, National Health Service; NSW-ACI, New South Wales Agency for Clinical Innovation; ONCO, ONCO guía; PGI, Post Graduate Institute of Medical Education & Research, India; S3, Consensus-based medical guidelines published by the Association of the Scientific Medical Societies in Germany; SBOC, Sociedade Brasileira de Oncologia Clínica; SCA, Saskatchewan Cancer Agency; UK, United Kingdom; USA, United States of America; VMoH, Vietnam Ministry of Health; WHO, World Health Organization.
      Fig. 3
      Fig. 3Global guideline coverage.a
      aAll countries with country-specific guidelines had 1 guideline unless indicated.

      3.2 Diagnosis and staging

      Thirty-nine guidelines discussed imaging tests for diagnosis or staging (Table S3). Distinctions between pretreatment imaging recommended for staging or treatment planning were often not clear. Chest X-ray and intravenous pyelogram were required by 26 and 9 guidelines, respectively. Magnetic resonance imaging (MRI; 38 guidelines) and positron emission tomography–computed tomography (PET-CT; 34 guidelines) were discussed for assessing nodal involvement and distant metastasis. MRI was recommended for a variety of measures, including staging, measurements of tumor size, extent, hydronephrosis, parametrial invasion, and lymph node involvement. India (INC, MHFW) and Belize guidelines mentioned that the availability of MRI might be limited [
      • Ministry of Health & Family Welfare, Government of India
      Standard Treatment Guidelines Oncology, Cancer Cervix.
      ,
      • Ministry of Health Belize
      ,
      • Tewari K.S.
      • Agarwal A.
      • Pathak A.
      • Ramesh A.
      • Parikh B.
      • Singhal M.
      • et al.
      Meeting report, “First Indian national conference on cervical cancer management - expert recommendations and identification of barriers to implementation”.
      ].
      Recommended staging criteria were included in 41 guidelines (Table S4). Most used the FIGO 2009 staging criteria (27/41 [66%]), as 25/41 [61%] guidelines were published prior to the release of the FIGO 2018 staging criteria (Table S4). Not all guidelines published after the release of the FIGO 2018 staging criteria chose to use the FIGO 2018 guidelines. For example, the German S3 guidelines published in 2021 stated explicitly that since the available clinical trials used FIGO 2009 criteria, there was not enough evidence available to give recommendations using the updated FIGO 2018 criteria [
      S3-leitlinie diagnostik, therapie und nachsorge der patientin mit zervixkarzinom [S3 Guideline Diagnostics, Therapy and Aftercare of Patients With Cervical Cancer].
      ]. Only 1 guideline used an alternative staging criteria: ESGO/ESTRO/ESP 2018 employed AJCC 8th edition TNM staging criteria [].
      The pervasive use of FIGO 2009 staging criteria dictated guidelines and practice in most countries. These criteria use clinical staging, therefore imaging techniques such as CT, MRI, and PET/PET-CT were often highly recommended supplemental procedures for staging and/or treatment planning but were not required. However, in guidelines that used FIGO 2018 criteria, CT, MRI, and/or PET-CT were required for staging. Of those that discussed PET-CT and MRI, 17 of 34 guidelines preferred PET-CT for staging to assess nodal and distant disease [
      • Bhatla N.
      • Aoki D.
      • Sharma D.N.
      • Sankaranarayanan R.
      Cancer of the cervix uteri.
      ,,
      • Agency for Clinical Innovation
      Gynaecological Cancer: A Guide to Clinical Practice in NSW.
      ,
      • All-Russian National Union
      Клинические рекомендации: Рак шейки матки [Clinical guidelines cervical cancer international statistical classification of diseases and related health problems].
      , ,
      • de Juan A.
      • Redondo A.
      • Rubio M.J.
      • Garcia Y.
      • Cueva J.
      • Gaba L.
      • et al.
      SEOM clinical guidelines for cervical cancer (2019).
      ,
      • Ebina Y.
      • Mikami M.
      • Nagase S.
      • Tabata T.
      • Kaneuchi M.
      • Tashiro H.
      • et al.
      Japan Society of Gynecologic Oncology guidelines 2017 for the treatment of uterine cervical cancer.
      ,
      • Italian Association of Medical Oncology 2019
      Linee guida neoplasie dell'utero: Endometrio e cervice [Guidelines neoplasms of the uterus: endometrial and cervical].
      ,
      • Manganaro L.
      • Lakhman Y.
      • Bharwani N.
      • Gui B.
      • Gigli S.
      • Vinci V.
      • et al.
      Staging, recurrence and follow-up of uterine cervical cancer using MRI: updated guidelines of the European Society of Urogenital Radiology after revised FIGO staging 2018.
      ,
      • Marth C.
      • Landoni F.
      • Mahner S.
      • McCormack M.
      • Gonzalez-Martin A.
      • Colombo N.
      • E.G.
      Committee, cervical cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up.
      ,
      • National Comprehensive Cancer Network
      NCCN Harmonized Guidelines™ for Sub-Saharan Africa.
      ,
      • National Comprehensive Cancer Network
      ,
      • National Health Commission Of The People’s Republic Of China
      Chinese guidelines for diagnosis and treatment of cervical cancer 2018 (English version).
      ,
      • Reed N.
      • Balega J.
      • Barwick T.
      • Buckley L.
      • Burton K.
      • Eminowicz G.
      • et al.
      British Gynaecological Cancer Society (BGCS) cervical cancer guidelines: recommendations for practice.
      ,
      • Sadikov E.
      • Lucero C.A.
      • Kakumanu S.
      • Mahmood S.
      ,
      • Siegel C.L.
      • Glanc P.
      • Deshmukh S.P.
      • Dudiak K.M.
      • Gaffney D.K.
      • Green E.D.
      • et al.
      American College of Radiology Appropriateness Criteria®: Pretreatment Planning of Invasive Cancer of the Cervix.
      ,
      • Sociedade Brasileira de Oncologia Clínica (SBOC)
      Diretrizes de tratamentos oncológicos recomendados pela Sociedade Brasileira de Oncologia Clínica-COLO DE ÚTERO [Guidelines for oncological treatments recommended by the Brazilian Society of Clinical Oncology – uterine cancer].
      , ]. Guidelines from Kenya and Gambia did not discuss pretreatment use of imaging modalities [,
      • The Ministry of Health and Social Welfare
      Strategic Plan for the Prevention and Control of Cervical Cancer in the Gambia: 2016–2020.
      ].

      3.3 LACC treatment recommendations

      Thirty-nine guidelines provided primary treatment recommendations by stage of disease, which included 4 types of treatment modalities for LACC stages: surgery, cCRT, radiotherapy (RT) alone, or chemotherapy alone (Table 1).
      Table 1Primary treatment recommendations for LACC by stage across geographic regions.
      Table thumbnail fx1a
      aCentral disease only.
      bSelected patients only.
      cInoperable.
      dChemotherapy optional.
      eWith or without radiotherapy.
      fWith palliative chemotherapy.
      gWertheim's hysterectomy.
      hWith palliative care.
      iOr radical trachelectomy if ≤2 cm.
      jPalliative.
      kWith brachytherapy.
      lFor adenocarcinoma only.
      mFor squamous cell carcinoma only.
      nCan be used for adenocarcinoma or for squamous cell carcinoma.
      oNodal involvement.
      pRefuses surgery.
      q≤3 cm.
      r>3 cm.
      s<4 cm.
      t≥4 cm.
      uBrachytherapy not specified.
      vMedically unfit.
      wPalliative or radical.
      xSmall.
      yUnsuitable for chemotherapy.
      zUnsuitable for radiation.
      ABS, American Brachytherapy Society; ACR, American College of Radiology; AHS, Alberta Health Services; AIOM, Italian Association of Medical Oncology; ARNU, All-Russian National Union; ASCO, American Society of Clinical Oncology; ASTRO, American Society for Radiation Oncology; BCCA, British Columbia Cancer Agency; BGCS, British Gynaecological Cancer Society; CCO, Cancer Care Ontario; CCPS, Cervical Cancer Prevention Singapore; CSS, CervicalScreen Singapore; ESGO, European Society of Gynaecological Oncology; ESMO, European Society for Medical Oncology; ESP, European Society of Pathology; ESTRO, European Society for Radiotherapy and Oncology; ESUR, European Society of Urogenital Radiology; FIGO, International Federation of Gynecology and Obstetrics; HAS, Haute Autorité de Santé; IAEA, International Atomic Energy Agency; ICMR, Indian Council of Medical Research; INC, Indian National Conference; JSGO, Japan Society of Gynecologic Oncology; KSGO, Korean Society of Gynecologic Oncology; MHB, Ministry of Health Belize; MHFW, Ministry of Health & Family Welfare, India; MHM, Ministry of Health Malaysia; MHSW, Ministry of Health and Social Welfare; MPHS/MMS, Ministry of Public Health and Sanitation and Ministry of Medical Services; NCCN, National Comprehensive Cancer Network; NCGI, National Cancer Grid of India; NCI, National Cancer Institute; NCIS, National University Cancer Institute, Singapore; NHC-PRC, National Health Commission of the People's Republic of China; NHS, National Health Service; NSW-ACI, New South Wales Agency for Clinical Innovation; ONCO, ONCO guía; PGI, Post Graduate Institute of Medical Education & Research, India; S3, Consensus-based medical guidelines published by the Association of the Scientific Medical Societies in Germany; SBOC, Sociedade Brasileira de Oncologia Clínica; SCA, Saskatchewan Cancer Agency; VMoH, Vietnam Ministry of Health; WHO, World Health Organization.
      Stage IB2 to IIA2 LACC had the most diverse treatment options within and between guidelines, which included radical hysterectomy, trachelectomy, cCRT, or RT alone (Table 1). Recommendations for radical hysterectomy often differed for stages IB2-IIA2, and cCRT was recommended in most guidelines as an option with equal efficacy to radical hysterectomy. Selection of treatment depended on resource availability, patient desire for fertility-sparing treatment, and risk factors such as operability, patient fitness, tumor size, and lymph node status. When lymph nodes were involved, the recommendations favored cCRT over radical hysterectomy [
      S3-leitlinie diagnostik, therapie und nachsorge der patientin mit zervixkarzinom [S3 Guideline Diagnostics, Therapy and Aftercare of Patients With Cervical Cancer].
      ,

      Ministry of Health Malaysia, Malaysian Gynaecological Cancer Society, Malaysian Oncological Society, Academy of Medicine Malaysia, Clinical Practice Guidelines: Management of Cervical Cancer (second edition). http://www.acadmed.org.my/view_file.cfm?fileid=748, 2015 (accessed October 20, 2021).

      ].
      There was consensus among geographic regions (except Africa) on cCRT as the standard of care for stage IIB LACC (Table 1). Kenya (MPHS/MMS) recommended RT with palliative care [], and Gambia (MHSW) offered RT with palliative chemotherapy [
      • The Ministry of Health and Social Welfare
      Strategic Plan for the Prevention and Control of Cervical Cancer in the Gambia: 2016–2020.
      ]. Only Japan (JSGO) recommended surgery as a treatment option for stage IIB due to a variety of factors, including the general health of Japanese patients, establishing suitable surgery candidacy and the use of a different surgical method (Okabayashi's radical hysterectomy) [
      • Ebina Y.
      • Mikami M.
      • Nagase S.
      • Tabata T.
      • Kaneuchi M.
      • Tashiro H.
      • et al.
      Japan Society of Gynecologic Oncology guidelines 2017 for the treatment of uterine cervical cancer.
      ]. Two guidelines from Canada (AHS, CCO) recommended RT alone as an alternative to cCRT in the case of unsuitability for chemotherapy, or being otherwise medically unfit for cCRT [
      • Alberta Provincial Gynecologic Oncology Team
      Cancer of the Uterine Cervix.
      ,
      • Cancer Care Ontario
      Cervical Cancer Treatment Pathway Map.
      ].
      For stage III to IVA disease, cCRT was considered the standard of care globally, except in Kenya (MPHS/MMS) and Gambia (MHSW) (Table 1). Kenya and Gambia guidelines recommended RT with palliative care for stage IIB to IVA disease [,
      • The Ministry of Health and Social Welfare
      Strategic Plan for the Prevention and Control of Cervical Cancer in the Gambia: 2016–2020.
      ]. Both sets of guidelines note the limited availability of RT in their respective country. The use of RT for palliative care aligns with ASCO recommendations for regions with limited RT availability [
      • Chuang L.T.
      • Temin S.
      • Camacho R.
      • Dueñas-Gonzalez A.
      • Feldman S.
      • Gultekin M.
      • et al.
      Management and care of women with invasive cervical cancer: American Society of Clinical Oncology resource-stratified clinical practice guideline.
      ]. Alternatives to cCRT were RT alone for stages III to IVA in Canada (AHS, CCO) when patients were unsuitable for cCRT [
      • Alberta Provincial Gynecologic Oncology Team
      Cancer of the Uterine Cervix.
      ,
      • Cancer Care Ontario
      Cervical Cancer Treatment Pathway Map.
      ] and pelvic exenteration for stage IVA recommended by FIGO 2018, Germany (S3), India (ICMR, NCGI), Mexico (ONCO), and Russia (ARNU) [
      • Bhatla N.
      • Aoki D.
      • Sharma D.N.
      • Sankaranarayanan R.
      Cancer of the cervix uteri.
      ,
      S3-leitlinie diagnostik, therapie und nachsorge der patientin mit zervixkarzinom [S3 Guideline Diagnostics, Therapy and Aftercare of Patients With Cervical Cancer].
      ,
      • All-Russian National Union
      Клинические рекомендации: Рак шейки матки [Clinical guidelines cervical cancer international statistical classification of diseases and related health problems].
      ,
      • 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.
      , ,
      • ICMR Subcommittee on Cancer Cervix
      ].
      Thirty-seven studies discussed details of the cCRT regimen (Table 2). The ideal consensus regimen was weekly cisplatin 40 mg/m2, concurrent with external beam radiation therapy (EBRT) at 40 to 50 Gy and followed by brachytherapy. The use of brachytherapy was not mentioned in certain guidelines; therefore, it was unclear if it was considered part of cCRT or RT.
      Table 2cCRT regimen recommendations across geographic regions.
      RegionCountryGuidelineYearChemotherapyEBRTBTTotal RT doseNo details
      Global
      FIGO2015Cisplatin40–50.4 Gy in 1.8 or 2 Gy fractions over a period of 4–6 weeks7 Gy per fraction and 3–5 fractions (depends on EBRT dose and cumulative dose)80–85 Gy EQD2 (equivalent dose in 2 Gy per fraction)
      FIGO2018Cisplatin 40 mg/m2 weekly for 5–6 cycles45–50 Gy to whole pelvis2 weekly fractions of 6 Gy each80–90 Gy (for EBRT and ICRT, ICRT at a dose of 30–40 Gy in 1/2 sessions)
      IAEA2013Cisplatin 40 mg/m2 weekly for 5 cycles45–46 Gy in fractions of 1.8 or 2.0, respectively18–35 Gy74.5–85.7 Gy
      WHO2014BT is a part of cCRT
      Africa
      Sub-SaharaNCCN2021Cisplatin40–50 Gy30–40 GyVery small 75–80

      Small 80 Gy

      Large ≥85 Gy
      GambiaMHSW2016YES
      KenyaMPHS/MMS2012YES
      Asia
      ChinaNHC-PRC2018Cisplatin-basedI-II:45 Gy

      III-IV: 45–50 Gy
      35–45 Gy75–90 Gy
      IndiaICMR2016Cisplatin 40 mg/m2 weekly40–50 GyDose not specified80 Gy
      INC2018Cisplatin-basedRequiredRequired
      MHFWUnknownCisplatin-basedRequiredRequired
      NCGI2018Cisplatin 40 mg/m2 weeklyRequiredRequired80–84 Gy
      PGI2013YES
      JapanJSGO2017Cisplatin-basedIIA1 (small): WP 20 Gy + MB 30 Gy

      IB2, II (bulky), III: WP 30 Gy + MB-WP 20 Gy or WP 40 Gy + MB-WP 10 Gy

      IVA: WP 40 Gy + MB-WP 10 Gy or WP 50 Gy
      IIA1 (small): HDR 4 fractions of 6 Gy

      IB2, II (bulky), III: HDR 3–4 fractions of 6 Gy

      IVA: HDR 2–3 fractions of 6 Gy
      KoreaKSGO2017Cisplatin-basedRequired
      MalaysiaMHM2015Cisplatin-based, weekly45–50.4 Gy in 25–28 fractionsRequired80–90 Gy
      SingaporeCCPS2020YES
      CSS2019YES
      NCIS2020YES
      VietnamVMoH2020Cisplatin 40 mg/m2 weekly40–50 Gy20 Gy
      Europe
      ESGO/ESTRO/ESP2018Cisplatin 40 mg/m2 weekly45–50 Gy40–45 Gy (EQD2)85–90 Gy EQD2
      ESMO2017Cisplatin 40 mg/m2 weeklyRequiredRequired
      ESUR2021Cisplatin-basedRequiredRequired
      FranceHAS2010Platinum-based, 5–6 coursesRequiredRequired
      GermanyS32021Cisplatin 40 mg/m2 weekly for 5 weeks45–50.4 Gy40–50 Gy EQD2≥85 Gy
      ItalyAIOM2019Cisplatin 40 mg/m2 weekly45–50 Gy25–30 GyIB2-IIA1: 80 Gy

      IIA2-IVA: 90–95 Gy
      RussiaARNU2020Cisplatin 40 mg/m2 weekly for 5 weeks45–50 Gy40–45 Gy85–90 Gy
      SpainSEOM2019Cisplatin 40 mg/m2 weekly45–50 GyRequired
      United KingdomBGCS2021Cisplatin 40 mg/m2 weekly45–50 Gy55–60 Gy85–90 Gy
      NHS2018Cisplatin-basedIB1, non-bulky IIA: 45 Gy

      IB2, IIB-IVA: 50.4 Gy
      7 Gy × 3 over 10 days
      Latin America
      ArgentinaASCO2017YES
      BelizeMHB2016YES
      BrazilSBOC2021Cisplatin 40 mg/m2 weeklyRequiredRequired80–85 Gy
      MexicoONCO2011Cisplatin 40 mg/m2 weekly45–50.4 Gy30–35 Gy> 85 Gy
      North America
      CanadaAHS2015Cisplatin-based, 5–6 cycles45–50.4 GyRequired
      BCCA2018Cisplatin 40 mg/m2 weekly for 5 weeks45–50 GyRequired
      CCO2020RequiredRequired80–96 Gy
      SCA2013Cisplatin 40 mg/m2 weekly for 5–6 cycles45–50.4 Gy30 Gy
      United StatesABS2012Cisplatin-based, weekly for 5–6 weeks45–50.4 GY27.5–30 Gy80–90 Gy
      ACR2015YES
      ACS2020Cisplatin for 5 weeksRequiredRequired
      ASCO2016Cisplatin-basedRequiredRequired
      ASTRO2020Cisplatin 40 mg/m2 weekly for 5–6 cycles45–50.4 Gy24–30 Gy≥80–85 Gy
      NCCN2021Cisplatin weekly40–50 Gy30–40 GyVery Small 75–80 Gy

      Small 80 Gy

      Larger ≥85 Gy
      NCI2021Cisplatin-basedRequiredRequiredSmall ∼70 Gy

      Large <90 Gy
      Oceania
      AustraliaNSW-ACI2019Cisplatin-based45–54 GyRequired
      ConsensusDiscussed cCRT treatment details: 37Cisplatin-based: 34/35

      Platinum-based: 1/35

      Weekly cisplatin 40 mg/m2: 17/35
      40–50 Gy: 22/23 that give dosesRequired80–90 Gy: 14/20 that give doses
      ABS, American Brachytherapy Society; ACR, American College of Radiology; AHS, Alberta Health Services; AIOM, Italian Association of Medical Oncology; ARNU, All-Russian National Union; ASCO, American Society of Clinical Oncology; ASTRO, American Society for Radiation Oncology; BCCA, British Columbia Cancer Agency; BGCS, British Gynaecological Cancer Society; BT, brachytherapy; CCO, Cancer Care Ontario; CCPS, Cervical Cancer Prevention Singapore; cCRT, concurrent chemoradiotherapy; CSS, CervicalScreen Singapore; EBRT, external beam radiotherapy; ESGO, European Society of Gynaecological Oncology; ESMO, European Society for Medical Oncology; ESP, European Society of Pathology; ESTRO, European Society for Radiotherapy and Oncology; ESUR, European Society of Urogenital Radiology; FIGO, International Federation of Gynecology and Obstetrics; HAS, Haute Autorité de Santé; HDR, high dose rate; IAEA, International Atomic Energy Agency; ICMR, Indian Council of Medical Research; ICRT, intracavitary radiation therapy; INC, Indian National Conference; JSGO, Japan Society of Gynecologic Oncology; KSGO, Korean Society of Gynecologic Oncology; MHB, Ministry of Health Belize; MHFW, Ministry of Health & Family Welfare, India; MHM, Ministry of Health Malaysia; MHSW, Ministry of Health and Social Welfare; MPHS/MMS, Ministry of Public Health and Sanitation and Ministry of Medical Services; NCCN, National Comprehensive Cancer Network; NCGI, National Cancer Grid of India; NCI, National Cancer Institute; NCIS, National University Cancer Institute, Singapore; NHC-PRC, National Health Commission of the People's Republic of China; NHS, National Health Service; NSW-ACI, New South Wales Agency for Clinical Innovation; ONCO, ONCO guía; PGI, Post Graduate Institute of Medical Education & Research, India; RT, radiotherapy; S3, Consensus-based medical guidelines published by the Association of the Scientific Medical Societies in Germany; SBOC, Sociedade Brasileira de Oncologia Clínica; SCA, Saskatchewan Cancer Agency; VMoH, Vietnam Ministry of Health; WHO, World Health Organization; WP, whole pelvis; MB-WP, whole pelvis with midline block.

      3.4 Adjuvant therapy recommendations

      Of the 32 guidelines that discussed adjuvant cCRT after surgery for early-stage LACC (IB-IIA), all, including NCCN, ESMO, and ESGO/ESTRO/ESP, recommended cCRT with a high risk of recurrence (defined by variations of the Peters criteria [
      • Peters III, W.A.
      • Liu P.Y.
      • Barrett II, R.J.
      • Stock R.J.
      • Monk B.J.
      • Berek J.S.
      • et al.
      Concurrent chemotherapy and pelvic radiation therapy compared with pelvic radiation therapy alone as adjuvant therapy after radical surgery in high-risk early-stage cancer of the cervix.
      ]) (Table 3) [
      • World Health Organization
      Comprehensive Cervical Cancer Control: A Guide to Essential Practice.
      ,
      • Bhatla N.
      • Aoki D.
      • Sharma D.N.
      • Sankaranarayanan R.
      Cancer of the cervix uteri.
      ,
      S3-leitlinie diagnostik, therapie und nachsorge der patientin mit zervixkarzinom [S3 Guideline Diagnostics, Therapy and Aftercare of Patients With Cervical Cancer].
      ,
      • Ministry of Health & Family Welfare, Government of India
      Standard Treatment Guidelines Oncology, Cancer Cervix.
      ,
      • Ministry of Health Belize
      ,
      • Tewari K.S.
      • Agarwal A.
      • Pathak A.
      • Ramesh A.
      • Parikh B.
      • Singhal M.
      • et al.
      Meeting report, “First Indian national conference on cervical cancer management - expert recommendations and identification of barriers to implementation”.
      , ,
      • All-Russian National Union
      Клинические рекомендации: Рак шейки матки [Clinical guidelines cervical cancer international statistical classification of diseases and related health problems].
      , ,
      • de Juan A.
      • Redondo A.
      • Rubio M.J.
      • Garcia Y.
      • Cueva J.
      • Gaba L.
      • et al.
      SEOM clinical guidelines for cervical cancer (2019).
      ,
      • Ebina Y.
      • Mikami M.
      • Nagase S.
      • Tabata T.
      • Kaneuchi M.
      • Tashiro H.
      • et al.
      Japan Society of Gynecologic Oncology guidelines 2017 for the treatment of uterine cervical cancer.
      ,
      • Italian Association of Medical Oncology 2019
      Linee guida neoplasie dell'utero: Endometrio e cervice [Guidelines neoplasms of the uterus: endometrial and cervical].
      ,
      • Marth C.
      • Landoni F.
      • Mahner S.
      • McCormack M.
      • Gonzalez-Martin A.
      • Colombo N.
      • E.G.
      Committee, cervical cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up.
      ,
      • National Comprehensive Cancer Network
      NCCN Harmonized Guidelines™ for Sub-Saharan Africa.
      ,
      • National Comprehensive Cancer Network
      ,
      • National Health Commission Of The People’s Republic Of China
      Chinese guidelines for diagnosis and treatment of cervical cancer 2018 (English version).
      ,
      • Reed N.
      • Balega J.
      • Barwick T.
      • Buckley L.
      • Burton K.
      • Eminowicz G.
      • et al.
      British Gynaecological Cancer Society (BGCS) cervical cancer guidelines: recommendations for practice.
      ,
      • Sadikov E.
      • Lucero C.A.
      • Kakumanu S.
      • Mahmood S.
      ,
      • Sociedade Brasileira de Oncologia Clínica (SBOC)
      Diretrizes de tratamentos oncológicos recomendados pela Sociedade Brasileira de Oncologia Clínica-COLO DE ÚTERO [Guidelines for oncological treatments recommended by the Brazilian Society of Clinical Oncology – uterine cancer].
      , , ,
      • The Ministry of Health and Social Welfare
      Strategic Plan for the Prevention and Control of Cervical Cancer in the Gambia: 2016–2020.
      ,

      Ministry of Health Malaysia, Malaysian Gynaecological Cancer Society, Malaysian Oncological Society, Academy of Medicine Malaysia, Clinical Practice Guidelines: Management of Cervical Cancer (second edition). http://www.acadmed.org.my/view_file.cfm?fileid=748, 2015 (accessed October 20, 2021).

      ,
      • Alberta Provincial Gynecologic Oncology Team
      Cancer of the Uterine Cervix.
      ,
      • Cancer Care Ontario
      Cervical Cancer Treatment Pathway Map.
      ,
      • Chuang L.T.
      • Temin S.
      • Camacho R.
      • Dueñas-Gonzalez A.
      • Feldman S.
      • Gultekin M.
      • et al.
      Management and care of women with invasive cervical cancer: American Society of Clinical Oncology resource-stratified 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.
      , ,
      • ICMR Subcommittee on Cancer Cervix
      ,
      • De Nucci A. Apas Perez
      • Minig L.
      • Perrotta M.
      Patterns of cervical cancer care in Argentina: applying ASCO recommendations adjusted by local resources.
      ,
      • Boyd L.R.
      • Muggia F.M.
      Cervical Cancer Treatment (PDQ®)–Health Professional Version.
      ,
      • 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.
      , ,
      • International Atomic Energy Agency
      Management of Cervical Cancer: Strategies For limited-Resource Centres - A Guide for Radiation Oncologists.
      ,
      • Lim M.C.
      • Lee M.
      • Shim S.H.
      • Nam E.J.
      • Lee J.Y.
      • Kim H.J.
      • et al.
      Practice guidelines for management of cervical cancer in Korea: a Korean Society of Gynecologic Oncology consensus statement.
      ]. One guideline each from Canada (CCO) and the UK (BGCS) noted that in cases of intermediate risk, cCRT may also be considered [
      • Reed N.
      • Balega J.
      • Barwick T.
      • Buckley L.
      • Burton K.
      • Eminowicz G.
      • et al.
      British Gynaecological Cancer Society (BGCS) cervical cancer guidelines: recommendations for practice.
      ,
      • Lukka H.
      • Hirte H.
      • Fyles A.
      • Thomas G.
      • Fung M. Fung Kee
      • Johnston M.
      • Members of the Gynecology Cancer Disease Site Group
      Primary Treatment for Locally Advanced Cervical Cancer: Concurrent Platinum-based Chemotherapy and Radiation.
      ].
      Table 3Adjuvant and neoadjuvant therapy recommendations.
      TreatmentStage of LACCConsensus on regimenReferences
      Adjuvant cCRT after radical hysterectomyIB-IIAAdvisable when a high risk of recurrence (32/32)[
      • Bhatla N.
      • Aoki D.
      • Sharma D.N.
      • Sankaranarayanan R.
      Cancer of the cervix uteri.
      ,
      S3-leitlinie diagnostik, therapie und nachsorge der patientin mit zervixkarzinom [S3 Guideline Diagnostics, Therapy and Aftercare of Patients With Cervical Cancer].
      ,
      • Ministry of Health & Family Welfare, Government of India
      Standard Treatment Guidelines Oncology, Cancer Cervix.
      ,
      • Ministry of Health Belize
      ,
      • Tewari K.S.
      • Agarwal A.
      • Pathak A.
      • Ramesh A.
      • Parikh B.
      • Singhal M.
      • et al.
      Meeting report, “First Indian national conference on cervical cancer management - expert recommendations and identification of barriers to implementation”.
      , ,
      • All-Russian National Union
      Клинические рекомендации: Рак шейки матки [Clinical guidelines cervical cancer international statistical classification of diseases and related health problems].
      , ,
      • de Juan A.
      • Redondo A.
      • Rubio M.J.
      • Garcia Y.
      • Cueva J.
      • Gaba L.
      • et al.
      SEOM clinical guidelines for cervical cancer (2019).
      ,
      • Ebina Y.
      • Mikami M.
      • Nagase S.
      • Tabata T.
      • Kaneuchi M.
      • Tashiro H.
      • et al.
      Japan Society of Gynecologic Oncology guidelines 2017 for the treatment of uterine cervical cancer.
      ,
      • Italian Association of Medical Oncology 2019
      Linee guida neoplasie dell'utero: Endometrio e cervice [Guidelines neoplasms of the uterus: endometrial and cervical].
      ,
      • Marth C.
      • Landoni F.
      • Mahner S.
      • McCormack M.
      • Gonzalez-Martin A.
      • Colombo N.
      • E.G.
      Committee, cervical cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up.
      ,
      • National Comprehensive Cancer Network
      NCCN Harmonized Guidelines™ for Sub-Saharan Africa.
      ,
      • National Health Commission Of The People’s Republic Of China
      Chinese guidelines for diagnosis and treatment of cervical cancer 2018 (English version).
      ,
      • Reed N.
      • Balega J.
      • Barwick T.
      • Buckley L.
      • Burton K.
      • Eminowicz G.
      • et al.
      British Gynaecological Cancer Society (BGCS) cervical cancer guidelines: recommendations for practice.
      ,
      • Sadikov E.
      • Lucero C.A.
      • Kakumanu S.
      • Mahmood S.
      ,
      • Sociedade Brasileira de Oncologia Clínica (SBOC)
      Diretrizes de tratamentos oncológicos recomendados pela Sociedade Brasileira de Oncologia Clínica-COLO DE ÚTERO [Guidelines for oncological treatments recommended by the Brazilian Society of Clinical Oncology – uterine cancer].
      ,]
      Adjuvant RT after radical hysterectomyIB-IIAAdvisable with an intermediate risk of recurrence (20/22)[
      • World Health Organization
      Comprehensive Cervical Cancer Control: A Guide to Essential Practice.
      ,
      • Bhatla N.
      • Aoki D.
      • Sharma D.N.
      • Sankaranarayanan R.
      Cancer of the cervix uteri.
      ,
      • Ministry of Health & Family Welfare, Government of India
      Standard Treatment Guidelines Oncology, Cancer Cervix.
      ,
      • Tewari K.S.
      • Agarwal A.
      • Pathak A.
      • Ramesh A.
      • Parikh B.
      • Singhal M.
      • et al.
      Meeting report, “First Indian national conference on cervical cancer management - expert recommendations and identification of barriers to implementation”.
      ,
      • All-Russian National Union
      Клинические рекомендации: Рак шейки матки [Clinical guidelines cervical cancer international statistical classification of diseases and related health problems].
      , ,
      • de Juan A.
      • Redondo A.
      • Rubio M.J.
      • Garcia Y.
      • Cueva J.
      • Gaba L.
      • et al.
      SEOM clinical guidelines for cervical cancer (2019).
      ,
      • Ebina Y.
      • Mikami M.
      • Nagase S.
      • Tabata T.
      • Kaneuchi M.
      • Tashiro H.
      • et al.
      Japan Society of Gynecologic Oncology guidelines 2017 for the treatment of uterine cervical cancer.
      ,
      • Italian Association of Medical Oncology 2019
      Linee guida neoplasie dell'utero: Endometrio e cervice [Guidelines neoplasms of the uterus: endometrial and cervical].
      ,
      • National Comprehensive Cancer Network
      NCCN Harmonized Guidelines™ for Sub-Saharan Africa.
      ,
      • National Comprehensive Cancer Network
      ,
      • National Health Commission Of The People’s Republic Of China
      Chinese guidelines for diagnosis and treatment of cervical cancer 2018 (English version).
      ,
      • Sadikov E.
      • Lucero C.A.
      • Kakumanu S.
      • Mahmood S.
      ,
      • Sociedade Brasileira de Oncologia Clínica (SBOC)
      Diretrizes de tratamentos oncológicos recomendados pela Sociedade Brasileira de Oncologia Clínica-COLO DE ÚTERO [Guidelines for oncological treatments recommended by the Brazilian Society of Clinical Oncology – uterine cancer].
      ,

      Ministry of Health Malaysia, Malaysian Gynaecological Cancer Society, Malaysian Oncological Society, Academy of Medicine Malaysia, Clinical Practice Guidelines: Management of Cervical Cancer (second edition). http://www.acadmed.org.my/view_file.cfm?fileid=748, 2015 (accessed October 20, 2021).

      ,
      • Alberta Provincial Gynecologic Oncology Team
      Cancer of the Uterine Cervix.
      ,
      • 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.
      ,
      • ICMR Subcommittee on Cancer Cervix
      ,
      • Boyd L.R.
      • Muggia F.M.
      Cervical Cancer Treatment (PDQ®)–Health Professional Version.
      ,
      • 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.
      ,
      • International Atomic Energy Agency
      Management of Cervical Cancer: Strategies For limited-Resource Centres - A Guide for Radiation Oncologists.
      ,
      • Lim M.C.
      • Lee M.
      • Shim S.H.
      • Nam E.J.
      • Lee J.Y.
      • Kim H.J.
      • et al.
      Practice guidelines for management of cervical cancer in Korea: a Korean Society of Gynecologic Oncology consensus statement.
      ]
      Adjuvant hysterectomy after cCRTIB2-IVAA treatment option (3/7)[
      • Ministry of Health & Family Welfare, Government of India
      Standard Treatment Guidelines Oncology, Cancer Cervix.
      ,
      • National Health Commission Of The People’s Republic Of China
      Chinese guidelines for diagnosis and treatment of cervical cancer 2018 (English version).
      ,
      • Lim M.C.
      • Lee M.
      • Shim S.H.
      • Nam E.J.
      • Lee J.Y.
      • Kim H.J.
      • et al.
      Practice guidelines for management of cervical cancer in Korea: a Korean Society of Gynecologic Oncology consensus statement.
      ]
      Special cases (unsuccessful cCRT, unable to have BT) (1/7)[
      • Alberta Provincial Gynecologic Oncology Team
      Cancer of the Uterine Cervix.
      ]
      Not recommended (3/7)[
      S3-leitlinie diagnostik, therapie und nachsorge der patientin mit zervixkarzinom [S3 Guideline Diagnostics, Therapy and Aftercare of Patients With Cervical Cancer].
      ,
      • All-Russian National Union
      Клинические рекомендации: Рак шейки матки [Clinical guidelines cervical cancer international statistical classification of diseases and related health problems].
      ,

      Ministry of Health Malaysia, Malaysian Gynaecological Cancer Society, Malaysian Oncological Society, Academy of Medicine Malaysia, Clinical Practice Guidelines: Management of Cervical Cancer (second edition). http://www.acadmed.org.my/view_file.cfm?fileid=748, 2015 (accessed October 20, 2021).

      ]
      Adjuvant chemotherapyIB2-IVANo consensus reached:
      Recommended (1/4)[,
      • The Ministry of Health and Social Welfare
      Strategic Plan for the Prevention and Control of Cervical Cancer in the Gambia: 2016–2020.
      ]
      Not recommended (1/4)[
      S3-leitlinie diagnostik, therapie und nachsorge der patientin mit zervixkarzinom [S3 Guideline Diagnostics, Therapy and Aftercare of Patients With Cervical Cancer].
      ]
      Investigational (1/4)[
      • Reed N.
      • Balega J.
      • Barwick T.
      • Buckley L.
      • Burton K.
      • Eminowicz G.
      • et al.
      British Gynaecological Cancer Society (BGCS) cervical cancer guidelines: recommendations for practice.
      ]
      Further studies needed (1/4)[

      Ministry of Health Malaysia, Malaysian Gynaecological Cancer Society, Malaysian Oncological Society, Academy of Medicine Malaysia, Clinical Practice Guidelines: Management of Cervical Cancer (second edition). http://www.acadmed.org.my/view_file.cfm?fileid=748, 2015 (accessed October 20, 2021).

      ]
      Neoadjuvant therapyIB2-IVANo consensus reached:
      Special cases, including pregnancy (6/16)[
      • Bhatla N.
      • Aoki D.
      • Sharma D.N.
      • Sankaranarayanan R.
      Cancer of the cervix uteri.
      ,
      • Agency for Clinical Innovation
      Gynaecological Cancer: A Guide to Clinical Practice in NSW.
      ,,
      • de Juan A.
      • Redondo A.
      • Rubio M.J.
      • Garcia Y.
      • Cueva J.
      • Gaba L.
      • et al.
      SEOM clinical guidelines for cervical cancer (2019).
      ,
      • Chuang L.T.
      • Temin S.
      • Camacho R.
      • Dueñas-Gonzalez A.
      • Feldman S.
      • Gultekin M.
      • et al.
      Management and care of women with invasive cervical cancer: American Society of Clinical Oncology resource-stratified clinical practice guideline.
      ,
      • Boyd L.R.
      • Muggia F.M.
      Cervical Cancer Treatment (PDQ®)–Health Professional Version.
      ]
      Clinician discretion (1/16)[

      Ministry of Health Malaysia, Malaysian Gynaecological Cancer Society, Malaysian Oncological Society, Academy of Medicine Malaysia, Clinical Practice Guidelines: Management of Cervical Cancer (second edition). http://www.acadmed.org.my/view_file.cfm?fileid=748, 2015 (accessed October 20, 2021).

      ]
      Not recommended (5/16)[
      • Reed N.
      • Balega J.
      • Barwick T.
      • Buckley L.
      • Burton K.
      • Eminowicz G.
      • et al.
      British Gynaecological Cancer Society (BGCS) cervical cancer guidelines: recommendations for practice.
      ,
      • Alberta Provincial Gynecologic Oncology Team
      Cancer of the Uterine Cervix.
      ,
      • 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.
      ,
      • 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.
      ,]
      Investigational (4/16)[
      S3-leitlinie diagnostik, therapie und nachsorge der patientin mit zervixkarzinom [S3 Guideline Diagnostics, Therapy and Aftercare of Patients With Cervical Cancer].
      ,
      • National Comprehensive Cancer Network
      NCCN Harmonized Guidelines™ for Sub-Saharan Africa.
      ,
      • National Comprehensive Cancer Network
      ,
      • International Atomic Energy Agency
      Management of Cervical Cancer: Strategies For limited-Resource Centres - A Guide for Radiation Oncologists.
      ]
      IB2-IIAAn option, including when RT is unavailable or limited 5/10[
      • Tewari K.S.
      • Agarwal A.
      • Pathak A.
      • Ramesh A.
      • Parikh B.
      • Singhal M.
      • et al.
      Meeting report, “First Indian national conference on cervical cancer management - expert recommendations and identification of barriers to implementation”.
      ,
      • All-Russian National Union
      Клинические рекомендации: Рак шейки матки [Clinical guidelines cervical cancer international statistical classification of diseases and related health problems].
      ,
      • Italian Association of Medical Oncology 2019
      Linee guida neoplasie dell'utero: Endometrio e cervice [Guidelines neoplasms of the uterus: endometrial and cervical].
      ,,
      • De Nucci A. Apas Perez
      • Minig L.
      • Perrotta M.
      Patterns of cervical cancer care in Argentina: applying ASCO recommendations adjusted by local resources.
      ]
      Recommended (3/10)[
      • Marth C.
      • Landoni F.
      • Mahner S.
      • McCormack M.
      • Gonzalez-Martin A.
      • Colombo N.
      • E.G.
      Committee, cervical cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up.
      ,
      • National Health Commission Of The People’s Republic Of China
      Chinese guidelines for diagnosis and treatment of cervical cancer 2018 (English version).
      ,
      • The Ministry of Health and Social Welfare
      Strategic Plan for the Prevention and Control of Cervical Cancer in the Gambia: 2016–2020.
      ]
      Clinician discretion (2/10)[
      • Ebina Y.
      • Mikami M.
      • Nagase S.
      • Tabata T.
      • Kaneuchi M.
      • Tashiro H.
      • et al.
      Japan Society of Gynecologic Oncology guidelines 2017 for the treatment of uterine cervical cancer.
      ,
      • Lim M.C.
      • Lee M.
      • Shim S.H.
      • Nam E.J.
      • Lee J.Y.
      • Kim H.J.
      • et al.
      Practice guidelines for management of cervical cancer in Korea: a Korean Society of Gynecologic Oncology consensus statement.
      ]
      IIBNot recommended (3/8)[
      • Tewari K.S.
      • Agarwal A.
      • Pathak A.
      • Ramesh A.
      • Parikh B.
      • Singhal M.
      • et al.
      Meeting report, “First Indian national conference on cervical cancer management - expert recommendations and identification of barriers to implementation”.
      ,
      • All-Russian National Union
      Клинические рекомендации: Рак шейки матки [Clinical guidelines cervical cancer international statistical classification of diseases and related health problems].
      ,
      • National Health Commission Of The People’s Republic Of China
      Chinese guidelines for diagnosis and treatment of cervical cancer 2018 (English version).
      ]
      An option, including for bulky tumors or when no RT is available (3/8)[
      • Ministry of Health Belize
      ,,
      • De Nucci A. Apas Perez
      • Minig L.
      • Perrotta M.
      Patterns of cervical cancer care in Argentina: applying ASCO recommendations adjusted by local resources.
      ]
      Clinician discretion (1/8)[
      • Ebina Y.
      • Mikami M.
      • Nagase S.
      • Tabata T.
      • Kaneuchi M.
      • Tashiro H.
      • et al.
      Japan Society of Gynecologic Oncology guidelines 2017 for the treatment of uterine cervical cancer.
      ]
      Recommended (1/8)[]
      IVANot recommended (4/5)[
      • Tewari K.S.
      • Agarwal A.
      • Pathak A.
      • Ramesh A.
      • Parikh B.
      • Singhal M.
      • et al.
      Meeting report, “First Indian national conference on cervical cancer management - expert recommendations and identification of barriers to implementation”.
      ,
      • All-Russian National Union
      Клинические рекомендации: Рак шейки матки [Clinical guidelines cervical cancer international statistical classification of diseases and related health problems].
      ,
      • Ebina Y.
      • Mikami M.
      • Nagase S.
      • Tabata T.
      • Kaneuchi M.
      • Tashiro H.
      • et al.
      Japan Society of Gynecologic Oncology guidelines 2017 for the treatment of uterine cervical cancer.
      ,
      • National Health Commission Of The People’s Republic Of China
      Chinese guidelines for diagnosis and treatment of cervical cancer 2018 (English version).
      ]
      For bulky tumors prior to cCRT (1/5)[
      • Ministry of Health Belize
      ]
      Twenty-two guidelines discussed adjuvant RT after surgery; 20 recommended it in cases of intermediate recurrence risk (Sedlis criteria [
      • Sedlis A.
      • Bundy B.N.
      • Rotman M.Z.
      • Lentz S.S.
      • Muderspach L.I.
      • Zaino R.J.
      A randomized trial of pelvic radiation therapy versus no further therapy in selected patients with stage IB carcinoma of the cervix after radical hysterectomy and pelvic lymphadenectomy: a Gynecologic Oncology Group study.
      ]), with the remaining guidelines from Malaysia (MHM) noting that RT alone should only be used in high-risk patients if they are unfit for cCRT, and the WHO stating that in cases of high-risk RT can be given with or without chemotherapy (Table 3) [
      • World Health Organization
      Comprehensive Cervical Cancer Control: A Guide to Essential Practice.
      ,

      Ministry of Health Malaysia, Malaysian Gynaecological Cancer Society, Malaysian Oncological Society, Academy of Medicine Malaysia, Clinical Practice Guidelines: Management of Cervical Cancer (second edition). http://www.acadmed.org.my/view_file.cfm?fileid=748, 2015 (accessed October 20, 2021).

      ].
      Few guidelines mentioned adjuvant hysterectomy, and the NHS noted it was controversial []. Three guidelines (Germany [S3], Malaysia [MHM], and Russia [ARNU]) directly recommended against it [
      S3-leitlinie diagnostik, therapie und nachsorge der patientin mit zervixkarzinom [S3 Guideline Diagnostics, Therapy and Aftercare of Patients With Cervical Cancer].
      ,
      • All-Russian National Union
      Клинические рекомендации: Рак шейки матки [Clinical guidelines cervical cancer international statistical classification of diseases and related health problems].
      ,

      Ministry of Health Malaysia, Malaysian Gynaecological Cancer Society, Malaysian Oncological Society, Academy of Medicine Malaysia, Clinical Practice Guidelines: Management of Cervical Cancer (second edition). http://www.acadmed.org.my/view_file.cfm?fileid=748, 2015 (accessed October 20, 2021).

      ], while Canadian (AHS) guidelines [
      • Alberta Provincial Gynecologic Oncology Team
      Cancer of the Uterine Cervix.
      ] only recommended it in special cases. Three guidelines listed it as a possible treatment option (China [NHC-PRC], India [MHFW], and Korea [KSGO]) [
      • Ministry of Health & Family Welfare, Government of India
      Standard Treatment Guidelines Oncology, Cancer Cervix.
      ,
      • National Health Commission Of The People’s Republic Of China
      Chinese guidelines for diagnosis and treatment of cervical cancer 2018 (English version).
      ,
      • Lim M.C.
      • Lee M.
      • Shim S.H.
      • Nam E.J.
      • Lee J.Y.
      • Kim H.J.
      • et al.
      Practice guidelines for management of cervical cancer in Korea: a Korean Society of Gynecologic Oncology consensus statement.
      ].
      Very few guidelines discussed adjuvant chemotherapy; it was recommended in Kenya (MPHS/MMS) [], not recommended in Germany (S3) [
      S3-leitlinie diagnostik, therapie und nachsorge der patientin mit zervixkarzinom [S3 Guideline Diagnostics, Therapy and Aftercare of Patients With Cervical Cancer].
      ], listed as investigational only in the UK (BGCS) [
      • Reed N.
      • Balega J.
      • Barwick T.
      • Buckley L.
      • Burton K.
      • Eminowicz G.
      • et al.
      British Gynaecological Cancer Society (BGCS) cervical cancer guidelines: recommendations for practice.
      ], and further studies were required in Malaysia (Table 3) [

      Ministry of Health Malaysia, Malaysian Gynaecological Cancer Society, Malaysian Oncological Society, Academy of Medicine Malaysia, Clinical Practice Guidelines: Management of Cervical Cancer (second edition). http://www.acadmed.org.my/view_file.cfm?fileid=748, 2015 (accessed October 20, 2021).

      ].

      3.5 Neoadjuvant therapy recommendations

      Neoadjuvant therapy was discussed in 28 guidelines; however, in most cases it was not specified if this referred to chemotherapy or other therapies that could be used in the neoadjuvant setting. Sixteen guidelines considered neoadjuvant therapy for LACC overall (stages IB2-IVA); 6 recommended it for special cases, including when RT was unavailable or during pregnancy, 1 guideline limited it to the clinician's discretion, and it was limited to investigational use only or not recommended in 4 and 5 guidelines, respectively (Table 3).
      Ten guidelines discussed neoadjuvant therapy for early-stage LACC (IB2 to IIA) (Table 3). Of these, 5 (Argentina [ASCO], India [INC], Italy [AIOM], Mexico [ONCO], and Russia [ARNU]) suggested it should be an option, including when RT is unavailable [
      • Tewari K.S.
      • Agarwal A.
      • Pathak A.
      • Ramesh A.
      • Parikh B.
      • Singhal M.
      • et al.
      Meeting report, “First Indian national conference on cervical cancer management - expert recommendations and identification of barriers to implementation”.
      ,
      • All-Russian National Union
      Клинические рекомендации: Рак шейки матки [Clinical guidelines cervical cancer international statistical classification of diseases and related health problems].
      ,
      • Italian Association of Medical Oncology 2019
      Linee guida neoplasie dell'utero: Endometrio e cervice [Guidelines neoplasms of the uterus: endometrial and cervical].
      ,,
      • De Nucci A. Apas Perez
      • Minig L.
      • Perrotta M.
      Patterns of cervical cancer care in Argentina: applying ASCO recommendations adjusted by local resources.
      ], 3 (China [NHC-PRC], ESMO, and Gambia [MHSW]) recommended neoadjuvant therapy [
      • Marth C.
      • Landoni F.
      • Mahner S.
      • McCormack M.
      • Gonzalez-Martin A.
      • Colombo N.
      • E.G.
      Committee, cervical cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up.
      ,
      • National Health Commission Of The People’s Republic Of China
      Chinese guidelines for diagnosis and treatment of cervical cancer 2018 (English version).
      ,
      • The Ministry of Health and Social Welfare
      Strategic Plan for the Prevention and Control of Cervical Cancer in the Gambia: 2016–2020.
      ], and 2 (Korea [KSGO] and Japan [JSGO]) recommended it be used at the clinician's discretion [
      • Ebina Y.
      • Mikami M.
      • Nagase S.
      • Tabata T.
      • Kaneuchi M.
      • Tashiro H.
      • et al.
      Japan Society of Gynecologic Oncology guidelines 2017 for the treatment of uterine cervical cancer.
      ,
      • Lim M.C.
      • Lee M.
      • Shim S.H.
      • Nam E.J.
      • Lee J.Y.
      • Kim H.J.
      • et al.
      Practice guidelines for management of cervical cancer in Korea: a Korean Society of Gynecologic Oncology consensus statement.
      ].
      Eight guidelines discussed neoadjuvant therapy specifically for stage IIB (Table 3), a general recommendation for in Vietnam (VMoH) [] and against in China [NHC-PRC], India [INC], and Russia [ARNU] guidelines [
      • Tewari K.S.
      • Agarwal A.
      • Pathak A.
      • Ramesh A.
      • Parikh B.
      • Singhal M.
      • et al.
      Meeting report, “First Indian national conference on cervical cancer management - expert recommendations and identification of barriers to implementation”.
      ,
      • All-Russian National Union
      Клинические рекомендации: Рак шейки матки [Clinical guidelines cervical cancer international statistical classification of diseases and related health problems].
      ,
      • National Health Commission Of The People’s Republic Of China
      Chinese guidelines for diagnosis and treatment of cervical cancer 2018 (English version).
      ]. It was considered an option in Mexico (ONCO) guidelines [] and for bulky tumors or when RT is unavailable in Argentina (ASCO) and Belize (MHB) guidelines [
      • Ministry of Health Belize
      ,
      • De Nucci A. Apas Perez
      • Minig L.
      • Perrotta M.
      Patterns of cervical cancer care in Argentina: applying ASCO recommendations adjusted by local resources.
      ], and was up to the discretion of the clinician in Japan (JSCO) [
      • Ebina Y.
      • Mikami M.
      • Nagase S.
      • Tabata T.
      • Kaneuchi M.
      • Tashiro H.
      • et al.
      Japan Society of Gynecologic Oncology guidelines 2017 for the treatment of uterine cervical cancer.
      ].
      Neoadjuvant therapy for stage IVA was not recommended in 4 of 5 guidelines; however, it was an option for bulky tumors prior to cCRT in Belize (MHB) (Table 3) [
      • Ministry of Health Belize
      ].

      4. Discussion

      To our knowledge, this is the first comprehensive, international review of current cervical cancer treatment guidelines with the goal of determining agreement among standard diagnostic imaging and treatment for LACC. For stage IIB to IVA LACC, there is global consensus, with few exceptions, for treatment with cCRT composed of weekly cisplatin concurrent with EBRT and followed by brachytherapy. For stage IB to IIA LACC, treatment recommendations varied significantly across guidelines, with different combinations of radical hysterectomy, cCRT, and RT considered as primary treatment options. Most guidelines recommended adjuvant cCRT after surgery for stages IB to IIA LACC with a high risk of recurrence, and many recommended adjuvant RT after surgery for an intermediate risk of recurrence. Other adjuvant options, such as adjuvant hysterectomy after cCRT and adjuvant chemotherapy were discussed by only a few guidelines, and no clear consensus emerged. Neoadjuvant therapy guidelines varied widely where discussed.
      In this analysis, FIGO 2009 and the updated FIGO 2018 staging criteria were used in 98% of guidelines [
      • Bhatla N.
      • Aoki D.
      • Sharma D.N.
      • Sankaranarayanan R.
      Cancer of the cervix uteri.
      ,
      • Pecorelli S.
      Revised FIGO staging for carcinoma of the vulva, cervix, and endometrium.
      ]. Key differences in the updated version may account for observed variation in standard treatments by stage between guidelines, especially in early-stage LACC. For example, FIGO 2009 staging does not account for lymph node status, which renders more complex treatment recommendations by stage [
      • Pecorelli S.
      Revised FIGO staging for carcinoma of the vulva, cervix, and endometrium.
      ]. The FIGO 2018 staging criteria incorporate lymph node status [
      • Bhatla N.
      • Aoki D.
      • Sharma D.N.
      • Sankaranarayanan R.
      Cancer of the cervix uteri.
      ], which may lead to more complete, unified staging, and less complex treatment recommendations. With increased use of the FIGO 2018 staging criteria, patients with node positivity who previously would have been defined as having early stage LACC will now be assigned to stage IIIC, and thus receive cCRT without consideration of radical hysterectomy. However, radiologic staging as recommended in the FIGO 2018 guidelines is imperfect and there will be patients who are found to have positive nodes during radical hysterectomy. Future studies should examine how these changes in staging due to the updated guidelines may change treatment outcomes.
      The variation in guideline-recommended management of stage IB-IIA disease is a critical issue and may be explained by basing treatment guidelines on older staging criteria as well as the availability of resources within a region. Additionally, India, Singapore, the United Kingdom, Canada, and the United States had more than 1 country-specific guideline. In some cases, there was intra-country variation in recommended treatment, some of which can be explained by the date of publication, and thus the staging criteria used. Resource limitations, including lack of RT or chemotherapy in certain countries, sparse treatment facilities, and lack of specialized personnel to provide treatment, may influence country-specific guidelines. This is evident in the radically different treatment recommendations from Kenya and Gambia, where there are limited resources to provide the global standard treatments for LACC [
      • Abdel-Wahab M.
      • Bourque J.M.
      • Pynda Y.
      • Izewska J.
      • Van der Merwe D.
      • Zubizarreta E.
      • Rosenblatt E.
      Status of radiotherapy resources in Africa: an International Atomic Energy Agency analysis.
      ,
      • Wu E.S.
      • Jeronimo J.
      • Feldman S.
      Barriers and challenges to treatment alternatives for early-stage cervical cancer in lower-resource settings.
      ]. In particular, RT centers needed to deliver EBRT are limited in Africa [
      • Stefan D.C.
      Cancer care in Africa: an overview of resources.
      ]. Guidelines from Gambia stated that RT was not available, and guidelines from Kenya listed only 4 hospitals or oncology centers with access [,
      • The Ministry of Health and Social Welfare
      Strategic Plan for the Prevention and Control of Cervical Cancer in the Gambia: 2016–2020.
      ]. Gambia is working to increase the number of doctors trained to perform RT, and planned to train 2 doctors in 2018 [
      • The Ministry of Health and Social Welfare
      Strategic Plan for the Prevention and Control of Cervical Cancer in the Gambia: 2016–2020.
      ]. In guidelines from Argentina and India, limited access to RT was a reason to provide neoadjuvant chemotherapy and prevent delays in treatment [
      • Tewari K.S.
      • Agarwal A.
      • Pathak A.
      • Ramesh A.
      • Parikh B.
      • Singhal M.
      • et al.
      Meeting report, “First Indian national conference on cervical cancer management - expert recommendations and identification of barriers to implementation”.
      ,
      • De Nucci A. Apas Perez
      • Minig L.
      • Perrotta M.
      Patterns of cervical cancer care in Argentina: applying ASCO recommendations adjusted by local resources.
      ]. India and Belize also noted that there may be limited availability of MRI facilities for diagnosis and staging [
      • Ministry of Health Belize
      ,
      • Tewari K.S.
      • Agarwal A.
      • Pathak A.
      • Ramesh A.
      • Parikh B.
      • Singhal M.
      • et al.
      Meeting report, “First Indian national conference on cervical cancer management - expert recommendations and identification of barriers to implementation”.
      ].
      Although a deficiency of trained radiation specialists is more pronounced in low-resource countries, such countries may also have limited availability of medical oncologists [
      • Vanderpuye V.
      • Hammad N.
      • Martei Y.
      • Hopman W.M.
      • Fundytus A.
      • Sullivan R.
      • et al.
      Cancer care workforce in Africa: perspectives from a global survey.
      ,
      • Ndlovu N.
      • Ndarukwa S.
      • Nyamhunga A.
      • Musiwa-Mba P.
      • Nyakabau A.M.
      • Kadzatsa W.
      • Mushonga M.
      Education and training of clinical oncologists-experience from a low-resource setting in Zimbabwe.
      ]. Where trained staff are available, oncologists often have a heavy case load and are likely to work in the private sector, which may be unaffordable for many patients [
      • Vanderpuye V.
      • Hammad N.
      • Martei Y.
      • Hopman W.M.
      • Fundytus A.
      • Sullivan R.
      • et al.
      Cancer care workforce in Africa: perspectives from a global survey.
      ]. In such instances, the burden of cancer screening and diagnosis may fall to general practitioners, who might not be aware of the local or international management guidelines for cervical cancer. Efforts to increase awareness, education, and access to affordable, sensitive screening tests for this common cancer type are needed globally, and particularly in low- and middle-income countries [
      • Cubie H.A.
      • Campbell C.
      Cervical cancer screening - the challenges of complete pathways of care in low-income countries: focus on Malawi.
      ].
      Both the ASCO and IAEA guidelines included in the SLR provide recommendations for resource-limited settings based on expert consensus, allowing healthcare providers to select the best treatment among available options [
      • Chuang L.T.
      • Temin S.
      • Camacho R.
      • Dueñas-Gonzalez A.
      • Feldman S.
      • Gultekin M.
      • et al.
      Management and care of women with invasive cervical cancer: American Society of Clinical Oncology resource-stratified clinical practice guideline.
      ,
      • De Nucci A. Apas Perez
      • Minig L.
      • Perrotta M.
      Patterns of cervical cancer care in Argentina: applying ASCO recommendations adjusted by local resources.
      ,
      • International Atomic Energy Agency
      Management of Cervical Cancer: Strategies For limited-Resource Centres - A Guide for Radiation Oncologists.
      ]. Moreover, some countries support the use of alternative therapies for LACC, such as the addition of gemcitabine to cisplatin-based cCRT followed by adjuvant gemcitabine or neoadjuvant therapy [
      • Bhatla N.
      • Aoki D.
      • Sharma D.N.
      • Sankaranarayanan R.
      Cancer of the cervix uteri.
      ,
      • Tewari K.S.
      • Agarwal A.
      • Pathak A.
      • Ramesh A.
      • Parikh B.
      • Singhal M.
      • et al.
      Meeting report, “First Indian national conference on cervical cancer management - expert recommendations and identification of barriers to implementation”.
      ,,

      Ministry of Health Malaysia, Malaysian Gynaecological Cancer Society, Malaysian Oncological Society, Academy of Medicine Malaysia, Clinical Practice Guidelines: Management of Cervical Cancer (second edition). http://www.acadmed.org.my/view_file.cfm?fileid=748, 2015 (accessed October 20, 2021).

      ]. Argentina (ASCO), Belize (MHB), and Mexico (ONCO) recommended neoadjuvant therapy for bulky, later-stage LACC, or when RT was unavailable [
      • Ministry of Health Belize
      ,,
      • De Nucci A. Apas Perez
      • Minig L.
      • Perrotta M.
      Patterns of cervical cancer care in Argentina: applying ASCO recommendations adjusted by local resources.
      ].
      There is an unmet need for global harmonization of diagnostic and treatment guidelines for LACC. Fostering international consensus guidelines similar to what was achieved for ovarian cancer with the ESMO-ESGO consensus conference, may help to begin the process of global harmonization [
      • Colombo N.
      • Sessa C.
      • du Bois A.
      • Ledermann J.
      • McCluggage W.G.
      • McNeish I.
      • et al.
      ESMO-ESGO consensus conference recommendations on ovarian cancer: pathology and molecular biology, early and advanced stages, borderline tumours and recurrent disease.
      ]. As mentioned above, differences in staging criteria, resource limitations, and deficits in prevention programs may contribute to how guidelines differ between countries. Addressing these deficiencies may go a long way toward improving outcomes globally. Unfortunately, previous studies of practice patterns indicate that treatment recommendations are not consistently followed in clinical practice [
      • Robin T.P.
      • Amini A.
      • Schefter T.E.
      • Behbakht K.
      • Fisher C.M.
      Disparities in standard of care treatment and associated survival decrement in patients with locally advanced cervical cancer.
      ,
      • Uppal S.
      • Del Carmen M.G.
      • Rice L.W.
      • Reynolds R.K.
      • Jolly S.
      • Bregar A.
      • Abdelsattar Z.M.
      • Rauh-Hain J.A.
      Variation in care in concurrent chemotherapy administration during radiation for locally advanced cervical cancer.
      ,
      • Espenel S.
      • Garcia M.A.
      • Trone J.C.
      • Guillaume E.
      • Harris A.
      • Rehailia-Blanchard A.
      • et al.
      From IB2 to IIIB locally advanced cervical cancers: report of a ten-year experience.
      ,
      • Watanabe T.
      • Mikami M.
      • Katabuchi H.
      • Kato S.
      • Kaneuchi M.
      • Takahashi M.
      • et al.
      Quality indicators for cervical cancer care in Japan.
      ]. Finally, as clinical trials for new therapies are being developed, a clear understanding of the international standard of care will provide a consistent definition for the control arm, enabling comparisons across trials.
      A recognized limitation of our study was that the English language requirement in the SLR may have excluded many countries. This was mitigated in part by the inclusion of a selection of non-English guidelines. We also note that some global regions are only represented by a few countries and most countries are only represented by 1 guideline, which may not be characteristic of the entire region or country. Also, this audit did not analyze the details of the recommended RT doses, which may vary by country or geographic region.
      Even in countries where modern cCRT is used consistently, patients with later-stage disease and lymph node involvement have poor prognosis. In the 20 years since cCRT became the standard of care [
      • Cancer Network
      NCI Urges Chemo-RT Combination for Invasive Cervical Cancer.
      ,
      • McNeil C.
      New standard of care for cervical cancer sets stage for next questions.
      ,
      • Potter R.
      • Tanderup K.
      • Schmid M.P.
      • Jurgenliemk-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.
      ,
      • Shrivastava S.
      • Mahantshetty U.
      • Engineer R.
      • Chopra S.
      • Hawaldar R.
      • Hande V.
      • et al.
      Cisplatin chemoradiotherapy vs radiotherapy in FIGO stage IIIB squamous cell carcinoma of the uterine cervix: a randomized clinical trial.
      ], no new treatments have been established. The most recent example of a well-designed study to improve the current standard of care was the phase 3, randomized OUTBACK trial (NCT01414608), which examined cCRT with or without adjuvant chemotherapy (carboplatin with paclitaxel) in LACC. This trial showed that adjuvant chemotherapy given after standard cCRT did not improve progression-free survival or overall survival [
      • Mileshkin L.R.
      • Moore K.N.
      • Barnes E.
      • Gebski V.
      • Narayan K.
      • Bradshaw N.
      • et al.
      Adjuvant chemotherapy following chemoradiation as primary treatment for locally advanced cervical cancer compared to chemoradiation alone: the randomized phase III OUTBACK Trial (ANZGOG 0902, RTOG 1174, NRG 0274).
      ]. Results from this trial may lead to revisions in the guidelines published pre-OUTBACK. Trials in progress include the phase 3 INTERLACE trial (NCT01566240), which examines whether neoadjuvant chemotherapy adds further benefit to cCRT; the TACO trial (NCT01561586), which is investigating tri-weekly cisplatin (75 mg/m2) with RT versus weekly cisplatin (40 mg/m2) with RT for LACC and has the potential to change the paradigm for cisplatin dosing in cCRT; and the GY006 trial (NCT02466971), which is evaluating RT and cisplatin with triapine versus RT and cisplatin alone for LACC or stage II-IVA vaginal cancer.
      Chronic HPV infection can induce a highly immunogenic microenvironment, and almost 90% of LACC tumors are positive for programmed cell death ligand-1 (PD-L1), using a ≥ 1% cutoff for positivity [
      • Enwere E.K.
      • Kornaga E.N.
      • Dean M.
      • Koulis T.A.
      • Phan T.
      • Kalantarian M.
      • et al.
      Expression of PD-L1 and presence of CD8-positive T cells in pre-treatment specimens of locally advanced cervical cancer.
      ]. Additionally, cCRT induces tumor cell death and recruitment of immune cells to the tumor [
      • Mayadev J.
      • Nunes A.T.
      • Li M.
      • Marcovitz M.
      • Lanasa M.C.
      • Monk B.J.
      CALLA: efficacy and safety of concurrent and adjuvant durvalumab with chemoradiotherapy versus chemoradiotherapy alone in women with locally advanced cervical cancer: a phase III, randomized, double-blind, multicenter study.
      ]. This scenario is ideal for the use of immune checkpoint inhibitors targeting PD-L1 and programmed cell death protein-1 (PD-1) to reactivate the innate antitumor immunity. The PD-L1 inhibitor pembrolizumab has shown activity as a single agent in the relapse of metastatic cervical cancer after 1st-line chemotherapy and more recently in combination with chemotherapy as 1st-line therapy of metastatic disease [
      • Colombo N.
      • Dubot C.
      • Lorusso D.
      • Caceres M.V.
      • Hasegawa K.
      • Shapira-Frommer R.
      • et al.
      Pembrolizumab for persistent, recurrent, or metastatic cervical cancer.
      ]. Immunotherapy is moving to earlier stages for patients who are high risk such as LACC. The phase 1/1b NRG-GY017 trial recently demonstrated safety and antitumor activity for the combination of atezolizumab prior to, and in combination with, cCRT for lymph node-positive LACC [
      • ASCO Post
      Atezolizumab Plus Chemoradiation is Safe, Demonstrates Signs of Immune Activation in Patients With Cervical Cancer.
      ]. Phase 2 and 3 trials are currently assessing various PD-L1 or PD-1 inhibitors in LACC in combination with cCRT [
      • Walsh R.J.
      • Tan D.S.P.
      The role of immunotherapy in the treatment of advanced cervical cancer: current status and future perspectives.
      ,
      • Wendel Naumann R.
      • Leath C.A.
      3rd, advances in immunotherapy for cervical cancer.
      ]. The phase 3 CALLA trial (NCT03830866) recently evaluated the efficacy and safety of durvalumab versus placebo, given during and after cCRT, in high-risk, immunotherapy naïve-patients who had no prior treatment for LACC; the trial did not achieve statistical significance for the primary endpoint of progression-free survival [
      • Mayadev J.
      • Nunes A.T.
      • Li M.
      • Marcovitz M.
      • Lanasa M.C.
      • Monk B.J.
      CALLA: efficacy and safety of concurrent and adjuvant durvalumab with chemoradiotherapy versus chemoradiotherapy alone in women with locally advanced cervical cancer: a phase III, randomized, double-blind, multicenter study.
      ,
      • AstraZeneca
      Update on CALLA phase III trial of concurrent use of imfinzi and chemoradiotherapy in locally advanced cervical cancer.
      ]. The phase 3 KEYNOTE-A18/ENGOT-Cx11 trial (NCT04221945) is investigating the addition of pembrolizumab or placebo to cCRT in LACC with pembrolizumab continued as adjuvant therapy [
      • Lorusso D.
      • Comlombo N.
      • Coleman R.L.
      • Randall L.M.
      • Duska L.R.
      • Xiang Y.
      • et al.
      ENGOT-cx11/KEYNOTE-A18: a phase III, randomized, double-blind study of pembrolizumab with chemoradiotherapy in patients with high-risk locally advanced cervical cancer.
      ].
      ATEZOLACC (NCT03612791) is a phase 2 trial evaluating cCRT ± atezolizumab for LACC with atezolizumab continued in the adjuvant setting. ATOMICC (NCT03833479), also a phase 2 trial, will investigate TSR-042 as maintenance therapy for patients with high-risk LACC, and BrUOG 355 is a phase 2 trial (NCT03527264) examining cCRT with nivolumab, either concurrently or as maintenance. A pembrolizumab phase 2 trial will test post-cCRT pembrolizumab and cCRT + pembrolizumab as adjuvant therapy (NCT02635360).
      In conclusion, although cCRT is recognized globally as the standard of care for stage IIB to IVA LACC, treatment recommendations vary for stages IB2 to IIA2; regional and country-specific guideline updates are expected as the treatment landscape changes with targeted and immuno-oncology therapies. It will be important for countries to be aware of recently completed and upcoming clinical trials to ensure that guidelines are fully up-to-date and harmonized. The consensus and differences between countries and regions observed in our review may serve as a guide for other countries seeking to develop their own guidelines, and furthermore lead to the achievement of global best practices to improve outcomes for patients with LACC.

      Funding

      This work was supported by AstraZeneca . The authors had full control over the content and development of this article. AstraZeneca provided financial support for medical writing, protocol development, systematic literature review, and targeted search.

      Data availability

      Hardcopies of all guidelines are available upon request.

      Credit authorship contribution statement

      Eric Pujade-Lauraine: Conceptualization, Methodology, Writing – review & editing. David S.P. Tan: Writing – review & editing. Alexandra Leary: Writing – review & editing. Mansoor Raza Mirza: Writing – review & editing. Takayuki Enomoto: Writing – review & editing. Jitender Takyar: Methodology, Investigation, Formal analysis, Writing – review & editing, Visualization. Ana Tablante Nunes: Conceptualization, Methodology, Writing – review & editing. José David Hernández Chagüi: Conceptualization, Methodology, Writing – review & editing. Michael J. Paskow: Methodology, Writing – review & editing. Bradley J. Monk: Conceptualization, Methodology, Writing – review & editing.

      Declaration of Competing Interest

      E. Pujade-Lauraine reports personal fees and non-financial support from AstraZeneca, personal fees and non-financial support from Tesaro/GSK, personal fees from Clovis, personal fees and non-financial support from Roche, personal fees from Incyte, and personal fees from Pfizer, other from ARCAGY-Research, outside the submitted work. D.S.P. Tan is supported by grants from the Singapore Ministry of Health's National Medical Research Council and Pangestu Family Foundation Gynaecological Cancer Research Fund. He also reports personal fees from AstraZeneca, Roche, MSD, Merck Serono, GSK, Tessa Therapeutics, Eisai, and Genmab, and research funding and support from AstraZeneca, Roche, Bayer, BMS, MSD, Eisai, and Karyopharm. He also reports stock ownership in the Asian Microbiome Library (AMiLi). All of these have been received outside the submitted work. A. Leary reports grants, personal fees, and non-financial support from AstraZeneca, Tesaro, and Clovis; grants and personal fees from MSD and Ability; personal fees from Biocad, Seattle Genetics, and Zentalis; other support from Merck Serono; and grants, non-financial support, and other from GSK, outside the submitted work. M.R. Mirza reports personal financial interests for AstraZeneca, Biocard, Clovis Oncology, Genmab, Karyopharm Therapeutics, Merck, Mersana, MSD, Oncology Venture, Pfizer, Roche, SeraPrognostics, Tesaro-GSK, ZaiLab; leadership roles for Karyopharm Therapeutics and Sera Prognostics; institutional financial interests (study grants) for AstraZeneca, Boehringer Ingelheim, Clovis Oncology, Pfizer, Tesaro-GSK, Ultimovacs. T. Enomoto reports personal fees from AstraZeneca, Takeda, MSD, and Chugai, outside the submitted work. J. Takyar has nothing to disclose. A.T. Nunes, J.D.H. Chagüi, and M.J. Paskow are employees and shareholders at AstraZeneca. B.J. Monk reports personal fees from AbbVie, Advaxis, Agenus, Amgen, AstraZeneca, Biodesix, Clovis, Conjupro, Genmab, Gradalis, ImmunoGen, Immunomedics, Incyte, Janssen/Johnson & Johnson, Mateon, Merck, Myriad, Perthera, Pfizer, Precision Oncology, Puma, Roche/Genentech, Samumed, Takeda, Tesaro, and VBL, outside the submitted work.

      Acknowledgments

      We thank Karma Rabon-Stith, PhD, MBA, for her contributions to the interpretation of earlier versions of the SLR results and feedback at the outline stage. Medical writing support, which was funded by AstraZeneca in accordance with Good Publication Practice (GPP3) guidelines, was provided by Lauren D. Van Wassenhove, PhD, of Parexel (Hackensack, NJ).

      Appendix A. Supplementary data

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