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State of the art treatment for stage I to III anal squamous cell carcinoma: A systematic review and meta-analysis

  • Ricardo N. Werner
    Correspondence
    Corresponding author at: Klinik für Dermatologie, Venerologie und Allergologie, Division of Evidence-Based Medicine (dEBM), Charité – Universitätsmedizin Berlin, Charitéplatz 1, D-10117 Berlin, Germany.
    Affiliations
    Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Department of Dermatology, Venerology and Allergy, Division of Evidence-Based Medicine (dEBM), Berlin, Germany
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  • Matthew Gaskins
    Affiliations
    Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Department of Dermatology, Venerology and Allergy, Division of Evidence-Based Medicine (dEBM), Berlin, Germany
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  • Gabriela Avila Valle
    Affiliations
    Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Department of Dermatology, Venerology and Allergy, Division of Evidence-Based Medicine (dEBM), Berlin, Germany
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  • Volker Budach
    Affiliations
    Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Department of Radiooncology and Radiotherapy, Berlin, Germany
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  • Stephan Koswig
    Affiliations
    Helios Klinikum Bad Saarow, Department of Radiooncology and Radiotherapy, Bad Saarow, Germany
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  • Franz A. Mosthaf
    Affiliations
    Practice for Haematology, Oncology and Infectiology (Gemeinschaftspraxis für Hämatologie, Onkologie und Infektiologie), Karlsruhe, Germany
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  • Hans-Rudolf Raab
    Affiliations
    Clinical Cancer Registry of Lower Saxony (Klinisches Krebsregister Niedersachsen, KKN), Hannover, Germany
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  • Claus Rödel
    Affiliations
    University Hospital Frankfurt, Department of Radiotherapy and Oncology, Frankfurt am Main, Germany
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  • Alexander Nast
    Affiliations
    Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Department of Dermatology, Venerology and Allergy, Division of Evidence-Based Medicine (dEBM), Berlin, Germany
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  • Author Footnotes
    1 These authors contributed equally to the work.
    Robert Siegel
    Footnotes
    1 These authors contributed equally to the work.
    Affiliations
    Helios Klinikum Berlin-Buch, Department of General, Visceral and Oncological Surgery, Berlin, Germany

    Witten/Herdecke University, Faculty of Health, Witten, Germany
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  • Author Footnotes
    1 These authors contributed equally to the work.
    ,
    Author Footnotes
    2 Present affiliation: Hospital of St. John of God (Krankenhaus der Barmherzigen Brüder) Graz, Department of Surgery, Graz, Austria.
    Felix Aigner
    Footnotes
    1 These authors contributed equally to the work.
    2 Present affiliation: Hospital of St. John of God (Krankenhaus der Barmherzigen Brüder) Graz, Department of Surgery, Graz, Austria.
    Affiliations
    Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Department of Surgery, Berlin, Germany
    Search for articles by this author
  • Author Footnotes
    1 These authors contributed equally to the work.
    2 Present affiliation: Hospital of St. John of God (Krankenhaus der Barmherzigen Brüder) Graz, Department of Surgery, Graz, Austria.
Published:February 04, 2021DOI:https://doi.org/10.1016/j.radonc.2021.01.031

      Highlights

      • Critically appraised data from controlled studies of interventions for anal cancer.
      • We identified only weak evidence for the treatment of early stages.
      • We included a series of RCTs in which modalities of chemoradiation were assessed.
      • More recent approaches (eg immune therapies) not yet evaluated in controlled studies.
      • GRADE evaluations may help clinicians and their patients take informed decisions.

      Abstract

      Background and purpose

      This systematic review summarised and critically appraised evidence on the efficacy and safety of interventions for anal cancer to support the panel of experts developing the national evidence-based anal cancer guideline in Germany.

      Materials and methods

      We conducted a systematic review and meta-analyses of interventions for the treatment of stage I to III anal squamous cell carcinoma (SCCA). We systematically searched several databases and included any randomised controlled trial (RCT) assessing the pre-specified patient populations, regardless of the interventions studied. Non-randomised controlled studies of selected, pre-specified interventions were included if RCTs were not available or contained insufficient information. Where possible, we conducted meta-analyses and critically assessed confidence in the effect estimates using the GRADE approach.

      Results

      Our searches yielded 10,325 (25 October 2018) and 889 hits (update search on 18 July 2019). Among the 41 studies (47 publications) included, we identified 19 comparisons of interventions for SCCA, and confidence in the effect estimates ranged from very low to high. Most RCTs compared various chemoradiation regimes. For other treatment options, such as local excision in early stages or different radiotherapies, we mostly identified comparative cohort studies.

      Conclusion

      Our findings indicate that, in most clinical situations, primary chemoradiation based on 5-FU and MMC is still the gold standard. However, treatment options for stage I anal cancer, particularly of the anal margin, as well as newer treatment approaches should be investigated in future RCTs. Overall, our findings may help health care professionals and patients make informed decisions about treatment choices.

      Abbreviations:

      5-FU (5-fluorouracil), CCB (capecitabine), CDDP (cisplatin), CFS (colostomy-free survival), CR (complete response), CSM (cancer-specific mortality), CSS (cancer-specific survival), DFS (disease-free survival), EM (early morbidity), ET (early toxicity), GRADE (Grading of Recommendations Assessment, Development and Evaluation), HR (hazard ratio), IMRT (intensity-modulated radiotherapy), LM (late morbidity), LT (late toxicity), MD (mean difference), MMC (mitomycin C), OR (odds ratio), OS (overall survival), PFS (progression-free survival), QoL (quality of life), RCT (randomised controlled trial), RFS (recurrence-free survival), RR (risk ratio), SoF (Summary of Findings), SCCA (squamous cell carcinoma of the anus)

      Keywords

      Anal cancer is a rare malignancy contributing to fewer than 3% of gastrointestinal malignant tumours [
      • Siegel R.L.
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      Cancer statistics, 2020.
      ]. With 1–2 cases per 100,000 population annually [
      • Gatta G.
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      • Mallone S.
      • De Angelis R.
      • Ardanaz E.
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      ], its incidence is low but has been rising in recent years [
      • Gatta G.
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      • Botta L.
      • Mallone S.
      • De Angelis R.
      • Ardanaz E.
      • et al.
      Burden and centralised treatment in Europe of rare tumours: results of RARECAREnet-a population-based study.
      ,
      • Islami F.
      • Ferlay J.
      • Lortet-Tieulent J.
      • Bray F.
      • Jemal A.
      International trends in anal cancer incidence rates.
      ,
      • Wilkinson J.R.
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      • Downing A.
      • Finan P.J.
      • Aravani A.
      • Thomas J.D.
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      • Van Dyne E.A.
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      • Markowitz L.E.
      • Benard V.B.
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      ]. In Europe, 5-year survival is approximately 57% [
      • Gatta G.
      • Capocaccia R.
      • Botta L.
      • Mallone S.
      • De Angelis R.
      • Ardanaz E.
      • et al.
      Burden and centralised treatment in Europe of rare tumours: results of RARECAREnet-a population-based study.
      ]. The most important specific cause is an infection with high-risk HPV types (most commonly HPV 16 or 18) [
      • Daling J.R.
      • Madeleine M.M.
      • Johnson L.G.
      • Schwartz S.M.
      • Shera K.A.
      • Wurscher M.A.
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      Human papillomavirus, smoking, and sexual practices in the etiology of anal cancer.
      ,
      • Lin C.
      • Franceschi S.
      • Clifford G.M.
      Human papillomavirus types from infection to cancer in the anus, according to sex and HIV status: a systematic review and meta-analysis.
      ], and risk factors are increased exposure (number of sex partners [
      • Daling J.R.
      • Madeleine M.M.
      • Johnson L.G.
      • Schwartz S.M.
      • Shera K.A.
      • Wurscher M.A.
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      Human papillomavirus, smoking, and sexual practices in the etiology of anal cancer.
      ], receptive anal sex [
      • Daling J.R.
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      • Schwartz S.M.
      • Shera K.A.
      • Wurscher M.A.
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      Human papillomavirus, smoking, and sexual practices in the etiology of anal cancer.
      ,
      • Daling J.R.
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      • Maden C.
      • Coates R.J.
      • Sherman K.J.
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      Sexual practices, sexually transmitted diseases, and the incidence of anal cancer.
      ], history of HPV-infections at other genital sites [
      • Daling J.R.
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      • Maden C.
      • Coates R.J.
      • Sherman K.J.
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      Sexual practices, sexually transmitted diseases, and the incidence of anal cancer.
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      • Chaturvedi A.K.
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      Second cancers among 104,760 survivors of cervical cancer: evaluation of long-term risk.
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      • Hemminki K.
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      • Lin C.
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      Cervical determinants of anal HPV infection and high-grade anal lesions in women: a collaborative pooled analysis.
      ]) and decreased clearance of HPV (immunodeficiency [
      • Sunesen K.G.
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      • Thorlacius-Ussing O.
      • Laurberg S.
      Immunosuppressive disorders and risk of anal squamous cell carcinoma: a nationwide cohort study in Denmark, 1978–2005.
      ,
      • Meeuwis K.A.
      • Melchers W.J.
      • Bouten H.
      • van de Kerkhof P.C.
      • Hinten F.
      • Quint W.G.
      • et al.
      Anogenital malignancies in women after renal transplantation over 40 years in a single center.
      ,
      • Grulich A.E.
      • van Leeuwen M.T.
      • Falster M.O.
      • Vajdic C.M.
      Incidence of cancers in people with HIV/AIDS compared with immunosuppressed transplant recipients: a meta-analysis.
      ,
      • Silverberg M.J.
      • Lau B.
      • Justice A.C.
      • Engels E.
      • Gill M.J.
      • Goedert J.J.
      • et al.
      Risk of anal cancer in HIV-infected and HIV-uninfected individuals in North America.
      ], smoking [
      • Daling J.R.
      • Madeleine M.M.
      • Johnson L.G.
      • Schwartz S.M.
      • Shera K.A.
      • Wurscher M.A.
      • et al.
      Human papillomavirus, smoking, and sexual practices in the etiology of anal cancer.
      ,
      • Daling J.R.
      • Sherman K.J.
      • Hislop T.G.
      • Maden C.
      • Mandelson M.T.
      • Beckmann A.M.
      • et al.
      Cigarette smoking and the risk of anogenital cancer.
      ,
      • Nordenvall C.
      • Nilsson P.J.
      • Ye W.M.
      • Nyren O.
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      ]). Treatment depends on the stage and localisation of the primary tumour.
      To inform the development of the national evidence-based guideline on the management of anal cancer in Germany, we conducted a systematic review and meta-analyses of controlled studies on the efficacy and safety of interventions in patients with stage I-III anal cancer, following the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach [
      • Guyatt G.
      • Oxman A.D.
      • Akl E.A.
      • Kunz R.
      • Vist G.
      • Brozek J.
      • et al.
      GRADE guidelines: 1. Introduction-GRADE evidence profiles and summary of findings tables.
      ,

      Schünemann H, Brozek J, Guyatt G, Oxman A. GRADE Handbook. 2013. https://gdt.gradepro.org/app/handbook/handbook.html. [accessed 08.04.2020].

      ]. This paper aims to appraise and summarise evidence from the review.

      Materials and methods

      Our systematic assessment and analysis followed the methods recommended by Cochrane [

      Higgins JPT, Green S. Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. 2011. http://handbook-5-1.cochrane.org/. [accessed 14.03.2018].

      ] and the GRADE approach [
      • Guyatt G.
      • Oxman A.D.
      • Akl E.A.
      • Kunz R.
      • Vist G.
      • Brozek J.
      • et al.
      GRADE guidelines: 1. Introduction-GRADE evidence profiles and summary of findings tables.
      ,

      Schünemann H, Brozek J, Guyatt G, Oxman A. GRADE Handbook. 2013. https://gdt.gradepro.org/app/handbook/handbook.html. [accessed 08.04.2020].

      ].

      Protocol and registration

      The key questions (PICOs) and inclusion criteria for primary literature were agreed by the methods group and expert panel of the national guideline [

      Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften (AWMF). Angemeldetes Leitlinienvorhaben: Analkarzinom (Diagnostik, Therapie und Nachsorge von Analkanal- und Analrandkarzinomen), AWMF-Register Nr.: 081 - 004OL. 2020. https://www.awmf.org/leitlinien/detail/anmeldung/1/ll/081-004OL.html. [accessed 20.08.2020].

      ], the latter of which was representative of the health professionals involved in the management of anal cancer and of affected patients. A protocol of the systematic review was registered at PROSPERO (CRD42019140829, https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=140829). In the present article, we only report the results obtained for selected populations (see eligibility criteria).

      Eligibility criteria

      We included controlled studies assessing the efficacy and safety of interventions for squamous cell carcinoma of the anus (SSCA). With regard to patients, we included those diagnosed with stage I, II or III anal margin or anal canal SCCA and assessed them separately, if possible. In the present report, patients with recurrent or persisting disease after primary treatment, stage IV anal cancer, and immunocompromised patients/patients living with HIV were not included. We included any RCT assessing the included patient populations, regardless of the interventions studied. Non-randomised controlled studies of pre-specified, selected interventions were included if RCTs were not available or contained insufficient information. These interventions were combined chemoradiation, radiotherapy, chemotherapy, local excision of primary tumour, excision of primary tumour and/or locoregional lymph node metastases, chemoradiation with brachytherapy boost, and chemoradiation with hyperthermia. Any of the included interventions, placebo or no therapy could serve as comparators. To be included, studies had to report the results of at least 10 participants who received the same intervention. Languages were restricted to English, German and French. No publication period restrictions were applied.

      Information sources and study selection

      We searched MEDLINE, Embase and Cochrane CENTRAL on 25 October 2018 and conducted an update search on 18 July 2019. Detailed search strategies for each database are provided in the online supplement (Appendix A.1). Two independent researchers (RNW, MG/GAV) screened titles and abstracts for eligibility and evaluated the full texts of eligible records.

      Data collection, data items and assumptions

      Data were abstracted independently by two reviewers (RNW, MG/GAV) using a standardised spreadsheet. Disagreements were resolved by re-evaluation and discussion. Data items are specified in Appendix A.2. For time-to-event outcomes, we used the approach reported by Tierney et al. [
      • Tierney J.F.
      • Stewart L.A.
      • Ghersi D.
      • Burdett S.
      • Sydes M.R.
      Practical methods for incorporating summary time-to-event data into meta-analysis.
      ] to estimate hazard ratios (HRs) and associated statistics appropriate for random-effects meta-analyses based on HRs reported in publications or, if these were not available, by manually extracting data from survival curves (as long as the number at risk was given). Absolute risks for the GRADE Summary-of-Findings (SoF) tables were calculated using the methods specified by Skoetz et al. [
      • Skoetz N.
      • Goldkuhle M.
      • Weigl A.
      • Dwan K.
      • Labonte V.
      • Dahm P.
      • et al.
      Methodological review showed correct absolute effect size estimates for time-to-event outcomes in less than one-third of cancer-related systematic reviews.
      ,
      • Skoetz N.
      • Goldkuhle M.
      • van Dalen E.C.
      • Akl E.A.
      • Trivella M.
      • Mustafa R.A.
      • et al.
      GRADE guidelines 27: how to calculate absolute effects for time-to-event outcomes in summary of findings tables and Evidence Profiles.
      ]. For dichotomous outcomes, we used the reported data to calculate risk ratios (RR) or odds ratios (OR), and for continuous outcomes we calculated mean differences (MD). Where possible, we reported 95% confidence intervals. The timing of the outcome assessment was not restricted.

      Risk of bias and confidence in the effect estimates

      To assess the risk of bias of individual studies, we used the Cochrane Risk of Bias Tool 2.0 (2016) [
      • Higgins J.P.T.
      • Sterne J.A.C.
      • Savović J.
      • Page M.J.
      • Hróbjartsson A.
      • Boutron I.
      • et al.
      A revised tool for assessing risk of bias in randomized trials.
      ,

      Higgins JPT, Savović J, Page MJ, Sterne JA. Revised Cochrane risk of bias tool for randomized trials (RoB 2.0). 2016. https://www.riskofbias.info/welcome/rob-2-0-tool/archive-rob-2-0-2016. [accessed 01 September 2018].

      ] for randomised controlled trials and ROBINS-I [
      • Sterne J.A.
      • Hernan M.A.
      • Reeves B.C.
      • Savovic J.
      • Berkman N.D.
      • Viswanathan M.
      • et al.
      ROBINS-I: a tool for assessing risk of bias in non-randomised studies of interventions.
      ] for non-randomised studies. For each outcome and comparison, our confidence in the effect estimates was quantified using the GRADE approach [
      • Guyatt G.
      • Oxman A.D.
      • Akl E.A.
      • Kunz R.
      • Vist G.
      • Brozek J.
      • et al.
      GRADE guidelines: 1. Introduction-GRADE evidence profiles and summary of findings tables.
      ,
      • Balshem H.
      • Helfand M.
      • Schunemann H.J.
      • Oxman A.D.
      • Kunz R.
      • Brozek J.
      • et al.
      GRADE guidelines: 3. Rating the quality of evidence.
      ]. The GRADE evaluation for each effect estimate comprises a comprehensive appraisal of study design, risk of bias [
      • Guyatt G.H.
      • Oxman A.D.
      • Vist G.
      • Kunz R.
      • Brozek J.
      • Alonso-Coello P.
      • et al.
      GRADE guidelines: 4. Rating the quality of evidence–study limitations (risk of bias).
      ], directness [
      • Guyatt G.H.
      • Oxman A.D.
      • Kunz R.
      • Woodcock J.
      • Brozek J.
      • Helfand M.
      • et al.
      GRADE guidelines: 8. Rating the quality of evidence–indirectness.
      ], consistency [
      • Guyatt G.H.
      • Oxman A.D.
      • Kunz R.
      • Woodcock J.
      • Brozek J.
      • Helfand M.
      • et al.
      GRADE guidelines: 7. Rating the quality of evidence–inconsistency.
      ], precision [
      • Guyatt G.H.
      • Oxman A.D.
      • Kunz R.
      • Brozek J.
      • Alonso-Coello P.
      • Rind D.
      • et al.
      GRADE guidelines 6. Rating the quality of evidence–imprecision.
      ], publication bias [
      • Guyatt G.H.
      • Oxman A.D.
      • Montori V.
      • Vist G.
      • Kunz R.
      • Brozek J.
      • et al.
      GRADE guidelines: 5. Rating the quality of evidence–publication bias.
      ], and further factors [
      • Guyatt G.H.
      • Oxman A.D.
      • Sultan S.
      • Glasziou P.
      • Akl E.A.
      • Alonso-Coello P.
      • et al.
      GRADE guidelines: 9. Rating up the quality of evidence.
      ]. Table 1 gives an overview of pragmatic interpretations of the GRADE evaluations. The criteria used to up- or downrate the GRADE confidence in the effect estimates are shown in Appendix A.2.
      Table 1GRADE evaluations of the confidence in the effect estimates (modified from Balshem et al.
      • Balshem H.
      • Helfand M.
      • Schunemann H.J.
      • Oxman A.D.
      • Kunz R.
      • Brozek J.
      • et al.
      GRADE guidelines: 3. Rating the quality of evidence.
      ).
      GRADE confidence in the effect estimateSymbolInterpretation
      High⨁⨁⨁⨁We are very confident that the true effect lies close to that of the estimate of the effect.
      Moderate⨁⨁⨁◯We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
      Low⨁⨁◯◯Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect.
      Very low⨁◯◯◯We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect.

      Synthesis and presentation of the results

      We used a random-effects model (DerSimonian-Laird) in ReviewManager 5.3 to meta-analyse results if at least two studies reported on the same outcome for the same comparison of interventions.
      We reported the data for each comparison in GRADE SoF tables [
      • Guyatt G.
      • Oxman A.D.
      • Akl E.A.
      • Kunz R.
      • Vist G.
      • Brozek J.
      • et al.
      GRADE guidelines: 1. Introduction-GRADE evidence profiles and summary of findings tables.
      ]. Where missing information made it impossible to include data in the meta-analyses, we reported data narratively. The detailed results for each comparison, including study characteristics and data on each outcome, are shown in the online supplement (Appendix A.3). In this paper, we report results that could not be included in the meta-analyses only if they differed substantially from results that were included.
      A large number of comparisons of interventions were considered when developing the guideline. In this paper, we present the results for the following outcomes only: quality of life (QoL), overall survival (OS), cancer-specific survival (CSS) or mortality (CSM), progression-free survival (PFS), recurrence- or disease-free survival (RFS or DFS), colostomy-free survival (CFS), complete response (CR), early morbidity or toxicity (EM/ET), and late morbidity or toxicity (LM/LT). Data on additional outcomes can be found in the SoF tables (Appendix A.3).

      Results

      Number of hits and included studies

      The systematic literature search yielded 10,325 (25 October 2018) and 889 hits (update search on 18 July 2019). We identified 33 additional records by manually reviewing the reference lists of existing reviews and guidelines. After excluding duplicates, we screened 7656 titles and abstracts, of which we reviewed 456 in full text (see PRISMA flowchart in Fig. 1). We ultimately included 41 studies (47 publications), 40 of which reported outcomes that we could include in our meta-analyses.
      Figure thumbnail gr1
      Fig. 1Identification and selection of studies.
      Three observational studies [
      • Chai C.Y.
      • Cao H.T.
      • Awad S.
      • Massarweh N.N.
      Management of stage i squamous cell carcinoma of the anal canal.
      ,
      • Chakrabarti S.
      • Jin Z.
      • Huffman B.M.
      • Yadav S.
      • Graham R.P.
      • Lam-Himlin D.M.
      • et al.
      Local excision for patients with stage I anal canal squamous cell carcinoma can be curative.
      ,
      • Jelinek S.K.
      • Patil N.
      • Gaisa M.M.
      • Goldstone S.E.
      Anal superfi cially invasive squamous cell carcinoma (SISCCA) treatments and outcomes.
      ], all of which were rated as being at serious risk of bias, compared local excision alone to chemoradiation in patients with early stage SSCA. The largest of these studies was a registry-based study [
      • Chai C.Y.
      • Cao H.T.
      • Awad S.
      • Massarweh N.N.
      Management of stage i squamous cell carcinoma of the anal canal.
      ] (N = 2243), the other two [
      • Chakrabarti S.
      • Jin Z.
      • Huffman B.M.
      • Yadav S.
      • Graham R.P.
      • Lam-Himlin D.M.
      • et al.
      Local excision for patients with stage I anal canal squamous cell carcinoma can be curative.
      ,
      • Jelinek S.K.
      • Patil N.
      • Gaisa M.M.
      • Goldstone S.E.
      Anal superfi cially invasive squamous cell carcinoma (SISCCA) treatments and outcomes.
      ] (N = 57 and N = 25) were retrospective cohort studies. No difference was seen between local excision and chemoradiation with respect to OS [HR 1.07 (0.80–1.44), GRADE: ⨁◯◯◯, 2,300 pts. from 2 studies [
      • Chai C.Y.
      • Cao H.T.
      • Awad S.
      • Massarweh N.N.
      Management of stage i squamous cell carcinoma of the anal canal.
      ,
      • Chakrabarti S.
      • Jin Z.
      • Huffman B.M.
      • Yadav S.
      • Graham R.P.
      • Lam-Himlin D.M.
      • et al.
      Local excision for patients with stage I anal canal squamous cell carcinoma can be curative.
      ]] or PFS [HR 0.94 (0.09–9.44), GRADE: ⨁◯◯◯, 57 pts. from 1 study [
      • Chakrabarti S.
      • Jin Z.
      • Huffman B.M.
      • Yadav S.
      • Graham R.P.
      • Lam-Himlin D.M.
      • et al.
      Local excision for patients with stage I anal canal squamous cell carcinoma can be curative.
      ]]. One of these studies reported that there was no significant difference with respect to OS for patients with a primary tumour of less or more than 1 cm diameter [
      • Chai C.Y.
      • Cao H.T.
      • Awad S.
      • Massarweh N.N.
      Management of stage i squamous cell carcinoma of the anal canal.
      ]. Data on additional outcomes can be found in Appendix A.3, Table 2.
      A registry-based study [
      • Deshmukh A.A.
      • Zhao H.
      • Das P.
      • Chiao E.Y.
      • You Y.N.
      • Franzini L.
      • et al.
      Clinical and economic evaluation of treatment strategies for T1N0 anal canal cancer.
      ] compared local excision with radiotherapy alone, albeit in patients older than 65 years. The authors applied a propensity score analysis, risk of bias was rated as moderate. No significant differences in OS were found [HR 0.46 (0.20–1.08), GRADE: ⨁◯◯◯, 94 pts [
      • Deshmukh A.A.
      • Zhao H.
      • Das P.
      • Chiao E.Y.
      • You Y.N.
      • Franzini L.
      • et al.
      Clinical and economic evaluation of treatment strategies for T1N0 anal canal cancer.
      ]].
      No comparative studies meeting the eligibility criteria were identified that specifically compared chemoradiation to another intervention in patients after incomplete excision.
      We identified two multicentre RCTs [

      Epidermoid anal cancer: Results from the UKCCCR randomised trial of radiotherapy alone versus radiotherapy, 5-fluorouracil, and mitomycin. UKCCCR Anal Cancer Trial Working Party. UK Co-ordinating Committee on Cancer Research. Lancet. 1996;348:1049-54. https://doi.org/10.1016/j.jpsychires.2015.07.009.

      ,
      • Bartelink H.
      • Roelofsen F.
      • Eschwege F.
      • Rougier P.
      • Bosset J.F.
      • Gonzalez D.G.
      • et al.
      Concomitant radiotherapy and chemotherapy is superior to radiotherapy alone in the treatment of locally advanced anal cancer: results of a phase III randomized trial of the European Organization for Research and Treatment of Cancer Radiotherapy and Gastrointestinal Cooperative Groups.
      ,
      • Northover J.
      • Glynne-Jones R.
      • Sebag-Montefiore D.
      • James R.
      • Meadows H.
      • Wan S.
      • et al.
      Chemoradiation for the treatment of epidermoid anal cancer: 13-year follow-up of the first randomised UKCCCR Anal Cancer Trial (ACT I).
      ] that compared chemoradiation to radiotherapy alone. Because these mostly included patients with stage II-III, and a small number of patients with stage I, SCCA, we additionally included three observational studies [
      • Buckstein M.
      • Arens Y.
      • Wisnivesky J.
      • Gaisa M.
      • Goldstone S.
      • Sigel K.
      A population-based cohort analysis of chemoradiation versus radiation alone for definitive treatment of stage I anal cancer in older patients.
      ,
      • De Bari B.
      • Lestrade L.
      • Pommier P.
      • Maddalo M.
      • Buglione M.
      • Magrini S.M.
      • et al.
      Could concomitant radio-chemotherapy improve the outcomes of early-stage node negative anal canal cancer patients? A retrospective analysis of 122 patients.
      ,
      • Zilli T.
      • Schick U.
      • Ozsahin M.
      • Gervaz P.
      • Roth A.D.
      • Allal A.S.
      Node-negative T1–T2 anal cancer: radiotherapy alone or concomitant chemoradiotherapy?.
      ] that compared these interventions in patients with stage I-II SCCA.
      The observational studies comprised one registry-based study [
      • Buckstein M.
      • Arens Y.
      • Wisnivesky J.
      • Gaisa M.
      • Goldstone S.
      • Sigel K.
      A population-based cohort analysis of chemoradiation versus radiation alone for definitive treatment of stage I anal cancer in older patients.
      ] with propensity score analysis (risk of bias: moderate) and two retrospective comparative cohort studies [
      • De Bari B.
      • Lestrade L.
      • Pommier P.
      • Maddalo M.
      • Buglione M.
      • Magrini S.M.
      • et al.
      Could concomitant radio-chemotherapy improve the outcomes of early-stage node negative anal canal cancer patients? A retrospective analysis of 122 patients.
      ,
      • Zilli T.
      • Schick U.
      • Ozsahin M.
      • Gervaz P.
      • Roth A.D.
      • Allal A.S.
      Node-negative T1–T2 anal cancer: radiotherapy alone or concomitant chemoradiotherapy?.
      ] (both rated as being at serious risk of bias). In these studies, no significant differences were seen with respect to OS [HR 0.70 (0.48–1.00), GRADE: ⨁◯◯◯, 299 pts aged 55–85 years from 1 study [
      • Buckstein M.
      • Arens Y.
      • Wisnivesky J.
      • Gaisa M.
      • Goldstone S.
      • Sigel K.
      A population-based cohort analysis of chemoradiation versus radiation alone for definitive treatment of stage I anal cancer in older patients.
      ]], CSS [HR 0.57 (0.29–1.12), GRADE: ⨁◯◯◯, 445 pts. from 2 studies [
      • Buckstein M.
      • Arens Y.
      • Wisnivesky J.
      • Gaisa M.
      • Goldstone S.
      • Sigel K.
      A population-based cohort analysis of chemoradiation versus radiation alone for definitive treatment of stage I anal cancer in older patients.
      ,
      • Zilli T.
      • Schick U.
      • Ozsahin M.
      • Gervaz P.
      • Roth A.D.
      • Allal A.S.
      Node-negative T1–T2 anal cancer: radiotherapy alone or concomitant chemoradiotherapy?.
      ]], RFS [HR 0.70 (0.37–1.34), GRADE: ⨁◯◯◯, 445 pts. from 2 studies [
      • Buckstein M.
      • Arens Y.
      • Wisnivesky J.
      • Gaisa M.
      • Goldstone S.
      • Sigel K.
      A population-based cohort analysis of chemoradiation versus radiation alone for definitive treatment of stage I anal cancer in older patients.
      ,
      • Zilli T.
      • Schick U.
      • Ozsahin M.
      • Gervaz P.
      • Roth A.D.
      • Allal A.S.
      Node-negative T1–T2 anal cancer: radiotherapy alone or concomitant chemoradiotherapy?.
      ]], CFS [HR 1.10 (0.49–2.46), GRADE: ⨁◯◯◯, 299 pts. aged 55–85 years from 1 study [
      • Buckstein M.
      • Arens Y.
      • Wisnivesky J.
      • Gaisa M.
      • Goldstone S.
      • Sigel K.
      A population-based cohort analysis of chemoradiation versus radiation alone for definitive treatment of stage I anal cancer in older patients.
      ]; two further studies [
      • De Bari B.
      • Lestrade L.
      • Pommier P.
      • Maddalo M.
      • Buglione M.
      • Magrini S.M.
      • et al.
      Could concomitant radio-chemotherapy improve the outcomes of early-stage node negative anal canal cancer patients? A retrospective analysis of 122 patients.
      ,
      • Zilli T.
      • Schick U.
      • Ozsahin M.
      • Gervaz P.
      • Roth A.D.
      • Allal A.S.
      Node-negative T1–T2 anal cancer: radiotherapy alone or concomitant chemoradiotherapy?.
      ] reported heterogeneous results], and LT [RR 1.51 (0.74–3.11), GRADE: ⨁◯◯◯, 146 pts. from 1 study [
      • Zilli T.
      • Schick U.
      • Ozsahin M.
      • Gervaz P.
      • Roth A.D.
      • Allal A.S.
      Node-negative T1–T2 anal cancer: radiotherapy alone or concomitant chemoradiotherapy?.
      ]]. Data on additional outcomes can be found in Appendix A.3, Table 5. For OS and RFS, de Bari et al. [
      • De Bari B.
      • Lestrade L.
      • Pommier P.
      • Maddalo M.
      • Buglione M.
      • Magrini S.M.
      • et al.
      Could concomitant radio-chemotherapy improve the outcomes of early-stage node negative anal canal cancer patients? A retrospective analysis of 122 patients.
      ] found that chemoradiation was significantly superior to radiotherapy alone, but we did not include data from the study due to reporting issues.
      Of the two RCTs, which mostly included stage II-III SCCA patients, one [

      Epidermoid anal cancer: Results from the UKCCCR randomised trial of radiotherapy alone versus radiotherapy, 5-fluorouracil, and mitomycin. UKCCCR Anal Cancer Trial Working Party. UK Co-ordinating Committee on Cancer Research. Lancet. 1996;348:1049-54. https://doi.org/10.1016/j.jpsychires.2015.07.009.

      ,
      • Northover J.
      • Glynne-Jones R.
      • Sebag-Montefiore D.
      • James R.
      • Meadows H.
      • Wan S.
      • et al.
      Chemoradiation for the treatment of epidermoid anal cancer: 13-year follow-up of the first randomised UKCCCR Anal Cancer Trial (ACT I).
      ] was rated as being subject to ‘some concerns’, while the other one [
      • Bartelink H.
      • Roelofsen F.
      • Eschwege F.
      • Rougier P.
      • Bosset J.F.
      • Gonzalez D.G.
      • et al.
      Concomitant radiotherapy and chemotherapy is superior to radiotherapy alone in the treatment of locally advanced anal cancer: results of a phase III randomized trial of the European Organization for Research and Treatment of Cancer Radiotherapy and Gastrointestinal Cooperative Groups.
      ] was rated as being at high risk of bias. A significant advantage was seen for the patients who received chemoradiation with respect to CSM [HR 0.67 (0.51–0.88), GRADE: ⨁⨁⨁◯, 577 pts. from 1 RCT [
      • Northover J.
      • Glynne-Jones R.
      • Sebag-Montefiore D.
      • James R.
      • Meadows H.
      • Wan S.
      • et al.
      Chemoradiation for the treatment of epidermoid anal cancer: 13-year follow-up of the first randomised UKCCCR Anal Cancer Trial (ACT I).
      ]], RFS [HR 0.70 (0.58–0.84), GRADE: ⨁⨁⨁◯, 577 pts. from 1 RCT [
      • Northover J.
      • Glynne-Jones R.
      • Sebag-Montefiore D.
      • James R.
      • Meadows H.
      • Wan S.
      • et al.
      Chemoradiation for the treatment of epidermoid anal cancer: 13-year follow-up of the first randomised UKCCCR Anal Cancer Trial (ACT I).
      ]], CFS [HR 0.71 (0.53–0.95), GRADE: ⨁⨁◯◯, 680 pts. from 2 RCTs [
      • Bartelink H.
      • Roelofsen F.
      • Eschwege F.
      • Rougier P.
      • Bosset J.F.
      • Gonzalez D.G.
      • et al.
      Concomitant radiotherapy and chemotherapy is superior to radiotherapy alone in the treatment of locally advanced anal cancer: results of a phase III randomized trial of the European Organization for Research and Treatment of Cancer Radiotherapy and Gastrointestinal Cooperative Groups.
      ,
      • Northover J.
      • Glynne-Jones R.
      • Sebag-Montefiore D.
      • James R.
      • Meadows H.
      • Wan S.
      • et al.
      Chemoradiation for the treatment of epidermoid anal cancer: 13-year follow-up of the first randomised UKCCCR Anal Cancer Trial (ACT I).
      ]], and CR [RR 1.49 (1.12–1.99), GRADE: ⨁⨁◯◯, 103 pts. from 1 RCT [
      • Bartelink H.
      • Roelofsen F.
      • Eschwege F.
      • Rougier P.
      • Bosset J.F.
      • Gonzalez D.G.
      • et al.
      Concomitant radiotherapy and chemotherapy is superior to radiotherapy alone in the treatment of locally advanced anal cancer: results of a phase III randomized trial of the European Organization for Research and Treatment of Cancer Radiotherapy and Gastrointestinal Cooperative Groups.
      ,
      • Northover J.
      • Glynne-Jones R.
      • Sebag-Montefiore D.
      • James R.
      • Meadows H.
      • Wan S.
      • et al.
      Chemoradiation for the treatment of epidermoid anal cancer: 13-year follow-up of the first randomised UKCCCR Anal Cancer Trial (ACT I).
      ]]. No significant difference was found for OS [HR 0.85 (0.70–1.02), GRADE: ⨁⨁◯◯, 680 pts. from 2 RCTs [

      Epidermoid anal cancer: Results from the UKCCCR randomised trial of radiotherapy alone versus radiotherapy, 5-fluorouracil, and mitomycin. UKCCCR Anal Cancer Trial Working Party. UK Co-ordinating Committee on Cancer Research. Lancet. 1996;348:1049-54. https://doi.org/10.1016/j.jpsychires.2015.07.009.

      ,
      • Bartelink H.
      • Roelofsen F.
      • Eschwege F.
      • Rougier P.
      • Bosset J.F.
      • Gonzalez D.G.
      • et al.
      Concomitant radiotherapy and chemotherapy is superior to radiotherapy alone in the treatment of locally advanced anal cancer: results of a phase III randomized trial of the European Organization for Research and Treatment of Cancer Radiotherapy and Gastrointestinal Cooperative Groups.
      ]]. EM was higher in the chemoradiation group [RR 1.24 (1.03–1.50), GRADE: ⨁⨁⨁◯, 577 pts. from 1 RCT [

      Epidermoid anal cancer: Results from the UKCCCR randomised trial of radiotherapy alone versus radiotherapy, 5-fluorouracil, and mitomycin. UKCCCR Anal Cancer Trial Working Party. UK Co-ordinating Committee on Cancer Research. Lancet. 1996;348:1049-54. https://doi.org/10.1016/j.jpsychires.2015.07.009.

      ]], whereas no significant difference was seen for LM [RR 1.10 (0.90–1.35), GRADE: ⨁⨁⨁◯, 577 pts. from 1 RCT [

      Epidermoid anal cancer: Results from the UKCCCR randomised trial of radiotherapy alone versus radiotherapy, 5-fluorouracil, and mitomycin. UKCCCR Anal Cancer Trial Working Party. UK Co-ordinating Committee on Cancer Research. Lancet. 1996;348:1049-54. https://doi.org/10.1016/j.jpsychires.2015.07.009.

      ]]. Data on additional outcomes can be found in Appendix A.3, Table 6.
      We identified one multicentre RCT that compared chemoradiation with 5-fluorouracil (5-FU) and mitomycin C (MMC) to chemoradiation with 5-FU alone in patients with stage I-III anal canal cancer [
      • Flam M.
      • John M.
      • Pajak T.F.
      • Petrelli N.
      • Myerson R.
      • Doggett S.
      • et al.
      Role of mitomycin in combination with fluorouracil and radiotherapy, and of salvage chemoradiation in the definitive nonsurgical treatment of epidermoid carcinoma of the anal canal: results of a phase III randomized intergroup study.
      ]. In the risk of bias evaluation, this trial was rated as being subject to ‘some concerns’. Although both interventions were roughly equivalent (i.e., had narrow confidence interval around the line of no effect) with respect to CR [RR 1.03 (0.92–1.15), GRADE: ⨁⨁⨁⨁, 291 pts. [
      • Flam M.
      • John M.
      • Pajak T.F.
      • Petrelli N.
      • Myerson R.
      • Doggett S.
      • et al.
      Role of mitomycin in combination with fluorouracil and radiotherapy, and of salvage chemoradiation in the definitive nonsurgical treatment of epidermoid carcinoma of the anal canal: results of a phase III randomized intergroup study.
      ]], chemoradiation with 5-FU and MMC was superior with respect to RFS [HR 0.50 (0.33–0.76), GRADE: ⨁⨁⨁⨁, 291 pts. [
      • Flam M.
      • John M.
      • Pajak T.F.
      • Petrelli N.
      • Myerson R.
      • Doggett S.
      • et al.
      Role of mitomycin in combination with fluorouracil and radiotherapy, and of salvage chemoradiation in the definitive nonsurgical treatment of epidermoid carcinoma of the anal canal: results of a phase III randomized intergroup study.
      ]] and CFS [HR 0.59 (0.39–0.90), GRADE: ⨁⨁⨁◯, 291 pts. [
      • Flam M.
      • John M.
      • Pajak T.F.
      • Petrelli N.
      • Myerson R.
      • Doggett S.
      • et al.
      Role of mitomycin in combination with fluorouracil and radiotherapy, and of salvage chemoradiation in the definitive nonsurgical treatment of epidermoid carcinoma of the anal canal: results of a phase III randomized intergroup study.
      ]]. No significant difference was seen for OS [HR 0.76 (0.47–1.21), GRADE: ⨁⨁⨁◯, 291 pts. [
      • Flam M.
      • John M.
      • Pajak T.F.
      • Petrelli N.
      • Myerson R.
      • Doggett S.
      • et al.
      Role of mitomycin in combination with fluorouracil and radiotherapy, and of salvage chemoradiation in the definitive nonsurgical treatment of epidermoid carcinoma of the anal canal: results of a phase III randomized intergroup study.
      ]]. ET was higher in the 5-FU + MMC chemoradiation group [RR 2.88 (1.46–5.69), GRADE: ⨁⨁⨁⨁, 291 pts. [
      • Flam M.
      • John M.
      • Pajak T.F.
      • Petrelli N.
      • Myerson R.
      • Doggett S.
      • et al.
      Role of mitomycin in combination with fluorouracil and radiotherapy, and of salvage chemoradiation in the definitive nonsurgical treatment of epidermoid carcinoma of the anal canal: results of a phase III randomized intergroup study.
      ]], whereas no significant difference was seen with respect to LT [RR 6.95 (0.87–55.80), GRADE: ⨁⨁⨁◯, 291 pts. [
      • Flam M.
      • John M.
      • Pajak T.F.
      • Petrelli N.
      • Myerson R.
      • Doggett S.
      • et al.
      Role of mitomycin in combination with fluorouracil and radiotherapy, and of salvage chemoradiation in the definitive nonsurgical treatment of epidermoid carcinoma of the anal canal: results of a phase III randomized intergroup study.
      ]]. Data on additional outcomes can be found in Appendix A.3, Table 8.
      We included two multicentre RCTs that compared chemoradiation with MMC and 5-FU to chemoradiation with cisplatin (CDDP) and 5-FU [
      • Ajani J.A.
      • Winter K.A.
      • Gunderson L.L.
      • Pedersen J.
      • Benson 3rd, A.B.
      • Thomas Jr, C.R.
      • et al.
      Fluorouracil, mitomycin, and radiotherapy vs fluorouracil, cisplatin, and radiotherapy for carcinoma of the anal canal: a randomized controlled trial.
      ,
      • Glynne-Jones R.
      • Kadalayil L.
      • Meadows H.M.
      • Cunningham D.
      • Samuel L.
      • Geh J.I.
      • et al.
      Tumour- and treatment-related colostomy rates following mitomycin C or cisplatin chemoradiation with or without maintenance chemotherapy in squamous cell carcinoma of the anus in the ACT II trial.
      ,
      • Gunderson L.L.
      • Winter K.A.
      • Ajani J.A.
      • Pedersen J.E.
      • Moughan J.
      • Benson 3rd, A.B.
      • et al.
      Long-term update of US GI intergroup RTOG 98–11 phase III trial for anal carcinoma: survival, relapse, and colostomy failure with concurrent chemoradiation involving fluorouracil/mitomycin versus fluorouracil/cisplatin.
      ,
      • James R.D.
      • Glynne-Jones R.
      • Meadows H.M.
      • Cunningham D.
      • Myint A.S.
      • Saunders M.P.
      • et al.
      Mitomycin or cisplatin chemoradiation with or without maintenance chemotherapy for treatment of squamous-cell carcinoma of the anus (ACT II): a randomised, phase 3, open-label, 2 × 2 factorial trial.
      ]. Both RCTs were rated as being subject to ‘some concerns’ in the risk of bias evaluation. The trial ACT II [
      • Glynne-Jones R.
      • Kadalayil L.
      • Meadows H.M.
      • Cunningham D.
      • Samuel L.
      • Geh J.I.
      • et al.
      Tumour- and treatment-related colostomy rates following mitomycin C or cisplatin chemoradiation with or without maintenance chemotherapy in squamous cell carcinoma of the anus in the ACT II trial.
      ,
      • James R.D.
      • Glynne-Jones R.
      • Meadows H.M.
      • Cunningham D.
      • Myint A.S.
      • Saunders M.P.
      • et al.
      Mitomycin or cisplatin chemoradiation with or without maintenance chemotherapy for treatment of squamous-cell carcinoma of the anus (ACT II): a randomised, phase 3, open-label, 2 × 2 factorial trial.
      ] was a 2x2 factorial RCT, in which chemoradiation with MMC and 5-FU was compared to chemoradiation with CDDP and 5-FU, each arm divided further into groups with or without maintenance chemotherapy consisting of CDDP and 5-FU. Because outcomes from these (sub)groups were not reported separately, the data we analysed for the comparison of MMC and 5-FU versus CDDP and 5-FU contain data both from patients who received maintenance chemotherapy and those who did not. In the second RCT [
      • Ajani J.A.
      • Winter K.A.
      • Gunderson L.L.
      • Pedersen J.
      • Benson 3rd, A.B.
      • Thomas Jr, C.R.
      • et al.
      Fluorouracil, mitomycin, and radiotherapy vs fluorouracil, cisplatin, and radiotherapy for carcinoma of the anal canal: a randomized controlled trial.
      ,
      • Gunderson L.L.
      • Winter K.A.
      • Ajani J.A.
      • Pedersen J.E.
      • Moughan J.
      • Benson 3rd, A.B.
      • et al.
      Long-term update of US GI intergroup RTOG 98–11 phase III trial for anal carcinoma: survival, relapse, and colostomy failure with concurrent chemoradiation involving fluorouracil/mitomycin versus fluorouracil/cisplatin.
      ], chemoradiation with MMC and 5-FU was compared to chemoradiation with CDDP and 5-FU, the latter following CDDP-based induction chemotherapy. With respect to the outcomes reported in this summary, a significant difference was seen only for DFS: patients who received MMC + 5-FU had an advantage compared with those who received CDDP + 5-FU [HR 0.72 (0.57–0.91), GRADE: ⨁⨁⨁◯, 649 pts. from 1 RCT [
      • Gunderson L.L.
      • Winter K.A.
      • Ajani J.A.
      • Pedersen J.E.
      • Moughan J.
      • Benson 3rd, A.B.
      • et al.
      Long-term update of US GI intergroup RTOG 98–11 phase III trial for anal carcinoma: survival, relapse, and colostomy failure with concurrent chemoradiation involving fluorouracil/mitomycin versus fluorouracil/cisplatin.
      ]]. Both interventions were roughly equivalent (i.e., had a narrow confidence interval around the line of no effect) with respect to CR [RR 1.01 (0.97–1.06), GRADE: ⨁⨁⨁⨁, 863 pts. from 1 RCT [
      • James R.D.
      • Glynne-Jones R.
      • Meadows H.M.
      • Cunningham D.
      • Myint A.S.
      • Saunders M.P.
      • et al.
      Mitomycin or cisplatin chemoradiation with or without maintenance chemotherapy for treatment of squamous-cell carcinoma of the anus (ACT II): a randomised, phase 3, open-label, 2 × 2 factorial trial.
      ]] and ET [RR 1.05 (0.98–1.12), GRADE: ⨁⨁⨁⨁, 644 pts. from 1 RCT [
      • Ajani J.A.
      • Winter K.A.
      • Gunderson L.L.
      • Pedersen J.
      • Benson 3rd, A.B.
      • Thomas Jr, C.R.
      • et al.
      Fluorouracil, mitomycin, and radiotherapy vs fluorouracil, cisplatin, and radiotherapy for carcinoma of the anal canal: a randomized controlled trial.
      ]]. No significant differences were seen for OS [HR 0.84 (0.65–1.08), GRADE: ⨁⨁⨁◯, 1589 pts. from 2 RCTs [
      • Gunderson L.L.
      • Winter K.A.
      • Ajani J.A.
      • Pedersen J.E.
      • Moughan J.
      • Benson 3rd, A.B.
      • et al.
      Long-term update of US GI intergroup RTOG 98–11 phase III trial for anal carcinoma: survival, relapse, and colostomy failure with concurrent chemoradiation involving fluorouracil/mitomycin versus fluorouracil/cisplatin.
      ,
      • James R.D.
      • Glynne-Jones R.
      • Meadows H.M.
      • Cunningham D.
      • Myint A.S.
      • Saunders M.P.
      • et al.
      Mitomycin or cisplatin chemoradiation with or without maintenance chemotherapy for treatment of squamous-cell carcinoma of the anus (ACT II): a randomised, phase 3, open-label, 2 × 2 factorial trial.
      ]], CSM [RR 0.71 (0.39–1.31), GRADE: ⨁⨁⨁◯, 1589 pts. from 2 RCTs [
      • Ajani J.A.
      • Winter K.A.
      • Gunderson L.L.
      • Pedersen J.
      • Benson 3rd, A.B.
      • Thomas Jr, C.R.
      • et al.
      Fluorouracil, mitomycin, and radiotherapy vs fluorouracil, cisplatin, and radiotherapy for carcinoma of the anal canal: a randomized controlled trial.
      ,
      • James R.D.
      • Glynne-Jones R.
      • Meadows H.M.
      • Cunningham D.
      • Myint A.S.
      • Saunders M.P.
      • et al.
      Mitomycin or cisplatin chemoradiation with or without maintenance chemotherapy for treatment of squamous-cell carcinoma of the anus (ACT II): a randomised, phase 3, open-label, 2 × 2 factorial trial.
      ]], PFS [HR 1.05 (0.84–1.33), GRADE: ⨁⨁⨁◯, 940 pts. from 1 RCT [
      • James R.D.
      • Glynne-Jones R.
      • Meadows H.M.
      • Cunningham D.
      • Myint A.S.
      • Saunders M.P.
      • et al.
      Mitomycin or cisplatin chemoradiation with or without maintenance chemotherapy for treatment of squamous-cell carcinoma of the anus (ACT II): a randomised, phase 3, open-label, 2 × 2 factorial trial.
      ]], CFS [HR 0.87 (0.71–1.07), GRADE: ⨁⨁⨁◯, 1589 pts. from 2 RCTs [
      • Gunderson L.L.
      • Winter K.A.
      • Ajani J.A.
      • Pedersen J.E.
      • Moughan J.
      • Benson 3rd, A.B.
      • et al.
      Long-term update of US GI intergroup RTOG 98–11 phase III trial for anal carcinoma: survival, relapse, and colostomy failure with concurrent chemoradiation involving fluorouracil/mitomycin versus fluorouracil/cisplatin.
      ,
      • James R.D.
      • Glynne-Jones R.
      • Meadows H.M.
      • Cunningham D.
      • Myint A.S.
      • Saunders M.P.
      • et al.
      Mitomycin or cisplatin chemoradiation with or without maintenance chemotherapy for treatment of squamous-cell carcinoma of the anus (ACT II): a randomised, phase 3, open-label, 2 × 2 factorial trial.
      ]], and LT [RR 1.25 (0.78–2.00), GRADE: ⨁⨁⨁◯, 625 pts. from 1 RCT [
      • Ajani J.A.
      • Winter K.A.
      • Gunderson L.L.
      • Pedersen J.
      • Benson 3rd, A.B.
      • Thomas Jr, C.R.
      • et al.
      Fluorouracil, mitomycin, and radiotherapy vs fluorouracil, cisplatin, and radiotherapy for carcinoma of the anal canal: a randomized controlled trial.
      ]]. Data on additional outcomes can be found in Appendix A.3, Table 12.
      We identified four comparative cohort studies [
      • Goodman K.A.
      • Julie D.
      • Cercek A.
      • Cambridge L.
      • Woo K.M.
      • Zhang Z.
      • et al.
      Capecitabine with mitomycin reduces acute hematologic toxicity and treatment delays in patients undergoing definitive chemoradiation using intensity modulated radiation therapy for anal cancer.
      ,
      • Jones C.M.
      • Adams R.
      • Downing A.
      • Glynne-Jones R.
      • Harrison M.
      • Hawkins M.
      • et al.
      Toxicity, tolerability, and compliance of concurrent capecitabine or 5-fluorouracil in radical management of anal cancer with single-dose mitomycin-c and intensity modulated radiation therapy: evaluation Of a national cohort.
      ,
      • Meulendijks D.
      • Dewit L.
      • Tomasoa N.B.
      • van Tinteren H.
      • Beijnen J.H.
      • Schellens J.H.
      • et al.
      Chemoradiotherapy with capecitabine for locally advanced anal carcinoma: an alternative treatment option.
      ,
      • Peixoto R.D.
      • Wan D.D.
      • Schellenberg D.
      • Lim H.J.
      A comparison between 5-fluorouracil/mitomycin and capecitabine/mitomycin in combination with radiation for anal cancer.
      ] in which a chemoradiation regimen with MMC and 5-FU was compared to chemoradiation with capecitabine (CCB) and 5-FU in patients with stage I-III anal cancer. These studies included one prospective cohort study [
      • Jones C.M.
      • Adams R.
      • Downing A.
      • Glynne-Jones R.
      • Harrison M.
      • Hawkins M.
      • et al.
      Toxicity, tolerability, and compliance of concurrent capecitabine or 5-fluorouracil in radical management of anal cancer with single-dose mitomycin-c and intensity modulated radiation therapy: evaluation Of a national cohort.
      ] (serious risk of bias), and three retrospective cohort studies (two of these [
      • Goodman K.A.
      • Julie D.
      • Cercek A.
      • Cambridge L.
      • Woo K.M.
      • Zhang Z.
      • et al.
      Capecitabine with mitomycin reduces acute hematologic toxicity and treatment delays in patients undergoing definitive chemoradiation using intensity modulated radiation therapy for anal cancer.
      ,
      • Meulendijks D.
      • Dewit L.
      • Tomasoa N.B.
      • van Tinteren H.
      • Beijnen J.H.
      • Schellens J.H.
      • et al.
      Chemoradiotherapy with capecitabine for locally advanced anal carcinoma: an alternative treatment option.
      ] rated as being at moderate and one [
      • Peixoto R.D.
      • Wan D.D.
      • Schellenberg D.
      • Lim H.J.
      A comparison between 5-fluorouracil/mitomycin and capecitabine/mitomycin in combination with radiation for anal cancer.
      ] rated as being at serious risk of bias). Both interventions were roughly equivalent (i.e., had a narrow confidence interval around the line of no effect) with respect to OS [RR 0.98 (0.89–1.08) after a median follow-up of 2 years, GRADE: ⨁◯◯◯, 100 pts. from 1 study [
      • Jones C.M.
      • Adams R.
      • Downing A.
      • Glynne-Jones R.
      • Harrison M.
      • Hawkins M.
      • et al.
      Toxicity, tolerability, and compliance of concurrent capecitabine or 5-fluorouracil in radical management of anal cancer with single-dose mitomycin-c and intensity modulated radiation therapy: evaluation Of a national cohort.
      ]] and CR [RR 1.01 (0.91–1.11), GRADE: ⨁◯◯◯, 205 pts. from 2 studies [
      • Jones C.M.
      • Adams R.
      • Downing A.
      • Glynne-Jones R.
      • Harrison M.
      • Hawkins M.
      • et al.
      Toxicity, tolerability, and compliance of concurrent capecitabine or 5-fluorouracil in radical management of anal cancer with single-dose mitomycin-c and intensity modulated radiation therapy: evaluation Of a national cohort.
      ,
      • Meulendijks D.
      • Dewit L.
      • Tomasoa N.B.
      • van Tinteren H.
      • Beijnen J.H.
      • Schellens J.H.
      • et al.
      Chemoradiotherapy with capecitabine for locally advanced anal carcinoma: an alternative treatment option.
      ]]. With respect to further outcomes reported in this summary, no significant differences were seen: CSS [Peixoto et al. [
      • Peixoto R.D.
      • Wan D.D.
      • Schellenberg D.
      • Lim H.J.
      A comparison between 5-fluorouracil/mitomycin and capecitabine/mitomycin in combination with radiation for anal cancer.
      ] did not find a significant difference; data not meta-analysed due to reporting issues], DFS [HR 1.13 (0.65–1.95), GRADE: ⨁◯◯◯, 300 pts. from 1 study [
      • Peixoto R.D.
      • Wan D.D.
      • Schellenberg D.
      • Lim H.J.
      A comparison between 5-fluorouracil/mitomycin and capecitabine/mitomycin in combination with radiation for anal cancer.
      ]], CFS [HR 0.66 (0.28–1.54), GRADE: ⨁◯◯◯, 300 pts. from 1 study [
      • Peixoto R.D.
      • Wan D.D.
      • Schellenberg D.
      • Lim H.J.
      A comparison between 5-fluorouracil/mitomycin and capecitabine/mitomycin in combination with radiation for anal cancer.
      ]], and ET [RR 0.49 (0.10–2.43), GRADE: ⨁◯◯◯, 105 pts. from 1 study [
      • Meulendijks D.
      • Dewit L.
      • Tomasoa N.B.
      • van Tinteren H.
      • Beijnen J.H.
      • Schellens J.H.
      • et al.
      Chemoradiotherapy with capecitabine for locally advanced anal carcinoma: an alternative treatment option.
      ]]. Data on additional outcomes can be found in Appendix A.3, Table 16. For OS and RFS, de Bari et al. [
      • De Bari B.
      • Lestrade L.
      • Pommier P.
      • Maddalo M.
      • Buglione M.
      • Magrini S.M.
      • et al.
      Could concomitant radio-chemotherapy improve the outcomes of early-stage node negative anal canal cancer patients? A retrospective analysis of 122 patients.
      ] found that chemoradiation was significantly superior to radiotherapy alone, but we did not include data from the study due to reporting issues.
      Two retrospective cohort studies [
      • White E.C.
      • Goldman K.
      • Aleshin A.
      • Lien W.W.
      • Rao A.R.
      Chemoradiotherapy for squamous cell carcinoma of the anal canal: comparison of one versus two cycles mitomycin-C.
      ,
      • Yeung R.
      • McConnell Y.
      • Roxin G.
      • Banerjee R.
      • Roldan Urgoiti G.B.
      • MacLean A.R.
      • et al.
      One compared with two cycles of mitomycin C in chemoradiotherapy for anal cancer: analysis of outcomes and toxicity.
      ] at moderate risk of bias compared chemoradiation with 5-FU and two cycles of MMC to chemoradiation with 5-FU and one cycle of MMC in patients with stage I-III anal cancer. No significant differences were seen with respect to OS [HR 0.83 (0.46–1.49), GRADE: ⨁◯◯◯, 386 pts. from 2 studies [
      • White E.C.
      • Goldman K.
      • Aleshin A.
      • Lien W.W.
      • Rao A.R.
      Chemoradiotherapy for squamous cell carcinoma of the anal canal: comparison of one versus two cycles mitomycin-C.
      ,
      • Yeung R.
      • McConnell Y.
      • Roxin G.
      • Banerjee R.
      • Roldan Urgoiti G.B.
      • MacLean A.R.
      • et al.
      One compared with two cycles of mitomycin C in chemoradiotherapy for anal cancer: analysis of outcomes and toxicity.
      ]], CSS [HR 0.32 (0.07–1.42), GRADE: ⨁◯◯◯, 217 pts. from 1 study [
      • White E.C.
      • Goldman K.
      • Aleshin A.
      • Lien W.W.
      • Rao A.R.
      Chemoradiotherapy for squamous cell carcinoma of the anal canal: comparison of one versus two cycles mitomycin-C.
      ]], PFS [HR 0.85 (0.37–1.92), GRADE: ⨁◯◯◯, 217 pts. from 1 study [
      • White E.C.
      • Goldman K.
      • Aleshin A.
      • Lien W.W.
      • Rao A.R.
      Chemoradiotherapy for squamous cell carcinoma of the anal canal: comparison of one versus two cycles mitomycin-C.
      ]], DFS [HR 1.17 (0.69–2.01), GRADE: ⨁◯◯◯, 169 pts. from 1 study [
      • Yeung R.
      • McConnell Y.
      • Roxin G.
      • Banerjee R.
      • Roldan Urgoiti G.B.
      • MacLean A.R.
      • et al.
      One compared with two cycles of mitomycin C in chemoradiotherapy for anal cancer: analysis of outcomes and toxicity.
      ]], CFS [HR 0.91 (0.31–2.67), GRADE: ⨁◯◯◯, 217 pts. from 1 study [
      • White E.C.
      • Goldman K.
      • Aleshin A.
      • Lien W.W.
      • Rao A.R.
      Chemoradiotherapy for squamous cell carcinoma of the anal canal: comparison of one versus two cycles mitomycin-C.
      ]], ET [RR 0.98 (0.69–1.38), GRADE: ⨁◯◯◯, 217 pts. from 1 study [
      • White E.C.
      • Goldman K.
      • Aleshin A.
      • Lien W.W.
      • Rao A.R.
      Chemoradiotherapy for squamous cell carcinoma of the anal canal: comparison of one versus two cycles mitomycin-C.
      ]], and LT [RR 0.67 (0.19–2.31), GRADE: ⨁◯◯◯, 217 pts. from 1 study [
      • White E.C.
      • Goldman K.
      • Aleshin A.
      • Lien W.W.
      • Rao A.R.
      Chemoradiotherapy for squamous cell carcinoma of the anal canal: comparison of one versus two cycles mitomycin-C.
      ]]. Data on additional outcomes can be found in Appendix A.3, Table 18.
      We identified one multicentre, 2 × 2 factorial RCT [
      • Peiffert D.
      • Tournier-Rangeard L.
      • Gerard J.P.
      • Lemanski C.
      • Francois E.
      • Giovannini M.
      • et al.
      Induction chemotherapy and dose intensification of the radiation boost in locally advanced anal canal carcinoma: final analysis of the randomized UNICANCER ACCORD 03 trial.
      ] that compared chemoradiation with and without induction chemotherapy consisting of CDDP and 5-FU in a sample of stage II-III anal canal cancer patients. The risk of bias was rated as being subject to ‘some concerns’. A standard- or high-dose radiotherapy boost was applied in both groups. To compare the induction versus no induction groups, we used pooled data from patients with standard- and with high-dose radiotherapy boost. No significant difference was seen for CFS [HR 0.93 (0.58–1.51), GRADE: ⨁⨁⨁◯, 307 pts.]. Peiffert et al. [
      • Peiffert D.
      • Tournier-Rangeard L.
      • Gerard J.P.
      • Lemanski C.
      • Francois E.
      • Giovannini M.
      • et al.
      Induction chemotherapy and dose intensification of the radiation boost in locally advanced anal canal carcinoma: final analysis of the randomized UNICANCER ACCORD 03 trial.
      ] did not find significant differences with respect to 5-year OS, CSS, and DFS between the groups of patients who received induction chemotherapy and those who did not. Due to the reporting issues, we did not meta-analyse these data; details and data on additional outcomes are shown in Appendix A.3, Table 20).
      We included one multicentre, 2x2 factorial RCT [
      • Glynne-Jones R.
      • Kadalayil L.
      • Meadows H.M.
      • Cunningham D.
      • Samuel L.
      • Geh J.I.
      • et al.
      Tumour- and treatment-related colostomy rates following mitomycin C or cisplatin chemoradiation with or without maintenance chemotherapy in squamous cell carcinoma of the anus in the ACT II trial.
      ,
      • James R.D.
      • Glynne-Jones R.
      • Meadows H.M.
      • Cunningham D.
      • Myint A.S.
      • Saunders M.P.
      • et al.
      Mitomycin or cisplatin chemoradiation with or without maintenance chemotherapy for treatment of squamous-cell carcinoma of the anus (ACT II): a randomised, phase 3, open-label, 2 × 2 factorial trial.
      ] that compared chemoradiation (consisting of either MMC and 5-FU or CDDP and 5-FU) followed by CDDP maintenance chemotherapy to chemoradiation (again consisting either of MMC and 5-FU or CDDP and 5-FU) not followed by maintenance chemotherapy in patients with stage I-III anal cancer. Risk of bias evaluation was ‘some concerns’. Because outcomes from the subgroups were not reported separately, the data we present for the comparison contain data both from patients whose main chemotherapy was CDDP-based and those whose main chemotherapy was MMC-based. No significant differences were seen for OS [HR 1.07 (0.81–1.41), GRADE: ⨁⨁⨁◯, 940 pts.], CSS [HR 1.11 (0.80–1.54), GRADE: ⨁⨁⨁◯, 940 pts.], PFS [HR 0.95 (0.75–1.21), GRADE: ⨁⨁⨁◯, 940 pts.], and CFS [HR 0.87 (0.69–1.10), GRADE: ⨁⨁⨁◯, 940 pts.]. Additional data on the outcome ‘treatment-associated deaths’ can be found in Appendix A.3, Table 22.
      One register-based comparative cohort study [
      • Prasad R.N.
      • Elson J.
      • Kharofa J.
      The effect of dose escalation for large squamous cell carcinomas of the anal canal.
      ] that was rated as being at serious risk of bias compared standard-dose (<59.4 Gy) to high-dose (≥59.4 Gy) radiotherapy in patients with stage I-III anal cancer. To be included, patients had to have received concomitant chemotherapy, which was not further specified. No significant difference between the groups was seen with respect to OS [HR 0.95 (0.76–1.19), GRADE: ⨁◯◯◯, 1,349 pts.].
      We included eight studies that compared chemoradiation with intensity-modulated radiotherapy (IMRT) to chemoradiation with 3D radiotherapy in stage I-III anal cancer patients. These included one single-centre RCT [
      • Rattan R.
      • Kapoor R.
      • Bahl A.
      • Gupta R.
      • Oinam A.S.
      • Kaur S.
      Comparison of bone marrow sparing intensity modulated radiotherapy (IMRT) and three-dimensional conformal radiotherapy (3DCRT) in carcinoma of anal canal: a prospective study.
      ] (N = 20, risk of bias: ‘some concerns’), three register-based cohort studies from the US [
      • Pollom E.L.
      • Wang G.
      • Harris J.P.
      • Koong A.C.
      • Bendavid E.
      • Bhattacharya J.
      • et al.
      The impact of intensity modulated radiation therapy on hospitalization outcomes in the SEER-medicare population with anal squamous cell carcinoma.
      ,
      • Bryant A.K.
      • Huynh-Le M.P.
      • Simpson D.R.
      • Mell L.K.
      • Gupta S.
      • Murphy J.D.
      Intensity modulated radiation therapy versus conventional radiation for anal cancer in the veterans affairs system.
      ,
      • Elson J.K.
      • Kachnic L.A.
      • Kharofa J.R.
      Intensity-modulated radiotherapy improves survival and reduces treatment time in squamous cell carcinoma of the anus: A National Cancer Data Base study.
      ] (moderate to serious risk of bias), and four single-centre retrospective cohort studies [
      • Chuong M.D.
      • Freilich J.M.
      • Hoffe S.E.
      • Fulp W.
      • Weber J.M.
      • Almhanna K.
      • et al.
      Intensity-modulated radiation therapy vs. 3D conformal radiation therapy for squamous cell carcinoma of the anal canal.
      ,

      Spencer CR, Cardenas M, DeWees TA, Jain R, Grigsby P, Tan B, et al. Outcomes after IMRT compared to 3DCRT for squamous cell carcinoma of the anus. Int J Radiat Oncol Biol Phys. 2014;1):S400-S1. https://doi.org/DOI 10.1016/j.ijrobp.2014.05.1278.

      ,
      • Weber H.E.
      • Droge L.H.
      • Hennies S.
      • Herrmann M.K.
      • Gaedcke J.
      • Wolff H.A.
      Volumetric intensity-modulated arc therapy vs. 3-dimensional conformal radiotherapy for primary chemoradiotherapy of anal carcinoma: effects on treatment-related side effects and survival.
      ,
      • Koerber S.A.
      • Seither B.
      • Slynko A.
      • Haefner M.F.
      • Krug D.
      • Liermann J.
      • et al.
      Chemoradiation in female patients with anal cancer: patient-reported outcome of acute and chronic side effects.
      ,
      • Koerber S.A.
      • Slynko A.
      • Haefner M.F.
      • Krug D.
      • Schoneweg C.
      • Kessel K.
      • et al.
      Efficacy and toxicity of chemoradiation in patients with anal cancer–a retrospective analysis.
      ] (moderate to serious risk of bias). A significant advantage for IMRT was seen with respect to OS [HR 0.86 (0.76–0.98), GRADE: ⨁◯◯◯, 5,246 pts. from 3 observational studies [
      • Bryant A.K.
      • Huynh-Le M.P.
      • Simpson D.R.
      • Mell L.K.
      • Gupta S.
      • Murphy J.D.
      Intensity modulated radiation therapy versus conventional radiation for anal cancer in the veterans affairs system.
      ,
      • Elson J.K.
      • Kachnic L.A.
      • Kharofa J.R.
      Intensity-modulated radiotherapy improves survival and reduces treatment time in squamous cell carcinoma of the anus: A National Cancer Data Base study.
      ,
      • Chuong M.D.
      • Freilich J.M.
      • Hoffe S.E.
      • Fulp W.
      • Weber J.M.
      • Almhanna K.
      • et al.
      Intensity-modulated radiation therapy vs. 3D conformal radiation therapy for squamous cell carcinoma of the anal canal.
      ]; however, Koerber et al. 2014 [
      • Koerber S.A.
      • Slynko A.
      • Haefner M.F.
      • Krug D.
      • Schoneweg C.
      • Kessel K.
      • et al.
      Efficacy and toxicity of chemoradiation in patients with anal cancer–a retrospective analysis.
      ] and Spencer et al. 2014 [

      Spencer CR, Cardenas M, DeWees TA, Jain R, Grigsby P, Tan B, et al. Outcomes after IMRT compared to 3DCRT for squamous cell carcinoma of the anus. Int J Radiat Oncol Biol Phys. 2014;1):S400-S1. https://doi.org/DOI 10.1016/j.ijrobp.2014.05.1278.

      ] did not find significant differences between IMRT and 3D radiotherapy – these data were not included in the meta-analysis due to the reporting issues] and CSS [HR 0.74 (0.55–0.99), GRADE: ⨁◯◯◯, 1944 pts. from 2 observational studies[
      • Pollom E.L.
      • Wang G.
      • Harris J.P.
      • Koong A.C.
      • Bendavid E.
      • Bhattacharya J.
      • et al.
      The impact of intensity modulated radiation therapy on hospitalization outcomes in the SEER-medicare population with anal squamous cell carcinoma.
      ,
      • Bryant A.K.
      • Huynh-Le M.P.
      • Simpson D.R.
      • Mell L.K.
      • Gupta S.
      • Murphy J.D.
      Intensity modulated radiation therapy versus conventional radiation for anal cancer in the veterans affairs system.
      ]]. No significant differences were seen with respect to the outcome ‘substantial reduction in quality of life’ [RR 0.71 (0.32–1.57), GRADE: ⨁◯◯◯, 47 female pts. from 1 observational study [
      • Koerber S.A.
      • Seither B.
      • Slynko A.
      • Haefner M.F.
      • Krug D.
      • Liermann J.
      • et al.
      Chemoradiation in female patients with anal cancer: patient-reported outcome of acute and chronic side effects.
      ]], CR [RR 1.00 (0.49–2.05), GRADE: ⨁⨁⨁◯, 20 pts. from 1 RCT [
      • Rattan R.
      • Kapoor R.
      • Bahl A.
      • Gupta R.
      • Oinam A.S.
      • Kaur S.
      Comparison of bone marrow sparing intensity modulated radiotherapy (IMRT) and three-dimensional conformal radiotherapy (3DCRT) in carcinoma of anal canal: a prospective study.
      ]], DFS [HR 0.31 (0.09–1.05, GRADE: ⨁◯◯◯, 103 pts. from 1 observational study [
      • Weber H.E.
      • Droge L.H.
      • Hennies S.
      • Herrmann M.K.
      • Gaedcke J.
      • Wolff H.A.
      Volumetric intensity-modulated arc therapy vs. 3-dimensional conformal radiotherapy for primary chemoradiotherapy of anal carcinoma: effects on treatment-related side effects and survival.
      ]], and CFS [HR 0.75 (0.07–8.18, GRADE: ⨁◯◯◯, 89 pts. from 1 observational study [
      • Chuong M.D.
      • Freilich J.M.
      • Hoffe S.E.
      • Fulp W.
      • Weber J.M.
      • Almhanna K.
      • et al.
      Intensity-modulated radiation therapy vs. 3D conformal radiation therapy for squamous cell carcinoma of the anal canal.
      ]]. Data on additional outcomes can be found in Appendix A.3, Table 26.
      We included a registry-based cohort study [

      Budde CN, Nabavizadeh N, Kim J, Lu KC, Billingsley KG, Thomas CR, et al. Boost radiation treatment for anal cancer decreases the risk for lifetime colostomy: analysis from the national cancer data base (NCDB). Ann Surg Oncol. 2014;1):S76.

      ,
      • Geltzeiler C.B.
      • Nabavizadeh N.
      • Kim J.
      • Lu K.C.
      • Billingsley K.G.
      • Thomas C.R.
      • et al.
      Chemoradiotherapy with a radiation boost for anal cancer decreases the risk for salvage abdominoperineal resection: analysis from the national cancer data base.
      ] in which the use of a radiotherapy boost (520 Gy) was investigated. The study was rated as being at serious risk of bias. In the study, none of the outcomes selected to be reported in this publication were presented. Data on the rate of abdominoperineal resections are shown in Appendix A.3, Table 32.
      In a retrospective comparative cohort study [
      • Franco P.
      • De Bari B.
      • Arcadipane F.
      • Lepinoy A.
      • Ceccarelli M.
      • Furfaro G.
      • et al.
      Comparing simultaneous integrated boost vs sequential boost in anal cancer patients: results of a retrospective observational study.
      ] that was rated as being at serious risk of bias, chemoradiation with an integrated radiation boost was compared to chemoradiation with a sequential radiotherapy boost. Patients in the sequential boost group received an overall radiation dose of 59.4 Gy (initially 36 Gy in 20 fractions, and after a break of 16 days, another 23.4 Gy in 13 fractions). In the integrated boost group, patients received an overall dose of 50.4 to 54 Gy in 28 to 30 fractions. Whereas the data on OS and CFS were taken from the propensity-score analysis, the data on local/regional failure, distant metastases, and hematologic toxicity (shown in the Appendix A.3, Table 34) are based on raw rates in the respective groups. No significant differences were seen with respect to OS [HR 1.51 (0.77–2.98), GRADE: ⨁◯◯◯, 190 pts.] and CFS [HR 1.15 (0.65–2.04), GRADE: ⨁◯◯◯, 190 pts.].
      We identified one multicentre, 2 × 2 factorial RCT [
      • Peiffert D.
      • Tournier-Rangeard L.
      • Gerard J.P.
      • Lemanski C.
      • Francois E.
      • Giovannini M.
      • et al.
      Induction chemotherapy and dose intensification of the radiation boost in locally advanced anal canal carcinoma: final analysis of the randomized UNICANCER ACCORD 03 trial.
      ] (risk of bias: ‘some concerns’) that compared chemoradiation with a high-dose radiotherapy boost to chemoradiation with a low-dose radiotherapy boost in a sample of stage II-III anal canal cancer patients, in both cases with or without induction chemotherapy. To compare outcomes for the high-dose versus low-dose boost groups, we used pooled data that contained patients both with and without induction chemotherapy. Peiffert et al. [
      • Peiffert D.
      • Tournier-Rangeard L.
      • Gerard J.P.
      • Lemanski C.
      • Francois E.
      • Giovannini M.
      • et al.
      Induction chemotherapy and dose intensification of the radiation boost in locally advanced anal canal carcinoma: final analysis of the randomized UNICANCER ACCORD 03 trial.
      ] did not find significant differences with respect to 5-year OS, CSS, and DFS between the groups of patients who received a high-dose versus a standard-dose boost. Due to the reporting issues, these data were not re-analysed. No significant difference was seen for CFS [HR 0.86 (0.53–1.39), GRADE: ⨁⨁⨁◯, 307 pts.]. Details and data on additional outcomes can be found in Appendix A.3, Table 36.
      We included four retrospective comparative cohort studies [

      Althaqfi S, Goel R, Chandni J, Biotech YXM, Grimard L. Results of brachytherapy in anal cancer from a cohort of 173 patients treated at the same institution over a 20 year period. Eur J Cancer. 2015;3):S126. https://doi.org/Doi 10.1016/S0959-8049(16)30367-7.

      ,
      • Hannoun-Levi J.M.
      • Ortholan C.
      • Resbeut M.
      • Teissier E.
      • Ronchin P.
      • Cowen D.
      • et al.
      High-dose split-course radiation therapy for anal cancer: outcome analysis regarding the boost strategy (CORS-03 study).
      ,
      • Oehler-Janne C.
      • Seifert B.
      • Lutolf U.M.
      • Studer G.
      • Glanzmann C.
      • Ciernik I.F.
      Clinical outcome after treatment with a brachytherapy boost versus external beam boost for anal carcinoma.
      ,
      • Arcelli A.
      • Buwenge M.
      • Macchia G.
      • Cammelli S.
      • Deodato F.
      • Cilla S.
      • et al.
      Long-term results of chemoradiation plus pulsed-dose-rate brachytherapy boost in anal canal carcinoma: a mono-institutional retrospective analysis.
      ] that compared chemoradiation with brachytherapy boost to chemoradiation with external beam radiation boost in patients with stage I-III anal cancer. A further study [
      • Moureau-Zabotto L.
      • Ortholan C.
      • Hannoun-Levi J.M.
      • Teissier E.
      • Cowen D.
      • Salem N.
      • et al.
      Role of brachytherapy in the boost management of anal carcinoma with node involvement (CORS-03 study).
      ] was not included in the analyses because of a possible substantial overlap of the study populations with one of the included studies [
      • Hannoun-Levi J.M.
      • Ortholan C.
      • Resbeut M.
      • Teissier E.
      • Ronchin P.
      • Cowen D.
      • et al.
      High-dose split-course radiation therapy for anal cancer: outcome analysis regarding the boost strategy (CORS-03 study).
      ]. The risk of bias evaluations ranged from critical to moderate. No significant differences were seen with respect to QoL (EORTC QLQ-C30) [MD: −13.5 (−28.63–1.63), GRADE: ⨁◯◯◯, 34 pts. from 1 study [
      • Oehler-Janne C.
      • Seifert B.
      • Lutolf U.M.
      • Studer G.
      • Glanzmann C.
      • Ciernik I.F.
      Clinical outcome after treatment with a brachytherapy boost versus external beam boost for anal carcinoma.
      ]], OS [HR 0.62 (0.30–1.31), GRADE: ⨁◯◯◯, 123 pts. from 1 study [
      • Arcelli A.
      • Buwenge M.
      • Macchia G.
      • Cammelli S.
      • Deodato F.
      • Cilla S.
      • et al.
      Long-term results of chemoradiation plus pulsed-dose-rate brachytherapy boost in anal canal carcinoma: a mono-institutional retrospective analysis.
      ]], CR [RR 1.13 (0.99–1.29), GRADE: ⨁◯◯◯, 165 pts. from 1 study [

      Althaqfi S, Goel R, Chandni J, Biotech YXM, Grimard L. Results of brachytherapy in anal cancer from a cohort of 173 patients treated at the same institution over a 20 year period. Eur J Cancer. 2015;3):S126. https://doi.org/Doi 10.1016/S0959-8049(16)30367-7.

      ]], CSM [RR 1.37 (0.63–2.99), GRADE: ⨁◯◯◯, 162 pts. from 1 study [
      • Hannoun-Levi J.M.
      • Ortholan C.
      • Resbeut M.
      • Teissier E.
      • Ronchin P.
      • Cowen D.
      • et al.
      High-dose split-course radiation therapy for anal cancer: outcome analysis regarding the boost strategy (CORS-03 study).
      ]], and CFS [HR 0.66 (0.38–1.15), GRADE: ⨁◯◯◯, 162 pts. from 1 study [
      • Hannoun-Levi J.M.
      • Ortholan C.
      • Resbeut M.
      • Teissier E.
      • Ronchin P.
      • Cowen D.
      • et al.
      High-dose split-course radiation therapy for anal cancer: outcome analysis regarding the boost strategy (CORS-03 study).
      ]]. In one study with 81 patients, [
      • Oehler-Janne C.
      • Seifert B.
      • Lutolf U.M.
      • Studer G.
      • Glanzmann C.
      • Ciernik I.F.
      Clinical outcome after treatment with a brachytherapy boost versus external beam boost for anal carcinoma.
      ] a significantly lower rate of ET was seen for brachytherapy [RR 0.35 (0.14–0.83), GRADE: ⨁◯◯◯], but no significant difference was seen with respect to LT [RR 0.59 (0.25–1.38), GRADE: ⨁◯◯◯]. Oehler-Janne et al. [
      • Oehler-Janne C.
      • Seifert B.
      • Lutolf U.M.
      • Studer G.
      • Glanzmann C.
      • Ciernik I.F.
      Clinical outcome after treatment with a brachytherapy boost versus external beam boost for anal carcinoma.
      ] did not find significant differences with respect to CSS and RFS, but these data were not meta-analysed due to reporting issues. Details and data on additional outcomes can be found in Appendix A.3, Table 38.
      We identified two studies that compared chemoradiation with hyperthermia to chemoradiation without hyperthermia in stage I-III anal cancer patients – one monocentric RCT [
      • Kouloulias V.
      • Plataniotis G.
      • Kouvaris J.
      • Dardoufas C.
      • Gennatas C.
      • Uzunoglu N.
      • et al.
      Chemoradiotherapy combined with intracavitary hyperthermia for anal cancer: feasibility and long-term results from a phase II randomized trial.
      ] (N = 49) that was rated as being at high risk of bias and one monocentric retrospective comparative cohort study [
      • Ott O.J.
      • Schmidt M.
      • Semrau S.
      • Strnad V.
      • Matzel K.E.
      • Schneider I.
      • et al.
      Chemoradiotherapy with and without deep regional hyperthermia for squamous cell carcinoma of the anus.
      ] that was rated as being at serious risk of bias. In the RCT, only stage II patients (T2/3 N0 M0) were included. Significant advantages for the application of hyperthermia were found for OS [HR 0.25 (0.07–0.92), GRADE: ⨁◯◯◯, 112 pts. from 1 observational study [
      • Ott O.J.
      • Schmidt M.
      • Semrau S.
      • Strnad V.
      • Matzel K.E.
      • Schneider I.
      • et al.
      Chemoradiotherapy with and without deep regional hyperthermia for squamous cell carcinoma of the anus.
      ]] and CFS [Ott et al. [
      • Ott O.J.
      • Schmidt M.
      • Semrau S.
      • Strnad V.
      • Matzel K.E.
      • Schneider I.
      • et al.
      Chemoradiotherapy with and without deep regional hyperthermia for squamous cell carcinoma of the anus.
      ], due to reporting issues, these data were not re-analysed; however, in the RCT [
      • Kouloulias V.
      • Plataniotis G.
      • Kouvaris J.
      • Dardoufas C.
      • Gennatas C.
      • Uzunoglu N.
      • et al.
      Chemoradiotherapy combined with intracavitary hyperthermia for anal cancer: feasibility and long-term results from a phase II randomized trial.
      ], a significant advantages was also seen with respect to the rate of colostomies: RR 0.12 (0.02–0.85), GRADE: ⨁⨁⨁◯, 49 pts.]. No significant differences were seen with respect to CSS [HR 0.32 (0.06–1.62), GRADE: ⨁◯◯◯, 112 pts. from 1 observational study [
      • Ott O.J.
      • Schmidt M.
      • Semrau S.
      • Strnad V.
      • Matzel K.E.
      • Schneider I.
      • et al.
      Chemoradiotherapy with and without deep regional hyperthermia for squamous cell carcinoma of the anus.
      ]], local RFS [HR 0.14 (0.02–1.09), GRADE: ⨁◯◯◯, 112 pts. from 1 observational study [
      • Ott O.J.
      • Schmidt M.
      • Semrau S.
      • Strnad V.
      • Matzel K.E.
      • Schneider I.
      • et al.
      Chemoradiotherapy with and without deep regional hyperthermia for squamous cell carcinoma of the anus.
      ]; however, in the RCT, [
      • Kouloulias V.
      • Plataniotis G.
      • Kouvaris J.
      • Dardoufas C.
      • Gennatas C.
      • Uzunoglu N.
      • et al.
      Chemoradiotherapy combined with intracavitary hyperthermia for anal cancer: feasibility and long-term results from a phase II randomized trial.
      ] a significant advantage was seen, data not included in meta-analysis due to reporting issues], and DFS [HR 0.45 (0.16–1.30), GRADE: ⨁◯◯◯, 112 pts. from 1 observational study [
      • Ott O.J.
      • Schmidt M.
      • Semrau S.
      • Strnad V.
      • Matzel K.E.
      • Schneider I.
      • et al.
      Chemoradiotherapy with and without deep regional hyperthermia for squamous cell carcinoma of the anus.
      ]]. Details and data on additional outcomes can be found in Appendix A.3, Table 40.
      We did not identify any comparative studies that assessed the efficacy and safety of immune checkpoint inhibitors or other immune therapies in patients with stage I to III anal cancer.
      We identified some further RCTs [
      • Gerard J.P.
      • Romestaing P.
      • Mornex F.
      • Ardiet J.M.
      Radiochemotherapy in anal canal carcinoma (ACC). A randomized clinical trial comparing FluoroUracil-Cispaltinum (5FU-CDDP) and CDDP alone.
      ,
      • Matzinger O.
      • Roelofsen F.
      • Mineur L.
      • Koswig S.
      • Van Der Steen-Banasik E.M.
      • Van Houtte P.
      • et al.
      Mitomycin C with continuous fluorouracil or with cisplatin in combination with radiotherapy for locally advanced anal cancer (European Organisation for Research and Treatment of Cancer phase II study 22011–40014).
      ] and observational studies [
      • Yeung R.
      • McConnell Y.
      • Warkentin H.
      • Graham D.
      • Warkentin B.
      • Joseph K.
      • et al.
      Intensity-Modulated Radiotherapy (IMRT) vs Helical Tomotherapy (HT) in Concurrent Chemoradiotherapy (CRT) for Patients with Anal Canal Carcinoma (ACC): an analysis of dose distribution and toxicities.
      ,
      • Konski A.
      • Garcia Jr., M.
      • John M.
      • Krieg R.
      • Pinover W.
      • Myerson R.
      • et al.
      Evaluation of planned treatment breaks during radiation therapy for anal cancer: update of RTOG 92–08.
      ] that assessed data on various comparisons of interventions. These data are shown in Appendix A.3, Tables 10, 14, 28 and 30.

      Discussion

      In this systematic review, we identified and critically appraised the published evidence on the efficacy and safety of interventions for stage I to III anal squamous cell carcinoma in immunocompetent patients. The quality of the studies was heterogeneous, and their design ranged from retrospective controlled cohort studies to well-conducted RCTs. Observational studies comparing two groups, be it retrospective cohort studies, prospective cohort studies or registry based studies, are inherently prone to selection, allocation and attrition bias. Estimates from these studies may therefore be subject to confounding and should be interpreted with caution. In our review, this is reflected by our GRADE evaluation of confidence in the effect estimates, which was often very low or low for estimates generated from data from observational studies.
      Because we assessed a very large number of comparisons and outcomes to inform the development of the German guideline on anal cancer treatment, we could present only a summary of our findings for selected outcomes in this paper. To obtain a comprehensive overview, it is important to consider the Summary of Findings tables in our online Appendix A.3: In some instances, such as the comparison of chemoradiation with induction chemotherapy to chemoradiation without induction therapy, no significant differences were seen with regard to the outcomes presented in this paper, but differences seen for other outcomes and reported only in Appendix A.3, such as hematologic toxicity, may be relevant to patients and therefore important for joint decision making.
      Generally, we identified only weak evidence for approaches to treat early stages of anal cancer, making it impossible to identify which approach is best. Although international guidelines [

      Benson AB, 3rd, Venook AP, Al-Hawary MM, Cederquist L, Chen YJ, Ciombor KK, et al. Anal carcinoma, Version 2.2018, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw. 2018;16:449-54. https://doi.org/https://doi.org/10.6004/jnccn.2018.0060.

      ,
      • Geh I.
      • Gollins S.
      • Renehan A.
      • Scholefield J.
      • Goh V.
      • Prezzi D.
      • et al.
      Association of Coloproctology of Great Britain & Ireland (ACPGBI): guidelines for the management of cancer of the colon, rectum and anus (2017) - anal cancer.
      ,
      • Glynne-Jones R.
      • Nilsson P.J.
      • Aschele C.
      • Goh V.
      • Peiffert D.
      • Cervantes A.
      • et al.
      Anal cancer: ESMO-ESSO-ESTRO Clinical Practice Guidelines for diagnosis, treatment and follow-up.
      ,
      • Moureau-Zabotto L.
      • Vendrely V.
      • Abramowitz L.
      • Borg C.
      • Francois E.
      • Goere D.
      • et al.
      Anal cancer: French Intergroup Clinical Practice Guidelines for diagnosis, treatment and follow-up (SNFGE, FFCD, GERCOR, UNICANCER, SFCD, SFED, SFRO, SNFCP).
      ] recommend local excision for stage I anal margin cancer, no controlled studies were available to compare local excision to chemoradiation in this specific population. This being said, we were able to identify observational studies on this comparison, albeit including mostly patients with cancer of the anal canal. In these studies, no significant differences between local excision and chemoradiation were seen for various outcomes, but we rated our confidence in these effect estimates as very low using GRADE methodology. Decisions about how best to treat the early stages of anal cancer, particularly of the anal margin, must therefore continue to be informed primarily by expert experience and consensus.
      In contrast, we identified a series of RCTs in which different modalities of chemoradiation were assessed, mostly in stage I to III or stage II to III anal cancer. Combined chemoradiation with 45–59.4 Gy radiation and MMC + 5-FU remains the standard for the treatment of stage II and III anal cancer. Although, radiotherapy alone or chemoradiation with 5-FU alone, with their lower rates of early morbidity/early toxicity, could be a sensible alternative for selected older and/or comorbid patients, combined chemoradiation with MMC + 5-FU was superior with respect to various highly relevant oncologic outcomes such as CR, RFS and CFS. As an alternative combined chemoradiation regimen, MMC may be replaced by CDDP in cases where MMC is contraindicated: For most of the outcomes, no significant difference was seen between combined chemoradiation with MMC + 5-FU compared with CDDP + 5-FU. However, the MMC + 5-FU regimen was significantly superior with respect to DFS, although on the other side, an increased risk of hematologic toxicity was seen. The use of induction or maintenance chemotherapy did not lead to an increase in relevant oncological outcomes such as OS, CSS, or CFS.
      We identified evidence from a series of observational studies suggesting that it might be possible to replace 5-FU in the chemoradiation regimen consisting of MMC and 5-FU with capecitabine, which has the advantage of being available as an oral drug. Indeed, no significant differences between the two regimens were seen for important oncological outcomes such as OS, CSS, CR, DFS, and CFS, albeit with confidence in the effect estimates rated as being very low. Similarly, we were not able to identify high-quality evidence on which number of MMC cycles to use. Whereas observational studies did not find significant differences with respect to the main oncological outcomes (OS, CSS, DFS, PFS, CFS), here, too, our confidence in the effect estimates was rates as very low, and some findings suggest that adverse events may be more frequent with two cycles of MMC (i.e., overall toxicity, hematologic toxicity).
      The evidence we identified to assess the modalities of radiotherapy within chemoradiation was generally of lower quality than the evidence on modalities of chemotherapy. The results from a registry-based study suggest that using a high dose of radiation (≥59.4 Gy) does not increase OS (very low confidence in the effect estimate). Using IMRT instead of 3D radiotherapy was shown to increase some survival-related outcomes while reducing some side-effects of the radiation. Although we identified only low-quality evidence to support the use of radiotherapy boost, an RCT served as the basis to show that there were no significant differences with respect to OS, DSS, DFS and CFS between a standard-dose (15 Gy) and a high-dose (20–25 Gy) boost.
      An interesting approach is the use of deep regional hyperthermia as a supplement to chemoradiation. We identified a small RCT and an observational study that found advantages of this intervention with respect to various relevant oncological outcomes including OS, loco-regional failure and the rate of colostomies. Although there are some limitations to its applicability, particularly in patients with larger or advanced tumours, hyperthermia as an additional intervention should be evaluated in further well-designed studies. One RCT was still being carried out at the time of writing [

      ClinicalTrials.gov. Effects of Deep Regional Hyperthermia in Patients With Anal Carcinoma Treated by Standard Radiochemotherapy (HYCAN). NCT02369939. 2015. https://clinicaltrials.gov/ct2/show/study/NCT02369939. [accessed 13.01.2021].

      ].
      More recent approaches such as checkpoint inhibitors or other targeted immune therapies have not yet been evaluated in controlled studies in stage I-III anal cancer. Some initial research has been undertaken to assess the response of immune therapies in stage IV and locoregionally advanced stage III anal cancer, [
      • Hong D.S.
      • Moore K.
      • Patel M.
      • Grant S.C.
      • Burris H.A.
      • William W.N.
      • et al.
      Evaluation of prexasertib, a checkpoint kinase 1 inhibitor, in a phase ib study of patients with squamous cell carcinoma.
      ,
      • Morris V.K.
      • Salem M.E.
      • Nimeiri H.
      • Iqbal S.
      • Singh P.
      • Ciombor K.
      • et al.
      Nivolumab for previously treated unresectable metastatic anal cancer (NCI9673): a multicentre, single-arm, phase 2 study.
      ,
      • Ott P.A.
      • Piha-Paul S.A.
      • Munster P.
      • Pishvaian M.J.
      • van Brummelen E.M.J.
      • Cohen R.B.
      • et al.
      Safety and antitumor activity of the anti-PD-1 antibody pembrolizumab in patients with recurrent carcinoma of the anal canal.
      ] but well-designed controlled studies are still needed. One randomized study assessing the effect of druvalumab in addition to chemoradiation in locally-advanced anal cancer was still recruiting at the time of writing [

      Fokas E. Radiochemotherapy +/- Durvalumab for Locally-advanced Anal Carcinoma. A Multicenter, Randomized, Phase II Trial of the German Anal Cancer Study Group (RADIANCE). 2020. https://clinicaltrials.gov/ct2/show/NCT04230759. [accessed 18.09.2020].

      ].
      Other studies still recruiting participants include the ‘Personalising anal cancer radiotherapy dose’ (PLATO) trials ACT 3, 4 and 5, which aim to optimise the radiotherapy dose as part of chemoradiation for anal cancer in different stages [

      Leeds Institute of Clinical Trials Research. PLATO - Personalising anal cancer radiotherapy dose, ISRCTN88455282. 2016. http://www.isrctn.com/ISRCTN88455282. [accessed 18.09.2020].

      ].

      Conclusions

      To inform the development of the German national anal cancer guideline, we meta-analysed efficacy and safety data from RCTs and observational studies identified in our systematic review of the literature on treatments for stage I-III anal squamous cell carcinoma. Our results indicate that, in most clinical situations, primary chemoradiation based on 5-FU and MMC is still the gold standard. However, there is sparse evidence for patients with stage I anal cancer, particularly of the anal margin, leading the guideline panel to draw upon clinical experience and expert consensus when they decided on recommendations for these patients. Treatment options for these patients, as well as newer treatment approaches, such as hyperthermia and immune therapy should be investigated in future RCTs. In addition to informing the decisions of the guideline panel, our results may help health care professionals and their patients make informed decisions about treatment choices.

      Data statement

      The dataset generated and analysed during the current study is available from the corresponding author on reasonable request.

      Funding

      This work was supported by the German Guideline Program in Oncology (Deutsche Krebsgesellschaft e.V., Arbeitsgemeinschaft der wissenschaftlichen medizinischen Fachgesellschaften and Stiftung Deutsche Krebshilfe) as part of the funding for the development of the German evidence-based guideline on the management of anal cancer [grant number 70113439].

      Conflicts of interest

      The authors declare that they have no conflicts of interest with regard to the topic discussed in the present manuscript.

      Aknowledgements

      We would like to acknowledge the support of this work by the German Guideline Program in Oncology (Deutsche Krebsgesellschaft e.V., Arbeitsgemeinschaft der wissenschaftlichen medizinischen Fachgesellschaften and Stiftung Deutsche Krebshilfe) as part of the funding for the development of the German evidence-based guideline on the management of anal cancer [grant number 70113439].

      Appendix A. Supplementary data

      The following are the Supplementary data to this article:

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