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High dose rate brachytherapy in the management of anal cancer: A review

      Highlights

      • Anal cancer is an uncommon tumour and has multiple treatment options that include combination of chemotherapy, radiation, surgery, and brachytherapy.
      • In this review 10 studies with total of 448 patients were included. 321 patients were treated with high dose rate brachytherapy in addition to external beam radiotherapy and chemotherapy.
      • Pooled analysis in this review suggests excellent response (complete response 80–93%), local control (mean local failure rate 12.3%), and survival outcomes (mean disease-free and overall survival rates of 77.3% and 82.5%, respectively), with limited toxicity. Most common long-term toxicities were incontinence (2.5%-9%) and proctitis (2.5%-19%); G3/4 toxicity ranged between 2.2%-7.1%. Mean sphincter preservation rate and colostomy free survival was 88.0% and 80.4%, respectively.
      • Prospective well conducted trials are needed to further establish role of HDRBT management of anal cancer with future focus on development of international consensus on patient selection, dosimetric parameters, treatment sequencing as well as defining uniform outcome and toxicity assessment.

      Abstract

      Purpose

      To conduct a systematic review evaluating the impact of high dose rate (HDR) brachytherapy (BT) on the clinical outcomes and toxicities of patients with anal cancer.

      Methods and materials

      A search of Medline, Embase, and Cochrane Library databases was performed using search terms: “anal”, “anal canal”, “squamous”, “adenocarcinoma”, “cancer”, “neoplasm”, in combination with “brachytherapy”, “high dose rate brachytherapy” or “HDR brachytherapy”. Additional studies were identified after scanning references. Studies published in English with ≥10 patients were included.

      Results

      Ten studies (n = 448) were included in this review. 321 patients were treated with curative intent external beam radiotherapy (EBRT), chemotherapy (CT) and HDRBT; of those, 312 and 9 received interstitial and intraluminal BT, respectively. Mean follow up was 39.9 months (range (R): 24–61 months). Complete response was noted between 80%-93% and local control ranged between 81%-88%. Mean rate of local failure was 12.3% (SD 3.6%, R: 8%-18%). Distant failure rate was reported between 2%-3% and metastasis free survival ranged between 82%-88%. Mean disease free survival and overall survival were 77.3% (SD 6.6%, R: 66%-100%) and 82.5% (SD 13.7%, R: 70%-87.7%). Acute toxicity was mostly grade 1/2 dermatitis, proctitis or cystitis; G3 or higher toxicity was reported only in 4 patients in 2 studies (dermatitis n = 3 and sphincter necrosis n = 1). Most common long term toxicities were incontinence (2.5%-9%) and proctitis (2.5%-19%); G3/4 toxicity ranged between 2.2%-7.1%. Mean sphincter preservation rate and colostomy free survival was 88.0% and 80.4%, respectively.

      Conclusion

      Pooled analysis in this review suggests excellent response, local control and survival with HDRBT in combination with EBRT and CT, with limited toxicity. Prospective well conducted trials are needed to further establish role of HDRBT management of anal cancer with future focus on development of international consensus on patient selection, dosimetric parameters, treatment sequencing as well as defining uniform outcome and toxicity assessment.

      Keywords

      Anal cancer (AC) is an uncommon disease, yet over the past decade the incidence of anal cancer has increased by 2.2% each year [

      Anon. National Cancer Institute. SEER Cancer Statistics Review (CSR) 1975-2014. SEER Cancer Stat. Rev. 1975-2014. 2018.

      ]. Development of anal cancer is strongly associated with the presence of human papilloma virus (HPV) infection, with >90% of anal cancers directly attributed to HPV [
      • Saraiya M.
      • Unger E.R.
      • Thompson T.D.
      • Lynch C.F.
      • Hernandez B.Y.
      • Lyu C.W.
      • et al.
      US assessment of HPV types in cancers: implications for current and 9-valent HPV vaccines.
      ].
      Historically surgical resection was the curative treatment option for operable anal cancer. However, surgical resection (abdominoperineal resection) does result in less favourable outcomes [
      • Kachnic L.A.
      • Winter K.
      • Myerson R.J.
      • et al.
      RTOG 0529: a phase 2 evaluation of dose-painted intensity modulated radiation therapy in combination with 5-fluorouracil and mitomycin-C for the reduction of acute morbidity in carcinoma of the anal canal.
      ] and the resultant colostomy can have a significant adverse effect on patients’ quality of life (QOL) [
      • Jansen F.
      • van Uden-Kraan C.F.
      • Braakman J.A.
      • van Keizerswaard P.M.
      • Witte B.I.
      • Verdonck-de Leeuw I.M.
      A mixed-method study on the generic and ostomy-specific quality of life of cancer and non-cancer ostomy patients.
      ,
      • Sprangers M.A.G.
      • Taal B.G.
      • Aaronson N.K.
      • te Velde A.
      Quality of life in colorectal cancer. Stoma vs. nonstoma patients.
      ]. Therefore, radiation plus chemotherapy is the current standard for treatment of anal cancer as it results in good control of primary disease while preserving normal anatomy and function [
      • Glynne-Jones R.
      • Nilsson P.J.
      • Aschele C.
      • et al.
      Anal cancer: ESMO-ESSO-ESTRO clinical practice guidelines for diagnosis, treatment and follow-up.
      ]. External beam radiation therapy (EBRT) is the standard approach for delivering radiation in anal cancer; however, it can result in high integral dose. In addition, it has been observed that locally advanced large HPV-related and non-HPV related tumours are more likely to fail locally [
      • Rusten E.
      • Rekstad B.L.
      • Undseth C.
      • et al.
      Anal cancer chemoradiotherapy outcome prediction using (18)F-fluorodeoxyglucose positron emission tomography and clinicopathological factors.
      ]. Therefore, there is a need to deliver higher dose for these locally advanced tumours. Unfortunately, an attempt to increase EBRT dose would further increase the integral dose and increase the probability of normal tissue complications. IMRT has been shown to reduce the dose to normal tissue and reduce acute toxicity, however, doses have not exceeded 63 Gy due to limited data on late toxicity [
      • Teoh S.
      • Muirhead R.
      Rectal Radiotherapy–Intensity-modulated Radiotherapy Delivery, Delineation and Doses.
      ]. Image-guided high-dose rate (HDR) brachytherapy (BT) is an attractive alternative for dose escalation. With its ability to place the source of radiation directly into the tumour, brachytherapy has an effective therapeutic range of 0.5–2 cm with a steep dose gradient that minimizes the effect on normal tissue while allowing for higher doses to be delivered to the tumour [
      • Sun Myint A.
      • Lee C.D.
      • Gerard J.-P.
      Rectal cancer.
      ]. Furthermore, image guided HDRBT has demonstrated improved tumour control, survival and reduction in toxicity in other pelvic tumours, such as cervix and prostate [
      • Pötter R.
      • Tanderup K.
      • Kirisits C.
      • et al.
      The EMBRACE II study: The outcome and prospect of two decades of evolution within the GEC-ESTRO GYN working group and the EMBRACE studies.
      ,
      • Rijkmans E.C.
      • Nout R.A.
      • Rutten I.H.H.M.
      • et al.
      Improved survival of patients with cervical cancer treated with image-guided brachytherapy compared with conventional brachytherapy.
      ].
      There are multiple studies published highlighting the benefit of HDRBT in treatment of AC. These studies, however, individually are too small to make a conclusive argument for or against role of brachytherapy in the treatment of this disease. Previously published systematic review by Frakulli et al. demonstrated efficacy of BT boost in AC patients [
      • Frakulli R.
      • Buwenge M.
      • Cammelli S.
      • Macchia G.
      • Farina E.
      • Arcelli A.
      • et al.
      Brachytherapy boost after chemoradiation in anal cancer: a systematic review.
      ]. However, 9 out 10 studies in that review performed low dose rate (LDR) and only one did HDRBT [
      • Frakulli R.
      • Buwenge M.
      • Cammelli S.
      • Macchia G.
      • Farina E.
      • Arcelli A.
      • et al.
      Brachytherapy boost after chemoradiation in anal cancer: a systematic review.
      ]. The aim of this review is to systematically review available literature in HDRBT and to synthesize conclusions regarding local control, overall survival, sphincter preservation, and complications.

      Methods

      An electronic literature search was performed to identify published studies exploring the use of HDRBT in AC patients. Medline, Embase and Cochrane databases were scanned for articles written in English and published in peer-reviewed journals until December 2020. Any combination of following terms: “anal”, “anus”, or “anal canal”, “squamous”, “adenocarcinoma”, “cancer”, or “neoplasm”, in combination with “brachytherapy”, “high dose rate brachytherapy” or “HDR brachytherapy” was used to detect potentially eligible studies (search strategy attached in supplementary file). Additional publications were identified by scanning references. Studies published in English and reporting outcomes of ≥ 10 patients treated with or without external beam radiotherapy (EBRT), chemotherapy, and surgery were included. Studies using LDBRT or studies with repeated data sets were excluded. If two or more publications reported on same series of patients, only data from the largest and/or more recent series were included in the analysis. The Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines were followed for screening and inclusion of papers in the final analysis and synthesis [

      M.J. Page D. Moher P.M. Bossuyt I. Boutron T.C. Hoffmann C.D. Mulrow et al. PRISMA 2020 explanation and elaboration: updated guidance and exemplars for reporting systematic reviews n160 n160.

      ,

      M.J. Page J.E. McKenzie P.M. Bossuyt I. Boutron T.C. Hoffmann C.D. Mulrow et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews n71 n71.

      ]. (Fig. 1).
      Two reviewers (E.S. and A.T.) independently screened the titles and abstracts for eligibility. Discrepancies were resolved through consensus. The eligible studies were then independently reviewed by three reviewers (Z.A., E.S., and A.T.). Data were extracted from the studies and tabulated in Excel (Microsoft, Redmond, WA).
      The treatment-related data extracted included tumour characteristics, surgical, chemotherapy, EBRT and HDRBT details. The clinical outcome measures extracted included complete response (CR)/partial response (PR) rate, sphincter preservation, local control (LC) local failure (LF), regional failure (RF), distant failure (DF), overall survival (OS), procedure related complications and radiation therapy toxicity. For studies that did not report numerical survival value, it was obtained by reading off a survival curve where available. Weighted means were calculated as a summary measure using the following formula: weighted mean = Σwx/Σw where “x” is the outcome and “w” is the sample size [
      • Buckley H.
      • Wilson C.
      • Ajithkumar T.
      High-Dose-Rate Brachytherapy in the Management of Operable Rectal Cancer: A Systematic Review.
      ].

      Results

      Ten studies with total of 448 patients from seven different countries were included in this review; eight were retrospective and two were prospective cohorts. The overall time period for all included studies ranged from 1987-2018. Eight out of 10 studies indicated the use of HDRBT as a curative modality in conjunction with EBRT and in 2 studies the intent was not specified. Eligibility criteria for individual studies included are listed in Table 1, and most of the studies included patients to be treated with BT if tumour circumference was ≤1/2 of the anal canal.
      Table 1Study Characteristics. NOS – Newcastle-Ottawa Scale for quality assessment of non-randomized studies. Overall survival (OS), local relapse free survival (LRFS), colostomy free survival (CFS), metastasis free survival (MFS), disease free survival (DFS), disease specific survival (DSS), local control (LC), local regional control (LRC), complete remission (CR), partial remission (PR).
      StudyCountryDesignStudy PeriodPatients, nInclusion CriteriaStudy EndpointsNOS Score
      Bertin et al, 2018
      • Bertin E.
      • Benezery K.
      • Kee D.L.C.
      • François E.
      • Evesque L.
      • Gautier M.
      • et al.
      Efficacy and tolerance of high-dose-rate brachytherapy boost after external radiotherapy in the treatment of squamous cell carcinoma of the anal canal.
      FranceRetrospective, Single Institution2005–201846Squamous Cell Carcinoma

      Circumference < 2/3 anal canal

      non-metastatic
      Primary: OS

      Secondary: LRFS, CFS, MFS, DFS
      6
      Varela Cagetti et al, 2019
      • Varela Cagetti L.
      • Zemmour C.
      • Salem N.
      • Minsat M.
      • Ferrè M.
      • Mailleux H.
      • et al.
      High-dose-rate vs. low-dose-rate interstitial brachytherapy boost for anal canal cancers.
      FranceRetrospective, Single Institution2000–2017100Biopsy proven anal carcinomaCircumference ≤ 1/2 of anal canal5-year LC, DFS, OS, and CFS8
      Doniec et al, 2006
      • Doniec J.M.
      • Schniewind B.
      • Kovács G.
      • et al.
      Multimodal therapy of anal cancer added by new endosonographic-guided brachytherapy.
      GermanyRetrospective, Single Institution1993–200150Histology confirmed (squamous, basaloid, or transitional)non-metastatic5-year DSS6
      Falk et al, 2014
      • Falk A.T.
      • Claren A.
      • Benezery K.
      • et al.
      Interstitial high-dose rate brachytherapy as boost for anal canal cancer.
      FranceRetrospective, Single Institution2005–201328Histology confirmed (squamous (n = 25), adenocarcinoma (n = 3))

      Circumference < 2/3 anal canal

      non-metastatic
      2-year LRFS, MFS, DFS, OS6
      Kapoor et al, 2014
      • Kapoor R.
      • Khosla D.
      • Shukla A.K.
      • Kumar R.
      • Gupta R.
      • Oinam A.S.
      • et al.
      Dosimetric and clinical outcome in image-based high-dose-rate interstitial brachytherapy for anal cancer.
      IndiaRetrospective, Single Institution2007–201116Biopsy proven anal Carcinoma

      Circumference < 2/3 anal canal

      Lesion < 1 cm thick
      1- and 2-year LC and OS6
      Kapp et al, 2001
      • Kapp K.S.
      • Geyer E.
      • Gebhart F.H.
      • et al.
      Experience with split-course external beam irradiation +/- chemotherapy and integrated Ir-192 high-dose-rate brachytherapy in the treatment of primary carcinomas of the anal canal.
      AustriaRetrospective, Single Institution1987–199839Biopsy proven epidermoid carcinoma of anal canal

      Stages T1-4, any N, M0

      Performance status ≥ 80

      Age ≥ 18
      LRC, DSS, Sphincter Preservation6
      Lohnert et al, 1998
      • Lohnert M.
      • Doniec J.M.
      • Kovacs G.
      • et al.
      New method of radiotherapy for anal cancer with three-dimensional tumor reconstruction based on endoanal ultrasound and ultrasound-guided afterloading therapy.
      GermanyProspective, Single Institution1992–199718Histology proven cancer of the Anal Canal

      M0
      CR6
      Oehler-Janne et al, 2007
      • Oehler-Jänne C.
      • Seifert B.
      • Lütolf U.M.
      • Studer G.
      • Glanzmann C.
      • Ciernik I.F.
      Clinical outcome after treatment with a brachytherapy boost versus external beam boost for anal carcinoma.
      SwitzerlandRetrospective, Single Institution1988–200381Histology proven invasive cancer of the Anal Canal9
      Saarilahti et al, 2008
      • Saarilahti K.
      • Arponen P.P.
      • Vaalavirta L.
      • et al.
      The effect of intensity-modulated radiotherapy and high dose rate brachytherapy on acute and late radiotherapy-related adverse events following chemoradiotherapy of anal cancer.
      FinlandRetrospective, Single Institution1996–200659Squamous cell carcinoma

      Patients deemed eligible for brachytherapy: tumors with ≤ 1/2 circumference of anal canal and without any adjacent organ infiltration.
      Acute and Late Toxicity, and LRC8
      Tagliaferri et al, 2015
      • Tagliaferri L.
      • Manfrida S.
      • Barbaro B.
      • Colangione M.M.
      • Masiello V.
      • Mattiucci G.C.
      • et al.
      MITHRA - multiparametric MR/CT image adapted brachytherapy (MR/CT-IABT) in anal canal cancer: a feasibility study.
      ItalyProspective, Single Institution2012–201411Histology confirmed anal carcinoma

      Patients with initial T4 or residual disease after EBRT)

      Tumor circumference ≤ 1/2 of anal canal

      KPS ≥ 80
      Safety, target coverage, acute and late Toxicity

      6

      Treatment, brachytherapy technique, dose and fractionation

      Treatment regimens were heterogeneous across the studies, as seen in Table 2. All patients (n = 448) received EBRT, while BT boost was administered to 371 (82.8%) patients; 77 (17.2%) patients in 2 studies [
      • Oehler-Jänne C.
      • Seifert B.
      • Lütolf U.M.
      • Studer G.
      • Glanzmann C.
      • Ciernik I.F.
      Clinical outcome after treatment with a brachytherapy boost versus external beam boost for anal carcinoma.
      ,
      • Saarilahti K.
      • Arponen P.P.
      • Vaalavirta L.
      • et al.
      The effect of intensity-modulated radiotherapy and high dose rate brachytherapy on acute and late radiotherapy-related adverse events following chemoradiotherapy of anal cancer.
      ] received EBRT boost. Combination of EBRT and chemotherapy was administered across all 10 studies to n = 345 (77%) patients. The most common chemotherapy regimen was Fluorouracil (5FU) plus Mitomycin C (MMC), followed by 5FU plus cisplatin. In instances where combination chemotherapy was contra-indicated, single agent 5FU, oral Capecitabine or weekly cisplatin was used. Median dose of EBRT was 45 Gy (range: 40–51) in 25 fractions (20–27 fractions), delivered in 1.8–2.0 Gy per fraction as per institutional practices.
      Table 2Treatment Details. EBRT – external beam radiotherapy, BT – brachytherapy, HDR – high dose rate, LDR – low dose rate, CTV – clinical target volume, GTVd – gross tumor volume at diagnosis, GTVBT– gross tumor at BT, TRUS – transrectal ultrasound, 5FU – 5Fluorouracil, APR – abdomino-perineal resection, NR – not reported.
      StudyEBRT details median dose (range) (Gy)/fractions (range)BT details Technique, (n) Median dose (range) (Gy)/# fractions (range)BT prescription & planning detailsSurgery, nChemotherapy, nChemotherapy DrugsOverall Treatment Time (Days)
      Bertin et al, 2018
      • Bertin E.
      • Benezery K.
      • Kee D.L.C.
      • François E.
      • Evesque L.
      • Gautier M.
      • et al.
      Efficacy and tolerance of high-dose-rate brachytherapy boost after external radiotherapy in the treatment of squamous cell carcinoma of the anal canal.
      45 (36–50.4)/25 (20–28)Interstitial, (n = 46)

      12 Gy (10–18)/3 (2–6)
      Implant/planning system: Paris

      Planning imaging: post-implant CT scan

      CTV = GTVd + GTVBT
      n = 7 colostomies, post RT33 pts (71.17%) ConcomitantT ≥ 2 or N ≥ 1

      1) 5FU + Mitomycin C (n = 26)

      2) 5FU + Cisplatin (n = 6)
      44–51
      Varela Cagetti et al, 2019
      • Varela Cagetti L.
      • Zemmour C.
      • Salem N.
      • Minsat M.
      • Ferrè M.
      • Mailleux H.
      • et al.
      High-dose-rate vs. low-dose-rate interstitial brachytherapy boost for anal canal cancers.
      44.5 (30–46)Interstitial HDR, (n = 50)

      12 Gy (12–20)/3–4 fractions

      Interstitial LDR, (n = 50)

      18.5 Gy (14–24)/4 wires, treatment time 25.5 hours
      Implant/planning system: Paris

      Needles placed using Papillon’s template.

      Planning imaging: post- implant CT scan

      CTV = GTVd + 10 mm
      n = 8 salvage APR (3 LDR and 5 HDR)

      n = 1 wide local resection
      61 pts (61%) Concomitant1) 5FU + Mitomycin C (n = 33)

      2) 5FU + Cisplatin (n = 18)3) Weekly Cisplatin

      (n = 6)4) Xeloda

      (n = 4)
      Median: 55.5 (35–111)
      Doniec et al, 2006
      • Doniec J.M.
      • Schniewind B.
      • Kovács G.
      • et al.
      Multimodal therapy of anal cancer added by new endosonographic-guided brachytherapy.
      45/25Interstitial (n = 50)

      10 Gy (8–12)/2
      Implant/planning system: TRUS generated pre-plan

      3D dose planning: No

      CTV = TRUS-guided visual tumor
      n = 5 (10%) salvage APR; 4 local recurrence, 1 necrosis50 pts (100%) Concomitant5FU + Mitomycin C65–100
      Falk et al, 2014
      • Falk A.T.
      • Claren A.
      • Benezery K.
      • et al.
      Interstitial high-dose rate brachytherapy as boost for anal canal cancer.
      45 (43.2–52)/25 (23–26)Interstitial (n = 28)

      12 Gy (10–15)/3
      Implant/planning system: NR

      3D dose planning:

      CT scan images

      CTV = GTVd + 10 mm
      21 pts (75%) Concomitant1) 5FU + Mitomycin C (n = 17)

      2) 5FU + Cisplatin (n = 4)
      Median: 63 (38–74)
      Kapoor et al, 2014
      • Kapoor R.
      • Khosla D.
      • Shukla A.K.
      • Kumar R.
      • Gupta R.
      • Oinam A.S.
      • et al.
      Dosimetric and clinical outcome in image-based high-dose-rate interstitial brachytherapy for anal cancer.
      n = 16: 40–45/20–25Interstitial

      n = 7: 21 Gy/7

      n = 9: 18 Gy/6
      Implant system: Syed-Neblett template

      3D dose planning:

      CT scan images

      CTV = clinical exam at time BT
      n = 2 salvage APR due to recurrence16 pts (100%) Concomitant1) 5FU + Mitomycin C (n = 10)

      2) 5FU + Cisplatin (n = 6)
      Median: 24 (15–38)
      Kapp et al, 2001
      • Kapp K.S.
      • Geyer E.
      • Gebhart F.H.
      • et al.
      Experience with split-course external beam irradiation +/- chemotherapy and integrated Ir-192 high-dose-rate brachytherapy in the treatment of primary carcinomas of the anal canal.
      50–50.4/25–28Interstitial (n = 35) or Intraluminal (n = 4) after initial 30 Gy EBRT

      6 Gy/1

      2nd interstitial in patients with residual after 50 Gy EBRT (n = 7)

      6 Gy/1
      Implant/planning system: Paris

      3D dose planning: No

      CTV = NR

      n = 8 salvage APR due to uncontrolled tumor28 pts (72.0%) Concomitant5FU + Mitomycin CMedian: 58 (34–120)
      Lohnert et al, 1998
      • Lohnert M.
      • Doniec J.M.
      • Kovacs G.
      • et al.
      New method of radiotherapy for anal cancer with three-dimensional tumor reconstruction based on endoanal ultrasound and ultrasound-guided afterloading therapy.
      45/25Interstitial (n = 13) or Intraluminal (n = 5)

      8 Gy (4–28)/2 (1–7)
      Implant/planning system: NR

      3D dose planning:

      TRUS

      CTV = NR

      5 pts - prior incomplete Local Excision

      1pt. - prior APR

      1pt. - prior Colostomy
      9 pts (50%), primarily for T3 or T45FU + Mitomycin C77–91
      Oehler-Janne et al, 2007
      • Oehler-Jänne C.
      • Seifert B.
      • Lütolf U.M.
      • Studer G.
      • Glanzmann C.
      • Ciernik I.F.
      Clinical outcome after treatment with a brachytherapy boost versus external beam boost for anal carcinoma.
      45/25

      EBRT Boost (n = 47):

      14.4/8
      Interstitial, (n = 34)

      14 Gy/7 (over 3 days given 21 days post EBRT)
      Implant/planning system: Paris

      3D dose planning: No

      CTV = NR
      5 pts - Radical Surgery w Colostomy, prior to RT11 pts - salvage surgery

      (7 pts with EBRT and 4 pts with BT Boost)
      58 pts (71.6%) Concomitant5-FU + Mitomycin C (or Cisplatin if MMC contraindicated)59 +/- 19
      Saarilahti et al, 2008
      • Saarilahti K.
      • Arponen P.P.
      • Vaalavirta L.
      • et al.
      The effect of intensity-modulated radiotherapy and high dose rate brachytherapy on acute and late radiotherapy-related adverse events following chemoradiotherapy of anal cancer.
      45/25

      EBRT Boost (n = 30):8.5

      (5.4–18)/3–10
      Interstitial (n = 29)

      5–6 Gy/1–2 fractions
      Implant/planning system: Paris

      3D dose planning: No

      CTV = NR
      12 pts - APR due to local recurrence59 pts (100%) Concomitant5FU + Mitomycin C43 (31–79)
      Tagliaferri et al, 2015
      • Tagliaferri L.
      • Manfrida S.
      • Barbaro B.
      • Colangione M.M.
      • Masiello V.
      • Mattiucci G.C.
      • et al.
      MITHRA - multiparametric MR/CT image adapted brachytherapy (MR/CT-IABT) in anal canal cancer: a feasibility study.
      51 (44–58.5)/35 (22–32)Interstitial, (n = 11)

      4 Gy (3.5–7)/1–2 fractions
      Implant/planning system: 3D

      3D dose planning: Pre-implant MRI and post-implant CT

      CTV: post EBRT scar seen on MRI
      1pt - APR10 pts (90.9%) Concomitant1) 5FU + Mitomycin C (n = 9)2) 5FU alone

      (n = 1)
      95 (59–165)
      Total of 371 patients underwent brachytherapy boost after chemoradiation: nine studies used HDRBT exclusively (n = 271) and Varela Cagetti et al. used both HDR (n = 50) and low dose rate (LDR, n = 50). Details for brachytherapy technique, type of anaesthesia, target volumes and image guidance for placement of catheters and treatment planning are highlighted in Table 3. The main criteria for patient selection for BT among all studies was that tumour must be ≤2/3rd the circumference of the anal canal to limit sphincter dysfunction. All 10 studies employed interstitial brachytherapy technique and most prescribed dose based on the Paris system [
      • Pierquin B.
      • Dutreix A.
      • Paine C.H.
      • et al.
      The Paris system in interstitial radiation therapy.
      ]. Kapp et al. used both interstitial and intraluminal techniques and delivered 6 Gy boost in single fraction. In most cases, interstitial needles were placed using a custom designed perineal template with a anal/rectal cylinder of 20–25 mm external diameter. Most studies utilized 3D imaging (CT n = 5, TRUS n = 2, CT + MR n = 1) for treatment planning. All, expect one study, performed BT implants under general anaesthesia. The median dose was 6 Gy (range: 4–21) in median of 2 fractions (range: 1–7).
      Table 3Brachytherapy details. BT – brachytherapy, CR – complete response, PR – partial response, US – ultrasound, CT – computed tomography, TRUS – transrectal ultrasound, MRI – magnetic resonance imaging, NR – not reported.
      StudyPatient SelectionDosing SystemImplant# Of implantsAnesthesia TypeBT target volumeBT planningDoseSafety Margin
      Bertin et al, 2018
      • Bertin E.
      • Benezery K.
      • Kee D.L.C.
      • François E.
      • Evesque L.
      • Gautier M.
      • et al.
      Efficacy and tolerance of high-dose-rate brachytherapy boost after external radiotherapy in the treatment of squamous cell carcinoma of the anal canal.
      Tumors with ≤ 2/3 circumference anal canal were includedParis SystemCustom perineal template with 10 holes (spaced 12 mm apart).

      Anal cylinder with 20 mm external diameter
      1GeneralResidual tumor at the time of implantation and pre- treatment tumor volumeCTCR: 12 Gy in 3 fractions over 2 days,

      PR: 15 Gy in 3 fractions over 2 days
      4–5 mm from needles to anal mucosa
      Varela Cagetti, et al 2019
      • Varela Cagetti L.
      • Zemmour C.
      • Salem N.
      • Minsat M.
      • Ferrè M.
      • Mailleux H.
      • et al.
      High-dose-rate vs. low-dose-rate interstitial brachytherapy boost for anal canal cancers.
      Tumors with ≤ 1/2 circumference of anal canal were includedParis SystemPapillon template with needles spaced at 1 cm intervals.

      Anal cylinder with 25 mm external diameter
      1GeneralPre-treatment tumor volumeCTCR: 12 Gy in 3 fractions over 24 hours

      PR: 16 Gy in 4 fractions over 48 hours
      10 mm
      Doniec et al, 2006
      • Doniec J.M.
      • Schniewind B.
      • Kovács G.
      • et al.
      Multimodal therapy of anal cancer added by new endosonographic-guided brachytherapy.
      NRUS based visible target volume optimizedCustom perineal (RASHA) applicator

      Anal cylinder with 25 mm external diameter
      2 (7–10 days apart)Spinal or GeneralResidual tumor based on US as well pre- treatment tumor volumeTRUS8 or 12 Gy in 2 fractions5–10 mm
      Falk et al, 2014
      • Falk A.T.
      • Claren A.
      • Benezery K.
      • et al.
      Interstitial high-dose rate brachytherapy as boost for anal canal cancer.
      Tumours with ≤ 2/3 circumference of anal canal were included

      Circumferential tumors were excluded
      NRCustom perineal template with 10 holes (spaced 12 mm spart)

      Anal cylinder with 20 mm external diameter
      1GeneralPre- treatment tumor volumeCTCR: 12 Gy in 3 fractions over 24 hours

      PR: 15 Gy in 3 fractions over 24 hours
      4–5 mm from needles to anal mucosa
      Kapoor et al, 2014
      • Kapoor R.
      • Khosla D.
      • Shukla A.K.
      • Kumar R.
      • Gupta R.
      • Oinam A.S.
      • et al.
      Dosimetric and clinical outcome in image-based high-dose-rate interstitial brachytherapy for anal cancer.
      Tumors with ≤ 2/3 circumference of anal canal were included

      Tumor thickness ≤ 1 cm

      Patients with > 50% tumor regression after EBRT
      Volume-based optimizationSyed Neblett perineal template.

      Catheter separation of 1 cm
      1GeneralCombination of clinical exam (clinical residual tumor) and CT scan abnormalityCT21 Gy in 7 fractions twice daily

      18 Gy in 6 fractions twice daily
      NR
      Kapp et al, 2001
      • Kapp K.S.
      • Geyer E.
      • Gebhart F.H.
      • et al.
      Experience with split-course external beam irradiation +/- chemotherapy and integrated Ir-192 high-dose-rate brachytherapy in the treatment of primary carcinomas of the anal canal.
      NRIntraluminal BT: prescribed to 0.5 cm from applicator surface.

      Interstitial BT: Paris System
      Intraluminal - custom made cylinder of 20 mm diameter1GeneralPre- treatment tumor volume plus 0.5 cm marginNR6 GyNR
      Lohnert et al, 1998
      • Lohnert M.
      • Doniec J.M.
      • Kovacs G.
      • et al.
      New method of radiotherapy for anal cancer with three-dimensional tumor reconstruction based on endoanal ultrasound and ultrasound-guided afterloading therapy.
      NRUS based visible target volume optimizedCustom perineal (RASHA) applicator

      Anal cylinder with 25 mm external diameter
      2Spinal or GeneralResidual tumor after EBRT based on endoscopic USTRUS2 fractions of 4 or 6 Gy5–10 mm
      Oehler-Janne et al, 2007
      • Oehler-Jänne C.
      • Seifert B.
      • Lütolf U.M.
      • Studer G.
      • Glanzmann C.
      • Ciernik I.F.
      Clinical outcome after treatment with a brachytherapy boost versus external beam boost for anal carcinoma.
      T1-T3 tumors with ≤ 1 cm thickness after EBRTParis SystemCustom perineal template1Local or GeneralNRNR14 Gy in 7 fractions over 3 daysNR
      Saarilahti et al, 2008
      • Saarilahti K.
      • Arponen P.P.
      • Vaalavirta L.
      • et al.
      The effect of intensity-modulated radiotherapy and high dose rate brachytherapy on acute and late radiotherapy-related adverse events following chemoradiotherapy of anal cancer.
      Tumors with ≤ 1/2 circumference of anal canal were included

      No organ infiltration

      Circumferential tumors were excluded
      Paris SystemCustom perineal template with rectal cylinder of 22 mm diameter1–2NRResidual tumor at the time of implantationNROne or Two weekly 5–6 Gy Fractions3–5 mm left to skin surface
      Tagliaferri et al, 2015
      • Tagliaferri L.
      • Manfrida S.
      • Barbaro B.
      • Colangione M.M.
      • Masiello V.
      • Mattiucci G.C.
      • et al.
      MITHRA - multiparametric MR/CT image adapted brachytherapy (MR/CT-IABT) in anal canal cancer: a feasibility study.
      Patients with local residual disease or T4 at the time of diagnosis

      Tumors with ≤ 1/2 circumference of anal canal were included
      Paris System plus manual volume optimizationMartinez Universal Perineal Interstitial Template (MUPIT) or TPS 081 perineal template1–2SpinalResidual tumor or scar at the time of implantationMRI and CT3.5–7 Gy in 1–2 fractions; 2 fractions delivered 1 week apartNR

      Clinical outcomes

      Local control

      Eight out of 10 studies reported on LC, CR, PR rates, Table 4. LC reported by 3 studies ranged from 94% at 1 year to 81% at 5 years [
      • Bertin E.
      • Benezery K.
      • Kee D.L.C.
      • François E.
      • Evesque L.
      • Gautier M.
      • et al.
      Efficacy and tolerance of high-dose-rate brachytherapy boost after external radiotherapy in the treatment of squamous cell carcinoma of the anal canal.
      ,
      • Varela Cagetti L.
      • Zemmour C.
      • Salem N.
      • Minsat M.
      • Ferrè M.
      • Mailleux H.
      • et al.
      High-dose-rate vs. low-dose-rate interstitial brachytherapy boost for anal canal cancers.
      ,
      • Kapoor R.
      • Khosla D.
      • Shukla A.K.
      • Kumar R.
      • Gupta R.
      • Oinam A.S.
      • et al.
      Dosimetric and clinical outcome in image-based high-dose-rate interstitial brachytherapy for anal cancer.
      ]. Rate of CR ranged between 79.5% to 100% in 5 studies and the weighted mean CR was 90.5% in 141 patients from those 5 studies [
      • Oehler-Jänne C.
      • Seifert B.
      • Lütolf U.M.
      • Studer G.
      • Glanzmann C.
      • Ciernik I.F.
      Clinical outcome after treatment with a brachytherapy boost versus external beam boost for anal carcinoma.
      ,
      • Doniec J.M.
      • Schniewind B.
      • Kovács G.
      • et al.
      Multimodal therapy of anal cancer added by new endosonographic-guided brachytherapy.
      ,
      • Kapp K.S.
      • Geyer E.
      • Gebhart F.H.
      • et al.
      Experience with split-course external beam irradiation +/- chemotherapy and integrated Ir-192 high-dose-rate brachytherapy in the treatment of primary carcinomas of the anal canal.
      ,
      • Lohnert M.
      • Doniec J.M.
      • Kovacs G.
      • et al.
      New method of radiotherapy for anal cancer with three-dimensional tumor reconstruction based on endoanal ultrasound and ultrasound-guided afterloading therapy.
      ,
      • Tagliaferri L.
      • Manfrida S.
      • Barbaro B.
      • Colangione M.M.
      • Masiello V.
      • Mattiucci G.C.
      • et al.
      MITHRA - multiparametric MR/CT image adapted brachytherapy (MR/CT-IABT) in anal canal cancer: a feasibility study.
      ]. Kapp et al reported PR rate of 20.5% and CR rate of 79.5%, indicating overall response in all patients treated with HDRBT [
      • Kapp K.S.
      • Geyer E.
      • Gebhart F.H.
      • et al.
      Experience with split-course external beam irradiation +/- chemotherapy and integrated Ir-192 high-dose-rate brachytherapy in the treatment of primary carcinomas of the anal canal.
      ].
      Table 4Clinical Outcomes. BT – brachytherapy, LC – local control, CR – complete response, PR – partial response, LF – local failure, RF – regional failure, DFR – distant failure rate, MFS – metastasis free survival, OS – overall survival, DFS – disease free survival, CFS – colostomy free survival.
      StudynPatients undergoing BT, nFollow-up (months), (range)LC, CR/PR rateLF, nRF, nDFR or MFSOSDFSSphincter Preservation Rate or Sphincter DysfunctionCFS
      Bertin et al, 2018
      • Bertin E.
      • Benezery K.
      • Kee D.L.C.
      • François E.
      • Evesque L.
      • Gautier M.
      • et al.
      Efficacy and tolerance of high-dose-rate brachytherapy boost after external radiotherapy in the treatment of squamous cell carcinoma of the anal canal.
      464661 (9–145)LC:

      5 yr − 81.2% (SE 6.6%)
      15.2% (SE 6.1%)NR5 yr MFS: 88.7% (SE 4.8%)5-yr: 90% (SE 4.7%)70% (SE 7.6%)Sphincter Dysfunction:

      n = 2 (4.4%), due to ulceration or severe incontinence
      80%
      Varela Cagetti, et al 2019
      • Varela Cagetti L.
      • Zemmour C.
      • Salem N.
      • Minsat M.
      • Ferrè M.
      • Mailleux H.
      • et al.
      High-dose-rate vs. low-dose-rate interstitial brachytherapy boost for anal canal cancers.
      10010042.2LC: 90%LDR 93% vs HDR 86%

      (p = 0.38)
      n = 9 (9%)LDR 8% vs HDR 10%

      (p = 0.73)
      NRNR5-yr: 94%

      LDR 97% vs HDR 93%
      5-yr DFS: 82%LDR 88% vs HDR 72%

      (p = 0.21)
      NR92%LDR 95% vs HDR 86%

      (p = 0.21)
      Doniec et al, 2006
      • Doniec J.M.
      • Schniewind B.
      • Kovács G.
      • et al.
      Multimodal therapy of anal cancer added by new endosonographic-guided brachytherapy.
      505034 (6–96)CR: n = 47 (92%)n = 4 (8%)NRDFR: n = 1 (2%)5-yr: 74%

      T1/T2: 88%

      T3/T4: 67%
      5-yr: 82%Sphincter Dysfunction: n = 10 (20%); 5 patients (10%) had recurrent/residual disease requiring APR
      Falk et al, 2014
      • Falk A.T.
      • Claren A.
      • Benezery K.
      • et al.
      Interstitial high-dose rate brachytherapy as boost for anal canal cancer.
      282827.5NR2-yr LRFS: 83% (SE 7.8%)NR2 yr MFS: 81.9% (SE 9.5%)2-yr: 71.8% (SE 10.7%)2-yr: 87.7% (SE 8.25)Sphincter Dysfunction:

      1pt definitive sphincter amputation
      75%
      Kapoor et al, 2014
      • Kapoor R.
      • Khosla D.
      • Shukla A.K.
      • Kumar R.
      • Gupta R.
      • Oinam A.S.
      • et al.
      Dosimetric and clinical outcome in image-based high-dose-rate interstitial brachytherapy for anal cancer.
      161641LC:

      1 yr − 93.8%

      2 yr − 87.5%
      n = 2 (16.5%)NRn = 1 (6%)NRNRSphincter preservation rate = 87.5%
      Kapp et al, 2001
      • Kapp K.S.
      • Geyer E.
      • Gebhart F.H.
      • et al.
      Experience with split-course external beam irradiation +/- chemotherapy and integrated Ir-192 high-dose-rate brachytherapy in the treatment of primary carcinomas of the anal canal.
      393933CR: n = 31 (79.5%)

      PR: n = 8 (20.5%)
      n = 7 (18%)Locoregional control:

      3-yr: 81%

      5-yr: 76%
      n = 1 (2.5%)NR3-yr: 80%

      5-yr: 76%
      Sphincter preservation: 77% (overall), 97% (in patients with LRC)Full anal continence

      (28/30, 93%)
      78%
      Lohnert et al, 1998
      • Lohnert M.
      • Doniec J.M.
      • Kovacs G.
      • et al.
      New method of radiotherapy for anal cancer with three-dimensional tumor reconstruction based on endoanal ultrasound and ultrasound-guided afterloading therapy.
      181824CR: 100%n = 2 (11.1%)NRNR2-yr: 100%NRSphincter preservation rate = 94%NR
      Oehler-Janne et al, 2007
      • Oehler-Jänne C.
      • Seifert B.
      • Lütolf U.M.
      • Studer G.
      • Glanzmann C.
      • Ciernik I.F.
      Clinical outcome after treatment with a brachytherapy boost versus external beam boost for anal carcinoma.
      8134EBRT: 45 (+/- 33)BT: 60

      (+/- 34)
      CR: 93.4% (in patients without prior surgery)5-yr (NSS)

      EBRT boost: 15.4%

      BT boost: 10.3%
      5-yr Inguinal Recurrence Rate

      EBRT: 5.3%

      BT: 7.2%
      EBRT: 6%

      BT: 3%
      5-yr (NSS)

      EBRT: 66%

      BT: 66%10-yr

      (NSS)

      EBRT: 52%

      BT: 44%
      5-yr (and 10-yr); NSS

      EBRT: 73%

      BT: 76%
      10-yr sphincter preservation rate

      EBRT: 82%

      BT: 85%
      NR
      Tagliaferri et al, 2015
      • Tagliaferri L.
      • Manfrida S.
      • Barbaro B.
      • Colangione M.M.
      • Masiello V.
      • Mattiucci G.C.
      • et al.
      MITHRA - multiparametric MR/CT image adapted brachytherapy (MR/CT-IABT) in anal canal cancer: a feasibility study.
      111125 (7–36)CR: 91%1 patient with persistent disease did not complete EBRT/CTNRNRNRNRNR81%

      Failure

      Local (LF), regional (RF) and distant (DF) failure are detailed in Table 4. Mean rate of LF across 9 studies was 12.3% (SD 3.6%, range: 8% − 18%). [
      • Oehler-Jänne C.
      • Seifert B.
      • Lütolf U.M.
      • Studer G.
      • Glanzmann C.
      • Ciernik I.F.
      Clinical outcome after treatment with a brachytherapy boost versus external beam boost for anal carcinoma.
      ,
      • Bertin E.
      • Benezery K.
      • Kee D.L.C.
      • François E.
      • Evesque L.
      • Gautier M.
      • et al.
      Efficacy and tolerance of high-dose-rate brachytherapy boost after external radiotherapy in the treatment of squamous cell carcinoma of the anal canal.
      ,
      • Varela Cagetti L.
      • Zemmour C.
      • Salem N.
      • Minsat M.
      • Ferrè M.
      • Mailleux H.
      • et al.
      High-dose-rate vs. low-dose-rate interstitial brachytherapy boost for anal canal cancers.
      ,
      • Kapoor R.
      • Khosla D.
      • Shukla A.K.
      • Kumar R.
      • Gupta R.
      • Oinam A.S.
      • et al.
      Dosimetric and clinical outcome in image-based high-dose-rate interstitial brachytherapy for anal cancer.
      ,
      • Doniec J.M.
      • Schniewind B.
      • Kovács G.
      • et al.
      Multimodal therapy of anal cancer added by new endosonographic-guided brachytherapy.
      ,
      • Kapp K.S.
      • Geyer E.
      • Gebhart F.H.
      • et al.
      Experience with split-course external beam irradiation +/- chemotherapy and integrated Ir-192 high-dose-rate brachytherapy in the treatment of primary carcinomas of the anal canal.
      ,
      • Lohnert M.
      • Doniec J.M.
      • Kovacs G.
      • et al.
      New method of radiotherapy for anal cancer with three-dimensional tumor reconstruction based on endoanal ultrasound and ultrasound-guided afterloading therapy.
      ,
      • Tagliaferri L.
      • Manfrida S.
      • Barbaro B.
      • Colangione M.M.
      • Masiello V.
      • Mattiucci G.C.
      • et al.
      MITHRA - multiparametric MR/CT image adapted brachytherapy (MR/CT-IABT) in anal canal cancer: a feasibility study.
      ,
      • Falk A.T.
      • Claren A.
      • Benezery K.
      • et al.
      Interstitial high-dose rate brachytherapy as boost for anal canal cancer.
      ] In the study by Varela Cagetti et al. rate of LF was similar in patients undergoing HDR or LDR brachytherapy (8% and 10%, respectively, p = 0.73) [
      • Varela Cagetti L.
      • Zemmour C.
      • Salem N.
      • Minsat M.
      • Ferrè M.
      • Mailleux H.
      • et al.
      High-dose-rate vs. low-dose-rate interstitial brachytherapy boost for anal canal cancers.
      ] Oehler-Janne et al. did not find a significant difference in 5-year LF among patients who underwent BT boost (10.3%) compared to those who received EBRT (15.4%), even though there were more failures in cohort not receiving BT [
      • Oehler-Jänne C.
      • Seifert B.
      • Lütolf U.M.
      • Studer G.
      • Glanzmann C.
      • Ciernik I.F.
      Clinical outcome after treatment with a brachytherapy boost versus external beam boost for anal carcinoma.
      ].
      RF was reported in 2 out of 10 studies [
      • Oehler-Jänne C.
      • Seifert B.
      • Lütolf U.M.
      • Studer G.
      • Glanzmann C.
      • Ciernik I.F.
      Clinical outcome after treatment with a brachytherapy boost versus external beam boost for anal carcinoma.
      ,
      • Kapp K.S.
      • Geyer E.
      • Gebhart F.H.
      • et al.
      Experience with split-course external beam irradiation +/- chemotherapy and integrated Ir-192 high-dose-rate brachytherapy in the treatment of primary carcinomas of the anal canal.
      ] The 3-year and 5-year locoregional control in Kapp et al. study was 81% and 76% respectively [
      • Kapp K.S.
      • Geyer E.
      • Gebhart F.H.
      • et al.
      Experience with split-course external beam irradiation +/- chemotherapy and integrated Ir-192 high-dose-rate brachytherapy in the treatment of primary carcinomas of the anal canal.
      ] Oehler-Janne et al. reported a 5-year inguinal recurrence of 7.2% in patients with BT boost compared to 5.3% in patients with EBRT boost (p > 0.05) [
      • Oehler-Jänne C.
      • Seifert B.
      • Lütolf U.M.
      • Studer G.
      • Glanzmann C.
      • Ciernik I.F.
      Clinical outcome after treatment with a brachytherapy boost versus external beam boost for anal carcinoma.
      ].
      Distant failure rate (DFR) or metastasis free survival (MFS) was reported in 6 studies, Table 4. One study reported a 2-year MFS of 81.9 (SE 9.5%) [
      • Falk A.T.
      • Claren A.
      • Benezery K.
      • et al.
      Interstitial high-dose rate brachytherapy as boost for anal canal cancer.
      ] Another reported 5-year MFS of 88.7 % (SE 4.8%).(19) All other 4 studies reported DFR ranging between 2% and 6% [
      • Oehler-Jänne C.
      • Seifert B.
      • Lütolf U.M.
      • Studer G.
      • Glanzmann C.
      • Ciernik I.F.
      Clinical outcome after treatment with a brachytherapy boost versus external beam boost for anal carcinoma.
      ,
      • Kapoor R.
      • Khosla D.
      • Shukla A.K.
      • Kumar R.
      • Gupta R.
      • Oinam A.S.
      • et al.
      Dosimetric and clinical outcome in image-based high-dose-rate interstitial brachytherapy for anal cancer.
      ,
      • Doniec J.M.
      • Schniewind B.
      • Kovács G.
      • et al.
      Multimodal therapy of anal cancer added by new endosonographic-guided brachytherapy.
      ,
      • Kapp K.S.
      • Geyer E.
      • Gebhart F.H.
      • et al.
      Experience with split-course external beam irradiation +/- chemotherapy and integrated Ir-192 high-dose-rate brachytherapy in the treatment of primary carcinomas of the anal canal.
      ].

      Survival

      Survival outcomes were reported in six studies with total of 226 patients, Table 4. [
      • Oehler-Jänne C.
      • Seifert B.
      • Lütolf U.M.
      • Studer G.
      • Glanzmann C.
      • Ciernik I.F.
      Clinical outcome after treatment with a brachytherapy boost versus external beam boost for anal carcinoma.
      ,
      • Bertin E.
      • Benezery K.
      • Kee D.L.C.
      • François E.
      • Evesque L.
      • Gautier M.
      • et al.
      Efficacy and tolerance of high-dose-rate brachytherapy boost after external radiotherapy in the treatment of squamous cell carcinoma of the anal canal.
      ,
      • Varela Cagetti L.
      • Zemmour C.
      • Salem N.
      • Minsat M.
      • Ferrè M.
      • Mailleux H.
      • et al.
      High-dose-rate vs. low-dose-rate interstitial brachytherapy boost for anal canal cancers.
      ,
      • Doniec J.M.
      • Schniewind B.
      • Kovács G.
      • et al.
      Multimodal therapy of anal cancer added by new endosonographic-guided brachytherapy.
      ,
      • Lohnert M.
      • Doniec J.M.
      • Kovacs G.
      • et al.
      New method of radiotherapy for anal cancer with three-dimensional tumor reconstruction based on endoanal ultrasound and ultrasound-guided afterloading therapy.
      ,
      • Falk A.T.
      • Claren A.
      • Benezery K.
      • et al.
      Interstitial high-dose rate brachytherapy as boost for anal canal cancer.
      ] The mean of median follow up was 41.5 months (SD 16 months, R 24 – 61 months).
      Five studies reported DFS for 219 patients, all treated with brachytherapy in combination with EBRT and chemo [
      • Oehler-Jänne C.
      • Seifert B.
      • Lütolf U.M.
      • Studer G.
      • Glanzmann C.
      • Ciernik I.F.
      Clinical outcome after treatment with a brachytherapy boost versus external beam boost for anal carcinoma.
      ,
      • Bertin E.
      • Benezery K.
      • Kee D.L.C.
      • François E.
      • Evesque L.
      • Gautier M.
      • et al.
      Efficacy and tolerance of high-dose-rate brachytherapy boost after external radiotherapy in the treatment of squamous cell carcinoma of the anal canal.
      ,
      • Varela Cagetti L.
      • Zemmour C.
      • Salem N.
      • Minsat M.
      • Ferrè M.
      • Mailleux H.
      • et al.
      High-dose-rate vs. low-dose-rate interstitial brachytherapy boost for anal canal cancers.
      ,
      • Doniec J.M.
      • Schniewind B.
      • Kovács G.
      • et al.
      Multimodal therapy of anal cancer added by new endosonographic-guided brachytherapy.
      ,
      • Kapp K.S.
      • Geyer E.
      • Gebhart F.H.
      • et al.
      Experience with split-course external beam irradiation +/- chemotherapy and integrated Ir-192 high-dose-rate brachytherapy in the treatment of primary carcinomas of the anal canal.
      ] The weighted mean 5-year DFS was 77.5 % (SD 3.12, R 70% − 82%). Two studies reported 2- and 3-year DFS of 87.7% (SE 8.25%), and 80%, respectively [
      • Kapp K.S.
      • Geyer E.
      • Gebhart F.H.
      • et al.
      Experience with split-course external beam irradiation +/- chemotherapy and integrated Ir-192 high-dose-rate brachytherapy in the treatment of primary carcinomas of the anal canal.
      ,
      • Falk A.T.
      • Claren A.
      • Benezery K.
      • et al.
      Interstitial high-dose rate brachytherapy as boost for anal canal cancer.
      ] None of the studies provided further information regarding additional local or systemic therapies.
      Four studies reported 5-year OS ranging from 74% to 93% [
      • Oehler-Jänne C.
      • Seifert B.
      • Lütolf U.M.
      • Studer G.
      • Glanzmann C.
      • Ciernik I.F.
      Clinical outcome after treatment with a brachytherapy boost versus external beam boost for anal carcinoma.
      ,
      • Bertin E.
      • Benezery K.
      • Kee D.L.C.
      • François E.
      • Evesque L.
      • Gautier M.
      • et al.
      Efficacy and tolerance of high-dose-rate brachytherapy boost after external radiotherapy in the treatment of squamous cell carcinoma of the anal canal.
      ,
      • Varela Cagetti L.
      • Zemmour C.
      • Salem N.
      • Minsat M.
      • Ferrè M.
      • Mailleux H.
      • et al.
      High-dose-rate vs. low-dose-rate interstitial brachytherapy boost for anal canal cancers.
      ,
      • Doniec J.M.
      • Schniewind B.
      • Kovács G.
      • et al.
      Multimodal therapy of anal cancer added by new endosonographic-guided brachytherapy.
      ]. Weighed mean 5-year OS among 180 patients included in these 4 studies was 81.9%. Two studies reported 2-year OS and the weighted mean was 82.8% in 46 patients [
      • Lohnert M.
      • Doniec J.M.
      • Kovacs G.
      • et al.
      New method of radiotherapy for anal cancer with three-dimensional tumor reconstruction based on endoanal ultrasound and ultrasound-guided afterloading therapy.
      ,
      • Falk A.T.
      • Claren A.
      • Benezery K.
      • et al.
      Interstitial high-dose rate brachytherapy as boost for anal canal cancer.
      ]. Oehler-Janne et al. did not show any difference in 5-year OS between patients treated with BT boost or EBRT boost [
      • Oehler-Jänne C.
      • Seifert B.
      • Lütolf U.M.
      • Studer G.
      • Glanzmann C.
      • Ciernik I.F.
      Clinical outcome after treatment with a brachytherapy boost versus external beam boost for anal carcinoma.
      ]. Similarly, there was no difference in 5-year OS between patients receiving HDR or LDR BT boost as reported by Varela Cagetti et al. [
      • Varela Cagetti L.
      • Zemmour C.
      • Salem N.
      • Minsat M.
      • Ferrè M.
      • Mailleux H.
      • et al.
      High-dose-rate vs. low-dose-rate interstitial brachytherapy boost for anal canal cancers.
      ] Patients with early (T1 or T2) disease had significantly better 5-year OS (88%) compared to those with advanced (T3 or T4) disease (67%) [
      • Doniec J.M.
      • Schniewind B.
      • Kovács G.
      • et al.
      Multimodal therapy of anal cancer added by new endosonographic-guided brachytherapy.
      ].

      Sphincter preservation and colostomy free survival

      Six studies with 185 patients treated with brachytherapy reported colostomy-free survival, an important surrogate for sphincter preservation [
      • Oehler-Jänne C.
      • Seifert B.
      • Lütolf U.M.
      • Studer G.
      • Glanzmann C.
      • Ciernik I.F.
      Clinical outcome after treatment with a brachytherapy boost versus external beam boost for anal carcinoma.
      ,
      • Kapoor R.
      • Khosla D.
      • Shukla A.K.
      • Kumar R.
      • Gupta R.
      • Oinam A.S.
      • et al.
      Dosimetric and clinical outcome in image-based high-dose-rate interstitial brachytherapy for anal cancer.
      ,
      • Doniec J.M.
      • Schniewind B.
      • Kovács G.
      • et al.
      Multimodal therapy of anal cancer added by new endosonographic-guided brachytherapy.
      ,
      • Kapp K.S.
      • Geyer E.
      • Gebhart F.H.
      • et al.
      Experience with split-course external beam irradiation +/- chemotherapy and integrated Ir-192 high-dose-rate brachytherapy in the treatment of primary carcinomas of the anal canal.
      ,
      • Lohnert M.
      • Doniec J.M.
      • Kovacs G.
      • et al.
      New method of radiotherapy for anal cancer with three-dimensional tumor reconstruction based on endoanal ultrasound and ultrasound-guided afterloading therapy.
      ,
      • Falk A.T.
      • Claren A.
      • Benezery K.
      • et al.
      Interstitial high-dose rate brachytherapy as boost for anal canal cancer.
      ] With mean follow up of 48.2 months, the weighted mean rate of colostomy free survival was 81.7% (range: 24–120). Based on available data from these studies, there does not appear to be a direct link of organ dysfunction leading to colostomy and brachytherapy treatments. Falk et al. had one patient with definitive sphincter amputation, prior to starting any treatment [
      • Falk A.T.
      • Claren A.
      • Benezery K.
      • et al.
      Interstitial high-dose rate brachytherapy as boost for anal canal cancer.
      ] Lohnert et al. had one patient who was incontinent due to internal sphincter damage, unrelated to radiation treatment [
      • Lohnert M.
      • Doniec J.M.
      • Kovacs G.
      • et al.
      New method of radiotherapy for anal cancer with three-dimensional tumor reconstruction based on endoanal ultrasound and ultrasound-guided afterloading therapy.
      ] Kapp et al. reported 77% sphincter preservation in their entire study population and 97% in those with complete locoregional control. Oehler-Janne et al. reported the 10-year sphincter preservation rate of 85% in patients who received BT boost compared to 82% in those that received EBRT boost [
      • Oehler-Jänne C.
      • Seifert B.
      • Lütolf U.M.
      • Studer G.
      • Glanzmann C.
      • Ciernik I.F.
      Clinical outcome after treatment with a brachytherapy boost versus external beam boost for anal carcinoma.
      ].

      Toxicity and complications

      Toxicity was reported by all studies, however reporting was not consistent among them, Table 5. Eight studies reported acute toxicity in patients undergoing brachytherapy. Most of the patients suffered from grade 2 or lower toxicity and there were only 9 cases of Grade 3 acute toxicity, which included rectal pain,[
      • Bertin E.
      • Benezery K.
      • Kee D.L.C.
      • François E.
      • Evesque L.
      • Gautier M.
      • et al.
      Efficacy and tolerance of high-dose-rate brachytherapy boost after external radiotherapy in the treatment of squamous cell carcinoma of the anal canal.
      ] dermatitis/mucositis [
      • Kapoor R.
      • Khosla D.
      • Shukla A.K.
      • Kumar R.
      • Gupta R.
      • Oinam A.S.
      • et al.
      Dosimetric and clinical outcome in image-based high-dose-rate interstitial brachytherapy for anal cancer.
      ], and sphincter necrosis [
      • Doniec J.M.
      • Schniewind B.
      • Kovács G.
      • et al.
      Multimodal therapy of anal cancer added by new endosonographic-guided brachytherapy.
      ] Oehler-Janne et al. compared rates of grade 3–4 acute toxicity between patients receiving EBRT an BT and found that significantly more patients treated with EBRT suffered toxicity 43% versus 15% with BT (p = 0.008) [
      • Oehler-Jänne C.
      • Seifert B.
      • Lütolf U.M.
      • Studer G.
      • Glanzmann C.
      • Ciernik I.F.
      Clinical outcome after treatment with a brachytherapy boost versus external beam boost for anal carcinoma.
      ].
      Table 5Acute and chronic toxicities. GI – gastrointestinal, GU – genitourinary.
      StudyGrade 1 (G1) and Grade 2 (G2)Grade

      ≥3
      Bertin et al, 2018
      • Bertin E.
      • Benezery K.
      • Kee D.L.C.
      • François E.
      • Evesque L.
      • Gautier M.
      • et al.
      Efficacy and tolerance of high-dose-rate brachytherapy boost after external radiotherapy in the treatment of squamous cell carcinoma of the anal canal.
      AcuteGI: G1 – 33 (71.7%), G2 – 3

      (6.5%)GU: G1 – 19 (41.3%)

      , G2 − 4.3%

      ChronicGI: G1 – 26 (56.5%), G2 – 4

      (8.7%)GU: G1 – 2 (4.3%), G2 – 1

      (2.2%)
      AcuteGI: G3 – 1

      (2.2%)

      ChronicGI: G3 – 1 (2.2%), G4 – 1

      (2.2%)GU: G3 – 1

      (2.2%)
      Varela Cagetti et al, 2019
      • Varela Cagetti L.
      • Zemmour C.
      • Salem N.
      • Minsat M.
      • Ferrè M.
      • Mailleux H.
      • et al.
      High-dose-rate vs. low-dose-rate interstitial brachytherapy boost for anal canal cancers.
      AcuteProctitis: G1 – 10 (10%), G2 – 15

      (15%)Rectal bleeding: G1 – 4 (4%), G2 – 3

      (3%)Diarrhea: G1 – 1 (1%), G2 – 4

      (4%)

      Chronic

      LDR (n= 28, 56%) vs HDR (n= 17, 34%) (p= 0.03)*Proctitis: G1 – 7 (7%), G2 – 13

      (13%)Rectal bleeding: G1 – 5 (5%), G2 – 10

      (10%)Incontinence: G1 – 2 (2%), G2 – 9

      (9%)Diarrhea: G1 – 1 (1%), G2 – 5

      (5%)Rectal stenosis: G2 – 1

      (1%)GU: G1 – 2 (2%), G2 – 5

      (5%)Dyspareunia: G2 – 1

      (1%)Vaginal stenosis: G2 – 2

      (2%)
      Chronic*Proctitis: G3 – 3

      (3%)Rectal bleeding: G3 – 1

      (1%)Bone fracture: G3 – 1

      (1%)

      *One patient underwent temporary colostomy
      Doniec et al, 2006
      • Doniec J.M.
      • Schniewind B.
      • Kovács G.
      • et al.
      Multimodal therapy of anal cancer added by new endosonographic-guided brachytherapy.
      NRAcuteSphincter Necrosis

      (n = 1, 2%)

      ChronicIncontinence*

      (n = 3, 6%)

      *2 patients required colostomy; both were incontinent prior to therapy due to tumor infiltration
      Falk et al, 2014
      • Falk A.T.
      • Claren A.
      • Benezery K.
      • et al.
      Interstitial high-dose rate brachytherapy as boost for anal canal cancer.
      Acute

      GI: G1 – 40.7%,

      GU: G1 – 37%

      Cutaneous: G1 – 3.7%

      Chronic

      Grade 1–43.1%; Grade 2–22%
      ChronicAnal ulceration

      (n = 1, 3.5%)Necrosis

      (n = 1, 3.5%)*

      *required colostomy
      Kapoor et al, 2014
      • Kapoor R.
      • Khosla D.
      • Shukla A.K.
      • Kumar R.
      • Gupta R.
      • Oinam A.S.
      • et al.
      Dosimetric and clinical outcome in image-based high-dose-rate interstitial brachytherapy for anal cancer.
      AcuteDermatitis: G1 – 7 (44%), G2 – 6

      (37%)

      Proctitis: G1 − 5 (31%), G2 − 2 (12.5%).

      Mucositis: G2 − 8 (50%)

      ChronicDermatitis

      (n = 3, 19%)Incontinence

      (n = 1, 6%)Fibrosis

      (n = 4, 25%)
      Acute:Dermatitis

      (n = 3, 19%)Mucositis

      (n = 3, 19%)

      Kapp et al, 2001
      • Kapp K.S.
      • Geyer E.
      • Gebhart F.H.
      • et al.
      Experience with split-course external beam irradiation +/- chemotherapy and integrated Ir-192 high-dose-rate brachytherapy in the treatment of primary carcinomas of the anal canal.
      AcuteDiarrhea

      (88%)Perineal, vulvar/scrotal dermatitis

      (75%)Dysuria

      (19%)

      ChronicProctitis:

      (n = 1, 2.5%)Sphincter Dysfunction (non-surgical)

      (n = 1, 2.5%),
      ChronicUlceration

      (n = 7, 18%)

      3 pts required temporary colostomy - occurred at the initial site of primary
      Lohnert et al, 1998
      • Lohnert M.
      • Doniec J.M.
      • Kovacs G.
      • et al.
      New method of radiotherapy for anal cancer with three-dimensional tumor reconstruction based on endoanal ultrasound and ultrasound-guided afterloading therapy.
      AcuteHematoma

      (n = 1) due to needle implantation

      ChronicProctitis

      (n = 1, 6%)Perianal ulcer

      (n = 1, 6%)
      ChronicIncontinence

      (n = 1, 6%)

      Required Hartmann procedure
      Oehler-Janne et al, 2007
      • Oehler-Jänne C.
      • Seifert B.
      • Lütolf U.M.
      • Studer G.
      • Glanzmann C.
      • Ciernik I.F.
      Clinical outcome after treatment with a brachytherapy boost versus external beam boost for anal carcinoma.
      Chronic:Overall: EBRT 30% vs BT 19%

      (p = 0.5)Proctitis G2: EBRT 32% vs BT 19%

      (p = 0.4)Incontinence G1-2: EBRT 28% vs BT 18%

      (p = 0.5)Qualitative sphincter digital pressure impairment: EBRT 29% vs BT 37%

      (p = 0.6)
      AcuteG3/4: EBRT 43% vs BT 15%,

      (p = 0.008)

      G3/4 dermatitis: EBRT 23% vs BT 8%

      Saarilahti et al, 2008
      • Saarilahti K.
      • Arponen P.P.
      • Vaalavirta L.
      • et al.
      The effect of intensity-modulated radiotherapy and high dose rate brachytherapy on acute and late radiotherapy-related adverse events following chemoradiotherapy of anal cancer.
      Acute

      Proctitis G ≥ 2: EBRT 37% vs BT 10% (p = 0.065)

      Skin toxicity G2-3: EBRT 21% vs BT 0%
      NR
      Tagliaferri et al, 2015
      • Tagliaferri L.
      • Manfrida S.
      • Barbaro B.
      • Colangione M.M.
      • Masiello V.
      • Mattiucci G.C.
      • et al.
      MITHRA - multiparametric MR/CT image adapted brachytherapy (MR/CT-IABT) in anal canal cancer: a feasibility study.
      AcuteFecal incontinence

      (n = 1, 9%)Hemorrhoids

      (n = 2, 18%)

      ChronicAnal fibrosis

      (n = 1, 9%)Incontinence

      (n = 1, 9%)Proctitis

      (n = 1, 9%)
      NR
      Nine studies reported on late toxicity in patients undergoing brachytherapy with a complication rate of 25.7% among 362 patients. There were six studies with 194 patients that graded late toxicity [
      • Oehler-Jänne C.
      • Seifert B.
      • Lütolf U.M.
      • Studer G.
      • Glanzmann C.
      • Ciernik I.F.
      Clinical outcome after treatment with a brachytherapy boost versus external beam boost for anal carcinoma.
      ,
      • Saarilahti K.
      • Arponen P.P.
      • Vaalavirta L.
      • et al.
      The effect of intensity-modulated radiotherapy and high dose rate brachytherapy on acute and late radiotherapy-related adverse events following chemoradiotherapy of anal cancer.
      ,
      • Bertin E.
      • Benezery K.
      • Kee D.L.C.
      • François E.
      • Evesque L.
      • Gautier M.
      • et al.
      Efficacy and tolerance of high-dose-rate brachytherapy boost after external radiotherapy in the treatment of squamous cell carcinoma of the anal canal.
      ,
      • Kapoor R.
      • Khosla D.
      • Shukla A.K.
      • Kumar R.
      • Gupta R.
      • Oinam A.S.
      • et al.
      Dosimetric and clinical outcome in image-based high-dose-rate interstitial brachytherapy for anal cancer.
      ,
      • Tagliaferri L.
      • Manfrida S.
      • Barbaro B.
      • Colangione M.M.
      • Masiello V.
      • Mattiucci G.C.
      • et al.
      MITHRA - multiparametric MR/CT image adapted brachytherapy (MR/CT-IABT) in anal canal cancer: a feasibility study.
      ,
      • Falk A.T.
      • Claren A.
      • Benezery K.
      • et al.
      Interstitial high-dose rate brachytherapy as boost for anal canal cancer.
      ]; across these studies. The most common late toxicity observed was grade 1 or 2 proctitis, and ranged from 2.5% to 20% [
      • Oehler-Jänne C.
      • Seifert B.
      • Lütolf U.M.
      • Studer G.
      • Glanzmann C.
      • Ciernik I.F.
      Clinical outcome after treatment with a brachytherapy boost versus external beam boost for anal carcinoma.
      ,
      • Saarilahti K.
      • Arponen P.P.
      • Vaalavirta L.
      • et al.
      The effect of intensity-modulated radiotherapy and high dose rate brachytherapy on acute and late radiotherapy-related adverse events following chemoradiotherapy of anal cancer.
      ,
      • Varela Cagetti L.
      • Zemmour C.
      • Salem N.
      • Minsat M.
      • Ferrè M.
      • Mailleux H.
      • et al.
      High-dose-rate vs. low-dose-rate interstitial brachytherapy boost for anal canal cancers.
      ,
      • Kapp K.S.
      • Geyer E.
      • Gebhart F.H.
      • et al.
      Experience with split-course external beam irradiation +/- chemotherapy and integrated Ir-192 high-dose-rate brachytherapy in the treatment of primary carcinomas of the anal canal.
      ,
      • Lohnert M.
      • Doniec J.M.
      • Kovacs G.
      • et al.
      New method of radiotherapy for anal cancer with three-dimensional tumor reconstruction based on endoanal ultrasound and ultrasound-guided afterloading therapy.
      ,
      • Tagliaferri L.
      • Manfrida S.
      • Barbaro B.
      • Colangione M.M.
      • Masiello V.
      • Mattiucci G.C.
      • et al.
      MITHRA - multiparametric MR/CT image adapted brachytherapy (MR/CT-IABT) in anal canal cancer: a feasibility study.
      ]. Incidence of grade 3 or higher proctitis was reported by Varela Cagetti et al. in 3 (3%) patients [
      • Varela Cagetti L.
      • Zemmour C.
      • Salem N.
      • Minsat M.
      • Ferrè M.
      • Mailleux H.
      • et al.
      High-dose-rate vs. low-dose-rate interstitial brachytherapy boost for anal canal cancers.
      ] Saarilahti et al. demonstrated that rate of proctitis was worse with EBRT compared to BT boost, 37% versus 10%, respectively (p = 0.065) [
      • Saarilahti K.
      • Arponen P.P.
      • Vaalavirta L.
      • et al.
      The effect of intensity-modulated radiotherapy and high dose rate brachytherapy on acute and late radiotherapy-related adverse events following chemoradiotherapy of anal cancer.
      ] Grade 1 and 2 incontinence was the second most common late toxicity and was observed in 6% to 18% of patients [
      • Oehler-Jänne C.
      • Seifert B.
      • Lütolf U.M.
      • Studer G.
      • Glanzmann C.
      • Ciernik I.F.
      Clinical outcome after treatment with a brachytherapy boost versus external beam boost for anal carcinoma.
      ,
      • Varela Cagetti L.
      • Zemmour C.
      • Salem N.
      • Minsat M.
      • Ferrè M.
      • Mailleux H.
      • et al.
      High-dose-rate vs. low-dose-rate interstitial brachytherapy boost for anal canal cancers.
      ,
      • Kapoor R.
      • Khosla D.
      • Shukla A.K.
      • Kumar R.
      • Gupta R.
      • Oinam A.S.
      • et al.
      Dosimetric and clinical outcome in image-based high-dose-rate interstitial brachytherapy for anal cancer.
      ,
      • Doniec J.M.
      • Schniewind B.
      • Kovács G.
      • et al.
      Multimodal therapy of anal cancer added by new endosonographic-guided brachytherapy.
      ,
      • Kapp K.S.
      • Geyer E.
      • Gebhart F.H.
      • et al.
      Experience with split-course external beam irradiation +/- chemotherapy and integrated Ir-192 high-dose-rate brachytherapy in the treatment of primary carcinomas of the anal canal.
      ,
      • Lohnert M.
      • Doniec J.M.
      • Kovacs G.
      • et al.
      New method of radiotherapy for anal cancer with three-dimensional tumor reconstruction based on endoanal ultrasound and ultrasound-guided afterloading therapy.
      ,
      • Tagliaferri L.
      • Manfrida S.
      • Barbaro B.
      • Colangione M.M.
      • Masiello V.
      • Mattiucci G.C.
      • et al.
      MITHRA - multiparametric MR/CT image adapted brachytherapy (MR/CT-IABT) in anal canal cancer: a feasibility study.
      ] There was no documented grade 3 or higher incontinence. Ulceration in the perianal skin or within the anal canal was documented in 2 studies: 1 (6%) patient in Lohnert et al. [
      • Lohnert M.
      • Doniec J.M.
      • Kovacs G.
      • et al.
      New method of radiotherapy for anal cancer with three-dimensional tumor reconstruction based on endoanal ultrasound and ultrasound-guided afterloading therapy.
      ] and 7 (18%) patients in Kapp et al. [
      • Kapp K.S.
      • Geyer E.
      • Gebhart F.H.
      • et al.
      Experience with split-course external beam irradiation +/- chemotherapy and integrated Ir-192 high-dose-rate brachytherapy in the treatment of primary carcinomas of the anal canal.
      ] Three of the 7 patients in Kapp et al. series required temporary colostomy due to substantial ulceration at the site of original disease. Rectal bleeding was a rare late complication and was reported in only one study.(20) Anal fibrosis and stenosis was reported in 10% to 25% of the patients [
      • Kapoor R.
      • Khosla D.
      • Shukla A.K.
      • Kumar R.
      • Gupta R.
      • Oinam A.S.
      • et al.
      Dosimetric and clinical outcome in image-based high-dose-rate interstitial brachytherapy for anal cancer.
      ,
      • Tagliaferri L.
      • Manfrida S.
      • Barbaro B.
      • Colangione M.M.
      • Masiello V.
      • Mattiucci G.C.
      • et al.
      MITHRA - multiparametric MR/CT image adapted brachytherapy (MR/CT-IABT) in anal canal cancer: a feasibility study.
      ]. Other rare long term toxicities include vaginal stenosis, dyspareunia, and early grade urinary irritable symptoms, listed in Table 4. Bertin et al. and Falk et al. did not formally reported on individual toxicities, but suggested grade 1–2 GI toxicity occurs in up to 2/3rd of patients, and grade 3 or higher toxicity occurs in 4.4%−7% of patients [
      • Bertin E.
      • Benezery K.
      • Kee D.L.C.
      • François E.
      • Evesque L.
      • Gautier M.
      • et al.
      Efficacy and tolerance of high-dose-rate brachytherapy boost after external radiotherapy in the treatment of squamous cell carcinoma of the anal canal.
      ,
      • Falk A.T.
      • Claren A.
      • Benezery K.
      • et al.
      Interstitial high-dose rate brachytherapy as boost for anal canal cancer.
      ].

      Discussion

      BT has been utilized for the treatment of anal cancer for many decades. A previous systematic review had shown benefit of BT boost in patients undergoing curative intent chemoradiotherapy for anal canal cancer [
      • Frakulli R.
      • Buwenge M.
      • Cammelli S.
      • Macchia G.
      • Farina E.
      • Arcelli A.
      • et al.
      Brachytherapy boost after chemoradiation in anal cancer: a systematic review.
      ]. However, 9 out 10 studies reviewed in that publication performed brachytherapy using LDR or PDR technique and only 1 study performed HDR brachytherapy. BT performed with LDR technique posed significant exposure risk to staff, patient and family members as well as required shielded hospital rooms. While PDR offer advantages of real-time dose-optimization similar to HDR and radiological benefit of longer treatment time similar to LDR, it also requires shielded hospital room, where patients have to admitted for the duration of pulsed treatment. HDRBT can have several advantages over LDR and PDR, and these include: outpatient treatment (same day implant and treatment), real-time dose optimization, ability to perform image-guided treatment (using MRI) and reduce dose to organs at risk, decrease risk to staff and patient’s family, as well as reduced recurring cost. The focus of this review is to summarize all available literature on HDRBT in anal cancer with regards to local control, overall survival, sphincter preservation, and complications.
      The pooled data demonstrated that the use of HDRBT in the treatment of anal cancer has a high rate of sphincter preservation and complete response to treatment as well as acceptable overall survival rate. Across seven studies with 194 patients, there was an 83.5% complete response to treatment [
      • Oehler-Jänne C.
      • Seifert B.
      • Lütolf U.M.
      • Studer G.
      • Glanzmann C.
      • Ciernik I.F.
      Clinical outcome after treatment with a brachytherapy boost versus external beam boost for anal carcinoma.
      ,
      • Doniec J.M.
      • Schniewind B.
      • Kovács G.
      • et al.
      Multimodal therapy of anal cancer added by new endosonographic-guided brachytherapy.
      ,
      • Kapp K.S.
      • Geyer E.
      • Gebhart F.H.
      • et al.
      Experience with split-course external beam irradiation +/- chemotherapy and integrated Ir-192 high-dose-rate brachytherapy in the treatment of primary carcinomas of the anal canal.
      ,
      • Lohnert M.
      • Doniec J.M.
      • Kovacs G.
      • et al.
      New method of radiotherapy for anal cancer with three-dimensional tumor reconstruction based on endoanal ultrasound and ultrasound-guided afterloading therapy.
      ,
      • Tagliaferri L.
      • Manfrida S.
      • Barbaro B.
      • Colangione M.M.
      • Masiello V.
      • Mattiucci G.C.
      • et al.
      MITHRA - multiparametric MR/CT image adapted brachytherapy (MR/CT-IABT) in anal canal cancer: a feasibility study.
      ]. Across six studies the weighted mean rate of sphincter preservation was 84.8% at a 39.7 month follow-up [
      • Oehler-Jänne C.
      • Seifert B.
      • Lütolf U.M.
      • Studer G.
      • Glanzmann C.
      • Ciernik I.F.
      Clinical outcome after treatment with a brachytherapy boost versus external beam boost for anal carcinoma.
      ,
      • Kapoor R.
      • Khosla D.
      • Shukla A.K.
      • Kumar R.
      • Gupta R.
      • Oinam A.S.
      • et al.
      Dosimetric and clinical outcome in image-based high-dose-rate interstitial brachytherapy for anal cancer.
      ,
      • Doniec J.M.
      • Schniewind B.
      • Kovács G.
      • et al.
      Multimodal therapy of anal cancer added by new endosonographic-guided brachytherapy.
      ,
      • Kapp K.S.
      • Geyer E.
      • Gebhart F.H.
      • et al.
      Experience with split-course external beam irradiation +/- chemotherapy and integrated Ir-192 high-dose-rate brachytherapy in the treatment of primary carcinomas of the anal canal.
      ,
      • Lohnert M.
      • Doniec J.M.
      • Kovacs G.
      • et al.
      New method of radiotherapy for anal cancer with three-dimensional tumor reconstruction based on endoanal ultrasound and ultrasound-guided afterloading therapy.
      ,
      • Falk A.T.
      • Claren A.
      • Benezery K.
      • et al.
      Interstitial high-dose rate brachytherapy as boost for anal canal cancer.
      ]. This is comparable, if not better than that published by Frakulli et al. for patients treated with LDR brachytherapy boost, where they demonstrated local/local–regional control of 78.6% and colostomy-free survival of 76.1% [
      • Frakulli R.
      • Buwenge M.
      • Cammelli S.
      • Macchia G.
      • Farina E.
      • Arcelli A.
      • et al.
      Brachytherapy boost after chemoradiation in anal cancer: a systematic review.
      ]. Most importantly, the biggest benefit of HDR over LDR is increased safety of patient, family members as well as staff monitoring the treatment. The 5-year overall survival and ranges between 74% and 95% and the weighted mean 5-year survival was 81.9%. This is similar to what has been observed after EBRT in randomized RTOG trials (9811 and 0529). [
      • Kachnic L.A.
      • Winter K.
      • Myerson R.J.
      • et al.
      RTOG 0529: a phase 2 evaluation of dose-painted intensity modulated radiation therapy in combination with 5-fluorouracil and mitomycin-C for the reduction of acute morbidity in carcinoma of the anal canal.
      ,
      • Gunderson L.L.
      • Winter K.A.
      • Ajani J.A.
      • 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.
      ] Gunderson et al reported 5-year OS of 78.% and 70.7% for patients who received mitomycin and cisplatin based chemotherapy, respectively [
      • Gunderson L.L.
      • Winter K.A.
      • Ajani J.A.
      • 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.
      ].
      The overall rate of acute toxicity with HDRBT was acceptable (74.8%) and comparable to RTOG 0529 trial that utilized modern imaging and EBRT (IMRT) techniques. [
      • Doniec J.M.
      • Schniewind B.
      • Kovács G.
      • et al.
      Multimodal therapy of anal cancer added by new endosonographic-guided brachytherapy.
      ] This is not unexpected as all patients included in this review also received EBRT in the first phase of treatment prior to HDRBT boost, suggesting that lower grade of toxicity is perhaps a function of low dose radiation to a larger area. Whereas, Grade 3 acute toxicity was only reported in 9 patients among 2 out of 10 studies analysed in this review [
      • Bertin E.
      • Benezery K.
      • Kee D.L.C.
      • François E.
      • Evesque L.
      • Gautier M.
      • et al.
      Efficacy and tolerance of high-dose-rate brachytherapy boost after external radiotherapy in the treatment of squamous cell carcinoma of the anal canal.
      ,
      • Kapoor R.
      • Khosla D.
      • Shukla A.K.
      • Kumar R.
      • Gupta R.
      • Oinam A.S.
      • et al.
      Dosimetric and clinical outcome in image-based high-dose-rate interstitial brachytherapy for anal cancer.
      ]. This is substantially lower than 21% and 15.7% reported in RTOG 9811 and 0529 trials, respectively [
      • Kachnic L.A.
      • Winter K.
      • Myerson R.J.
      • et al.
      RTOG 0529: a phase 2 evaluation of dose-painted intensity modulated radiation therapy in combination with 5-fluorouracil and mitomycin-C for the reduction of acute morbidity in carcinoma of the anal canal.
      ,
      • Gunderson L.L.
      • Winter K.A.
      • Ajani J.A.
      • 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.
      ]. There were no documented cases of sphincter necrosis in the acute or late term setting. Furthermore, direct comparison of patients receiving EBRT or BT boost by Oehler-Janne et al., demonstrated significantly lower late toxicity in patients treated with BT [
      • Oehler-Jänne C.
      • Seifert B.
      • Lütolf U.M.
      • Studer G.
      • Glanzmann C.
      • Ciernik I.F.
      Clinical outcome after treatment with a brachytherapy boost versus external beam boost for anal carcinoma.
      ].
      Current evidence suggests high degree of association in development of anal cancer with human papilloma virus (HPV) infection. Dose de-escalation has been suggested for HPV positive cancers [

      Dietz A, Wichmann G, Wiegand S. Should We De-escalate the Treatment for HPV-Positive Tumors? Recent results cancer Res. Fortschritte der Krebsforsch. Prog. dans les Rech. sur le cancer. 2017;206:173–181.

      ]. Presently, there are various prospective trials investigating de-escalation in HPV related anal cancers; these trials are assessing loco-regional failure rate (ACT3) or the ability to sufficiently control disease while improving health-related quality of life (QOL) (ACT4) [

      E. Miller J. Bazan De-Escalation of Therapy for Patients with Early-Stage Squamous Cell Carcinoma of the Anus Cancers 13 9 2099.

      ]. At our institution we have successfully implemented lower-dose EBRT regimens for HPV-related anal cancers. Preliminary (unpublished) data suggests excellent tumor control and survival for patients treated in this protocol. On the other hand dose escalation may be warranted for large or HPV-negative tumors [
      • Rusten E.
      • Rekstad B.L.
      • Undseth C.
      • et al.
      Anal cancer chemoradiotherapy outcome prediction using (18)F-fluorodeoxyglucose positron emission tomography and clinicopathological factors.
      ,
      • Joo JiHyeon
      • Park J.-H.
      • Yoon SangMin
      • Kim JinCheon
      • Yu ChangSik
      • Kim TaeWon
      • et al.
      Long-term oncologic and complication outcomes in anal cancer patients treated with radiation therapy.
      ,
      • Johnsson A.
      • Leon O.
      • Gunnlaugsson A.
      • et al.
      Determinants for local tumour control probability after radiotherapy of anal cancer.
      ]. Unfortunately, the studies reviewed in this review did not provide information on HPV status, therefore we cannot draw conclusions about the effect of BT on HPV positive or negative tumors. Nonetheless, the low rates of toxicity illustrated by analysis in this review suggest benefit of BT for all AC patients. Based on the survival and toxicity analysis, BT would be the most effective method to decrease the dose to normal tissue and organs at risk while escalating dose to the gross tumor, as also demonstrated in cervix and prostate cancer patients [
      • Han K.
      • Milosevic M.
      • Fyles A.
      • Pintilie M.
      • Viswanathan A.N.
      Trends in the utilization of brachytherapy in cervical cancer in the United States.
      ,
      • Morris W.J.
      • Tyldesley S.
      • Rodda S.
      • et al.
      Androgen suppression combined with elective nodal and dose escalated radiation therapy (the ASCENDE-RT Trial): an analysis of survival endpoints for a randomized trial comparing a low-dose-rate brachytherapy boost to a dose-escalated external beam boost.
      ]. Thus BT would be an excellent tool improve overall efficacy of radiotherapy treatment for both HPV-positive and negative tumors.

      Limitations and future directions

      There are several important limitations to this review. Firstly, the ultimate quality of the collection of data is limited by the heterogeneity and flaws of the individual series. The heterogeneity of data may be expected due to the data ranging over 30 years, resulting in variability of both stage and treatment technique over time [
      • Gunderson L.L.
      • Moughan J.
      • Ajani J.A.
      • et al.
      Anal carcinoma: impact of TN category of disease on survival, disease relapse, and colostomy failure in US Gastrointestinal Intergroup RTOG 98–11 phase 3 trial.
      ]. Furthermore, it is possible that stage migration might improve outcomes over time and therefore limit the accuracy of interpretation. Next, most of the studies included are retrospective and have a small number of patients and suffer from selection bias. Additionally, lack of large-scale studies or randomized clinical trials in the data means that individually these studies are not adequate to guide management decisions. Therefore, this review provides a pooled analysis of outcomes from multiple small studies and demonstrates effectiveness of HDRBT for tumour control and survival while maintaining sphincter function as well as low toxicity, and generate hypothesis for future prospective studies.
      While this review suggests favourable findings towards the use of HDRBT in the treatment of anal cancer in combination with EBRT and chemotherapy in curative setting, its role in salvage setting is yet to be defined. For patients with local recurrence, who are not surgical candidates, BT perhaps provides an alternate to abdomino-perineal resection and provides a chance for sphincter preservation. Therefore, this should also be an area of future studies, where HDRBT is offered on protocol and patients carefully monitored.
      Due to the heterogeneity of the data, this review was unable to ascertain a strong conclusion on the impact of overall treatment time (OTT) in the context of brachytherapy. The CORS-03 study in the treatment of squamous cell cancer of the anal canal demonstrated that prolonged OTT resulted in worse clinical outcomes [
      • Ortholan C.
      • Resbeut M.
      • Hannoun-Levi J.M.
      • et al.
      Anal Canal Cancer: Management of Inguinal Nodes and Benefit of Prophylactic Inguinal Irradiation (CORS-03 Study).
      ]. In cervical cancer, the EMBRACE II study demonstrated similar findings, citing that OTT greater than seven weeks results in a negative impact on local control [
      • Potter R.
      • Tanderup K.
      • Kirisits C.
      • et al.
      The EMBRACE II study: The outcome and prospect of two decades of evolution within GEC-ESTRO GYN working group and the EMBRACE studies.
      ]. With this in mind, it is prudent for future studies to consider the impact of OTT in the context of brachytherapy for anal cancer in their study designs.
      While brachytherapy has demonstrated excellent outcomes in retrospective series and in this pooled analysis, but lack of robust level-1 data has impeded it widespread application for anal cancers. Therefore, future studies must be designed by standardizing the optimum HDRBT dose, fractionation and techniques. Quality of life (QOL) is also an important factor to consider for physicians and patients when choosing a treatment option. There is little or no data available on the whether HDRBT has a QOL benefit, and there are no current prospective studies evaluating QOL in AC patients treated with HDRBT. Future prospective studies should consider incorporating validated QOL tools such as EORTC QLQ-C30 and QLQ-ANL27 [
      • Fayers P.
      • Bottomley A.
      Quality of life research within the EORTC-the EORTC QLQ-C30. European Organisation for Research and Treatment of Cancer.
      ,
      • Sodergren S.C.
      • Johnson C.D.
      • Gilbert A.
      • et al.
      Phase I-III development of the EORTC QLQ-ANL27, a health-related quality of life questionnaire for anal cancer.
      ].

      Conclusion

      Anal cancer is an uncommon tumour and has multiple treatment options that include RT, combination of chemotherapy and radiation, surgery and BT. Pooled analysis in this review suggests excellent response, local control and survival outcomes with HDRBT in combination with EBRT and CT, with limited toxicity. Prospective well conducted trials are needed to further establish role of HDRBT management of anal cancer with future focus on development of international consensus on patient selection, dosimetric parameters, treatment sequencing as well as defining uniform outcome and toxicity assessment.

      Funding

      None.

      Author contribution

      Concept: AST, SW and KC
      Data acquisition: ES, ZSA, PM and AST
      Analysis: ZSA, AST
      Manuscript writing: ZSA, AST
      Manuscript editing and approval: all authors
      Research data are stored in an institutional repository and will be shared upon request to the corresponding author.

      Declaration of Competing Interest

      The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

      Acknowledgements

      None.

      Appendix A. Supplementary data

      The following are the Supplementary data to this article:

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