Advertisement

Anal cancer brachytherapy: From radon seeds to interstitial Papillon technique in a century. What does the future hold?

Open AccessPublished:February 09, 2022DOI:https://doi.org/10.1016/j.radonc.2022.02.006

      Highlights

      • BT compares favorably with EBRT boost inanal cancer chemoradiation.
      • MRI-guided adaptive BT is expected to improve results further.
      • Some favorable physical & biological properties of BT cannot be matched by EBRT.
      • Despite this, the use of BT boost remains limited to selected centers.
      • BT boost for anal cancer should be reevaluated in a prospective clinical study.

      Abstract

      Evidence from studies which combined 2D-3D external beam radiotherapy (EBRT) ± chemotherapy with 2D brachytherapy (BT) for anal cancer suggest favorable outcomes when compared with chemo-EBRT alone. Further improvement of results can be expected in the era of intensity modulated EBRT and MRI-guided adaptive BT. Despite this, BT is not discussed as a therapeutic option in the prominent international guidelines and its use remains limited to selected institutions. Special skills, complexity, equipment, cost and reimbursement policies have been highlighted as barriers for its wider implementation. However, these factors are relevant for modern radiotherapy in general. Therefore, it can be argued that the role of BT as a component of chemoradiation should be redefined. We describe the historical evolution and current role of BT boost for anal cancer and outline its potential in the context of combined intensity modulated EBRT, chemotherapy and MRI-guided adaptive BT.

      Keywords

      With annual incidence of 0.5 per 100,000, anal cancer accounts for <3% of lower gastrointestinal tract malignancies [

      Cancer Today - International Agency for Research of Cancer, World Health Organization [Internet]. Global Cancer Observatory. 2020. Available from: https://gco.iarc.fr/today/home.

      ,
      • Siegel R.L.
      • Miller K.D.
      • Jemal A.
      Cancer statistics, 2019.
      ]. It is more common in immunocompromised patients and smokers [
      • Nelson V.M.
      • Benson A.B.
      Epidemiology of Anal Canal Cancer.
      ]. Rise of incidence over past decades [
      • Nielsen A.
      • Munk C.
      • Kjaer S.K.
      Trends in incidence of anal cancer and high-grade anal intraepithelial neoplasia in Denmark, 1978–2008.
      ] can be attributed to the increased prevalence of HPV infection which is the most important cause [
      • Nelson V.M.
      • Benson A.B.
      Epidemiology of Anal Canal Cancer.
      ,
      • Jones C.M.
      • Goh V.
      • Sebag-Montefiore D.
      • Gilbert D.C.
      Biomarkers in anal cancer: from biological understanding to stratified treatment.
      ]. Abdominoperineal resection was the main treatment in the past, but resulted in suboptimal locoregional control and high morbidity due to sphincter loss [
      • Ryan D.P.
      • Compton C.C.
      • Mayer R.J.
      Carcinoma of the Anal Canal.
      ]. Following encouraging first experience with chemoradiation [
      • Nigro N.
      • Vaitkevicius V.
      • Considine B.J.
      Combined therapy for cancer of the anal canal: a preliminary report.
      ,
      • Nigro N.D.
      • Seydel H.G.
      • Considine B.
      • Vaitkevicius V.K.
      • Leichman L.
      • Kinzie J.J.
      Combined preoperative radiation and chemotherapy for squamous cell carcinoma of the anal canal.
      ], its effectiveness was confirmed by several retrospective and phase II studies [
      • Cummings B.
      • Keane T.
      • Thomas G.
      • Harwood A.
      • Rider W.
      Results and toxicity of the treatment of anal canal carcinoma by radiation therapy or radiation therapy and chemotherapy.
      ,

      Sischy B, Doggett R, Krall J, Taylor D, Sause W, Lipsett J, et al. Definitive irradiation and chemotherapy for radiosensitization in management of anal carcinoma: interim report on Radiation Therapy Oncology Group study no. 8314. J Natl Cancer Inst. 1989 Jun;81(11):850–6.

      ,
      • Papillon J.
      • Montbarbon J.F.
      Epidermoid carcinoma of the anal canal. A series of 276 cases.
      ,
      • Allal A.
      • Kurtz J.M.
      • Pipard G.
      • Marti M.-C.
      • Miralbell R.
      • Popowski Y.
      • et al.
      Chemoradiotherapy verus radiotherapy alone for anal cancer: a retrospective comparison.
      ,
      • Myerson R.J.
      • Karnell L.H.
      • Menck H.R.
      The National Cancer Data Base report on carcinoma of the anus.
      ]. Randomized trials showed superiority of chemoradiation over radiotherapy alone [
      • 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).
      ,
      • 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.
      ] with 5-fluorouracil and mitomycin-C as concomitant regimen of choice [
      • Gunderson L.L.
      • Winter K.A.
      • Ajani J.A.
      • Pedersen J.E.
      • Moughan J.
      • Benson 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.
      ,
      • Peiffert D.
      • Tournier-Rangeard L.
      • Gérard J.-P.
      • Lemanski C.
      • François 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.
      ]. Pelvic external beam radiotherapy (EBRT) with concurrent chemotherapy and simultaneous integrated EBRT or sequential brachytherapy (BT) boost is nowadays standard treatment [

      National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Anal Carcinoma Version 2.2021 [Internet]. NCCN.org; 2021. Available from: https://www.nccn.org/professionals/physician_gls/pdf/anal.pdf

      ,
      • 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.
      ]. Old studies used radiography-based or 3D conformal EBRT [
      • Frakulli R.
      • Buwenge M.
      • Cammelli S.
      • Macchia G.
      • Farina E.
      • Arcelli A.
      • et al.
      Brachytherapy boost after chemoradiation in anal cancer: a systematic review.
      ]. Implementation of intensity modulated and image guided radiotherapy (IMRT/IGRT) enabled tighter treatment margins and adaptive approach, resulting in improved outcomes [
      • De Bari B.
      • Lestrade L.
      • Franzetti-Pellanda A.
      • Jumeau R.
      • Biggiogero M.
      • Kountouri M.
      • et al.
      Modern intensity-modulated radiotherapy with image guidance allows low toxicity rates and good local control in chemoradiotherapy for anal cancer patients.
      ,
      • Olsen J.R.
      • Moughan J.
      • Myerson R.
      • Abitbol A.
      • Doncals D.E.
      • Johnson D.
      • et al.
      Predictors of Radiation Therapy-Related Gastrointestinal Toxicity From Anal Cancer Dose-Painted Intensity Modulated Radiation Therapy: Secondary Analysis of NRG Oncology RTOG 0529.
      ,
      • Han K.
      • Cummings B.J.
      • Lindsay P.
      • Skliarenko J.
      • Craig T.
      • Le L.W.
      • et al.
      Prospective Evaluation of Acute Toxicity and Quality of Life After IMRT and Concurrent Chemotherapy for Anal Canal and Perianal Cancer.
      ,
      • Devisetty K.
      • Mell L.K.
      • Salama J.K.
      • Schomas D.A.
      • Miller R.C.
      • Jani A.B.
      • et al.
      A multi-institutional acute gastrointestinal toxicity analysis of anal cancer patients treated with concurrent intensity-modulated radiation therapy (IMRT) and chemotherapy.
      ,
      • Saarilahti K.
      • Arponen P.
      • Vaalavirta L.
      • Tenhunen M.
      The effect of intensity-modulated radiotherapy and high dose rate brachytherapy on acute and late radiotherapy-related adverse events following chemoradiotherapy of anal cancer.
      ,
      • Kachnic L.A.
      • Winter K.
      • Myerson R.J.
      • Goodyear M.D.
      • Willins J.
      • Esthappan 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.
      ,
      • Kachnic L.A.
      • Tsai H.K.
      • Coen J.J.
      • Blaszkowsky L.S.
      • Hartshorn K.
      • Kwak E.L.
      • et al.
      Dose-painted intensity-modulated radiation therapy for anal cancer: A multi-institutional report of acute toxicity and response to therapy.
      ]. BT was historically performed according to the Paris system rules [
      • Pierquin B.
      • Dutreix A.
      • Paine C.H.
      • Chassagne D.
      • Marinello G.
      • Ash D.
      The Paris system in interstitial radiation therapy.
      ], without specific guidelines for target volume definition. The pace of progress in EBRT was not paralleled in BT, where the techniques from the 1980s [

      Papillon J, Mayer M, Bailly C. A new approach to the management of epidermoid carcinoma of the anal canal. 1983;(10):8.

      ] remain conceptually unchanged even nowadays. We describe the evolution and current role of BT boost for anal cancer chemoradiation and outline its potential advancements in the context of image guided adaptive BT (IGABT).

      Literature search

      We performed a PubMed search from the earliest date through January 31, 2020, using the terms “anal cancer” AND “brachytherapy”. Secondary search among the references in the identified reports was done to find publications addressing the topic of this review. We included studies of any design. Case reports, commentaries and editorials were excluded.

      The dawn of anal cancer brachytherapy

      Beginnings of anal cancer BT date back to the 1920’s, when it was suggested as alternative to surgery for operable tumours [
      • Binkley G.E.
      Results of radiation therapy in primary operable rectal and anal cancer.
      ]. Interstitial BT was scheduled 2 weeks after EBRT. Gold-filtered radon seeds with activity of 1–2.5 mCi per seed were inserted with trocar needles under proctoscopic or palpatory guidance to deliver 1000–5000 mCi*h, depending on the tumour size. Alternative technique was based on an intracavitary applicator similar to a proctoscope. After applicator insertion, the obturator was replaced by a holder, containing a tandem of brass-filtered sources. Lead was used to protect the uninvolved side. At a rate of 100–250 mCi/day, a total dose of 2000–5000 mCi*h was delivered over 3–6 weeks. In <4 cm tumours, the results were described as promising with “long-standing cures and preservation of anus and rectum in most cases”. In more advanced tumors, the outcome was disappointing [
      • Binkley G.E.
      Results of radiation therapy in primary operable rectal and anal cancer.
      ]. In the 1950’s, interstitial BT with 226-Ra was introduced [
      • Dalby J.
      • Pointon R.
      The treatment of anal carcinoma by interstitial irradiation.
      ,
      • Papillon J.
      Radiation therapy in the management of epidermoid carcinoma of the anal region.
      ]. In a series from Manchester, 59 patients were treated for moderately advanced and advanced disease. Poor 5-year overall survival (OS) was accompanied by a high radionecrosis rate [
      • Dalby J.
      • Pointon R.
      The treatment of anal carcinoma by interstitial irradiation.
      ]. In the 1960s, the Lyon group introduced a fractionated technique for carefully selected patients. Interstitial needles were loaded with 2.6 or 4 mg of 226-Ra over 3.2 cm. They were inserted through the skin or mucosa and fixed by sutures or intraanal tube. Most applications were one-plane, but selected cases received volume implants. The dose of first-session was up to 4000 rads over 2–3 days. In incomplete responders at 6 weeks, a second implant was used to deliver 2500 to 3000 rads. In rare cases, a third implant of additional 2000 rads was applied 2 months later. 5-year survival was 68% and necrosis rate 5% [
      • Papillon J.
      Radiation therapy in the management of epidermoid carcinoma of the anal region.
      ].

      Reneissance by Papillon

      Papillon et al. introduced the novel Lyon approach in 1971 and published it in1983 [

      Papillon J, Mayer M, Bailly C. A new approach to the management of epidermoid carcinoma of the anal canal. 1983;(10):8.

      ]. Radium was replaced by 192-Ir wires, and BT technique refined according to the improved understanding of the natural history of the disease and technical developments. Papillon described 3 protocols, adapted to tumour characteristics. Protocol 1 was designed for T1-T3 N0 disease, considered to have high probability of tumor control and anal function preservation. It started with Co-60 EBRT, delivering 3000 rad transperineally at 5 cm and 1800 rad presacrally at 8 cm depth. This was followed by a 2-months interval to allow for toxicity resolution and tumor downsizing to a volume, suitable for a single-plane implant. At BT, a crescent-shaped or circular 15 mm thick plastic template with guiding holes was sutured to the skin. The distance between adjacent and opposite holes was 1 and 3.2 cm, respectively. The implant volume corresponded to the quadrant and depth of initial tumour extension, underscoring the importance of tumor assessment at diagnosis. A single row of equidistant and parallel needles was inserted through the template under guidance of palpating finger approximately 5 mm below the mucosa. Needle position was checked with fluoroscopy. 5–7 Ir-192 wires with activity of 1.5–2.5 mCi/cm and 5 cm length were applied to deliver 1500–2000 rad at the 85% isodose over 18–28 hours according to the Paris system [
      • Pierquin B.
      • Dutreix A.
      • Paine C.H.
      • Chassagne D.
      • Marinello G.
      • Ash D.
      The Paris system in interstitial radiation therapy.
      ]. The dose was chosen depending on the findings at diagnosis and BT. To minimize the complications risk, BT was not used upfront or as monotherapy, was limited to single-plane implants and was kept <30 Gy [

      Papillon J, Mayer M, Bailly C. A new approach to the management of epidermoid carcinoma of the anal canal. 1983;(10):8.

      ,
      • Papillon J.
      • Montbarbong J.F.
      • Gerard J.P.
      • Chassard J.L.
      • Ardiet J.M.
      Interstitial curietherapy in the conservative treatment of anal and rectal cancers.
      ]. Protocol 2 included preoperative chemoradiation and surgery. Protocol 3 was used for fixed lesions and cases with nodal metastases. 18 MV photons and electrons were used to deliver 4000 rad to the inguino-pelvic nodal regions, followed by a 6–7 weeks break and an EBRT or BT boost of up to 5500 rad to the tumor and enlarged nodes [

      Papillon J, Mayer M, Bailly C. A new approach to the management of epidermoid carcinoma of the anal canal. 1983;(10):8.

      ].

      Modern era

      Papillon’s split-course Protocol 1 evolved in the context of the European BT experience [
      • Mazeron J.J.
      • Van Limbergen E.
      Anorectal Cancer.
      ]. Built on this tradition, a typical modern conventional regimen starts with EBRT + concomitant chemotherapy to the primary tumour and elective nodal volumes, followed by an EBRT or BT boost [
      • Mazeron J.J.
      • Van Limbergen E.
      Anorectal Cancer.
      ]. A treatment gap was applied between sequences in most series [
      • Cordoba A.
      • Escande A.
      • Leroy T.
      • Mirabel X.
      • Coche-Dequéant B.
      • Lartigau E.
      Low-dose-rate interstitial brachytherapy boost for the treatment of anal canal cancers.
      ,
      • 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).
      ,
      • Weber D.C.
      • Kurtz J.M.
      • Allal A.S.
      The impact of gap duration on local control in anal canal carcinoma treated by split-course radiotherapy and concomitant chemotherapy.
      ,
      • Oblak I.
      • Petric P.
      • Anderluh F.
      • Velenik V.
      • Fras PA.
      Long term outcome after combined modality treatment for anal cancer.
      ,
      • Widder J.
      • Kastenberger R.
      • Fercher E.
      • Schmid R.
      • Langendijk J.A.
      • Dobrowsky W.
      • et al.
      Radiation dose associated with local control in advanced anal cancer: Retrospective analysis of 129 patients.
      ,
      • Falk A.T.
      • Claren A.
      • Benezery K.
      • François E.
      • Gautier M.
      • Gerard J.-P.
      • et al.
      Interstitial high-dose rate brachytherapy as boost for anal canal cancer.
      ].
      Reports using conventional radiography-based BT boost are listed in Table 1. EBRT dose in these series ranged from 33 Gy to 50 Gy (biologically equivalent estimates in 2 Gy/fraction; linear-quadratic model; α/β = 10 Gy). Concomitant chemotherapy was used in 10–100% of cases. At BT, around 3–10 parallel and equidistant needles were inserted through a Papillon-type interstitial template to a depth of 3–10 cm, according to the Paris system rules for curved planar implants [
      • Pierquin B.
      • Dutreix A.
      • Paine C.H.
      • Chassagne D.
      • Marinello G.
      • Ash D.
      The Paris system in interstitial radiation therapy.
      ]. Target concepts were not consistently detailed and were generally based on the residual tumour or scar at BT, while taking the initial tumour into account. Radiography was used for dose planning and documentation. Dose was specified at 85% of the mean basal dose [
      • Pierquin B.
      • Dutreix A.
      • Paine C.H.
      • Chassagne D.
      • Marinello G.
      • Ash D.
      The Paris system in interstitial radiation therapy.
      ]. A dose of 10–30 Gy was delivered with low dose rate (LDR) or pulsed dose rate (PDR) technique in most series [
      • Papillon J.
      • Montbarbong J.F.
      • Gerard J.P.
      • Chassard J.L.
      • Ardiet J.M.
      Interstitial curietherapy in the conservative treatment of anal and rectal cancers.
      ,
      • Cordoba A.
      • Escande A.
      • Leroy T.
      • Mirabel X.
      • Coche-Dequéant B.
      • Lartigau E.
      Low-dose-rate interstitial brachytherapy boost for the treatment of anal canal cancers.
      ,
      • 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).
      ,
      • Weber D.C.
      • Kurtz J.M.
      • Allal A.S.
      The impact of gap duration on local control in anal canal carcinoma treated by split-course radiotherapy and concomitant chemotherapy.
      ,
      • Widder J.
      • Kastenberger R.
      • Fercher E.
      • Schmid R.
      • Langendijk J.A.
      • Dobrowsky W.
      • et al.
      Radiation dose associated with local control in advanced anal cancer: Retrospective analysis of 129 patients.
      ,
      • Lestrade L.
      • De Bari B.
      • Pommier P.
      • Montbarbon X.
      • Lavergne E.
      • Ardiet J.-M.
      • et al.
      Role of brachytherapy in the treatment of cancers of the anal canal: Long-term follow-up and multivariate analysis of a large monocentric retrospective seriesStellenwert der Brachytherapie bei der Behandlung von Tumoren des Analkanals: Langzeit-Follow-up und multivariate Analyse einer großen monozentrischen, retrospektiven Studie.
      ,
      • Chapet O.
      • Gerard J.-P.
      • Riche B.
      • Alessio A.
      • Mornex F.
      • Romestaing P.
      Prognostic value of tumor regression evaluated after first course of radiotherapy for anal canal cancer.
      ,
      • Gerard J.-P.
      • Ayzac L.
      • Hun D.
      • Romestaing P.
      • Coquard R.
      • Ardiet J.-M.
      • et al.
      Treatment of anal canal carcinoma with high dose radiation therapy and concomitant fluorouracil-cisplatinum. Long-term results in 95 patients.
      ,
      • Tournier-Rangeard L.
      • Peiffert D.
      • Lafond C.
      • Mege A.
      • Metayer Y.
      • Marchesi V.
      • et al.
      Résultats à long terme et facteurs pronostiques des carcinomes épidermoïdes du canal anal traités par irradiation.
      ,
      • Bruna A.
      • Gastelblum P.
      • Thomas L.
      • Chapet O.
      • Bollet M.A.
      • Ardiet J.-M.
      • et al.
      Treatment of squamous cell anal canal carcinoma (SCACC) with pulsed dose rate brachytherapy: A retrospective study.
      ,
      • Ortholan C.
      • Ramaioli A.
      • Peiffert D.
      • Lusinchi A.
      • Romestaing P.
      • Chauveinc L.
      • et al.
      Anal canal carcinoma: Early-stage tumors ≤10 mm (T1 or Tis): Therapeutic options and original pattern of local failure after radiotherapy.
      ,
      • Kent C.
      • Bessell E.M.
      • Scholefield J.H.
      • Chappell S.
      • Marsh L.
      • Mills J.
      • et al.
      Chemoradiotherapy with Brachytherapy or Electron Therapy Boost for Locally Advanced Squamous Cell Carcinoma of the Anus—Reducing the Colostomy Rate.
      ,
      • Sandhu A.P.S.
      • Paul Symonds R.
      • Robertson A.G.
      • Reed N.S.
      • McNee S.G.
      • Paul J.
      Interstitial iridium-192 implantation combined with external radiotherapy in anal cancer: ten years experience.
      ,
      • López Guerra J.L.
      • Lozano A.J.
      • Pera J.
      • Gutiérrez C.
      • Cambray M.
      • Ferrer F.
      • et al.
      Twenty-year experience in the management of squamous cell anal canal carcinoma with interstitial brachytherapy.
      ,
      • Gerard J.-P.
      • Mauro F.
      • Thomas L.
      • Castelain B.
      • Mazeron J.-J.
      • Ardiet J.-M.
      • et al.
      Treatment of squamous cell anal canal carcinoma with pulsed dose rate brachytherapy. Feasibility study of a French cooperative group.
      ,
      • 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.
      ]. Experience with high dose rate (HDR) BT is emerging [
      • Saarilahti K.
      • Arponen P.
      • Vaalavirta L.
      • Tenhunen M.
      The effect of intensity-modulated radiotherapy and high dose rate brachytherapy on acute and late radiotherapy-related adverse events following chemoradiotherapy of anal cancer.
      ,
      • Widder J.
      • Kastenberger R.
      • Fercher E.
      • Schmid R.
      • Langendijk J.A.
      • Dobrowsky W.
      • et al.
      Radiation dose associated with local control in advanced anal cancer: Retrospective analysis of 129 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.
      ]. Single plane implants were used by majority of authors, indicating that residual tumours >10 mm in thickness were typically deemed unsuitable for BT boost. Several authors used a plastic tube or cylinder in the anus to stabilize implant geometry, displace uninvolved tissue from the high-dose and allow flatus and faeces escape [
      • Cordoba A.
      • Escande A.
      • Leroy T.
      • Mirabel X.
      • Coche-Dequéant B.
      • Lartigau E.
      Low-dose-rate interstitial brachytherapy boost for the treatment of anal canal cancers.
      ,
      • Sandhu A.P.S.
      • Paul Symonds R.
      • Robertson A.G.
      • Reed N.S.
      • McNee S.G.
      • Paul J.
      Interstitial iridium-192 implantation combined with external radiotherapy in anal cancer: ten years experience.
      ,
      • López Guerra J.L.
      • Lozano A.J.
      • Pera J.
      • Gutiérrez C.
      • Cambray M.
      • Ferrer F.
      • et al.
      Twenty-year experience in the management of squamous cell anal canal carcinoma with interstitial brachytherapy.
      ,
      • Gerard J.-P.
      • Mauro F.
      • Thomas L.
      • Castelain B.
      • Mazeron J.-J.
      • Ardiet J.-M.
      • et al.
      Treatment of squamous cell anal canal carcinoma with pulsed dose rate brachytherapy. Feasibility study of a French cooperative group.
      ]. Studies in Table 2 used ultrasound, CT or MRI for insertion guidance. This “2D to 3D experience” was typically limited to optimization of implant geometry without systematic dose adaptation in the context of standardized target concepts (Table 2).
      Table 1Series on pelvic chemoradiation and brachytherapy boost which used conventional Papillon technique, Paris system and radiography for brachytherapy optimization. Some reports included non-radiotherapy patients in outcome analysis. Brackets: ranges. Standard deviation specified by ±. Pts–patients; N-number; EBRT-external beam radiotherapy; Fx-Fractions: TL-treatment length (target, active or insertion length). D-Dose; ChT-chemotherapy; BT-Brachytherapy; DR-dose rate; Ref. DR-reference dose rate; Y-years; LC-local control; DFS-disease free survival; OS-overall survival; CFS-colostomy free surivival; Ch–channel; NS-not specified; NA-not applicable; St-stage; L-low; P-pulsed; H-high; aCrude rate.
      Reference and pt. NEBRT [Gy/Fx]ChT [%]Boost [N]Brachytherapy detailsOutcome [%]
      BTEBRTPlanesNeedlesDRTL [cm]D [Gy]Ref. DR [cGy/h]YLCDFSOSCFS
      Papillon
      • Papillon J.
      • Montbarbong J.F.
      • Gerard J.P.
      • Chassard J.L.
      • Ardiet J.M.
      Interstitial curietherapy in the conservative treatment of anal and rectal cancers.


      N = 369
      48/16NS221014–8L5–7NS

      (15–20)
      NS66a61a
      Peiffert
      • Peiffert D.
      • Bey P.
      • Pernot M.
      • Guillemin F.
      • Luporsi E.
      • Hoffstetter S.
      • et al.
      Conservative treatment by irradiation of epidermoid cancers of the anal canal: Prognostic factors of tumoral control and complications.


      N = 118
      45–48/21–25

      3110131 – 23–8L4–822

      (15–29)
      92

      (40–138)
      580a60apre-1989: 75a

      post-1989: 84a
      Gerard
      • Gerard J.-P.
      • Ayzac L.
      • Hun D.
      • Romestaing P.
      • Coquard R.
      • Ardiet J.-M.
      • et al.
      Treatment of anal canal carcinoma with high dose radiation therapy and concomitant fluorouracil-cisplatinum. Long-term results in 95 patients.


      N = 95
      48/16

      39/13
      10085513–9L4–919

      (14–28)
      110

      (59–158)
      585a8472
      Sandhu
      • Sandhu A.P.S.
      • Paul Symonds R.
      • Robertson A.G.
      • Reed N.S.
      • McNee S.G.
      • Paul J.
      Interstitial iridium-192 implantation combined with external radiotherapy in anal cancer: ten years experience.


      N = 79
      30–50/10–251679015–10L6–1024

      (20–40)
      43

      (36–57)
      378 aT1-2: 93

      T3-4: 65
      71a
      Gerard
      • Gerard J.-P.
      • Mauro F.
      • Thomas L.
      • Castelain B.
      • Mazeron J.-J.
      • Ardiet J.-M.
      • et al.
      Treatment of squamous cell anal canal carcinoma with pulsed dose rate brachytherapy. Feasibility study of a French cooperative group.


      N = 19
      44–50/22–25471901 – 24–9P4–715

      (10–25)
      50

      (50–50)
      Weber
      • Weber D.C.
      • Kurtz J.M.
      • Allal A.S.
      The impact of gap duration on local control in anal canal carcinoma treated by split-course radiotherapy and concomitant chemotherapy.


      N = 90
      median 40/221004941NSNSLNS19

      NS)
      51.8

      (NS)
      577
      Chapet
      • Chapet O.
      • Gerard J.-P.
      • Riche B.
      • Alessio A.
      • Mornex F.
      • Romestaing P.
      Prognostic value of tumor regression evaluated after first course of radiotherapy for anal canal cancer.


      N = 252
      48/16

      39/13
      672183415–6L5–620 ±5NS583aT1-2: 66

      T3-4: 47
      T1-2:77

      T3-4: 63
      61
      Ortholan
      • Ortholan C.
      • Ramaioli A.
      • Peiffert D.
      • Lusinchi A.
      • Romestaing P.
      • Chauveinc L.
      • et al.
      Anal canal carcinoma: Early-stage tumors ≤10 mm (T1 or Tis): Therapeutic options and original pattern of local failure after radiotherapy.


      N = 69
      27–55/9–25

      -
      1146201NSLNS20 (NS)55 (NS)NS591a899485
      Bruna
      • Bruna A.
      • Gastelblum P.
      • Thomas L.
      • Chapet O.
      • Bollet M.A.
      • Ardiet J.-M.
      • et al.
      Treatment of squamous cell anal canal carcinoma (SCACC) with pulsed dose rate brachytherapy: A retrospective study.


      N = 71
      44–50/25

      36/12
      667101 – 23–12P4–818

      (10–25)
      70

      (50–150)
      290a819089
      Saarilahti
      • Saarilahti K.
      • Arponen P.
      • Vaalavirta L.
      • Tenhunen M.
      • Blomqvist C.
      Chemoradiotherapy of anal cancer is feasible in elderly patients: Treatment results of mitomycin–5-FU combined with radiotherapy at Helsinki University Central Hospital 1992–2003.


      N = 62
      45/25100293014–7H4–71–2 × 5–6NA58177100
      Tournier-R.
      • Tournier-Rangeard L.
      • Peiffert D.
      • Lafond C.
      • Mege A.
      • Metayer Y.
      • Marchesi V.
      • et al.
      Résultats à long terme et facteurs pronostiques des carcinomes épidermoïdes du canal anal traités par irradiation.


      N = 286
      30–50/7–25

      17–50/10–30
      44233241 – 22–16L, P4–1019

      (10–37)
      NS5St I: 89

      St II: 77

      St IIIA; 96

      St IIIB: 77
      St I: 82

      St II: 67

      St IIIA: 54

      St IIIB: 49
      -St I: 88

      St II: 70

      St IIIA: 75

      St IIIB: 56
      Oehler J.
      • 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.


      N = 81
      45/2572 h344713–8H4–97 × 2NA5BT: 90

      EBRT: 85
      BT: 76

      EBRT: 73
      BT: 66

      EBRT: 66
      BT: 85

      EBRT: 82
      Widder
      • Widder J.
      • Kastenberger R.
      • Fercher E.
      • Schmid R.
      • Langendijk J.A.
      • Dobrowsky W.
      • et al.
      Radiation dose associated with local control in advanced anal cancer: Retrospective analysis of 129 patients.


      N = 129
      46/2374 h2310614–7P, H4–813

      (5–26)
      NS5St I: 94

      St II: 86

      St III: 80
      St I: 70

      St II: 57

      St III: 27
      St I: 76

      St II: 64

      St III: 32
      St I: 76

      St II: 58

      St III: 25
      Hannoun-L.
      • 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).


      N = 162
      40–50/20–257286761 – 23–6L4–617

      (10–25)
      NS

      (50–70)
      5T1-2: 85

      T3-4: 64
      T1-2: 84

      T3-4: 68
      T1-2: 72

      T3-4: 51
      López-G.
      • López Guerra J.L.
      • Lozano A.J.
      • Pera J.
      • Gutiérrez C.
      • Cambray M.
      • Ferrer F.
      • et al.
      Twenty-year experience in the management of squamous cell anal canal carcinoma with interstitial brachytherapy.


      N = 38
      32–50/2558 i32 + 6 BT only014–8L

      P
      3–1020

      (15–35)
      68 (50–70)

      52 (50–70)
      587587684a
      Lestrade
      • Lestrade L.
      • De Bari B.
      • Pommier P.
      • Montbarbon X.
      • Lavergne E.
      • Ardiet J.-M.
      • et al.
      Role of brachytherapy in the treatment of cancers of the anal canal: Long-term follow-up and multivariate analysis of a large monocentric retrospective seriesStellenwert der Brachytherapie bei der Behandlung von Tumoren des Analkanals: Langzeit-Follow-up und multivariate Analyse einer großen monozentrischen, retrospektiven Studie.


      N = 219

      30–56/10–2872209014–12L, P4–918

      (10–32)
      75

      (23–125)
      5T1-2: 80

      T3-4: 77
      T1-2: 70

      T3-4: 68
      T1-2: 85

      T3-4: 76
      T1-2: 81

      T3-4: 78
      Cordoba
      • Cordoba A.
      • Escande A.
      • Leroy T.
      • Mirabel X.
      • Coche-Dequéant B.
      • Lartigau E.
      Low-dose-rate interstitial brachytherapy boost for the treatment of anal canal cancers.


      N = 103
      median 45/NS38103012–12L4–1017

      (10–30)
      NS58986%86%
      Kent
      • Kent C.
      • Bessell E.M.
      • Scholefield J.H.
      • Chappell S.
      • Marsh L.
      • Mills J.
      • et al.
      Chemoradiotherapy with Brachytherapy or Electron Therapy Boost for Locally Advanced Squamous Cell Carcinoma of the Anus—Reducing the Colostomy Rate.


      N = 52
      45/25100361615LNSNS

      (15–20)
      NS5BT: 91

      EBRT: 78
      BT: 75

      EBRT: 68
      BT: 97

      EBRT: 80
      Arcelli
      • 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.


      N = 123
      45/259410221NS2–7P5–820

      (13–25)
      67–805T1-2: 84

      T3-4: 79
      T1-2: 84

      T3-4: 64
      T1-2: 64

      T3-4: 49
      Table 2Series on pelvic chemoradiation and brachytherapy boost which used 2-3D technique and limited dose optimization. Brackets: ranges. Standard deviation specified by +/−. N-number; EBRT-external beam radiotherapy; Fx-Fractions; D-Dose; ChT-chemotherapy; BT-brachytherapy; DR-dose rate; D-dose; Ref. DR-reference dose rate; Y-years; LC-local control; DFS-disease free survival; OS-overall survival; CFS-colostomy free surivival; Clin-clinical; US-ultrasound; TRUS-transrectal ultrasound; MUPIT-Martinez universal perineal template; TV-target volume; P-pulsed; H-high; CT-computed tomography; MRI-magnetic resonance imaging; T-tumor; NS-not specified; NA-not applicable; P-pulsed; H-high. aAll patients in this series received EBRT boost; in incomplete responders at 4–6 weeks, BT boost was added. bDose of 6 Gy per fraction was omitted after 5 patients, experiencing proctitis (n = 2) or sphincter necrosis (n = 3). cCrude rate.
      Reference and pt. NEBRT [Gy/Fx]ChT [%]Boost [N]Brachytherapy detailsOutcome [%]
      BTEBRTTechniqueTarget conceptTreatment planningDRD [Gy]Ref. DR [cGy/h]YLCDFSOSCFS
      Gryc
      • Gryc T.
      • Ott O.
      • Putz F.
      • Knippen S.
      • Raptis D.
      • Fietkau R.
      • et al.
      Interstitial brachytherapy as a boost to patients with anal carcinoma and poor response to chemoradiation: Single-institution long-term results.


      N = 190a
      50.4–59.4

      /28–33
      8947143Papillon 80%

      Free hand 20%
      Residual T (Clin., US, CT)

      +5 mm margin
      CT based

      Paris system

      Geometric

      Manual
      P15.5

      (8–36)
      0.45

      (0.25–0.7)
      5BTa: 76

      EBRT: 81
      BTa: 64

      EBRT: 69
      BTa: 75

      EBRT: 72
      BTa: 76

      EBRT: 83
      Doniec
      • Doniec J.M.
      • Schniewind B.
      • Kovács G.
      • Kahlke V.
      • Loehnert M.
      • Kremer B.
      Multimodal therapy of anal cancer added by new endosonographic-guided brachytherapy.


      N = 50
      45/25

      NS500Papillon

      TRUS guided
      Residual T (Clin., US)

      Or initial T
      D specified

      @TV surface
      H2 x

      4-6b
      NA592T1-2: 88

      T3-4: 67
      7490

      Oblak
      • Oblak I.
      • Petric P.
      • Anderluh F.
      • Velenik V.
      • Fras PA.
      Long term outcome after combined modality treatment for anal cancer.


      N = 84
      45/25894933Papillon/MUPIT

      TRUS guided

      Anal & vaginal dilator
      Residual T

      (Clin., US, CT)
      CT based

      Paris system

      Manual
      PNS

      (15–30)
      <705T1-2: 80

      T3-4: 55
      T1-2: 80

      T3-4: 47
      T1-2: 75

      T3-4: 58
      T1-2: 94

      T3-4: 46
      Tagliaferri
      • 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.


      N = 11
      44–58

      /22–29
      100110MUPIT

      Off-line MRI

      Anal & vaginal dilator
      Residual T (Clin., MRI)CT based

      Paris system

      Manual
      H1–2 × 3.5–7NA-----
      Falk
      • Falk A.T.
      • Claren A.
      • Benezery K.
      • François E.
      • Gautier M.
      • Gerard J.-P.
      • et al.
      Interstitial high-dose rate brachytherapy as boost for anal canal cancer.


      N = 28
      43.2–50

      /24–26
      75280Papillon

      Anal tube
      Initial T

      (Clin., CT)
      CT based

      Graphical
      H2–6 x

      3–5
      NA283727875
      Boukhelif
      • Boukhelif W
      • Ferri-Molina M
      • Mazeron R
      • Maroun P
      • Duhamel-Oberlander AS
      • Dumas I
      • et al.
      Interstitial pulsed-dose-rate brachytherapy for the treatment of squamous cell anal carcinoma: A retrospective single institution analysis.
      N = 21
      30–54

      /15–30
      33210Papillon

      Anal dilator
      Residual T

      + 5–10 mm
      CT based

      Paris system
      P20

      (10–30)
      40

      (38–50)
      586c81c95c-
      Kapoor
      • 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

      /20–25
      100160Syed Neblett

      Residual T

      (Clin., CT)
      CT basedH6–7 × 3NA288--88

      Patient selection for brachytherapy boost

      Patients need to be fit for anaesthesia and tolerate immobilization. Advanced age is not a contraindication for BT. Lestrade et al. reported on 76 patients >70 years treated with a median EBRT dose of 45 Gy (range: 36–56 Gy), concomitant chemotherapy (51%) and BT boost of 18 Gy (range: 10–31.7 Gy). Five-year local control (LC) and OS were 76%. Acute and late Grade 3–4 toxicities were 14% and 7%, respectively. Modified Charlson Comorbidity index [
      • Charlson M.
      • Szatrowski T.P.
      • Peterson J.
      • Gold J.
      Validation of a combined comorbidity index.
      ] had no impact on outcome [
      • Lestrade L.
      • De Bari B.
      • Montbarbon X.
      • Pommier P.
      • Carrie C.
      Radiochemotherapy and brachytherapy could be the standard treatment for anal canal cancer in elderly patients? A retrospective single-centre analysis.
      ]. Good tolerance among elderly and comparable tumour control with the younger cohorts was confirmed by others [
      • Saarilahti K.
      • Arponen P.
      • Vaalavirta L.
      • Tenhunen M.
      The effect of intensity-modulated radiotherapy and high dose rate brachytherapy on acute and late radiotherapy-related adverse events following chemoradiotherapy of anal cancer.
      ,
      • Saarilahti K.
      • Arponen P.
      • Vaalavirta L.
      • Tenhunen M.
      • Blomqvist C.
      Chemoradiotherapy of anal cancer is feasible in elderly patients: Treatment results of mitomycin–5-FU combined with radiotherapy at Helsinki University Central Hospital 1992–2003.
      ]. In the original Papillon experience, BT was applied in tumours <4 cm, involving <2/3 of circumference and with good response to EBRT [

      Papillon J, Mayer M, Bailly C. A new approach to the management of epidermoid carcinoma of the anal canal. 1983;(10):8.

      ]. Others have suggested that BT target should extend <5 cm craniocaudally and involve <1/2 of circumference [
      • Mazeron J.J.
      • Van Limbergen E.
      Anorectal Cancer.
      ]. These criteria correspond to T2 and well-responding T3 tumors, which constitute 75–95% cases from published series [
      • Cordoba A.
      • Escande A.
      • Leroy T.
      • Mirabel X.
      • Coche-Dequéant B.
      • Lartigau E.
      Low-dose-rate interstitial brachytherapy boost for the treatment of anal canal cancers.
      ,
      • 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).
      ,
      • Weber D.C.
      • Kurtz J.M.
      • Allal A.S.
      The impact of gap duration on local control in anal canal carcinoma treated by split-course radiotherapy and concomitant chemotherapy.
      ,
      • Oblak I.
      • Petric P.
      • Anderluh F.
      • Velenik V.
      • Fras PA.
      Long term outcome after combined modality treatment for anal cancer.
      ,
      • Lestrade L.
      • De Bari B.
      • Pommier P.
      • Montbarbon X.
      • Lavergne E.
      • Ardiet J.-M.
      • et al.
      Role of brachytherapy in the treatment of cancers of the anal canal: Long-term follow-up and multivariate analysis of a large monocentric retrospective seriesStellenwert der Brachytherapie bei der Behandlung von Tumoren des Analkanals: Langzeit-Follow-up und multivariate Analyse einer großen monozentrischen, retrospektiven Studie.
      ,
      • Chapet O.
      • Gerard J.-P.
      • Riche B.
      • Alessio A.
      • Mornex F.
      • Romestaing P.
      Prognostic value of tumor regression evaluated after first course of radiotherapy for anal canal cancer.
      ,
      • Tournier-Rangeard L.
      • Peiffert D.
      • Lafond C.
      • Mege A.
      • Metayer Y.
      • Marchesi V.
      • et al.
      Résultats à long terme et facteurs pronostiques des carcinomes épidermoïdes du canal anal traités par irradiation.
      ,
      • Bruna A.
      • Gastelblum P.
      • Thomas L.
      • Chapet O.
      • Bollet M.A.
      • Ardiet J.-M.
      • et al.
      Treatment of squamous cell anal canal carcinoma (SCACC) with pulsed dose rate brachytherapy: A retrospective study.
      ]. The proportion of T1 and T4 tumors in the reported cohorts ranges from 5-20% [
      • Cordoba A.
      • Escande A.
      • Leroy T.
      • Mirabel X.
      • Coche-Dequéant B.
      • Lartigau E.
      Low-dose-rate interstitial brachytherapy boost for the treatment of anal canal cancers.
      ,
      • 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).
      ,
      • Weber D.C.
      • Kurtz J.M.
      • Allal A.S.
      The impact of gap duration on local control in anal canal carcinoma treated by split-course radiotherapy and concomitant chemotherapy.
      ,
      • Weber D.C.
      • Kurtz J.M.
      • Allal A.S.
      The impact of gap duration on local control in anal canal carcinoma treated by split-course radiotherapy and concomitant chemotherapy.
      ,
      • Oblak I.
      • Petric P.
      • Anderluh F.
      • Velenik V.
      • Fras PA.
      Long term outcome after combined modality treatment for anal cancer.
      ,
      • Lestrade L.
      • De Bari B.
      • Pommier P.
      • Montbarbon X.
      • Lavergne E.
      • Ardiet J.-M.
      • et al.
      Role of brachytherapy in the treatment of cancers of the anal canal: Long-term follow-up and multivariate analysis of a large monocentric retrospective seriesStellenwert der Brachytherapie bei der Behandlung von Tumoren des Analkanals: Langzeit-Follow-up und multivariate Analyse einer großen monozentrischen, retrospektiven Studie.
      ,
      • Chapet O.
      • Gerard J.-P.
      • Riche B.
      • Alessio A.
      • Mornex F.
      • Romestaing P.
      Prognostic value of tumor regression evaluated after first course of radiotherapy for anal canal cancer.
      ,
      • Tournier-Rangeard L.
      • Peiffert D.
      • Lafond C.
      • Mege A.
      • Metayer Y.
      • Marchesi V.
      • et al.
      Résultats à long terme et facteurs pronostiques des carcinomes épidermoïdes du canal anal traités par irradiation.
      ,
      • Bruna A.
      • Gastelblum P.
      • Thomas L.
      • Chapet O.
      • Bollet M.A.
      • Ardiet J.-M.
      • et al.
      Treatment of squamous cell anal canal carcinoma (SCACC) with pulsed dose rate brachytherapy: A retrospective study.
      ,
      • 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.
      ,
      • Gryc T.
      • Ott O.
      • Putz F.
      • Knippen S.
      • Raptis D.
      • Fietkau R.
      • et al.
      Interstitial brachytherapy as a boost to patients with anal carcinoma and poor response to chemoradiation: Single-institution long-term results.
      ]. Evidence on effectiveness of BT as single or upfront therapy in small tumours is limited [
      • 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.
      ,
      • Ortholan C.
      • Ramaioli A.
      • Peiffert D.
      • Lusinchi A.
      • Romestaing P.
      • Chauveinc L.
      • et al.
      Anal canal carcinoma: Early-stage tumors ≤10 mm (T1 or Tis): Therapeutic options and original pattern of local failure after radiotherapy.
      ,
      • López Guerra J.L.
      • Lozano A.J.
      • Pera J.
      • Gutiérrez C.
      • Cambray M.
      • Ferrer F.
      • et al.
      Twenty-year experience in the management of squamous cell anal canal carcinoma with interstitial brachytherapy.
      ]. Several authors have demonstrated that node-positive patients benefit from anal BT [
      • Chapet O.
      • Gerard J.-P.
      • Riche B.
      • Alessio A.
      • Mornex F.
      • Romestaing P.
      Prognostic value of tumor regression evaluated after first course of radiotherapy for anal canal cancer.
      ,
      • 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).
      ]. In oligometastatic disease pelvic chemoradiation, local BT and ablative treatment of metastases can offer a chance of cure. In metastatic disease, BT may be used to palliate or prevent local symptoms.

      Local control and survival

      In a recent systematic review, median 5-year local/locoregional control (LC/LRC) after EBRT and BT was 79% (range: 71–92%), disease free survival (DFS) 76% (range: 66–86%), OS 69% (range: 63–82%) and colostomy free survival (CFS) 76% (range: 61–86%) [
      • Frakulli R.
      • Buwenge M.
      • Cammelli S.
      • Macchia G.
      • Farina E.
      • Arcelli A.
      • et al.
      Brachytherapy boost after chemoradiation in anal cancer: a systematic review.
      ]. Published series are detailed in Table 1, Table 2. Node-negative status at diagnosis and good response to EBRT are prognostic of superior outcome in most series [
      • Frakulli R.
      • Buwenge M.
      • Cammelli S.
      • Macchia G.
      • Farina E.
      • Arcelli A.
      • et al.
      Brachytherapy boost after chemoradiation in anal cancer: a systematic review.
      ,
      • Cordoba A.
      • Escande A.
      • Leroy T.
      • Mirabel X.
      • Coche-Dequéant B.
      • Lartigau E.
      Low-dose-rate interstitial brachytherapy boost for the treatment of anal canal cancers.
      ,
      • Oblak I.
      • Petric P.
      • Anderluh F.
      • Velenik V.
      • Fras PA.
      Long term outcome after combined modality treatment for anal cancer.
      ,
      • Widder J.
      • Kastenberger R.
      • Fercher E.
      • Schmid R.
      • Langendijk J.A.
      • Dobrowsky W.
      • et al.
      Radiation dose associated with local control in advanced anal cancer: Retrospective analysis of 129 patients.
      ,
      • Chapet O.
      • Gerard J.-P.
      • Riche B.
      • Alessio A.
      • Mornex F.
      • Romestaing P.
      Prognostic value of tumor regression evaluated after first course of radiotherapy for anal canal cancer.
      ,
      • Sandhu A.P.S.
      • Paul Symonds R.
      • Robertson A.G.
      • Reed N.S.
      • McNee S.G.
      • Paul J.
      Interstitial iridium-192 implantation combined with external radiotherapy in anal cancer: ten years experience.
      ,
      • 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.
      ,
      • Peiffert D.
      • Bey P.
      • Pernot M.
      • Guillemin F.
      • Luporsi E.
      • Hoffstetter S.
      • et al.
      Conservative treatment by irradiation of epidermoid cancers of the anal canal: Prognostic factors of tumoral control and complications.
      ]. Stage T3-4 and poor pre-boost regression are negative prognostic factors [
      • Chapet O.
      • Gerard J.-P.
      • Riche B.
      • Alessio A.
      • Mornex F.
      • Romestaing P.
      Prognostic value of tumor regression evaluated after first course of radiotherapy for anal canal cancer.
      ].
      Data on comparative effectiveness of BT and EBRT boost come from indirect estimates and retrospective series. Keeping the limitations of such comparisons in mind, the available evidence demonstrates superior or similar effectiveness of BT when compared with EBRT boost. These findings could be attributed to the physical and biological advantages of BT over EBRT (Fig. 1, Table 3). Series in which BT boost was used in majority of 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.
      ] compare favourably with trials, based predominantly on EBRT alone [
      • 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).
      ,
      • 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.
      ,
      • Gunderson L.L.
      • Winter K.A.
      • Ajani J.A.
      • Pedersen J.E.
      • Moughan J.
      • Benson 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.
      ,
      • Peiffert D.
      • Tournier-Rangeard L.
      • Gérard J.-P.
      • Lemanski C.
      • François 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.
      ,
      • UKCCCR Anal Cancer Trial Working Party
      Epidermoid anal cancer: results from the UKCCCR randomised trial of radiotherapy alone versus radiotherapy, 5-fluorouracil, and mitomycin.
      ,
      • 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.
      ,
      • Ajani J.A.
      Fluorouracil, Mitomycin, and Radiotherapy vs Fluorouracil, Cisplatin, and Radiotherapy for Carcinoma of the Anal Canal: A Randomized Controlled Trial.
      ]. In the CORS-03 study, boost type was one of the prognostic factors for 5-year local recurrence (LR) (BT: 12% vs. EBRT: 33%; p = 0.002) and CFS (BT: 71% vs. EBRT: 56%; p = 0.04). This was in spite of a trend for a lower nominal BT (mean: 17.4 Gy; range: 10–25 Gy) than EBRT dose (mean: 18.3 Gy; range 8–25 Gy; p = 0.07). Importantly, characteristics of patients and tumours were balanced across the two groups of patients in this study. For LR, prognostic significance of boost type was maintained on multivariate analysis (hazard ratio 0.62; 95% CI: 0.41–0.92). Surgery for progression or complications was needed in 26% EBRT and 8% BT boost patients (p = 0.003) [
      • 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 analysis of node-positive patients from the CORS-03 cohort, BT boost maintained a positive impact with lower 5-year LR when compared with EBRT (4% vs. 31%, p = 0.003; hazard ratio 0.08; p = 0.042) [
      • 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).
      ]. In a series from Lyon, BT boost was associated with superior OS (75.8% vs. 47.5%; p < 0.0001) and DFS (63.4 % vs. 37.9%; p < 0.001) when compared with EBRT [
      • Chapet O.
      • Gerard J.-P.
      • Riche B.
      • Alessio A.
      • Mornex F.
      • Romestaing P.
      Prognostic value of tumor regression evaluated after first course of radiotherapy for anal canal cancer.
      ]. Similar advantage of BT was published recently by an Italian group demonstrating a 5-year OS of 79% vs. 52%; p = 0.015 and distant metastases free survival (DMFS) of 95% vs. 77%; p = 0.015 [
      • 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.
      ]. Other reports which used both types of boost offer similar results, but should be interpreted cautiously due to unbalanced samples and bias with large tumours being boosted more often with EBRT [
      • 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).
      ,
      • Weber D.C.
      • Kurtz J.M.
      • Allal A.S.
      The impact of gap duration on local control in anal canal carcinoma treated by split-course radiotherapy and concomitant chemotherapy.
      ,
      • Oblak I.
      • Petric P.
      • Anderluh F.
      • Velenik V.
      • Fras PA.
      Long term outcome after combined modality treatment for anal cancer.
      ,
      • Chapet O.
      • Gerard J.-P.
      • Riche B.
      • Alessio A.
      • Mornex F.
      • Romestaing P.
      Prognostic value of tumor regression evaluated after first course of radiotherapy for anal canal cancer.
      ,
      • Gryc T.
      • Ott O.
      • Putz F.
      • Knippen S.
      • Raptis D.
      • Fietkau R.
      • et al.
      Interstitial brachytherapy as a boost to patients with anal carcinoma and poor response to chemoradiation: Single-institution long-term results.
      ,
      • Deniaud-Alexandre E.
      • Touboul E.
      • Tiret E.
      • Sezeur A.
      • Houry S.
      • Gallot D.
      • et al.
      Results of definitive irradiation in a series of 305 epidermoid carcinomas of the anal canal.
      ]. Some authors found no impact of boost-type. In one study, 5-year DFS was 86.5% for BT and 71.6% for EBRT boost (p = 0.07), but only 6% of patients received BT boost [
      • Deniaud-Alexandre E.
      • Touboul E.
      • Tiret E.
      • Sezeur A.
      • Houry S.
      • Gallot D.
      • et al.
      Results of definitive irradiation in a series of 305 epidermoid carcinomas of the anal canal.
      ]. Another series with a more balanced cohort found similar results [
      • Oblak I.
      • Petric P.
      • Anderluh F.
      • Velenik V.
      • Fras PA.
      Long term outcome after combined modality treatment for anal cancer.
      ]. In a report from Switzerland, a median of 20 Gy EBRT and 18 Gy BT boost was applied in 41 (46%) and 49 (54%) cases, resulting in a 5-year LRC of 70.7% and 75.5%, respectively (p = 0.82) [
      • Weber D.C.
      • Kurtz J.M.
      • Allal A.S.
      The impact of gap duration on local control in anal canal carcinoma treated by split-course radiotherapy and concomitant chemotherapy.
      ]. Kent et al. reported on non-significant differences at 5 years between BT for anal canal (cancer specific survival-CSS: 91%, OS: 75%) and electron boost for anal margin tumors (CSS: 78%, OS: 68%) [48]. In another series, BT (n = 34) and EBRT (n = 47) boost resulted in similar 5-year LR rate (10% vs. 15%; p = 0.5) and OS (66% in both groups) [
      • 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.
      ].
      Figure thumbnail gr1
      Fig. 1Comparison of volumetric modulated arc therapy (VMAT) with virtual image guided adaptive brachytherapy (IGABT) boost in a patient with a T3 N0 tumor, who underwent planning CT both for VMAT and IGABT. To compare dose distributions, iso-effective prescriptions were selected and D98 was normalized to 95% of prescribed dose both for the PTVEBRT and CTV-T HRBT (). (A) VMAT plan, optimized to PTV (CTV-T HR + 5 mm). Color wash: 95% to 105% of prescribed dose. (B) Virtual IGABT with a 2 cm anal dilator. Virtual perineal template was projected on CT to place 15 virtual needles in 3 planes at a median depth of 63 mm (range: 37–88 mm). Paris-system plan, specifying the dose at 85% isodose of basal dose-points was used as the starting point and optimized to meet the planning aims. Color-wash: 95% to 200% of prescribed dose. Absence of CTV to PTV margin, sharp dose fall-off and displacement of healthy tissues result in a lower dose to the sphincter and anorectum when compared with VMAT. Simultaneously, superior coverage and dose escalation inside the GTV-Tres is achieved. GTV-Tres – residual gross tumor volume; CTV-T HR – high risk clinical target volume of the primary tumor.
      Table 3Dose-volume histogram parameters of volumetric modulated arc therapy (VMAT) and image guided adaptive brachytherapy (IGABT) plans, presented in Fig. 1. GTV-Tres: residual gross tumor volume; CTV-T HR: high risk clinical target volume of primary tumor; PTV: planning target volume; EQD2: equivalent biological dose in 2 Gy fractions, according to the LQ model and α/β ratio of 10 Gy and 3 Gy for tumor and late-reacting normal tissues, respectively. a For IGABT there is no PTV margin and PTV is identical to CTV-T HR. b Selected EBRT and BT prescriptions are almost iso-effective in terms of EQD2.
      VMATIGABT
      Target volume size [cm3]
      GTV-Tres1111
      CTV-T HR3131
      PTV67a 31
      b PTV dose prescription
      Nominal D / Fractions16 Gy / 8 Fractions15 Gy / 25 Pulses
      EQD2 [Gy10]1615.5
      EQD2 [Gy3]1616.2
      PTV EQD2 [Gy10]
      D 98%15.114.6
      D 90%15.616.6
      D mean1623
      PTV V 100%59%95%
      GTV-Tres EQD2 [Gy10]
      D 98%1619.3
      D 90%1621.8
      D mean16.235.4
      Ano/Rectum EQD2 [Gy3]
      D 0.1 cm316.520.2
      D 2 cm315.88.7
      D 5 cm315.35.2
      D mean12.24.9
      Ano/Rectum V 50% [cm3]125
      Sphincter EQD2 [Gy3]
      D 0.1 cm316.537.9
      D 2 cm315.810.8
      D 5 cm314.25.4
      D mean7.75.2
      Sphincter V 50% [cm3]125
      Body Volumes [cm3]
      V 50%250112
      V 150%06.7
      V 200%01.6
      Average D to Basal points [Gy]1620

      Toxicity

      Radiosensitivity and functional stress make anal region prone to treatment toxicity, but data interpretation is challenging. Majority of studies reported crude rates, different scoring systems were used, and grading criteria were often not specified. Further, approximately 1/4 of patients received EBRT boost, but toxicity was reported jointly with BT, making it difficult to corelate specific endpoints with specific boost technique. Heterogeneity of tumours, RT schedules and sample sizes complicates interpretations further. Notwithstanding all these challenges, the available evidence demonstrates that the toxicity profile after BT compares favorably with EBRT boost, which can be attributed to the sparing of the healthy mucosa, uninvolved sphincter complex and the contralateral nerves and vessels afforded by BT (Fig. 1, Table 3).
      Acute local and hematologic toxicity during (chemo)radiation develops in majority of patients. G1-2 dermato-mucositis in the published studies ranged from 30–60% and proctitis from 10–30% [
      • Oblak I.
      • Petric P.
      • Anderluh F.
      • Velenik V.
      • Fras PA.
      Long term outcome after combined modality treatment for anal cancer.
      ,
      • Chapet O.
      • Gerard J.-P.
      • Riche B.
      • Alessio A.
      • Mornex F.
      • Romestaing P.
      Prognostic value of tumor regression evaluated after first course of radiotherapy for anal canal cancer.
      ,
      • Gerard J.-P.
      • Ayzac L.
      • Hun D.
      • Romestaing P.
      • Coquard R.
      • Ardiet J.-M.
      • et al.
      Treatment of anal canal carcinoma with high dose radiation therapy and concomitant fluorouracil-cisplatinum. Long-term results in 95 patients.
      ,
      • López Guerra J.L.
      • Lozano A.J.
      • Pera J.
      • Gutiérrez C.
      • Cambray M.
      • Ferrer F.
      • et al.
      Twenty-year experience in the management of squamous cell anal canal carcinoma with interstitial brachytherapy.
      ]. While side effects were limited to G1-2 in some series [
      • Falk A.T.
      • Claren A.
      • Benezery K.
      • François E.
      • Gautier M.
      • Gerard J.-P.
      • et al.
      Interstitial high-dose rate brachytherapy as boost for anal canal 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.
      ], G3-4 acute toxicity was common, ranging from 10-30% and often necessitating un-planned treatment breaks [
      • Oblak I.
      • Petric P.
      • Anderluh F.
      • Velenik V.
      • Fras PA.
      Long term outcome after combined modality treatment for anal cancer.
      ,
      • Lestrade L.
      • De Bari B.
      • Pommier P.
      • Montbarbon X.
      • Lavergne E.
      • Ardiet J.-M.
      • et al.
      Role of brachytherapy in the treatment of cancers of the anal canal: Long-term follow-up and multivariate analysis of a large monocentric retrospective seriesStellenwert der Brachytherapie bei der Behandlung von Tumoren des Analkanals: Langzeit-Follow-up und multivariate Analyse einer großen monozentrischen, retrospektiven Studie.
      ,
      • Ortholan C.
      • Ramaioli A.
      • Peiffert D.
      • Lusinchi A.
      • Romestaing P.
      • Chauveinc L.
      • et al.
      Anal canal carcinoma: Early-stage tumors ≤10 mm (T1 or Tis): Therapeutic options and original pattern of local failure after radiotherapy.
      ,
      • López Guerra J.L.
      • Lozano A.J.
      • Pera J.
      • Gutiérrez C.
      • Cambray M.
      • Ferrer F.
      • et al.
      Twenty-year experience in the management of squamous cell anal canal carcinoma with interstitial brachytherapy.
      ]. In a report from Switzerland, Grade 3–4 toxicity was higher in patients after EBRT when compared with BT boost (43% vs. 15%; p = 0.008). This was due to worse hematologic (13% vs 0%) and cutaneous (23% vs. 8%) reactions, while severe diarrhea occurred in 6% in both subgroups [
      • 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.
      ]. In another study, acute G3-4 toxicity didn’t differ between EBRT and BT boost [
      • Gryc T.
      • Ott O.
      • Putz F.
      • Knippen S.
      • Raptis D.
      • Fietkau R.
      • et al.
      Interstitial brachytherapy as a boost to patients with anal carcinoma and poor response to chemoradiation: Single-institution long-term results.
      ].
      Collectively, most common late toxicity for EBRT and BT-boost cohorts is sphincter dysfunction with G1-2, G3 and G4 incontinence in up to 25%, 10% and 4%, respectively [
      • 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.
      ,
      • Saarilahti K.
      • Arponen P.
      • Vaalavirta L.
      • Tenhunen M.
      The effect of intensity-modulated radiotherapy and high dose rate brachytherapy on acute and late radiotherapy-related adverse events following chemoradiotherapy of anal cancer.
      ,
      • Cordoba A.
      • Escande A.
      • Leroy T.
      • Mirabel X.
      • Coche-Dequéant B.
      • Lartigau E.
      Low-dose-rate interstitial brachytherapy boost for the treatment of anal canal cancers.
      ,
      • Oblak I.
      • Petric P.
      • Anderluh F.
      • Velenik V.
      • Fras PA.
      Long term outcome after combined modality treatment for anal cancer.
      ,
      • Widder J.
      • Kastenberger R.
      • Fercher E.
      • Schmid R.
      • Langendijk J.A.
      • Dobrowsky W.
      • et al.
      Radiation dose associated with local control in advanced anal cancer: Retrospective analysis of 129 patients.
      ,
      • Lestrade L.
      • De Bari B.
      • Pommier P.
      • Montbarbon X.
      • Lavergne E.
      • Ardiet J.-M.
      • et al.
      Role of brachytherapy in the treatment of cancers of the anal canal: Long-term follow-up and multivariate analysis of a large monocentric retrospective seriesStellenwert der Brachytherapie bei der Behandlung von Tumoren des Analkanals: Langzeit-Follow-up und multivariate Analyse einer großen monozentrischen, retrospektiven Studie.
      ,
      • Gerard J.-P.
      • Ayzac L.
      • Hun D.
      • Romestaing P.
      • Coquard R.
      • Ardiet J.-M.
      • et al.
      Treatment of anal canal carcinoma with high dose radiation therapy and concomitant fluorouracil-cisplatinum. Long-term results in 95 patients.
      ,
      • Ortholan C.
      • Ramaioli A.
      • Peiffert D.
      • Lusinchi A.
      • Romestaing P.
      • Chauveinc L.
      • et al.
      Anal canal carcinoma: Early-stage tumors ≤10 mm (T1 or Tis): Therapeutic options and original pattern of local failure after radiotherapy.
      ,
      • Sandhu A.P.S.
      • Paul Symonds R.
      • Robertson A.G.
      • Reed N.S.
      • McNee S.G.
      • Paul J.
      Interstitial iridium-192 implantation combined with external radiotherapy in anal cancer: ten years experience.
      ,
      • López Guerra J.L.
      • Lozano A.J.
      • Pera J.
      • Gutiérrez C.
      • Cambray M.
      • Ferrer F.
      • et al.
      Twenty-year experience in the management of squamous cell anal canal carcinoma with interstitial brachytherapy.
      ,
      • Gerard J.-P.
      • Mauro F.
      • Thomas L.
      • Castelain B.
      • Mazeron J.-J.
      • Ardiet J.-M.
      • et al.
      Treatment of squamous cell anal canal carcinoma with pulsed dose rate brachytherapy. Feasibility study of a French cooperative group.
      ,
      • 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.
      ,
      • 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.
      ,
      • Doniec J.M.
      • Schniewind B.
      • Kovács G.
      • Kahlke V.
      • Loehnert M.
      • Kremer B.
      Multimodal therapy of anal cancer added by new endosonographic-guided brachytherapy.
      ,
      • 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.
      ]. Mild to moderate fibrosis ranges from 0–25%, G3 stricture occurs in ≤5%, and complete obstruction is extremely rare [
      • Peiffert D.
      • Tournier-Rangeard L.
      • Gérard J.-P.
      • Lemanski C.
      • François 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.
      ,
      • Saarilahti K.
      • Arponen P.
      • Vaalavirta L.
      • Tenhunen M.
      The effect of intensity-modulated radiotherapy and high dose rate brachytherapy on acute and late radiotherapy-related adverse events following chemoradiotherapy of anal cancer.
      ,
      • Cordoba A.
      • Escande A.
      • Leroy T.
      • Mirabel X.
      • Coche-Dequéant B.
      • Lartigau E.
      Low-dose-rate interstitial brachytherapy boost for the treatment of anal canal cancers.
      ,
      • Oblak I.
      • Petric P.
      • Anderluh F.
      • Velenik V.
      • Fras PA.
      Long term outcome after combined modality treatment for anal cancer.
      ,
      • Widder J.
      • Kastenberger R.
      • Fercher E.
      • Schmid R.
      • Langendijk J.A.
      • Dobrowsky W.
      • et al.
      Radiation dose associated with local control in advanced anal cancer: Retrospective analysis of 129 patients.
      ,
      • Ortholan C.
      • Ramaioli A.
      • Peiffert D.
      • Lusinchi A.
      • Romestaing P.
      • Chauveinc L.
      • et al.
      Anal canal carcinoma: Early-stage tumors ≤10 mm (T1 or Tis): Therapeutic options and original pattern of local failure after radiotherapy.
      ,
      • Sandhu A.P.S.
      • Paul Symonds R.
      • Robertson A.G.
      • Reed N.S.
      • McNee S.G.
      • Paul J.
      Interstitial iridium-192 implantation combined with external radiotherapy in anal cancer: ten years experience.
      ,
      • Gerard J.-P.
      • Mauro F.
      • Thomas L.
      • Castelain B.
      • Mazeron J.-J.
      • Ardiet J.-M.
      • et al.
      Treatment of squamous cell anal canal carcinoma with pulsed dose rate brachytherapy. Feasibility study of a French cooperative group.
      ,
      • 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.
      ,
      • 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.
      ]. Mild and transient late anorectal bleeding can occur in up to 15–70%, but G3-4 bleeding is uncommon, reported in ≤2% of patients (36,43,44,47,59). G2 and G3-4 necrosis occurrs in <10% and ≤5%, respectively. Peiffert et al., using the Chassagne grading system [
      • Chassagne D.
      • Sismondi P.
      • Horiot J.
      • Sinistrero G.
      • Bey P.
      • Zola P.
      • et al.
      A glossary for reporting complications of the treatment in gynecological cancer.
      ], reported on 13% of G3 necrosis [
      • Peiffert D.
      • Bey P.
      • Pernot M.
      • Guillemin F.
      • Luporsi E.
      • Hoffstetter S.
      • et al.
      Conservative treatment by irradiation of epidermoid cancers of the anal canal: Prognostic factors of tumoral control and complications.
      ]. Other chronic toxicities of any grade include proctitis (0–26%), chronic pain (0–15%), skin toxicity (0–10%) and fistulae (0–1%). Grade 3 genitourinary problems occur in up to approximately 5% [
      • Saarilahti K.
      • Arponen P.
      • Vaalavirta L.
      • Tenhunen M.
      The effect of intensity-modulated radiotherapy and high dose rate brachytherapy on acute and late radiotherapy-related adverse events following chemoradiotherapy of anal cancer.
      ,
      • Cordoba A.
      • Escande A.
      • Leroy T.
      • Mirabel X.
      • Coche-Dequéant B.
      • Lartigau E.
      Low-dose-rate interstitial brachytherapy boost for the treatment of anal canal cancers.
      ,
      • Widder J.
      • Kastenberger R.
      • Fercher E.
      • Schmid R.
      • Langendijk J.A.
      • Dobrowsky W.
      • et al.
      Radiation dose associated with local control in advanced anal cancer: Retrospective analysis of 129 patients.
      ,
      • Falk A.T.
      • Claren A.
      • Benezery K.
      • François E.
      • Gautier M.
      • Gerard J.-P.
      • et al.
      Interstitial high-dose rate brachytherapy as boost for anal canal cancer.
      ,
      • Ortholan C.
      • Ramaioli A.
      • Peiffert D.
      • Lusinchi A.
      • Romestaing P.
      • Chauveinc L.
      • et al.
      Anal canal carcinoma: Early-stage tumors ≤10 mm (T1 or Tis): Therapeutic options and original pattern of local failure after radiotherapy.
      ,
      • Kent C.
      • Bessell E.M.
      • Scholefield J.H.
      • Chappell S.
      • Marsh L.
      • Mills J.
      • et al.
      Chemoradiotherapy with Brachytherapy or Electron Therapy Boost for Locally Advanced Squamous Cell Carcinoma of the Anus—Reducing the Colostomy Rate.
      ,
      • Sandhu A.P.S.
      • Paul Symonds R.
      • Robertson A.G.
      • Reed N.S.
      • McNee S.G.
      • Paul J.
      Interstitial iridium-192 implantation combined with external radiotherapy in anal cancer: ten years experience.
      ,
      • López Guerra J.L.
      • Lozano A.J.
      • Pera J.
      • Gutiérrez C.
      • Cambray M.
      • Ferrer F.
      • et al.
      Twenty-year experience in the management of squamous cell anal canal carcinoma with interstitial brachytherapy.
      ,
      • 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.
      ,
      • Gryc T.
      • Ott O.
      • Putz F.
      • Knippen S.
      • Raptis D.
      • Fietkau R.
      • et al.
      Interstitial brachytherapy as a boost to patients with anal carcinoma and poor response to chemoradiation: Single-institution long-term results.
      ,
      • Peiffert D.
      • Bey P.
      • Pernot M.
      • Guillemin F.
      • Luporsi E.
      • Hoffstetter S.
      • et al.
      Conservative treatment by irradiation of epidermoid cancers of the anal canal: Prognostic factors of tumoral control and complications.
      ,
      • 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.
      ]. Colostomy or abdominoperineal resection rate due to toxicity is typically ≤5% [
      • Saarilahti K.
      • Arponen P.
      • Vaalavirta L.
      • Tenhunen M.
      The effect of intensity-modulated radiotherapy and high dose rate brachytherapy on acute and late radiotherapy-related adverse events following chemoradiotherapy of anal cancer.
      ,
      • Cordoba A.
      • Escande A.
      • Leroy T.
      • Mirabel X.
      • Coche-Dequéant B.
      • Lartigau E.
      Low-dose-rate interstitial brachytherapy boost for the treatment of anal canal cancers.
      ,
      • 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).
      ,
      • Oblak I.
      • Petric P.
      • Anderluh F.
      • Velenik V.
      • Fras PA.
      Long term outcome after combined modality treatment for anal cancer.
      ,
      • Widder J.
      • Kastenberger R.
      • Fercher E.
      • Schmid R.
      • Langendijk J.A.
      • Dobrowsky W.
      • et al.
      Radiation dose associated with local control in advanced anal cancer: Retrospective analysis of 129 patients.
      ,
      • Falk A.T.
      • Claren A.
      • Benezery K.
      • François E.
      • Gautier M.
      • Gerard J.-P.
      • et al.
      Interstitial high-dose rate brachytherapy as boost for anal canal cancer.
      ,
      • Lestrade L.
      • De Bari B.
      • Pommier P.
      • Montbarbon X.
      • Lavergne E.
      • Ardiet J.-M.
      • et al.
      Role of brachytherapy in the treatment of cancers of the anal canal: Long-term follow-up and multivariate analysis of a large monocentric retrospective seriesStellenwert der Brachytherapie bei der Behandlung von Tumoren des Analkanals: Langzeit-Follow-up und multivariate Analyse einer großen monozentrischen, retrospektiven Studie.
      ,
      • Chapet O.
      • Gerard J.-P.
      • Riche B.
      • Alessio A.
      • Mornex F.
      • Romestaing P.
      Prognostic value of tumor regression evaluated after first course of radiotherapy for anal canal cancer.
      ,
      • Bruna A.
      • Gastelblum P.
      • Thomas L.
      • Chapet O.
      • Bollet M.A.
      • Ardiet J.-M.
      • et al.
      Treatment of squamous cell anal canal carcinoma (SCACC) with pulsed dose rate brachytherapy: A retrospective study.
      ,
      • Ortholan C.
      • Ramaioli A.
      • Peiffert D.
      • Lusinchi A.
      • Romestaing P.
      • Chauveinc L.
      • et al.
      Anal canal carcinoma: Early-stage tumors ≤10 mm (T1 or Tis): Therapeutic options and original pattern of local failure after radiotherapy.
      ,
      • Kent C.
      • Bessell E.M.
      • Scholefield J.H.
      • Chappell S.
      • Marsh L.
      • Mills J.
      • et al.
      Chemoradiotherapy with Brachytherapy or Electron Therapy Boost for Locally Advanced Squamous Cell Carcinoma of the Anus—Reducing the Colostomy Rate.
      ,
      • López Guerra J.L.
      • Lozano A.J.
      • Pera J.
      • Gutiérrez C.
      • Cambray M.
      • Ferrer F.
      • et al.
      Twenty-year experience in the management of squamous cell anal canal carcinoma with interstitial brachytherapy.
      ,
      • Gerard J.-P.
      • Mauro F.
      • Thomas L.
      • Castelain B.
      • Mazeron J.-J.
      • Ardiet J.-M.
      • et al.
      Treatment of squamous cell anal canal carcinoma with pulsed dose rate brachytherapy. Feasibility study of a French cooperative group.
      ,
      • 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.
      ,
      • Doniec J.M.
      • Schniewind B.
      • Kovács G.
      • Kahlke V.
      • Loehnert M.
      • Kremer B.
      Multimodal therapy of anal cancer added by new endosonographic-guided brachytherapy.
      ], but was up to 9% in selected series. [
      • Papillon J.
      • Montbarbong J.F.
      • Gerard J.P.
      • Chassard J.L.
      • Ardiet J.M.
      Interstitial curietherapy in the conservative treatment of anal and rectal cancers.
      ,
      • Sandhu A.P.S.
      • Paul Symonds R.
      • Robertson A.G.
      • Reed N.S.
      • McNee S.G.
      • Paul J.
      Interstitial iridium-192 implantation combined with external radiotherapy in anal cancer: ten years experience.
      ,
      • Peiffert D.
      • Bey P.
      • Pernot M.
      • Guillemin F.
      • Luporsi E.
      • Hoffstetter S.
      • et al.
      Conservative treatment by irradiation of epidermoid cancers of the anal canal: Prognostic factors of tumoral control and complications.
      ]. The most frequent cause of treatment-induced colostomy is necrosis, followed by severe incontinence, hemorrhage, pain and fistula [
      • Cordoba A.
      • Escande A.
      • Leroy T.
      • Mirabel X.
      • Coche-Dequéant B.
      • Lartigau E.
      Low-dose-rate interstitial brachytherapy boost for the treatment of anal canal cancers.
      ,
      • Widder J.
      • Kastenberger R.
      • Fercher E.
      • Schmid R.
      • Langendijk J.A.
      • Dobrowsky W.
      • et al.
      Radiation dose associated with local control in advanced anal cancer: Retrospective analysis of 129 patients.
      ,
      • Falk A.T.
      • Claren A.
      • Benezery K.
      • François E.
      • Gautier M.
      • Gerard J.-P.
      • et al.
      Interstitial high-dose rate brachytherapy as boost for anal canal cancer.
      ,
      • Chapet O.
      • Gerard J.-P.
      • Riche B.
      • Alessio A.
      • Mornex F.
      • Romestaing P.
      Prognostic value of tumor regression evaluated after first course of radiotherapy for anal canal cancer.
      ,
      • Gerard J.-P.
      • Ayzac L.
      • Hun D.
      • Romestaing P.
      • Coquard R.
      • Ardiet J.-M.
      • et al.
      Treatment of anal canal carcinoma with high dose radiation therapy and concomitant fluorouracil-cisplatinum. Long-term results in 95 patients.
      ,
      • Kent C.
      • Bessell E.M.
      • Scholefield J.H.
      • Chappell S.
      • Marsh L.
      • Mills J.
      • et al.
      Chemoradiotherapy with Brachytherapy or Electron Therapy Boost for Locally Advanced Squamous Cell Carcinoma of the Anus—Reducing the Colostomy Rate.
      ,
      • Sandhu A.P.S.
      • Paul Symonds R.
      • Robertson A.G.
      • Reed N.S.
      • McNee S.G.
      • Paul J.
      Interstitial iridium-192 implantation combined with external radiotherapy in anal cancer: ten years experience.
      ,
      • Doniec J.M.
      • Schniewind B.
      • Kovács G.
      • Kahlke V.
      • Loehnert M.
      • Kremer B.
      Multimodal therapy of anal cancer added by new endosonographic-guided brachytherapy.
      ].
      In most of the published series offering direct comparisons, BT results in a more favorable profile of late toxicities than the EBRT boost. A group from Finland reported on biologically equivalent doses (EQD23Gy: linear quadratic model, 2 Gy/fraction, α/β = 3 Gy) to the anal canal after pelvic chemoradiation followed by BT (n = 29) or EBRT boost (n = 30). BT boost resulted in a lower mean EQD23Gy to the uninvolved anus than EBRT (44.8 Gy vs. 50.2 Gy; p < 0.01), and higher EQD23Gy to the tumor-infiltrated portion (56.5 vs. 50.2 Gy; p < 0.01). Rate of late G2-3 proctitis corelated with the EQD23Gy to the uninvolved anus and was non-significantly higher after EBRT (12%) than BT boost (3%) (p = 0.065) [
      • Saarilahti K.
      • Arponen P.
      • Vaalavirta L.
      • Tenhunen M.
      The effect of intensity-modulated radiotherapy and high dose rate brachytherapy on acute and late radiotherapy-related adverse events following chemoradiotherapy of anal cancer.
      ]. Three out of 129 patients from Vienna series (23 BT, 106 EBRT boost) developed post-treatment necrosis, all after EBRT boost [
      • Widder J.
      • Kastenberger R.
      • Fercher E.
      • Schmid R.
      • Langendijk J.A.
      • Dobrowsky W.
      • et al.
      Radiation dose associated with local control in advanced anal cancer: Retrospective analysis of 129 patients.
      ]. In a series from Ljubljana, late toxicity was lower after BT than EBRT boost [
      • Oblak I.
      • Petric P.
      • Anderluh F.
      • Velenik V.
      • Fras PA.
      Long term outcome after combined modality treatment for anal cancer.
      ]. Ortholan et al. treated early stage tumours with EBRT alone, EBRT + BT or BT alone and found overall complication rates of 30%, 26% and 25%, respectively [
      • Ortholan C.
      • Ramaioli A.
      • Peiffert D.
      • Lusinchi A.
      • Romestaing P.
      • Chauveinc L.
      • et al.
      Anal canal carcinoma: Early-stage tumors ≤10 mm (T1 or Tis): Therapeutic options and original pattern of local failure after radiotherapy.
      ]. In the CORS 3 study, abdominoperineal resection due to toxicity was needed in 5% of patients after EBRT and 3% after BT boost [
      • 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).
      ]. Recent Italian series reported on similar results with a 5% colostomy rate for both boost types [
      • 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.
      ]. In the report by Gryc et al., there was no significant increase of late G3-4 toxicity in patients who received additional BT boost after EBRT. Most common G3-4 toxicity was proctitis, occurring in 23% after EBRT and 16% after BT boost. Overall rates of severe skin and genitourinary side effects were below 3% and all cases occurred in the non-BT group [
      • Gryc T.
      • Ott O.
      • Putz F.
      • Knippen S.
      • Raptis D.
      • Fietkau R.
      • et al.
      Interstitial brachytherapy as a boost to patients with anal carcinoma and poor response to chemoradiation: Single-institution long-term results.
      ]. Oehler-Jänne et al. found no significant impact of BT (n = 34) and EBRT (n = 47) boost on quality of life, overall late side effects (19% vs. 30%; p = 0.5), G1-2 incontinence (18% vs. 28%; p = 0.5), G3-4 diarrhea (6% vs. 4%; p = NS) and sphincter pressure impairment (37% vs. 29%; p = 0.6) [
      • 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.
      ].
      In the series of Lestrade et al., severe toxicity correlated with the total dose and was 3% for doses ≤63 Gy and 10% for >63 Gy (p = 0.02) [
      • Lestrade L.
      • De Bari B.
      • Pommier P.
      • Montbarbon X.
      • Lavergne E.
      • Ardiet J.-M.
      • et al.
      Role of brachytherapy in the treatment of cancers of the anal canal: Long-term follow-up and multivariate analysis of a large monocentric retrospective seriesStellenwert der Brachytherapie bei der Behandlung von Tumoren des Analkanals: Langzeit-Follow-up und multivariate Analyse einer großen monozentrischen, retrospektiven Studie.
      ]. In another study, a homogeneous cohort of patients who received single-plane implants was assessed. Severe complications were curtailed (2% vs. 11%; p = 0.03) without compromising the LC by a personalized reduction of the mean number of 192-Ir wires (5 vs. 6), shorter wire length (54 mm vs. 63 mm), lower BT reference dose (20 Gy vs. 23 Gy) and smaller volume of 85% isodose (12 vs. 17 cm3). In multivariate analysis, total equivalent dose for late responding tissues remained prognostic for late toxicity (p = 0.01) [
      • Peiffert D.
      • Bey P.
      • Pernot M.
      • Guillemin F.
      • Luporsi E.
      • Hoffstetter S.
      • et al.
      Conservative treatment by irradiation of epidermoid cancers of the anal canal: Prognostic factors of tumoral control and complications.
      ].

      Inter-sequence gap and overall treatment time

      Detrimental effect of tumour cell repopulation due to prolonged overall treatment time (OTT) was demonstrated for various tumours, including anal cancer [
      • Weber D.C.
      • Kurtz J.M.
      • Allal A.S.
      The impact of gap duration on local control in anal canal carcinoma treated by split-course radiotherapy and concomitant chemotherapy.
      ,
      • Oblak I.
      • Petric P.
      • Anderluh F.
      • Velenik V.
      • Fras PA.
      Long term outcome after combined modality treatment for anal cancer.
      ,
      • Widder J.
      • Kastenberger R.
      • Fercher E.
      • Schmid R.
      • Langendijk J.A.
      • Dobrowsky W.
      • et al.
      Radiation dose associated with local control in advanced anal cancer: Retrospective analysis of 129 patients.
      ,
      • Deniaud-Alexandre E.
      • Touboul E.
      • Tiret E.
      • Sezeur A.
      • Houry S.
      • Gallot D.
      • et al.
      Results of definitive irradiation in a series of 305 epidermoid carcinomas of the anal canal.
      ,
      • Withers H.R.
      • Taylor J.M.G.
      • Maciejewski B.
      The hazard of accelerated tumor clonogen repopulation during radiotherapy.
      ,
      • Graf R.
      • Wust P.
      • Hildebrandt B.
      • Gögler H.
      • Ullrich R.
      • Herrmann R.
      • et al.
      Impact of overall treatment time on local control of anal cancer treated with radiochemotherapy.
      ,
      • Mehta S.
      • Ramey S.J.
      • Kwon D.
      • Rich B.J.
      • Ahmed A.A.
      • Wolfson A.
      • et al.
      Impact of radiotherapy duration on overall survival in squamous cell carcinoma of the anus.
      ]. Gaps are difficult to avoid in anal cancer chemoradiation and doses of 60–65 Gy were applied historically to counteract the effect of prolonged OTT [
      • Bruna A.
      • Gastelblum P.
      • Thomas L.
      • Chapet O.
      • Bollet M.A.
      • Ardiet J.-M.
      • et al.
      Treatment of squamous cell anal canal carcinoma (SCACC) with pulsed dose rate brachytherapy: A retrospective study.
      ,
      • Gerard J.-P.
      • Mauro F.
      • Thomas L.
      • Castelain B.
      • Mazeron J.-J.
      • Ardiet J.-M.
      • et al.
      Treatment of squamous cell anal canal carcinoma with pulsed dose rate brachytherapy. Feasibility study of a French cooperative group.
      ]. Landmark trials on chemoradiation mandated a 6-week gap between pelvic EBRT and tumour boost [
      • 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).
      ,
      • 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.
      ]. In the RTOG 92-08 and ECOG E4292 studies, planned break was associated with lower complete response, LRC and CFS, when compared with the no-break cohort [
      • Konski A.
      • Garcia 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.
      ,
      • Chakravarthy A.B.
      • Catalano P.J.
      • Martenson J.A.
      • Mondschein J.K.
      • Wagner H.
      • Mansour E.G.
      • et al.
      Long-term follow-up of a phase II trial of high-dose radiation with concurrent 5-fluorouracil and cisplatin in patients with anal cancer (ECOG E4292).
      ].
      OTT comparisons between sequential EBRT and BT boost are scarce. Available evidence indicates advantage of BT which enables dose delivery over a shorter time than sequential EBRT. In CORS-03 study, the mean inter-sequence gap was 36 (range: 0–106) days and OTT 75 (range: 37–143) days. When compared with sequential EBRT boost, BT boost was associated with a shorter gap (39 vs. 30 days; p = 0.02) and OTT (82 vs 69 days; p < 0.001). Shorter OTT (<80 days vs. ≥80 days) was prognostic of lower 5-year local relapse (LR: 14% vs. 34%; p = 0.005), and higher OS (84% vs 67%; p < 0.001) and CFS (74% vs. 50%; p = 0.004). This was maintained on multivariate analysis with a hazard ratio of 0.47 for LR (95% CI: 0.22–1.0), 0.39 for OS (95% CI: 0.2–0.74) and 0.51 for CFS (95% CI:0.29–0.9) [
      • 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).
      ]. Short OTT was not the only factor leading to improved outcome: there was a positive impact of BT vs. EBRT boost on LR, which was most pronounced when OTT was <80 days (BT: 9% vs. EBRT: 28%; p = 0.03) and non-significant for longer OTTs (BT: 29% vs. EBRT: 38%; p = 0.21). In another series, median OTT was 63 (range: 20–143) days. It was shorter for BT-boost when compared with EBRT-only subgroup (55 vs. 63 days; p = NS). Shorter OTT had positive impact on LC in stage T1-2 (p = 0.021) [
      • Widder J.
      • Kastenberger R.
      • Fercher E.
      • Schmid R.
      • Langendijk J.A.
      • Dobrowsky W.
      • et al.
      Radiation dose associated with local control in advanced anal cancer: Retrospective analysis of 129 patients.
      ].
      Nowadays, anal cancer chemoradiation is predominantly based on pelvic EBRT with simultaneous integrated EBRT boost to the primary tumor without planned treatment breaks. The results of this approach can therefore not be compared directly with the historical data from the published BT studies which are typically characterized by often long inter-sequence gaps and OTTs. Series which used sequential BT boost report on an average gap of around 1 month [
      • Cordoba A.
      • Escande A.
      • Leroy T.
      • Mirabel X.
      • Coche-Dequéant B.
      • Lartigau E.
      Low-dose-rate interstitial brachytherapy boost for the treatment of anal canal cancers.
      ,
      • 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).
      ,
      • Weber D.C.
      • Kurtz J.M.
      • Allal A.S.
      The impact of gap duration on local control in anal canal carcinoma treated by split-course radiotherapy and concomitant chemotherapy.
      ,
      • Falk A.T.
      • Claren A.
      • Benezery K.
      • François E.
      • Gautier M.
      • Gerard J.-P.
      • et al.
      Interstitial high-dose rate brachytherapy as boost for anal canal cancer.
      ] and even up to 3–4 months in individual cases [
      • Cordoba A.
      • Escande A.
      • Leroy T.
      • Mirabel X.
      • Coche-Dequéant B.
      • Lartigau E.
      Low-dose-rate interstitial brachytherapy boost for the treatment of anal canal cancers.
      ,
      • Weber D.C.
      • Kurtz J.M.
      • Allal A.S.
      The impact of gap duration on local control in anal canal carcinoma treated by split-course radiotherapy and concomitant chemotherapy.
      ]. Correspondingly, average OTT in these reports ranged from 60–80 days [
      • 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).
      ,
      • Weber D.C.
      • Kurtz J.M.
      • Allal A.S.
      The impact of gap duration on local control in anal canal carcinoma treated by split-course radiotherapy and concomitant chemotherapy.
      ,
      • Oblak I.
      • Petric P.
      • Anderluh F.
      • Velenik V.
      • Fras PA.
      Long term outcome after combined modality treatment for anal cancer.
      ,
      • Widder J.
      • Kastenberger R.
      • Fercher E.
      • Schmid R.
      • Langendijk J.A.
      • Dobrowsky W.
      • et al.
      Radiation dose associated with local control in advanced anal cancer: Retrospective analysis of 129 patients.
      ,
      • Falk A.T.
      • Claren A.
      • Benezery K.
      • François E.
      • Gautier M.
      • Gerard J.-P.
      • et al.
      Interstitial high-dose rate brachytherapy as boost for anal canal cancer.
      ]. Cordoba et al. found that the OTT cut-off for superior LC was at ≤58 days (p = 0.008) [
      • Cordoba A.
      • Escande A.
      • Leroy T.
      • Mirabel X.
      • Coche-Dequéant B.
      • Lartigau E.
      Low-dose-rate interstitial brachytherapy boost for the treatment of anal canal cancers.
      ]. Another group identified the gap-threshold of ≤38 days as independent prognostic factor for DFS (HR 1.33; 95%CI: 1.04–1.7; p = 0.0025) [
      • Deniaud-Alexandre E.
      • Touboul E.
      • Tiret E.
      • Sezeur A.
      • Houry S.
      • Gallot D.
      • et al.
      Results of definitive irradiation in a series of 305 epidermoid carcinomas of the anal canal.
      ]. In another series with a median OTT of 57 (range 30–98) days, an OTT < 73 was associated with superior 5-year LRC (73% vs. 56%; p = 0.04) [
      • Oblak I.
      • Petric P.
      • Anderluh F.
      • Velenik V.
      • Fras PA.
      Long term outcome after combined modality treatment for anal cancer.
      ]. Weber et al. reported on a median inter-sequence gap of 37.5 days (range: 4–97 days) and OTT of 73.5 days (range: 50–155 days). Factors associated with poorer locoregional control on univariate analysis were age ≤65 years, male gender and inter-sequence gap. Five-year LRC was 84.5% when gap was ≤37.5 days and 61.5% with longer intervals (p = 0.03). On multivariate analysis, only age (p = 0.01) and gap duration (p = 0.02) retained prognostic significance. The authors improved the LRC by limiting the gap to 2 weeks [
      • Weber D.C.
      • Kurtz J.M.
      • Allal A.S.
      The impact of gap duration on local control in anal canal carcinoma treated by split-course radiotherapy and concomitant chemotherapy.
      ].
      Therefore, future studies with strategies to minimize or abolish the gap between pelvic EBRT and BT are required to enable comparisons between simultaneous EBRT boost and sequential BT boost. Modern techniques of pelvic EBRT, performed by experienced institutions play a central role in this context. In a recently published population-based analysis including 8948 patients, the use of IMRT, treatment at an academic center and treatment in more recent years were associated with a shorter overall duration of treatment [
      • Mehta S.
      • Ramey S.J.
      • Kwon D.
      • Rich B.J.
      • Ahmed A.A.
      • Wolfson A.
      • et al.
      Impact of radiotherapy duration on overall survival in squamous cell carcinoma of the anus.
      ]. Pelvic IMRT has been shown to reduce the acute adverse events and un-planned gaps when compared with conventional EBRT [
      • De Bari B.
      • Lestrade L.
      • Franzetti-Pellanda A.
      • Jumeau R.
      • Biggiogero M.
      • Kountouri M.
      • et al.
      Modern intensity-modulated radiotherapy with image guidance allows low toxicity rates and good local control in chemoradiotherapy for anal cancer patients.
      ,
      • Olsen J.R.
      • Moughan J.
      • Myerson R.
      • Abitbol A.
      • Doncals D.E.
      • Johnson D.
      • et al.
      Predictors of Radiation Therapy-Related Gastrointestinal Toxicity From Anal Cancer Dose-Painted Intensity Modulated Radiation Therapy: Secondary Analysis of NRG Oncology RTOG 0529.
      ,
      • Han K.
      • Cummings B.J.
      • Lindsay P.
      • Skliarenko J.
      • Craig T.
      • Le L.W.
      • et al.
      Prospective Evaluation of Acute Toxicity and Quality of Life After IMRT and Concurrent Chemotherapy for Anal Canal and Perianal Cancer.
      ,
      • Devisetty K.
      • Mell L.K.
      • Salama J.K.
      • Schomas D.A.
      • Miller R.C.
      • Jani A.B.
      • et al.
      A multi-institutional acute gastrointestinal toxicity analysis of anal cancer patients treated with concurrent intensity-modulated radiation therapy (IMRT) and chemotherapy.
      ,
      • Kachnic L.A.
      • Winter K.
      • Myerson R.J.
      • Goodyear M.D.
      • Willins J.
      • Esthappan 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.
      ,
      • Kachnic L.A.
      • Tsai H.K.
      • Coen J.J.
      • Blaszkowsky L.S.
      • Hartshorn K.
      • Kwak E.L.
      • et al.
      Dose-painted intensity-modulated radiation therapy for anal cancer: A multi-institutional report of acute toxicity and response to therapy.
      ]. Comparison between RTOG studies demonstrated reduction of acute toxicity in favour of IMRT. Treatment breaks occurred less frequently (49% vs. 62%; p = 0.09), were shorter (0–12 days vs. 0–33 days; p = 0.0047) and resulted in a shorter median OTT (43 vs. 49 days; p < 0.01) with IMRT than with conventional EBRT (27). In a series from Finland, pelvic IMRT (n = 20) or 3D conformal radiotherapy (3D CRT) (n = 39), was followed by HDR BT boost. There was significantly less grade 3–4 diarrhoea and dermato-mucositis and shorter inter-sequence gap in IMRT than 3D CRT group [
      • Saarilahti K.
      • Arponen P.
      • Vaalavirta L.
      • Tenhunen M.
      • Blomqvist C.
      Chemoradiotherapy of anal cancer is feasible in elderly patients: Treatment results of mitomycin–5-FU combined with radiotherapy at Helsinki University Central Hospital 1992–2003.
      ]. In summary, under a premise of equivalent OTTs, it can be reasonable to hypothesize superiority of BT over EBRT boost due to inherent radiobiological and physical advantages of BT (Fig. 1, Table 3). Well-designed prospective studies are required to address this research question.

      Number of brachytherapy channels and planes

      Traditionally, it was postulated that multiple-plane implants lead to increased risk of late necrosis and proctitis [
      • 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.
      ,
      • Papillon J.
      • Montbarbong J.F.
      • Gerard J.P.
      • Chassard J.L.
      • Ardiet J.M.
      Interstitial curietherapy in the conservative treatment of anal and rectal cancers.
      ] and were avoided in conventional BT cohorts (Table 1). In a French series, late toxicity of any grade was 56% after BT with <6 and 72% with ≥6 interstitial needles (p = 0.014) [
      • Lestrade L.
      • De Bari B.
      • Pommier P.
      • Montbarbon X.
      • Lavergne E.
      • Ardiet J.-M.
      • et al.
      Role of brachytherapy in the treatment of cancers of the anal canal: Long-term follow-up and multivariate analysis of a large monocentric retrospective seriesStellenwert der Brachytherapie bei der Behandlung von Tumoren des Analkanals: Langzeit-Follow-up und multivariate Analyse einer großen monozentrischen, retrospektiven Studie.
      ]. In another report, double-plane implant was applied in 4/71 patients due to a large residual tumour. One of these patients required temporary colostomy for G4 necrosis, but was free of disease and toxicity on long-term follow up. None of the remaining 3 developed severe toxicity [
      • Bruna A.
      • Gastelblum P.
      • Thomas L.
      • Chapet O.
      • Bollet M.A.
      • Ardiet J.-M.
      • et al.
      Treatment of squamous cell anal canal carcinoma (SCACC) with pulsed dose rate brachytherapy: A retrospective study.
      ]. Gerard et al. reported on 95 patients, 85 of whom received BT boost. There were 5 cases of severe necrosis, all occurring in T3-4 lesions treated with single-plane implants, one of them following previous bladder cancer EBRT [
      • Gerard J.-P.
      • Ayzac L.
      • Hun D.
      • Romestaing P.
      • Coquard R.
      • Ardiet J.-M.
      • et al.
      Treatment of anal canal carcinoma with high dose radiation therapy and concomitant fluorouracil-cisplatinum. Long-term results in 95 patients.
      ]. It is likely that the implants with large number of channels and/or multiple planes are a surrogate for a higher tumour volume. In cases where residual tumour thickness at BT exceeds 10 mm, carefully performed multiple-plane implants according to the rules of the Paris system may be beneficial [
      • Mazeron J.J.
      • Van Limbergen E.
      Anorectal Cancer.
      ]. This approach has been used safely in a substantial proportion of patients by several authors [
      • 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).
      ,
      • Tournier-Rangeard L.
      • Peiffert D.
      • Lafond C.
      • Mege A.
      • Metayer Y.
      • Marchesi V.
      • et al.
      Résultats à long terme et facteurs pronostiques des carcinomes épidermoïdes du canal anal traités par irradiation.
      ,
      • Bruna A.
      • Gastelblum P.
      • Thomas L.
      • Chapet O.
      • Bollet M.A.
      • Ardiet J.-M.
      • et al.
      Treatment of squamous cell anal canal carcinoma (SCACC) with pulsed dose rate brachytherapy: A retrospective study.
      ,
      • Gerard J.-P.
      • Mauro F.
      • Thomas L.
      • Castelain B.
      • Mazeron J.-J.
      • Ardiet J.-M.
      • et al.
      Treatment of squamous cell anal canal carcinoma with pulsed dose rate brachytherapy. Feasibility study of a French cooperative group.
      ,
      • Peiffert D.
      • Bey P.
      • Pernot M.
      • Guillemin F.
      • Luporsi E.
      • Hoffstetter S.
      • et al.
      Conservative treatment by irradiation of epidermoid cancers of the anal canal: Prognostic factors of tumoral control and complications.
      ].

      Radiotherapy dose

      In majority of studies, BT was tailored to tumour response after EBRT, with poorly responding tumors receiving higher boost doses [
      • Lestrade L.
      • De Bari B.
      • Pommier P.
      • Montbarbon X.
      • Lavergne E.
      • Ardiet J.-M.
      • et al.
      Role of brachytherapy in the treatment of cancers of the anal canal: Long-term follow-up and multivariate analysis of a large monocentric retrospective seriesStellenwert der Brachytherapie bei der Behandlung von Tumoren des Analkanals: Langzeit-Follow-up und multivariate Analyse einer großen monozentrischen, retrospektiven Studie.
      ,
      • Chapet O.
      • Gerard J.-P.
      • Riche B.
      • Alessio A.
      • Mornex F.
      • Romestaing P.
      Prognostic value of tumor regression evaluated after first course of radiotherapy for anal canal cancer.
      ,
      • 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.
      ]. Therefore, conclusions regarding dose–response relationships are challenging, since pre-boost tumor regression is an important prognostic factor for disease control [
      • Lestrade L.
      • De Bari B.
      • Pommier P.
      • Montbarbon X.
      • Lavergne E.
      • Ardiet J.-M.
      • et al.
      Role of brachytherapy in the treatment of cancers of the anal canal: Long-term follow-up and multivariate analysis of a large monocentric retrospective seriesStellenwert der Brachytherapie bei der Behandlung von Tumoren des Analkanals: Langzeit-Follow-up und multivariate Analyse einer großen monozentrischen, retrospektiven Studie.
      ,
      • Chapet O.
      • Gerard J.-P.
      • Riche B.
      • Alessio A.
      • Mornex F.
      • Romestaing P.
      Prognostic value of tumor regression evaluated after first course of radiotherapy for anal canal cancer.
      ,
      • Tournier-Rangeard L.
      • Peiffert D.
      • Lafond C.
      • Mege A.
      • Metayer Y.
      • Marchesi V.
      • et al.
      Résultats à long terme et facteurs pronostiques des carcinomes épidermoïdes du canal anal traités par irradiation.
      ,
      • Gerard J.-P.
      • Mauro F.
      • Thomas L.
      • Castelain B.
      • Mazeron J.-J.
      • Ardiet J.-M.
      • et al.
      Treatment of squamous cell anal canal carcinoma with pulsed dose rate brachytherapy. Feasibility study of a French cooperative group.
      ,
      • Peiffert D.
      Comment on pulsed dose rate (PDR) brachytherapy of anal carcinoma by Roed et al..
      ]. In a series from Vienna, pelvic chemoradiation was followed by BT or additional EBRT. Total nominal dose was 60 Gy (range: 46–66 Gy) for BT and 60 Gy (range: 30–70 Gy) for EBRT. Radiobiologically equivalent doses were not reported. In T3-4 tumours, 5-year LR was 14% after ≥54 Gy and 70% after <54 Gy (p = 0.007) (40). In T1-2 tumours, no impact of dose was observed. A randomized 4-arm ACCORD 03 trial investigated the impact of chemotherapy prior to pelvic chemoradiation and boost-dose escalation [
      • Peiffert D.
      • Tournier-Rangeard L.
      • Gérard J.-P.
      • Lemanski C.
      • François 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.
      ]. LDR BT was used to apply 15 Gy in the standard arm and 20 Gy or 25 Gy (depending on response) in experimental arm. The trial didn’t demonstrate the benefit of interventions on CFS. However, high LC and low toxicity was observed in the most intensive arm, consisting of induction chemotherapy, chemoradiation and high-dose BT boost [
      • Peiffert D.
      • Tournier-Rangeard L.
      • Gérard J.-P.
      • Lemanski C.
      • François 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.
      ]. On the contrary, the CORS 3 study in which a mean of 18.3 Gy (range: 8–25 Gy) was applied for EBRT and 17.4 Gy (range: 10–25 Gy) for BT boost, demonstrated no influence of boost dose on 5-year OS, LC and CFS [
      • 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 the large series from Lyon, a BT boost of 20 ± 5 Gy was applied depending on the degree of tumour regression. No significant impact of dose on the outcome was found [
      • Chapet O.
      • Gerard J.-P.
      • Riche B.
      • Alessio A.
      • Mornex F.
      • Romestaing P.
      Prognostic value of tumor regression evaluated after first course of radiotherapy for anal canal cancer.
      ]. Cordoba et al. applied a similar response-adapted approach, delivering a 10–30 Gy BT boost and found no association between the dose and outcome [
      • Cordoba A.
      • Escande A.
      • Leroy T.
      • Mirabel X.
      • Coche-Dequéant B.
      • Lartigau E.
      Low-dose-rate interstitial brachytherapy boost for the treatment of anal canal cancers.
      ]. A group from Bologna aimed for a BT boost of ≥20 Gy in patients with residual disease after chemoradiation, and ≤16 Gy in complete responders. Five-year OS, LC and DMFS were non-significantly higher in patients, receiving ≤18 Gy when compared with >18 Gy [
      • 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.
      ]. Similar results were obtained by Lestrade et al., with BT doses of ≥18 Gy associated with significantly inferior 5-year LC, OS, CSS and CFS when compared with lower doses [
      • Lestrade L.
      • De Bari B.
      • Pommier P.
      • Montbarbon X.
      • Lavergne E.
      • Ardiet J.-M.
      • et al.
      Role of brachytherapy in the treatment of cancers of the anal canal: Long-term follow-up and multivariate analysis of a large monocentric retrospective seriesStellenwert der Brachytherapie bei der Behandlung von Tumoren des Analkanals: Langzeit-Follow-up und multivariate Analyse einer großen monozentrischen, retrospektiven Studie.
      ]. The apparent lack of impact of BT dose or even the inverse relationship in some studies can be attributed to the selection of poor responders for higher doses [
      • Lestrade L.
      • De Bari B.
      • Pommier P.
      • Montbarbon X.
      • Lavergne E.
      • Ardiet J.-M.
      • et al.
      Role of brachytherapy in the treatment of cancers of the anal canal: Long-term follow-up and multivariate analysis of a large monocentric retrospective seriesStellenwert der Brachytherapie bei der Behandlung von Tumoren des Analkanals: Langzeit-Follow-up und multivariate Analyse einer großen monozentrischen, retrospektiven Studie.
      ,
      • Chapet O.
      • Gerard J.-P.
      • Riche B.
      • Alessio A.
      • Mornex F.
      • Romestaing P.
      Prognostic value of tumor regression evaluated after first course of radiotherapy for anal canal cancer.
      ]. This standpoint is supported by the results by Gryc et al. who reported on the outcome of 190 patients treated with pelvic (chemo)radiation to a mean dose of 48.7 Gy and EBRT boost of 15.5 ± 7.5 Gy. At 6 weeks after treatment, 47 (25%) poor responders received an additional BT boost (10.1 ± 9.7 Gy), resulting in a mean total dose of 67.5 ± 7.8 Gy. This dose escalation in poor responders resulted in similar outcome as in good responders treated with EBRT alone [
      • Gryc T.
      • Ott O.
      • Putz F.
      • Knippen S.
      • Raptis D.
      • Fietkau R.
      • et al.
      Interstitial brachytherapy as a boost to patients with anal carcinoma and poor response to chemoradiation: Single-institution long-term results.
      ].

      Brachytherapy dose rate

      LDR Papillon‘s interstitial technique and the Paris system remained the cornerstones of anal cancer BT for decades. After the introduction of remote afterloaders, PDR BT has been recognized as an attractive alternative. Based on the linear quadratic formalism, Brenner et al. suggested PDR combinations of pulse-widths and -frequencies that would result in equivalent biological effects on the target volume as LDR BT. The model estimated a 2% increase of late toxicity, showing promise of PDR BT for clinical use with small irradiated volumes [
      • Brenner D.J.
      • Hall E.J.
      Conditions for the equivalence of continuous to pulsed low dose rate brachytherapy.
      ]. The first report on PDR BT for anal cancer by Roed et al. reported on good LC, but unacceptable necrosis and colostomy rates. This series was characterized by tumor stages similar to other reports, but the volumes receiving ≥25 Gy were exscessive, ranging from 20 to 400 cm3 and were larger than 200 cm3 in 47% of cases. Furthermore, the application technique consisted of one or two rows of concentric channels with a large needle spacing from 1.3 to 2 cm. The boost dose converted to the Paris system was excessive, ranging from 23–47 Gy. Toxicity was high: lasting necrosis occurred in 76% of cases and 59% of patients received colostomy [
      • Roed H.
      • Engelholm S.A.
      • Svendsen L.B.
      • Rosendal F.
      • Olsen K.J.
      Pulsed dose rate (PDR) brachytherapy of anal carcinoma.
      ]. The main advantage of BT over EBRT boost is to deliver a dose of 15–20 Gy to a smaller volume, encompassing only the residual tumor (Table 1, Table 2). The results of Roed et al. should be therefore interpreted critically and the high toxicity has been ascribed to suboptimal implantation technique, deviation from the Paris system and delivery of high doses to large volumes. The potential small increase of risk due to PDR technique as postulated by Brenner [
      • Brenner D.J.
      • Hall E.J.
      Conditions for the equivalence of continuous to pulsed low dose rate brachytherapy.
      ] was not a toxicity-inducing factor in this series [
      • Peiffert D.
      Comment on pulsed dose rate (PDR) brachytherapy of anal carcinoma by Roed et al..
      ].
      A study by the French cooperative group has later confirmed feasibility, reliability, safety and good tolerance of PDR technique [
      • Gerard J.-P.
      • Mauro F.
      • Thomas L.
      • Castelain B.
      • Mazeron J.-J.
      • Ardiet J.-M.
      • et al.
      Treatment of squamous cell anal canal carcinoma with pulsed dose rate brachytherapy. Feasibility study of a French cooperative group.
      ]. Excellent local control rates and toxicity profiles of PDR BT were consequently confirmed by several authors (Table 1, Table 2). Nowadays, PDR BT with nominal doses and hourly pulses corresponding to the historic LDR experience, represents the most common approach with long-term follow up, demonstrating comparable results to LDR BT [
      • Oblak I.
      • Petric P.
      • Anderluh F.
      • Velenik V.
      • Fras PA.
      Long term outcome after combined modality treatment for anal cancer.
      ,
      • Lestrade L.
      • De Bari B.
      • Pommier P.
      • Montbarbon X.
      • Lavergne E.
      • Ardiet J.-M.
      • et al.
      Role of brachytherapy in the treatment of cancers of the anal canal: Long-term follow-up and multivariate analysis of a large monocentric retrospective seriesStellenwert der Brachytherapie bei der Behandlung von Tumoren des Analkanals: Langzeit-Follow-up und multivariate Analyse einer großen monozentrischen, retrospektiven Studie.
      ,
      • Tournier-Rangeard L.
      • Peiffert D.
      • Lafond C.
      • Mege A.
      • Metayer Y.
      • Marchesi V.
      • et al.
      Résultats à long terme et facteurs pronostiques des carcinomes épidermoïdes du canal anal traités par irradiation.
      ,
      • Bruna A.
      • Gastelblum P.
      • Thomas L.
      • Chapet O.
      • Bollet M.A.
      • Ardiet J.-M.
      • et al.
      Treatment of squamous cell anal canal carcinoma (SCACC) with pulsed dose rate brachytherapy: A retrospective 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.
      ,
      • Gryc T.
      • Ott O.
      • Putz F.
      • Knippen S.
      • Raptis D.
      • Fietkau R.
      • et al.
      Interstitial brachytherapy as a boost to patients with anal carcinoma and poor response to chemoradiation: Single-institution long-term results.
      ,
      • Charra-Brunaud C.
      • Harter V.
      • Delannes M.
      • Haie-Meder C.
      • Quetin P.
      • Kerr C.
      • et al.
      Impact of 3D image-based PDR brachytherapy on outcome of patients treated for cervix carcinoma in France: Results of the French STIC prospective study.
      ,
      • Oblak I.
      • Petric P.
      • Anderluh F.
      • Velenik V.
      • Hudej R.
      • Fras A.
      Anal cancer chemoirradiation with curative intent – a single institution experience.
      ]. In this context, the importance of respecting the longstanding experience of the Paris system rules cannot be over-emphasized.
      HDR BT offers some practical advantages over the PDR/LDR method and experience with this technique is growing [
      • Widder J.
      • Kastenberger R.
      • Fercher E.
      • Schmid R.
      • Langendijk J.A.
      • Dobrowsky W.
      • et al.
      Radiation dose associated with local control in advanced anal cancer: Retrospective analysis of 129 patients.
      ,
      • Falk A.T.
      • Claren A.
      • Benezery K.
      • François E.
      • Gautier M.
      • Gerard J.-P.
      • et al.
      Interstitial high-dose rate brachytherapy as boost for anal canal cancer.
      ,
      • 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.
      ,
      • 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.
      ,
      • Doniec J.M.
      • Schniewind B.
      • Kovács G.
      • Kahlke V.
      • Loehnert M.
      • Kremer B.
      Multimodal therapy of anal cancer added by new endosonographic-guided brachytherapy.
      ,
      • 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.
      ,
      • Kapp K.S.
      • Geyer E.
      • Gebhart F.H.
      • Oechs A.C.
      • Berger A.
      • Hebenstreit J.
      • 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.
      ,
      • Niehoff P.
      • Kovács G.
      HDR brachytherapy for anal cancer.
      ]. The published regimens typically consist of initial pelvic EBRT and concurrent chemotherapy, followed by 2–7 HDR fractions of 3–7 Gy (Table 2). LC ranges from 80–90%, OS from 70–80%, and CFS from 75–90%. The reported rates of toxicity compare favorably with the PDR approach. Doniec et al. reported on their HDR experience with 50 patients who received pelvic chemoradiation to 45 Gy in 25 fractions, followed by an HDR boost. First five patients received a boost of 2 × 6 Gy, but two of them developed sphincter necrosis, after which the dose was reduced to 2 × 4 Gy. Local control at 5 years was 92% and sphincter function was completely preserved in 80% [
      • Doniec J.M.
      • Schniewind B.
      • Kovács G.
      • Kahlke V.
      • Loehnert M.
      • Kremer B.
      Multimodal therapy of anal cancer added by new endosonographic-guided brachytherapy.
      ]. In a series by Falk et al., 25 patients received an HDR boost with 2–6 fractions of 3–5 Gy for a total nominal boost dose of 10–15 Gy. Acute genitourinary, gastrointestinal and cutaneous toxicities were limited to G1 and occurred in 37%, 41%, and 4%, respectively. Late G3 toxicity occurred in 2 (7%), but persisted beyond 5 years only in one patient. There was no late G4 toxicity. Local control, overall survival and colostomy-free survival at 2 years were 83%, 78% and 75%, respectively. Further research with longer follow up is required to define the optimal fractionation of HDR BT and compare the results with PDR/LDR experience.

      What does the future hold?

      Available reports consistently show favorable outcomes after anal BT when compared with EBRT boost (Table 1, Table 2). Despite the evidence suggesting an important role of BT in anal cancer chemoradiation, BT is not discussed as therapeutic option in prominent international guidelines [

      National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Anal Carcinoma Version 2.2021 [Internet]. NCCN.org; 2021. Available from: https://www.nccn.org/professionals/physician_gls/pdf/anal.pdf

      ], it is not part of the ongoing trials on anal cancer, and its use remains limited to selected institutions with long traditions (Table 1, Table 2). Operator skills, treatment complexity, special equipment and cost have been considered as barriers for the use of gynecological BT [
      • Han K.
      • Viswanathan A.N.
      Brachytherapy in Gynecologic Cancers: Why Is It Underused?.
      ] and could be extrapolated to anal cancer. However, these factors are also relevant for adoption of complex EBRT, which remains unimpeded and favoured by the reimbursement policies over BT [
      • Han K.
      • Viswanathan A.N.
      Brachytherapy in Gynecologic Cancers: Why Is It Underused?.
      ,
      • Vaios E.J.
      • Wo J.Y.
      Proton beam radiotherapy for anal and rectal cancers.
      ]. Furthermore, a cost-utility analysis of MRI-based IAGBT for cervical cancer demonstrated reduced cost and increased effectiveness when compared with CT-based or conventional 2D techniques [
      • Perdrizet J.
      • D’Souza D.
      • Skliarenko J.
      • Ang M.
      • Barbera L.
      • Gutierrez E.
      • et al.
      A Cost-Utility Analysis of Magnetic Resonance (MR) Guided Brachytherapy Versus Two-Dimensional and Computed Tomography (CT) Guided Brachytherapy for Locally Advanced Cervical Cancer.
      ]. It can be hypothesized that similar health-economy effects of IGABT could be observed also for anal cancer. Non-invasiveness of EBRT is a commonly cited argument in its favor over BT boost [
      • Han K.
      • Viswanathan A.N.
      Brachytherapy in Gynecologic Cancers: Why Is It Underused?.
      ]. However, BT is a minimally invasive treatment with negligible mechanical injury caused by the needle insertion. In fact, the invasiveness of radiotherapy is more appropriately described in terms of radiation damage to uninvolved normal tissues due to exposure to high, moderate and low doses. In this context, anal cancer BT is theoretically superior to EBRT boost at most dose levels (Fig. 1, Table 3). This can be attributed to its intrinsic physical and biological principles, which cannot be matched by even the most complex EBRT techniques:
      • 1.
        Steep gradients within a BT implant enable dose escalation inside the target volume, high conformity at its periphery, and rapid fall-of in surrounding tissue with small volumes receiving low to moderate doses.
      • 2.
        Dose-heterogeneity has favourable biological implications due to different sensitivity of the tumour and organs at risk (OAR) to varying time-dose patterns.
      • 3.
        Since CTV to PTV margin is not used for BT, smaller volumes of healthy tissues are exposed to high doses when compared with EBRT boost.
      • 4.
        Anal dilatation during BT can further reduce the exposure of uninvolved tissues by displacing them from the high-dose region.
      • 5.
        BT boost is delivered over a short time, enabling a meaningful reduction of OTT when compared with sequential EBRT boost.
      • 6.
        BT boost is adapted to the residual tumor, enabling a meaningful reduction of irradiated volume when compared with simultaneous integrated EBRT boost.
      In summary, the reasons for BT underutilisation are controversial if not frustrating, underscoring the need for an objective redefinition of its role in anal cancer.
      Published experience with anal cancer BT comes mainly from studies which combined 2D EBRT or 3D CRT, inconsistent chemotherapy regimens, and conventional 2D BT after long median inter-sequence gaps (Table 1). Full impact of dose optimization afforded by modern EBRT techniques and IGABT was thus not exploited so far. Pelvic IMRT reduces the acute adverse events and un-planned gaps when compared with conventional EBRT [
      • De Bari B.
      • Lestrade L.
      • Franzetti-Pellanda A.
      • Jumeau R.
      • Biggiogero M.
      • Kountouri M.
      • et al.
      Modern intensity-modulated radiotherapy with image guidance allows low toxicity rates and good local control in chemoradiotherapy for anal cancer patients.
      ,
      • Olsen J.R.
      • Moughan J.
      • Myerson R.
      • Abitbol A.
      • Doncals D.E.
      • Johnson D.
      • et al.
      Predictors of Radiation Therapy-Related Gastrointestinal Toxicity From Anal Cancer Dose-Painted Intensity Modulated Radiation Therapy: Secondary Analysis of NRG Oncology RTOG 0529.
      ,
      • Han K.
      • Cummings B.J.
      • Lindsay P.
      • Skliarenko J.
      • Craig T.
      • Le L.W.
      • et al.
      Prospective Evaluation of Acute Toxicity and Quality of Life After IMRT and Concurrent Chemotherapy for Anal Canal and Perianal Cancer.
      ,
      • Devisetty K.
      • Mell L.K.
      • Salama J.K.
      • Schomas D.A.
      • Miller R.C.
      • Jani A.B.
      • et al.
      A multi-institutional acute gastrointestinal toxicity analysis of anal cancer patients treated with concurrent intensity-modulated radiation therapy (IMRT) and chemotherapy.
      ,
      • Kachnic L.A.
      • Winter K.
      • Myerson R.J.
      • Goodyear M.D.
      • Willins J.
      • Esthappan 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.
      ,
      • Kachnic L.A.
      • Tsai H.K.
      • Coen J.J.
      • Blaszkowsky L.S.
      • Hartshorn K.
      • Kwak E.L.
      • et al.
      Dose-painted intensity-modulated radiation therapy for anal cancer: A multi-institutional report of acute toxicity and response to therapy.
      ,
      • Mehta S.
      • Ramey S.J.
      • Kwon D.
      • Rich B.J.
      • Ahmed A.A.
      • Wolfson A.
      • et al.
      Impact of radiotherapy duration on overall survival in squamous cell carcinoma of the anus.
      ]. Volumetric modulated arc therapy (VMAT) offers dosimetric and clinical advantage over fixed-beam IMRT [
      • De Bari B.
      • Lestrade L.
      • Franzetti-Pellanda A.
      • Jumeau R.
      • Biggiogero M.
      • Kountouri M.
      • et al.
      Modern intensity-modulated radiotherapy with image guidance allows low toxicity rates and good local control in chemoradiotherapy for anal cancer patients.
      ] and intensity modulated proton therapy (IMPT) can further reduce the volume of bone marrow, bowel and skin receiving low- to moderate doses. Through improved toxicity profile and patient compliance, IMPT can minimize treatment breaks and OTT [
      • Vaios E.J.
      • Wo J.Y.
      Proton beam radiotherapy for anal and rectal cancers.
      ]. Favourable outcomes of anal cancer BT published so far were achieved with techniques which could be considered suboptimal by modern standards (Table 1). Some authors used ultrasound and 3D imaging for insertion guidance and limited dose optimization, but this was done in the absence of standardized target concepts (Table 2). Meanwhile, IGABT led to an unprecedented improvement of clinical outcomes in gynecological tumors [
      • Pötter R.
      • Tanderup K.
      • Schmid M.P.
      • Jürgenliemk-Schulz I.
      • Haie-Meder C.
      • Fokdal L.U.
      • et al.
      MRI-guided adaptive brachytherapy in locally advanced cervical cancer (EMBRACE-I): a multicentre prospective cohort study.
      ,
      • Westerveld H.
      • Schmid M.
      • Nout R.
      • Chargari C.
      • Pieters B.
      • Creutzberg C.
      • et al.
      Image-Guided Adaptive Brachytherapy (IGABT) for Primary Vaginal Cancer: Results of the International Multicenter RetroEMBRAVE Cohort Study.
      ]. Attempts to achieve similar results with sophisticated EBRT in place of BT resulted in decreased survival [
      • Han K.
      • Milosevic M.
      • Fyles A.
      • Pintilie M.
      • Viswanathan A.N.
      Trends in the Utilization of Brachytherapy in Cervical Cancer in the United States.
      ].
      It is therefore reasonable to assume that the demonstrated effectiveness of anal cancer BT would be even more pronounced in the era of modern technologies, superseding the results of EBRT-only cohorts. Novel regimens should be investigated in frame of a multicenter study protocol, possibly of randomized design, redefining the role of BT boost in treatment of this rare disease. A combination of pelvic VMAT or IMPT with concurrent chemotherapy +/- immunotherapy, and MRI-based IGABT with a minimal or no inter-sequence gap could provide improved outcomes. In this context, VMAT and IMPT should be regarded as a method for individualized dose de-escalation outside the macroscopic target. Dose to regional lymph-node metastases should be complemented with the simultaneous integrated boost and coverage-probability planning [
      • Ramlov A.
      • Assenholt M.S.
      • Jensen M.F.
      • Grønborg C.
      • Nout R.
      • Alber M.
      • et al.
      Clinical implementation of coverage probability planning for nodal boosting in locally advanced cervical cancer.
      ]. Finally, the implementation of MRI-based IGABT would enable personalized dose-tailoring to the shrinking primary tumor and establishment of dose-volume-effect relations for the OAR and target volume. Definition and contouring of new OAR (i.e. pudendal nerves, vessels, anal sphincter, healthy anus) implicated in toxicity would become a meaningful task due to the superb ability of IGABT to avoid these structures [
      • Haas S.
      • Faaborg P.
      • Liao D.
      • Laurberg S.
      • Gregersen H.
      • Lundby L.
      • et al.
      Anal sphincter dysfunction in patients treated with primary radiotherapy for anal cancer: a study with the functional lumen imaging probe.
      ,
      • Loganathan A.
      • Schloithe A.C.
      • Hutton J.
      • Yeoh E.K.
      • Fraser R.
      • Dinning P.G.
      • et al.
      Pudendal nerve injury in men with fecal incontinence after radiotherapy for prostate cancer.
      ,
      • Sunesen K.G.
      • Nørgaard M.
      • Lundby L.
      • Havsteen H.
      • Buntzen S.
      • Thorlacius-Ussing O.
      • et al.
      Long-term anorectal, urinary and sexual dysfunction causing distress after radiotherapy for anal cancer: a Danish multicentre cross-sectional questionnaire study.
      ,
      • Yeoh E.(.
      • Botten R.
      • Di Matteo A.
      • Tippett M.
      • Hutton J.
      • Fraser R.
      • et al.
      Pudendal nerve injury impairs anorectal function and health related quality of life measures ≥2 years after 3D conformal radiotherapy for prostate cancer.
      ]. The definition of concepts and terms regarding the target volumes could benefit from the existent recommendations on gynecological cancer due to some similarities between these tumors [
      • Haie-Meder C.
      • Pötter R.
      • Van Limbergen E.
      • Briot E.
      • De Brabandere M.
      • Dimopoulos J.
      • et al.
      Recommendations from Gynaecological (GYN) GEC-ESTRO Working Group☆ (I): concepts and terms in 3D image based 3D treatment planning in cervix cancer brachytherapy with emphasis on MRI assessment of GTV and CTV.
      ,
      • Schmid M.P.
      • Fokdal L.
      • Westerveld H.
      • Chargari C.
      • Rohl L.
      • Morice P.
      • et al.
      Recommendations from gynaecological (GYN) GEC-ESTRO working group – ACROP: Target concept for image guided adaptive brachytherapy in primary vaginal cancer.
      ]. Nonetheless, even in the era of IGABT, meticulous attention to application technique based on the Paris system rules remains a precondition for treatment success. In this context, carefully designed perineal templates with appropriate inter-channel distance, reliable needle fixation mechanism, and opening for the palpating finger and ultrasound probe for real-time guidance are of major importance. Adaptive dose optimization should be performed with utmost care, taking the longstanding experience with the Paris system dosimetry into account.

      Conclusion

      Historically, BT boost generated excellent outcomes and should be considered a component of anal cancer chemoradiation in selected patients in the future. Novel regimens employing VMAT, IMPT, systemic therapy and MRI-based IGABT without treatment gaps are expected to improve the results further and should be tested in frame of a prospective clinical study. In the context of IGABT, the definition of concepts and terms for response-adaptive target volume and organs at risk contouring is required. Adaptive dose-optimization and dosimetry strategies should build on extensive clinical experience from the past, with Paris system representing the cornerstone for future developments.

      Disclosures

      No relevant conflict of interest.

      Funding source

      No funding.

      Acknowledgements

      This work was completed without funding.

      References

      1. Cancer Today - International Agency for Research of Cancer, World Health Organization [Internet]. Global Cancer Observatory. 2020. Available from: https://gco.iarc.fr/today/home.

        • Siegel R.L.
        • Miller K.D.
        • Jemal A.
        Cancer statistics, 2019.
        CA Cancer J Clin. 2019; 69: 7-34
        • Nelson V.M.
        • Benson A.B.
        Epidemiology of Anal Canal Cancer.
        Surg Oncol Clin N Am. 2017; 26: 9-15
        • Nielsen A.
        • Munk C.
        • Kjaer S.K.
        Trends in incidence of anal cancer and high-grade anal intraepithelial neoplasia in Denmark, 1978–2008.
        Int J Cancer. 2012; 130: 1168-1173
        • Jones C.M.
        • Goh V.
        • Sebag-Montefiore D.
        • Gilbert D.C.
        Biomarkers in anal cancer: from biological understanding to stratified treatment.
        Br J Cancer. 2017; 116: 156-162
        • Ryan D.P.
        • Compton C.C.
        • Mayer R.J.
        Carcinoma of the Anal Canal.
        N Engl J Med. 2000; 342: 792-800
        • Nigro N.
        • Vaitkevicius V.
        • Considine B.J.
        Combined therapy for cancer of the anal canal: a preliminary report.
        Dis Colon Rectum. 1974 May; 17: 354-356
        • Nigro N.D.
        • Seydel H.G.
        • Considine B.
        • Vaitkevicius V.K.
        • Leichman L.
        • Kinzie J.J.
        Combined preoperative radiation and chemotherapy for squamous cell carcinoma of the anal canal.
        Cancer. 1983; 51: 1826-1829
        • Cummings B.
        • Keane T.
        • Thomas G.
        • Harwood A.
        • Rider W.
        Results and toxicity of the treatment of anal canal carcinoma by radiation therapy or radiation therapy and chemotherapy.
        Cancer. 1984; 54: 2062-2068
      2. Sischy B, Doggett R, Krall J, Taylor D, Sause W, Lipsett J, et al. Definitive irradiation and chemotherapy for radiosensitization in management of anal carcinoma: interim report on Radiation Therapy Oncology Group study no. 8314. J Natl Cancer Inst. 1989 Jun;81(11):850–6.

        • Papillon J.
        • Montbarbon J.F.
        Epidermoid carcinoma of the anal canal. A series of 276 cases.
        Dis Colon Rectum. 1987 May; 30: 324-333
        • Allal A.
        • Kurtz J.M.
        • Pipard G.
        • Marti M.-C.
        • Miralbell R.
        • Popowski Y.
        • et al.
        Chemoradiotherapy verus radiotherapy alone for anal cancer: a retrospective comparison.
        Int J Radiat Oncol Biol Phys. 1993; 27: 59-66
        • Myerson R.J.
        • Karnell L.H.
        • Menck H.R.
        The National Cancer Data Base report on carcinoma of the anus.
        Cancer. 1997; 80: 805-815
        • 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).
        Br J Cancer. 2010; 102: 1123-1128
        • 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.
        J Clin Oncol. 1997; 15: 2040-2049
        • Gunderson L.L.
        • Winter K.A.
        • Ajani J.A.
        • Pedersen J.E.
        • Moughan J.
        • Benson 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.
        J Clin Oncol. 2012; 30: 4344-4351
        • 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.
        Lancet Oncol. 2013; 14: 516-524
        • Peiffert D.
        • Tournier-Rangeard L.
        • Gérard J.-P.
        • Lemanski C.
        • François 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.
        J Clin Oncol. 2012; 30: 1941-1948
      3. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Anal Carcinoma Version 2.2021 [Internet]. NCCN.org; 2021. Available from: https://www.nccn.org/professionals/physician_gls/pdf/anal.pdf

        • 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.
        Eur J Surg Oncol EJSO. 2014; 40: 1165-1176
        • Frakulli R.
        • Buwenge M.
        • Cammelli S.
        • Macchia G.
        • Farina E.
        • Arcelli A.
        • et al.
        Brachytherapy boost after chemoradiation in anal cancer: a systematic review.
        J Contemp Brachytherapy. 2018; 10: 246-253
        • De Bari B.
        • Lestrade L.
        • Franzetti-Pellanda A.
        • Jumeau R.
        • Biggiogero M.
        • Kountouri M.
        • et al.
        Modern intensity-modulated radiotherapy with image guidance allows low toxicity rates and good local control in chemoradiotherapy for anal cancer patients.
        J Cancer Res Clin Oncol. 2018; 144: 781-789
        • Olsen J.R.
        • Moughan J.
        • Myerson R.
        • Abitbol A.
        • Doncals D.E.
        • Johnson D.
        • et al.
        Predictors of Radiation Therapy-Related Gastrointestinal Toxicity From Anal Cancer Dose-Painted Intensity Modulated Radiation Therapy: Secondary Analysis of NRG Oncology RTOG 0529.
        Int J Radiat Oncol. 2017; 98: 400-408
        • Han K.
        • Cummings B.J.
        • Lindsay P.
        • Skliarenko J.
        • Craig T.
        • Le L.W.
        • et al.
        Prospective Evaluation of Acute Toxicity and Quality of Life After IMRT and Concurrent Chemotherapy for Anal Canal and Perianal Cancer.
        Int J Radiat Oncol. 2014; 90: 587-594
        • Devisetty K.
        • Mell L.K.
        • Salama J.K.
        • Schomas D.A.
        • Miller R.C.
        • Jani A.B.
        • et al.
        A multi-institutional acute gastrointestinal toxicity analysis of anal cancer patients treated with concurrent intensity-modulated radiation therapy (IMRT) and chemotherapy.
        Radiother Oncol. 2009; 93: 298-301
        • Saarilahti K.
        • Arponen P.
        • Vaalavirta L.
        • Tenhunen M.
        The effect of intensity-modulated radiotherapy and high dose rate brachytherapy on acute and late radiotherapy-related adverse events following chemoradiotherapy of anal cancer.
        Radiother Oncol. 2008; 87: 383-390
        • Kachnic L.A.
        • Winter K.
        • Myerson R.J.
        • Goodyear M.D.
        • Willins J.
        • Esthappan 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.
        Int J Radiat Oncol. 2013; 86: 27-33
        • Kachnic L.A.
        • Tsai H.K.
        • Coen J.J.
        • Blaszkowsky L.S.
        • Hartshorn K.
        • Kwak E.L.
        • et al.
        Dose-painted intensity-modulated radiation therapy for anal cancer: A multi-institutional report of acute toxicity and response to therapy.
        Int J Radiat Oncol. 2012; 82: 153-158
        • Pierquin B.
        • Dutreix A.
        • Paine C.H.
        • Chassagne D.
        • Marinello G.
        • Ash D.
        The Paris system in interstitial radiation therapy.
        Acta Radiol Oncol Radiat Phys Biol. 1978; 17: 33-48
      4. Papillon J, Mayer M, Bailly C. A new approach to the management of epidermoid carcinoma of the anal canal. 1983;(10):8.

        • Binkley G.E.
        Results of radiation therapy in primary operable rectal and anal cancer.
        Radiology. 1938; 31: 724-728
        • Dalby J.
        • Pointon R.
        The treatment of anal carcinoma by interstitial irradiation.
        Am J Roentgenol Radium Ther Nucl Med. 1961; 85: 515-520
        • Papillon J.
        Radiation therapy in the management of epidermoid carcinoma of the anal region.
        Dis Colon Rectum. 1974; 17: 181-187
        • Papillon J.
        • Montbarbong J.F.
        • Gerard J.P.
        • Chassard J.L.
        • Ardiet J.M.
        Interstitial curietherapy in the conservative treatment of anal and rectal cancers.
        Int J Radiat Oncol. 1989; 17: 1161-1169
        • Mazeron J.J.
        • Van Limbergen E.
        Anorectal Cancer.
        in: The GEC ESTRO Handbook of Brachytherapy. 1st ed. ESTRO, Brussels, Belgium2002: 505-514
        • Cordoba A.
        • Escande A.
        • Leroy T.
        • Mirabel X.
        • Coche-Dequéant B.
        • Lartigau E.
        Low-dose-rate interstitial brachytherapy boost for the treatment of anal canal cancers.
        Brachytherapy. 2017; 16: 230-235
        • 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).
        Int J Radiat Oncol. 2011; 80: 712-720
        • Weber D.C.
        • Kurtz J.M.
        • Allal A.S.
        The impact of gap duration on local control in anal canal carcinoma treated by split-course radiotherapy and concomitant chemotherapy.
        Int J Radiat Oncol. 2001; 50: 675-680
        • Oblak I.
        • Petric P.
        • Anderluh F.
        • Velenik V.
        • Fras PA.
        Long term outcome after combined modality treatment for anal cancer.
        Radiol Oncol. 2012; 46: 145-152
        • Widder J.
        • Kastenberger R.
        • Fercher E.
        • Schmid R.
        • Langendijk J.A.
        • Dobrowsky W.
        • et al.
        Radiation dose associated with local control in advanced anal cancer: Retrospective analysis of 129 patients.
        Radiother Oncol. 2008; 87: 367-375
        • Falk A.T.
        • Claren A.
        • Benezery K.
        • François E.
        • Gautier M.
        • Gerard J.-P.
        • et al.
        Interstitial high-dose rate brachytherapy as boost for anal canal cancer.
        Radiat Oncol. 2014; 9https://doi.org/10.1186/s13014-014-0240-4
        • Lestrade L.
        • De Bari B.
        • Pommier P.
        • Montbarbon X.
        • Lavergne E.
        • Ardiet J.-M.
        • et al.
        Role of brachytherapy in the treatment of cancers of the anal canal: Long-term follow-up and multivariate analysis of a large monocentric retrospective seriesStellenwert der Brachytherapie bei der Behandlung von Tumoren des Analkanals: Langzeit-Follow-up und multivariate Analyse einer großen monozentrischen, retrospektiven Studie.
        Strahlenther Onkol. 2014; 190: 546-554
        • Chapet O.
        • Gerard J.-P.
        • Riche B.
        • Alessio A.
        • Mornex F.
        • Romestaing P.
        Prognostic value of tumor regression evaluated after first course of radiotherapy for anal canal cancer.
        Int J Radiat Oncol. 2005; 63: 1316-1324
        • Gerard J.-P.
        • Ayzac L.
        • Hun D.
        • Romestaing P.
        • Coquard R.
        • Ardiet J.-M.
        • et al.
        Treatment of anal canal carcinoma with high dose radiation therapy and concomitant fluorouracil-cisplatinum. Long-term results in 95 patients.
        Radiother Oncol. 1998; 46: 249-256
        • Tournier-Rangeard L.
        • Peiffert D.
        • Lafond C.
        • Mege A.
        • Metayer Y.
        • Marchesi V.
        • et al.
        Résultats à long terme et facteurs pronostiques des carcinomes épidermoïdes du canal anal traités par irradiation.
        Cancer/Radiothérapie. 2007 Jun; 11: 169-177
        • Bruna A.
        • Gastelblum P.
        • Thomas L.
        • Chapet O.
        • Bollet M.A.
        • Ardiet J.-M.
        • et al.
        Treatment of squamous cell anal canal carcinoma (SCACC) with pulsed dose rate brachytherapy: A retrospective study.
        Radiother Oncol. 2006; 79: 75-79
        • Ortholan C.
        • Ramaioli A.
        • Peiffert D.
        • Lusinchi A.
        • Romestaing P.
        • Chauveinc L.
        • et al.
        Anal canal carcinoma: Early-stage tumors ≤10 mm (T1 or Tis): Therapeutic options and original pattern of local failure after radiotherapy.
        Int J Radiat Oncol. 2005; 62: 479-485
        • Kent C.
        • Bessell E.M.
        • Scholefield J.H.
        • Chappell S.
        • Marsh L.
        • Mills J.
        • et al.
        Chemoradiotherapy with Brachytherapy or Electron Therapy Boost for Locally Advanced Squamous Cell Carcinoma of the Anus—Reducing the Colostomy Rate.
        J Gastrointest Cancer. 2017; 48: 1-7
        • Sandhu A.P.S.
        • Paul Symonds R.
        • Robertson A.G.
        • Reed N.S.
        • McNee S.G.
        • Paul J.
        Interstitial iridium-192 implantation combined with external radiotherapy in anal cancer: ten years experience.
        Int J Radiat Oncol Biol Phys. 1998; 40: 575-581
        • López Guerra J.L.
        • Lozano A.J.
        • Pera J.
        • Gutiérrez C.
        • Cambray M.
        • Ferrer F.
        • et al.
        Twenty-year experience in the management of squamous cell anal canal carcinoma with interstitial brachytherapy.
        Clin Transl Oncol. 2011; 13: 472-479
        • Gerard J.-P.
        • Mauro F.
        • Thomas L.
        • Castelain B.
        • Mazeron J.-J.
        • Ardiet J.-M.
        • et al.
        Treatment of squamous cell anal canal carcinoma with pulsed dose rate brachytherapy. Feasibility study of a French cooperative group.
        Radiother Oncol. 1999; 51: 129-131
        • 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.
        J Contemp Brachytherapy. 2019; 11: 21-27
        • 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.
        Brachytherapy. 2007; 6: 218-226
        • Charlson M.
        • Szatrowski T.P.
        • Peterson J.
        • Gold J.
        Validation of a combined comorbidity index.
        J Clin Epidemiol. 1994; 47: 1245-1251
        • Lestrade L.
        • De Bari B.
        • Montbarbon X.
        • Pommier P.
        • Carrie C.
        Radiochemotherapy and brachytherapy could be the standard treatment for anal canal cancer in elderly patients? A retrospective single-centre analysis.
        Med Oncol. 2013 Mar; 30: 402
        • Saarilahti K.
        • Arponen P.
        • Vaalavirta L.
        • Tenhunen M.
        • Blomqvist C.
        Chemoradiotherapy of anal cancer is feasible in elderly patients: Treatment results of mitomycin–5-FU combined with radiotherapy at Helsinki University Central Hospital 1992–2003.
        Acta Oncol. 2006; 45: 736-742
        • Gryc T.
        • Ott O.
        • Putz F.
        • Knippen S.
        • Raptis D.
        • Fietkau R.
        • et al.
        Interstitial brachytherapy as a boost to patients with anal carcinoma and poor response to chemoradiation: Single-institution long-term results.
        Brachytherapy. 2016; 15: 865-872
        • 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).
        Int J Radiat Oncol. 2013; 85: e135-e142
        • Peiffert D.
        • Bey P.
        • Pernot M.
        • Guillemin F.
        • Luporsi E.
        • Hoffstetter S.
        • et al.
        Conservative treatment by irradiation of epidermoid cancers of the anal canal: Prognostic factors of tumoral control and complications.
        Int J Radiat Oncol. 1997; 37: 313-324
        • UKCCCR Anal Cancer Trial Working Party
        Epidermoid anal cancer: results from the UKCCCR randomised trial of radiotherapy alone versus radiotherapy, 5-fluorouracil, and mitomycin.
        The Lancet. 1996 Oct; 348: 1049-1054
        • 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.
        J Clin Oncol. 1996; 14: 2527-2539
        • Ajani J.A.
        Fluorouracil, Mitomycin, and Radiotherapy vs Fluorouracil, Cisplatin, and Radiotherapy for Carcinoma of the Anal Canal: A Randomized Controlled Trial.
        JAMA. 2008; 299: 1914https://doi.org/10.1001/jama.299.16.1914
        • Deniaud-Alexandre E.
        • Touboul E.
        • Tiret E.
        • Sezeur A.
        • Houry S.
        • Gallot D.
        • et al.
        Results of definitive irradiation in a series of 305 epidermoid carcinomas of the anal canal.
        Int J Radiat Oncol. 2003; 56: 1259-1273
        • 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.
        J Contemp Brachytherapy. 2015; 5: 336-345
        • Doniec J.M.
        • Schniewind B.
        • Kovács G.
        • Kahlke V.
        • Loehnert M.
        • Kremer B.
        Multimodal therapy of anal cancer added by new endosonographic-guided brachytherapy.
        Surg Endosc. 2006; 20: 673-678
        • 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.
        Brachytherapy. 2014; 13: 388-393
        • Chassagne D.
        • Sismondi P.
        • Horiot J.
        • Sinistrero G.
        • Bey P.
        • Zola P.
        • et al.
        A glossary for reporting complications of the treatment in gynecological cancer.
        Radiother Oncol. 1993; 26: 195-202
        • Withers H.R.
        • Taylor J.M.G.
        • Maciejewski B.
        The hazard of accelerated tumor clonogen repopulation during radiotherapy.
        Acta Oncol. 1988; 27: 131-146
        • Graf R.
        • Wust P.
        • Hildebrandt B.
        • Gögler H.
        • Ullrich R.
        • Herrmann R.
        • et al.
        Impact of overall treatment time on local control of anal cancer treated with radiochemotherapy.
        Oncology. 2003; 65: 14-22
        • Mehta S.
        • Ramey S.J.
        • Kwon D.
        • Rich B.J.
        • Ahmed A.A.
        • Wolfson A.
        • et al.
        Impact of radiotherapy duration on overall survival in squamous cell carcinoma of the anus.
        J Gastrointest Oncol. 2020; 11: 277-290
        • Konski A.
        • Garcia 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.
        Int J Radiat Oncol Biol Phys. 2008; 72: 114-118
        • Chakravarthy A.B.
        • Catalano P.J.
        • Martenson J.A.
        • Mondschein J.K.
        • Wagner H.
        • Mansour E.G.
        • et al.
        Long-term follow-up of a phase II trial of high-dose radiation with concurrent 5-fluorouracil and cisplatin in patients with anal cancer (ECOG E4292).
        Int J Radiat Oncol Biol Phys. 2011; 81: e607-e613
        • Peiffert D.
        Comment on pulsed dose rate (PDR) brachytherapy of anal carcinoma by Roed et al..
        Radiother Oncol. 1997; 44: 296-297
        • Brenner D.J.
        • Hall E.J.
        Conditions for the equivalence of continuous to pulsed low dose rate brachytherapy.
        Int J Radiat Oncol. 1991; 20: 181-190
        • Roed H.
        • Engelholm S.A.
        • Svendsen L.B.
        • Rosendal F.
        • Olsen K.J.
        Pulsed dose rate (PDR) brachytherapy of anal carcinoma.
        Radiother Oncol. 1996; 41: 131-134
        • Charra-Brunaud C.
        • Harter V.
        • Delannes M.
        • Haie-Meder C.
        • Quetin P.
        • Kerr C.
        • et al.
        Impact of 3D image-based PDR brachytherapy on outcome of patients treated for cervix carcinoma in France: Results of the French STIC prospective study.
        Radiother Oncol. 2012; 103: 305-313
        • Oblak I.
        • Petric P.
        • Anderluh F.
        • Velenik V.
        • Hudej R.
        • Fras A.
        Anal cancer chemoirradiation with curative intent – a single institution experience.
        Neoplasma. 2009; 56: 150-155
        • Kapp K.S.
        • Geyer E.
        • Gebhart F.H.
        • Oechs A.C.
        • Berger A.
        • Hebenstreit J.
        • 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.
        Int J Radiat Oncol. 2001; 49: 997-1005
        • Niehoff P.
        • Kovács G.
        HDR brachytherapy for anal cancer.
        J Gastrointest Oncol. 2014; 5: 218-222
        • Han K.
        • Viswanathan A.N.
        Brachytherapy in Gynecologic Cancers: Why Is It Underused?.
        Curr Oncol Rep. 2016; 18https://doi.org/10.1007/s11912-016-0508-y
        • Vaios E.J.
        • Wo J.Y.
        Proton beam radiotherapy for anal and rectal cancers.
        J Gastrointest Oncol. 2020; 11: 176-186
        • Perdrizet J.
        • D’Souza D.
        • Skliarenko J.
        • Ang M.
        • Barbera L.
        • Gutierrez E.
        • et al.
        A Cost-Utility Analysis of Magnetic Resonance (MR) Guided Brachytherapy Versus Two-Dimensional and Computed Tomography (CT) Guided Brachytherapy for Locally Advanced Cervical Cancer.
        Int J Radiat Oncol Biol Phys. 2020; 107: 512-521
        • Pötter R.
        • Tanderup K.
        • Schmid M.P.
        • Jürgenliemk-Schulz I.
        • Haie-Meder C.
        • Fokdal L.U.
        • et al.
        MRI-guided adaptive brachytherapy in locally advanced cervical cancer (EMBRACE-I): a multicentre prospective cohort study.
        Lancet Oncol. 2021; 22: 538-547
        • Westerveld H.
        • Schmid M.
        • Nout R.
        • Chargari C.
        • Pieters B.
        • Creutzberg C.
        • et al.
        Image-Guided Adaptive Brachytherapy (IGABT) for Primary Vaginal Cancer: Results of the International Multicenter RetroEMBRAVE Cohort Study.
        Cancers. 2021 Mar 23; 13: 1459https://doi.org/10.3390/cancers13061459
        • Han K.
        • Milosevic M.
        • Fyles A.
        • Pintilie M.
        • Viswanathan A.N.
        Trends in the Utilization of Brachytherapy in Cervical Cancer in the United States.
        Int J Radiat Oncol. 2013; 87: 111-119
        • Ramlov A.
        • Assenholt M.S.
        • Jensen M.F.
        • Grønborg C.
        • Nout R.
        • Alber M.
        • et al.
        Clinical implementation of coverage probability planning for nodal boosting in locally advanced cervical cancer.
        Radiother Oncol. 2017; 123: 158-163
        • Haas S.
        • Faaborg P.
        • Liao D.
        • Laurberg S.
        • Gregersen H.
        • Lundby L.
        • et al.
        Anal sphincter dysfunction in patients treated with primary radiotherapy for anal cancer: a study with the functional lumen imaging probe.
        Acta Oncol. 2018; 57: 465-472
        • Loganathan A.
        • Schloithe A.C.
        • Hutton J.
        • Yeoh E.K.
        • Fraser R.
        • Dinning P.G.
        • et al.
        Pudendal nerve injury in men with fecal incontinence after radiotherapy for prostate cancer.
        Acta Oncol. 2015; 54: 882-888
        • Sunesen K.G.
        • Nørgaard M.
        • Lundby L.
        • Havsteen H.
        • Buntzen S.
        • Thorlacius-Ussing O.
        • et al.
        Long-term anorectal, urinary and sexual dysfunction causing distress after radiotherapy for anal cancer: a Danish multicentre cross-sectional questionnaire study.
        Colorectal Dis. 2015; 17: O230-O239
        • Yeoh E.(.
        • Botten R.
        • Di Matteo A.
        • Tippett M.
        • Hutton J.
        • Fraser R.
        • et al.
        Pudendal nerve injury impairs anorectal function and health related quality of life measures ≥2 years after 3D conformal radiotherapy for prostate cancer.
        Acta Oncol. 2018; 57: 456-464
        • Haie-Meder C.
        • Pötter R.
        • Van Limbergen E.
        • Briot E.
        • De Brabandere M.
        • Dimopoulos J.
        • et al.
        Recommendations from Gynaecological (GYN) GEC-ESTRO Working Group☆ (I): concepts and terms in 3D image based 3D treatment planning in cervix cancer brachytherapy with emphasis on MRI assessment of GTV and CTV.
        Radiother Oncol. 2005; 74: 235-245
        • Schmid M.P.
        • Fokdal L.
        • Westerveld H.
        • Chargari C.
        • Rohl L.
        • Morice P.
        • et al.
        Recommendations from gynaecological (GYN) GEC-ESTRO working group – ACROP: Target concept for image guided adaptive brachytherapy in primary vaginal cancer.
        Radiother Oncol. 2020; 145: 36-44
        • Boukhelif W
        • Ferri-Molina M
        • Mazeron R
        • Maroun P
        • Duhamel-Oberlander AS
        • Dumas I
        • et al.
        Interstitial pulsed-dose-rate brachytherapy for the treatment of squamous cell anal carcinoma: A retrospective single institution analysis.
        Brachytherapy. 2015; 14: 549-553https://doi.org/10.1016/j.brachy.2015.03.006