Springer Nature is making SARS-CoV-2 and COVID-19 research free. View research | View latest news | Sign up for updates

Intensity-modulated radiotherapy (IMRT) in the treatment of squamous cell anal canal cancer: acute and early-late toxicity, outcome, and efficacy



To retrospectively review our experience on 84 patients with squamous cell anal canal cancer (SCAC) within 12 months after combined treatment with intensity-modulated RT (IMRT), in terms of acute and early-late toxicity, overall treatment time and interruptions, colostomy-free survival (CFS), and tumor response.


Acute gastrointestinal (GI), genitourinary (GU), and cutaneous (CU) toxicities were assessed according to Common Toxicity Criteria for Adverse Events (CTCAE) version 4.03. Early-late toxicity was scored using the Radiation Therapy Oncology Group (RTOG) late radiation morbidity scoring system. Tumor response was evaluated with response evaluation criteria in solid tumors (RECIST) v1.1.


Acute toxicity for 84 subjects (100%): severe (≥ G3) GI and skin toxicity was observed in 4 (5%) and 19 patients (23%), respectively. Early-late toxicity for 73 subjects (87%): severe (≥ G3) GI and vulvo-vaginal toxicity was observed in 2 (3%) and 2 (3%) patients, respectively. No acute or early-late severe GU toxicity was reported. A treatment interruption occurred in 65 patients (77%). CFS was 96% (95% CI 89–99) at 6 months and 92% (95% CI 83–96) at 12 months. At 6 months complete response (CR), partial response (PR) and progressive disease (PD) was observed in 70 (83%), 3 (4%), and 7 patients (8%), respectively. At 12 months, CR was observed in 60 patients (81%); eleven patients (15%) experienced PD.


Our study showed an excellent clinical result and very low acute toxicity rates, confirming the IMRT as standard of care for curative treatment of anal cancer patients.

The current trial was registered with the number IEO N87/11

This is a preview of subscription content, log in to check access.

Fig. 1


  1. 1.

    Nigro ND, Vaitkevicius VK, Considine B (1974) Combined therapy for cancer of the anal canal: a preliminary report. Dis Colon Rectum 17:354–356

  2. 2.

    Cummings BJ, Keane TJ, O’Sullivan B et al (1991) Epidermoid anal cancer: treatment by radiation alone or by radiation and 5-fluorouracil with and without mitomycin C. Int J Radiat Oncol Biol Phys 21:1115–1125

  3. 3.

    Papillon J, Chassard JL (1992) Respective roles of radiotherapy and surgery in the management of epidermoid carcinoma of the anal margin. Series of 57 patients. Dis Colon Rectum 35:422–429

  4. 4.

    Uronis HE, Bendell JC (2007) Anal cancer: an overview. Oncologist 12:524–534

  5. 5.

    Pepek JM, Willett CG, Czito BG (2010) Radiation therapy advances for treatment of anal cancer. J Natl Compr Cancer Netw 8:123–129

  6. 6.

    Kachnic LA, Winter K, Myerson RJ et al (2013) 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 Biol Phys 86(1):27–33

  7. 7.

    Milano MT, Jani AB, Farrey KJ et al (2005) Intensity-modulated radiation therapy (IMRT) in the treatment of anal cancer: toxicity and clinical outcome. Int J Radiat Oncol Biol Phys 63:354–361

  8. 8.

    Mitchell MP, Abboud M, Eng C, Beddar AS, Krishnan S, Delclos ME, Crane CH, Das P (2014) Intensity-modulated radiation therapy with concurrent chemotherapy for anal cancer: outcomes and toxicity. Am J Clin Oncol 37:461–466

  9. 9.

    Salama JK, Mell LK, Schomas DA et al (2007) Concurrent chemotherapy and intensity-modulated radiation therapy for anal canal cancer patients: a multicenter experience. J Clin Oncol 25:4581–4586

  10. 10.

    Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J (2009) New response evaluation criteria in solid tumours: revised RECIST guideline (version1.1). Eur J Cancer 45(2):228–247

  11. 11.

    Ng M, Leong T, Chander S, Chu J et al (2012) Australasian gastrointestinal trials group (AGITG) contouring atlas and planning guidelines for intensity-modulated radiotherapy in anal cancer. Int J Radiat Oncol Biol Phys 83(5):1455–1462

  12. 12.

    ICRU Report 83. Prescribing, recording, and reporting intensity-modulated photon-beam therapy (IMRT) (ICRU Report 83). International Commission on Radiation Units and Measurements, Bethesda, MD (2010)

  13. 13.

    Menkarios C, Azria D, Laliberté B et al (2007) Optimal organ-sparing intensity-modulated radiation therapy (IMRT) regimen for the treatment of locally advanced anal canal carcinoma: a comparison of conventional and IMRT plans. Radiat Oncol 15(2):41

  14. 14.

    Viswanathan AN, Moughan J, Miller BE, Xiao Y, Jhingran A, Portelance L, Bosch WR, Matulonis UA, Horowitz NS, Mannel RS, Souhami L, Erickson BA, Winter KA, Small W Jr, Gaffney DK (2015) NRG oncology/ RTOG 0921: a phase 2 study of postoperative intensity-modulated radiotherapy with concurrent cisplatin and bevacizumab followed by carboplatin and paclitaxel for patients with endometrial cancer. Cancer. 121(13):2156–2163

  15. 15.

    Cancer Therapy Evaluation Program (CTEP) of the National Cancer Institute (NCI). Common Terminology Criteria for Adverse Events (CTCAE): version 4.0. US Department of Health and Human Services, National Institutes of Health, National Cancer Institute, Bethesda: Maryland; 2009. v4.02: 2009

  16. 16.

    Cox JD, Stetz J, Pajak TF (1995) Toxicity criteria of the radiation therapy oncology group (RTOG) and the European Organization for Research and Treatment of Cancer (EORTC). Int J Radiat Oncol Biol Phys 31(5):1341–1346

  17. 17.

    Kalbfleisch JD, Prentice RL. The statistical analysis of failure time data. Wiley & Sons Ltd; 1980

  18. 18.

    Dewas CV, Maingon P, Dalban C et al (2012) Does gap-free intensity modulated chemoradiation therapy provide a greater clinical benefit than 3D conformal chemoradiation in patients with anal cancer? Radiat Oncol 7:201

  19. 19.

    De Bari B, Lestrade L, Franzetti-Pellanda A et al (2018) 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 144(4):781–789

  20. 20.

    Ajani JA, Winter KA, Gunderson LL et al (2006) Intergroup RTOG 98–11: a phase III randomized study of 5-fluorouracil (5-FU), mitomycin, and radiotherapy versus 5-fluorouracil, cisplatin and radiotherapy in carcinoma of the anal canal. J Clin Oncol 24(18_suppl):4009–4009

  21. 21.

    Chuong M, Freilich J, Hoffe S, Fulp W, Weber JM, Almhanna K, Dinwoodie W, Rao N, Meredith KL, Shridhar R (2013) Intensity-modulated radiation therapy versus conventional radiation therapy for squamous cell carcinoma of the anal canal. Gastrointest Cancer Res 6:39–45

  22. 22.

    Glynne-Jones R, Sebag-Montefiore D, Adams R et al (2011) “Mind the gap”—the impact of variations in the duration of the treatment gap and overall treatment time in the first UK anal cancer trial (act I). Int J Radiation Oncology Biol Phys 81(5):1488–1494

  23. 23.

    Ben-Josef E, Moughan J, Ajani JA, Flam M, Gunderson L, Pollock J, Myerson R, Anne R, Rosenthal SA, Willett C (2010) Impact of overall treatment time on survival and local control in patients with anal cancer: a pooled data analysis of radiation therapy oncology group trials 87-04 and 98-11. J Clin Oncol 28(34):5061–5066

  24. 24.

    Dell’Acqua V, Kobiela J, Kraja F et al (2018) Genital marginal failures after intensity-modulated radiation therapy (IMRT) in squamous cell anal cancer: no higher risk with IMRT when compared to 3DCRT. Med Oncol 35:59

  25. 25.

    Chen AM, Farwell DG, Luu Q et al (2011) Marginal misses after post- operative intensity-modulated radiotherapy for head and neck cancer. Int J Radiat Oncol Biol Phys 80(5):1423–1429

  26. 26.

    Koeck J, Lohr F, Buergy D et al (2016) Genital invasion or perigenital spread may pose a risk of marginal misses for intensity modulated radiotherapy (IMRT) in anal cancer. Radiat Oncol 4(11):53

  27. 27.

    Call JA, Prendergast BM, Jensen LG et al (2016) Intensity-modulated radiation therapy for anal cancer: results from a multi-institutional retrospective cohort study. Am J Clin Oncol 39(1):8–12

  28. 28.

    Bazan JG, Hara W, Hsu A, Kunz PA, Ford J, Fisher GA, Welton ML, Shelton A, Kapp DS, Koong AC, Goodman KA, Chang DT (2011) Intensity modulated radiation therapy versus conventional radiation therapy for squamous cell carcinoma of the anal canal. Cancer. 117:3342–3351

  29. 29.

    Glynne-Jones R, Kadalayil L, Meadows HM, Cunningham D, Samuel L, Geh JI, Lowdell C, James R, Beare S, Begum R, Ledermann JA, Sebag-Montefiore D, ACT II Study Group (2014) Tumour- and treatment-related colostomy rates following mitomycin C or cisplatin chemoradiation with or without maintenance chemotherapy in squamous cell carcinoma of the anus in the ACT II trial. Ann Oncol 25(8):1616–1622

  30. 30.

    Faivre JC, Peiffert D, Vendrely V, Lemanski C, Hannoun-Levi JM, Mirabel X, Stanbury T, Salleron J, Guillemin F (2018) Prognostic factors of colostomy free survival in patients presenting with locally advanced anal canal carcinoma: a pooled analysis of two prospective trials (KANAL 2 and ACCORD 03). Radiother Oncol 129(3):463–470

  31. 31.

    Hosni A, Han K, Le Lisa W et al (2018) The ongoing challenge of large anal cancers: prospective long term outcomes of intensity-modulated radiation therapy with concurrent chemotherapy. Oncotarget. 9(29):20439–20450

  32. 32.

    John M, Pajak T, Flam M et al (1996) Dose escalation in chemoradiation for anal cancer: preliminary results of RTOG 92-08. Cancer J Sci Am 2(4):205–211

  33. 33.

    Tomasoa NB, Meulendijks D, Nijkamp J, Cats A, Dewit L (2016) Clinical outcome in patients treated with simultaneous integrated boost - intensity modulated radiation therapy (SIB-IMRT) with and without concurrent chemotherapy for squamous cell carcinoma of the anal canal. Acta Oncol 55(6):760–766

  34. 34.

    Arcadipane F, Franco P, Ceccarelli M et al (2018) Image-guided IMRT with simultaneous integrated boost as per RTOG 0529 for the treatment of anal cancer. Asia Pac J Clin Oncol 14(3):217–223

  35. 35.

    Franco P, De Bari B, Arcadipane F et al (2018) Comparing simultaneous integrated boost vs sequential boost in anal cancer patients: results of a retrospective observational study. Radiat Oncol 13(1):172

  36. 36.

    Dalby JE, Pointon RS (1961) The treatment of anal carcinoma by interstitial irradiation. Am J Roentgenol Radium Therapy, Nucl Med 85:515–520

  37. 37.

    Oehler-Jänne C, Seifert B, Lütolf UM et al (2007) Clinical outcome after treatment with brachytherapy boost versus external beam boost for anal carcinoma. Brachytherapy. 6(3):218–226

  38. 38.

    Moureau-Zabotto L, Ortholan C, Hannoun-Levi JM et al (2013) Role of brachytherapy in the boost management of anal carcinoma with node involvement (CORS-03 study). Int J Radiat Oncol Biol Phys 85(3):e135–e142

  39. 39.

    Niehoff P, Kovács G (2014) HDR brachytherapy for anal cancer. J Gastrointest Oncol 5(3):218–222

  40. 40.

    Shridhar R, Shibata D, Chan E et al (2015) Anal cancer: current standards in care and recent changes in practice. CA Cancer J Clin 65(2):139–162

  41. 41.

    Gunderson LL, Winter KA, Ajani JA et al (2012) 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 30:4344–4351

  42. 42.

    James RD, Glynne-Jones R, Meadows HM et al (2013) 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 14:516–524

  43. 43.

    Goodman KA, Julie D, Cercek A et al (2017) Capecitabine with mitomycin reduces acute hematologic toxicity and treatment delays in patients undergoing definitive Chemoradiation using intensity modulated radiation therapy for anal Cancer. Int J Radiat Oncol Biol Phys 98:1087–1095

  44. 44.

    Glynne-Jones R, Meadows H, Wan S et al (2008) EXTRA-A multicenter phase II study of Chemoradiation using a 5 day per week Oral regimen of capecitabine and intravenous mitomycin C in anal Cancer. Int J Radiat Oncol Biol Phys 72:119–126

  45. 45.

    Thind G, Johal B, Follwell M et al (2014) Chemoradiation with capecitabine and mitomycin-C for stage I-III anal squamous cell carcinoma. Radiat Oncol 9:124

  46. 46.

    Jones CM, Adams R, Downing A et al (2018) Toxicity, tolerability, and compliance of concurrent capecitabine or 5-fluorouracil in radical management of anal cancer with single-dose mitomycin-C and intensity modulated radiation therapy: evaluation of a national cohort. Int J Radiat Oncol Biol Phys 101:1202–1211

  47. 47.

    Eng C, Chang GJ, You YN et al (2013) Long-term results of weekly/daily cisplatin-based chemoradiation for locally advanced squamous cell carcinoma of the anal canal. Cancer 119:3769

  48. 48.

    Souza K, Pereira A, Araujo R et al (2016) Replacing 5-fluorouracil by capecitabine in localised squamous cell carcinoma of the anal canal: systematic review and meta-analysis. Ecancermedicalscience. 10:699

  49. 49.

    Glynne-Jones R, Nilsson PJ, Aschele C et al (2014) Anal cancer: ESMO-ESSO-ESTRO clinical practice guidelines for diagnosis, treatment and follow-up. Eur J Surg Oncol 40(10):1165–1176

  50. 50.

    Repka M, Aghdam N, Karlin A et al (2017) Social determinants of stage IV anal cancer and the impact of pelvic radiotherapy in the metastatic setting. Cancer Med 6(11):2497–2506

  51. 51.

    Elson JK, Kachnic LA, Kharofa JR (2018) Intensity-modulated radiotherapy improves survival and reduces treatment time in squamous cell carcinoma of the anus: a National Cancer Data Base Study. Cancer. 124(22):4383–4392

  52. 52.

    Flam M, John M, Pajak TF et al (1996) 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 II randomized intergroup study. J Clin Oncol 14:2526–2539

Download references


This study was partially supported by Fondazione IEO-CCM, project title: “AXILL-ART: Biology-based radiotherapy volume definition for 1-2 macrometastatic sentinel lymph nodes without further dissection in breast cancer conservative surgery” and by the Italian Ministry of Health with Ricerca Corrente and 5 × 1000 funds.

Author information

All authors contributed to the study conception and design in terms of material preparation, data collection, and analysis. All authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Correspondence to Maria Alessia Zerella.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee (research project entitled “Image guided radiotherapy in gastrointestinal malignancies” notified to the Ethical Committee of the IEO, Milan, Italy No. IEO N87/11) and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Veronica Dell’Acqua and Alessia Surgo are the Co-first author.

Maria Cristina Leonardi and Barbara Alicja Jereczek-Fossa are the Co-last author.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Dell’Acqua, V., Surgo, A., Arculeo, S. et al. Intensity-modulated radiotherapy (IMRT) in the treatment of squamous cell anal canal cancer: acute and early-late toxicity, outcome, and efficacy. Int J Colorectal Dis (2020). https://doi.org/10.1007/s00384-020-03517-x

Download citation


  • Radiotherapy
  • Anal cancer
  • Chemotherapy
  • IMRT
  • Toxicity
  • Colostomy