Predictors of acute and late diarrhea in the treatment of anal cancer with concurrent chemoradiotherapy

Authors

DOI:

https://doi.org/10.2340/1651-226X.2025.43975

Keywords:

Anal canal carcinoma, radiation induced toxicity, contouring methods, NTCP models

Abstract

Background and purpose: Treatment-related diarrhea is a challenge for patients treated with chemo-radiotherapy (CRT) for anal cancer in a curative setting. This study aims to investigate dosimetric and clinical predictors of acute and late diarrhea for patients treated with CRT or radiotherapy (RT) alone for anal cancer. Additionally, to investigate different bowel contouring methods ability to predict diarrhea.

Patient/material and methods: Patients treated with CRT or RT alone in the prospective, observational DACG-I Plan-A study (2015–2021) were included.

Toxicity endpoints were acute grade ≥2 diarrhea, and late grade ≥1 diarrhea recorded at 1 year after treatment (Common Terminology Criteria of Adverse Events (CTCAE), v4.0).

Bowel volumes were contoured on the planning computed tomography (CT) as bowel cavity, bowel bag, individual bowel loops, and terminal ileum. Dosimetric variables included V15Gy, V30Gy, and V45Gy for the different bowel volumes. Clinical variables included tumor size, N-stage, and chemotherapy regimen. Logistic regression was used to evaluate the association between variables and toxicity.

Results: Of the 290 patients included in this study, 116 (40%) experienced acute grade ≥2 diarrhea, and 56 of 256 (22%) had late grade ≥1 diarrhea. Patients treated with 5-FU/Capecitabine had a threefold higher risk of acute diarrhea compared to those receiving weekly Cisplatin or RT alone (p < 0.001). A trend indicating an increased risk of acute grade ≥2 diarrhea for patients with larger bowel volumes receiving radiation was observed. This was most pronounced for bowel bag V30Gy (p = 0.09); however, results from the different bowel contouring methods were similar. No parameters were predictive of late diarrhea.

Interpretation: No dosimetric or clinical predictors of late diarrhea were found and only a trend was found between higher dose to bowel and risk of acute diarrhea. Treatment with 5-FU/Capecitabine showed a notable association with acute diarrhea. No contouring method was superior in predicting diarrhea.

Downloads

Download data is not yet available.

References

Bentzen AG, Guren MG, Wanderås EH, Frykholm G, Tveit KM, Wilsgaard T, et al. Chemoradiotherapy of anal carcinoma: survival and recurrence in an unselected national cohort. Int J Radiat Oncol Biol Phys. 2012;83:e173–80.

https://doi.org/10.1016/j.ijrobp.2011.12.062 DOI: https://doi.org/10.1016/j.ijrobp.2011.12.062

Brooks CJ, Lee YK, Aitken K, Hansen VN, Tait DM, Hawkins MA. Organ-sparing Intensity-modulated radiotherapy for anal cancer using the ACTII schedule: a comparison of conventional and intensity-modulated radiotherapy plans. Clin Oncol (R Coll Radiol). 2013;25:155–61.

https://doi.org/10.1016/j.clon.2012.08.008 DOI: https://doi.org/10.1016/j.clon.2012.08.008

Flam M, John M, Pajak TF, 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;14:2527–39.

https://doi.org/10.1200/JCO.1996.14.9.2527 DOI: https://doi.org/10.1200/JCO.1996.14.9.2527

Bartelink H, Roelofsen F, Eschwege F, Rougier P, Bosset JF, Gonzalez DG, 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 Gastro. J Clin Oncol. 1997;15:2040–9.

https://doi.org/10.1200/JCO.1997.15.5.2040 DOI: https://doi.org/10.1200/JCO.1997.15.5.2040

Kachnic LA, Winter K, Myerson RJ, Goodyear MD, 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 Biol Phys. 2013;86:27–33.

https://doi.org/10.1016/j.ijrobp.2012.09.023 DOI: https://doi.org/10.1016/j.ijrobp.2012.09.023

Ben-Josef E, Moughan J, Ajani JA, Flam M, Gunderson L, Pollock J, et al. 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. 2010;28:5061–6.

https://doi.org/10.1200/JCO.2010.29.1351 DOI: https://doi.org/10.1200/JCO.2010.29.1351

Sterner A, Derwinger K, Staff C, Nilsson H, Angenete E. Quality of life in patients treated for anal carcinoma—a systematic literature review. Int J Colorectal Dis. 2019;34:1517–28.

https://doi.org/10.1007/s00384-019-03342-x DOI: https://doi.org/10.1007/s00384-019-03342-x

Ng M, Ho H, Skelton J, Guerrieri M, Guiney M, Chao M, et al. Intensity-modulated Radiotherapy for anal cancer: dose-volume relationship of acute gastrointestinal toxicity and disease outcomes. Clin Oncol (R Coll Radiol). 2018;30:634–41.

https://doi.org/10.1016/j.clon.2018.07.020 DOI: https://doi.org/10.1016/j.clon.2018.07.020

Han K, Cummings BJ, Lindsay P, Skliarenko J, Craig T, Le LW, 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 Biol Phys. 2014;90:587–94.

https://doi.org/10.1016/j.ijrobp.2014.06.061 DOI: https://doi.org/10.1016/j.ijrobp.2014.06.061

Julie DA, Oh JH, Apte AP, Deasy JO, Tom A, Wu AJ, et al. Predictors of acute toxicities during definitive chemoradiation using intensity-modulated radiotherapy for anal squamous cell carcinoma. Acta Oncol. 2016;55:208–16.

https://doi.org/10.3109/0284186X.2015.1043396 DOI: https://doi.org/10.3109/0284186X.2015.1043396

Nilsson MP, Gunnlaugsson A, Johnsson A, Scherman J. Dosimetric and clinical predictors for acute and late gastrointestinal toxicity following chemoradiotherapy of locally advanced anal cancer. Clin Oncol. 2022;34:e35–44.

https://doi.org/10.1016/j.clon.2021.09.011 DOI: https://doi.org/10.1016/j.clon.2021.09.011

Devisetty K, Mell LK, Salama JK, Schomas DA, Miller RC, Jani AB, 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.

https://doi.org/10.1016/j.radonc.2009.07.006 DOI: https://doi.org/10.1016/j.radonc.2009.07.006

Olsen JR, Moughan J, Myerson R, Abitbol A, Doncals DE, 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 Biol Phys. 2017;98:400–8.

https://doi.org/10.1016/j.ijrobp.2017.02.005 DOI: https://doi.org/10.1016/j.ijrobp.2017.02.005

Jadon R, Higgins E, Hanna L, Evans M, Coles B, Staffurth J. A systematic review of dose-volume predictors and constraints for late bowel toxicity following pelvic radiotherapy. Radiat Oncol. 2019;14:57.

https://doi.org/10.1186/s13014-019-1262-8

Kavanagh BD, Pan CC, Dawson LA, Das SK, Li XA, Ten Haken RK, et al. Radiation dose-volume effects in the stomach and small bowel. Int J Radiat Oncol Biol Phys. 2010;76:S101–7.

https://doi.org/10.1016/j.ijrobp.2009.05.071 DOI: https://doi.org/10.1016/j.ijrobp.2009.05.071

Lukovic J, Hosni A, Liu A, Chen J, Tadic T, Patel T, et al. Evaluation of dosimetric predictors of toxicity after IMRT with concurrent chemotherapy for anal cancer. Radiother Oncol. 2023;178:109429.

https://doi.org/10.1016/j.radonc.2022.11.018 DOI: https://doi.org/10.1016/j.radonc.2022.11.018

DeFoe SG, Kabolizadeh P, Heron DE, Beriwal S. Dosimetric parameters predictive of acute gastrointestinal toxicity in patients with anal carcinoma treated with concurrent chemotherapy and intensity-modulated radiation therapy. Oncology. 2013;85:1–7.

https://doi.org/10.1159/000348387 DOI: https://doi.org/10.1159/000348387

Elhaminia B, Gilbert A, Lilley J, Abdar M, Frangi AF, Scarsbrook A, et al. Toxicity prediction in pelvic radiotherapy using multiple instance learning and cascaded attention layers. IEEE J Biomed Health Inform. 2023;27(4):1958–66.

https://doi.org/10.1109/JBHI.2023.3238825 DOI: https://doi.org/10.1109/JBHI.2023.3238825

Goulart RA, Barbalho SM, Gasparini RG, De Carvalho ACA. Facing terminal ileitis: going beyond Crohn’s disease. Gastroenterol Res. 2016;9:1–9.

https://doi.org/10.14740/gr698w DOI: https://doi.org/10.14740/gr698w

Danish Anal Cancer Group. Primary treatment of localized anal cancer [Internet]. 2.0. 2019. [Cited date: 22 June 2024]Available from: https://dacgnet.dk/wp-content/uploads/2022/03/dacg_onkologisk-bh-lokaliseret-anal-cancer_v2.0_admgodk110122.pdf

Dahl O, Myklebust MP, Dale JE, Leon O, Serup-Hansen E, Jakobsen A, et al. Evaluation of the stage classification of anal cancer by the TNM 8th version versus the TNM 7th version. Acta Oncol. 2020;59:1016–23.

https://doi.org/10.1080/0284186X.2020.1778180 DOI: https://doi.org/10.1080/0284186X.2020.1778180

Ng M, Leong T, Chander S, Chu J, Kneebone A, Carroll S, et al. Australasian Gastrointestinal Trials Group (AGITG) contouring atlas and planning guidelines for intensity-modulated radiotherapy in anal cancer. Int J Radiat Oncol Biol Phys. 2012;83:1455–62.

https://doi.org/10.1016/j.ijrobp.2011.12.058 DOI: https://doi.org/10.1016/j.ijrobp.2011.12.058

Gay HA, Barthold HJ, O’Meara E, Bosch WR, El Naqa I, Al-Lozi R, et al. Pelvic normal tissue contouring guidelines for radiation therapy: a Radiation Therapy Oncology Group consensus panel atlas. Int J Radiat Oncol Biol Phys. 2012;83:e353–62.

https://doi.org/10.1016/j.ijrobp.2012.01.023 DOI: https://doi.org/10.1016/j.ijrobp.2012.01.023

Leon O, Guren M, Hagberg O, Glimelius B, Dahl O, Havsteen H, et al. Anal carcinoma – survival and recurrence in a large cohort of patients treated according to Nordic guidelines. Radiother Oncol. 2014;113:352–8.

https://doi.org/10.1016/j.radonc.2014.10.002 DOI: https://doi.org/10.1016/j.radonc.2014.10.002

Jackson A, Marks LB, Bentzen SM, Eisbruch A, Yorke ED, Ten Haken RK, et al. The lessons of QUANTEC: recommendations for reporting and gathering data on dose-volume dependencies of treatment outcome. Int J Radiat Oncol Biol Phys. 2010;76:S155–S160.

https://doi.org/10.1016/j.ijrobp.2009.08.074 DOI: https://doi.org/10.1016/j.ijrobp.2009.08.074

McDonald F, Waters R, Gulliford S, Hall E, James N, Huddart RA. Defining bowel dose volume constraints for bladder radiotherapy treatment planning. Clin Oncol. 2015;27:22–9.

https://doi.org/10.1016/j.clon.2014.09.016 DOI: https://doi.org/10.1016/j.clon.2014.09.016

Jadon R, Higgins E, Hanna L, Evans M, Coles B, Staffurth J. A systematic review of dose-volume predictors and constraints for late bowel toxicity following pelvic radiotherapy. Radiat Oncol. 2019;14:57.

https://doi.org/10.1186/s13014-019-1262-8 DOI: https://doi.org/10.1186/s13014-019-1262-8

Marth C, Landoni F, Mahner S, McCormack M, Gonzalez-Martin A, Colombo N. Cervical cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2017;28:iv72–83.

https://doi.org/10.1093/annonc/mdx220 DOI: https://doi.org/10.1093/annonc/mdx220

Vittrup Jakobsen A, Jensenius Skovhus Kronborg C, Kjer Oksen R, Mayland Havelund B, Lycke Wind K, Garm Spindler K-L. Feasibility of weekly cisplatin and radiotherapy for localized anal cancer – a Danish anal cancer group report. Radiother Oncol. 2024;199:110422.

https://doi.org/10.1016/j.radonc.2024.110422 DOI: https://doi.org/10.1016/j.radonc.2024.110422

Rao S, Guren MG, Khan K, Brown G, Renehan AG, Steigen SE, et al. Anal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up☆. Ann Oncol.2021;32:1087–100.

https://doi.org/10.1016/j.annonc.2021.06.015 DOI: https://doi.org/10.1016/j.annonc.2021.06.015

James RD, Glynne-Jones R, Meadows HM, Cunningham D, Myint AS, Saunders MP, 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;14:516–24.

https://doi.org/10.1016/S1470-2045(13)70086-X DOI: https://doi.org/10.1016/S1470-2045(13)70086-X

Ajani JA, Winter KA, Gunderson LL, Pedersen J, Benson AB, 3rd, Thomas CRJ, et al. Fluorouracil, mitomycin, and radiotherapy vs fluorouracil, cisplatin, and radiotherapy for carcinoma of the anal canal: a randomized controlled trial. JAMA. 2008;299:1914–21.

https://doi.org/10.1001/jama.299.16.1914 DOI: https://doi.org/10.1001/jama.299.16.1914

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;102:1123–8.

https://doi.org/10.1038/sj.bjc.6605605 DOI: https://doi.org/10.1038/sj.bjc.6605605

UKCCCR Anal Cancer Trial Working Party. Epidermoid anal cancer: results from the UKCCCR randomised trial of radiotherapy alone versus radiotherapy, 5-fluorouracil, and mitomycin. UK Co-ordinating Committee on Cancer Research. Lancet. 1996;348:1049–54.

https://doi.org/10.1016/S0140-6736(96)03409-5 DOI: https://doi.org/10.1016/S0140-6736(96)03409-5

Deniaud-Alexandre E, Touboul E, Tiret E, Sezeur A, Houry S, Gallot D, et al. [Epidermoid carcinomas of the anal canal treated with definitive radiation therapy in a series of 305 patients]. Cancer Radiother. 2003;7:237–53.

https://doi.org/10.1016/S1278-3218(03)00042-8 DOI: https://doi.org/10.1016/S1278-3218(03)00042-8

Wiesendanger-Wittmer EM, Sijtsema NM, Muijs CT, Beukema JC. Systematic review of the role of a belly board device in radiotherapy delivery in patients with pelvic malignancies. Radiother Oncol. 2012;102:325–34.

https://doi.org/10.1016/j.radonc.2012.02.004 DOI: https://doi.org/10.1016/j.radonc.2012.02.004

Kronborg C, Serup-Hansen E, Lefevre A, Wilken EE, Petersen JB, Hansen J, et al. Prospective evaluation of acute toxicity and patient reported outcomes in anal cancer and plan optimization. Radiother Oncol. 2018;128:375–9.

https://doi.org/10.1016/j.radonc.2018.06.006 DOI: https://doi.org/10.1016/j.radonc.2018.06.006

Additional Files

Published

2025-09-15

How to Cite

Storm, K. S., Spindler, K.-L. G., Persson, G. F., Behrens, C., Sibolt, P., Homburg, S., … Serup-Hansen, E. (2025). Predictors of acute and late diarrhea in the treatment of anal cancer with concurrent chemoradiotherapy. Acta Oncologica, 64, 1217–1226. https://doi.org/10.2340/1651-226X.2025.43975

Issue

Section

Original article

Categories