Very Late-Onset Serious Chronic Adverse Effects After Radical Chemoradiotherapy for Anal Canal Cancer
Status PubMed-not-MEDLINE Language English Country Switzerland Media electronic
Document type Case Reports, Journal Article
PubMed
40507604
PubMed Central
PMC12156259
DOI
10.3390/jcm14113841
PII: jcm14113841
Knihovny.cz E-resources
- Keywords
- anal cancer, electron boost, fibroatrophy, hyperbaric oxygen, late effects, osteoradionecrosis, radical radiotherapy,
- Publication type
- Journal Article MeSH
- Case Reports MeSH
Radical chemoradiotherapy has been used as a frontline treatment for squamous cell cancer of the anus for the last 30-40 years. Considerable acute and chronic adverse effects have been observed following radiotherapy using 2D and 3D techniques. A case of very late-onset severe chronic toxicity in a patient 26 years after radiotherapy is presented. The patient underwent radical chemoradiotherapy for squamous anal cancer stage T3N3M0 in 1998. In the anal region, cumulative doses up to 77.6 Gy (including electron boost) were administered. Durable complete regression of the disease was achieved. Fourteen years after treatment, the patient developed vast fibroatrophy of the anus and perineum, progressing within the subsequent four years to necrosis and sphincter loss. Twenty years after treatment, the asymptomatic osteonecrotic foci in the left femur appeared on MRI scans. Despite two courses of hyperbaric oxygen treatment, the fibroatrophy and subsequent necrosis of soft tissues remained progressive, but the osteonecrosis was stable. Twenty-six years after treatment, the progressive changes induced symptomatic osteomyelitis of the ischium and pubic bone. The patient now requires permanent supportive treatment. The presented case is exceptional in the very late-onset typical chronic adverse effects developing after non-conformal radiotherapy administered at high doses as part of contemporary treatment protocols. There is little evidence regarding the late onset of chronic adverse effects, since the follow-up period is usually shorter than that of the case presented. Moreover, a significant portion of patients do not survive to reach the late-onset period of adverse effects. The presented case shows that there may be long-term survivors of anal cancer in the population who were treated with outdated techniques and who still carry a risk of late-onset severe, progressive adverse effects.
See more in PubMed
Northover J., Glynne-Jones R., Sebag-Montefiore D., James R., Meadows H., Wan S., Jitlal M., Ledermann J. 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. doi: 10.1038/sj.bjc.6605605. PubMed DOI PMC
Ajani J.A., Winter K.A., Gunderson L.L., Pedersen J., Benson A.B., Thomas C.R., Mayer R.J., Haddock M.G., Rich T.A., Willett C. Fluorouracil, mitomycin, and radiotherapy vs fluorouracil, cisplatin, and radiotherapy for carcinoma of the anal canal: A randomized controlled trial. JAMA. 2008;299:1914. doi: 10.1001/jama.299.16.1914. PubMed DOI
John M., Pajak T., Flam M., Hoffman J., Markoe A., Wolkov H., Paris K. Dose escalation in chemoradiation for anal cancer: Preliminary results of RTOG 92-08. Cancer J. Sci. Am. 1996;2:205–211. PubMed
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;30:402. doi: 10.1007/s12032-012-0402-x. PubMed DOI
Ferrigno R., Nakamura R.A., Novaes P.E.R.D.S., Pellizzon A.C.A., Maia M.A.C., Fogarolli R.C., Salvajoli J.V., Filho W.J.D., Lopes A. Radiochemotherapy in the conservative treatment of anal canal carcinoma: Retrospective analysis of results and radiation dose effectiveness. Int. J. Radiat. Oncol. Biol. Phys. 2005;61:1136–1142. doi: 10.1016/j.ijrobp.2004.07.687. PubMed DOI
Mai S.K., Welzel G., Hermann B., Bohrer M., Wenz F. Long-term outcome after combined radiochemotherapy for anal cancer—Retrospective analysis of efficacy, prognostic factors, and toxicity. Onkologie. 2008;31:251–257. doi: 10.1159/000121362. PubMed DOI
De Bari B., Lestrade L., Pommier P., Maddalo M., Buglione M., Magrini S.M., Carrie C. Could concomitant radio-chemotherapy improve the outcomes of early-stage node negative anal canal cancer patients? A retrospective analysis of 122 patients. Cancer Investig. 2015;33:114–120. doi: 10.3109/07357907.2014.1001898. PubMed DOI
Pan Y.B., Maeda Y., Wilson A., Glynne-Jones R., Vaizey C.J. Late gastrointestinal toxicity after radiotherapy for anal cancer: A systematic literature review. Acta Oncol. 2018;57:1427–1437. doi: 10.1080/0284186X.2018.1503713. PubMed DOI
Haas S., Mikkelsen A.H., Kronborg C., Oggesen B.T., Faaborg P.M., Serup-Hansen E., Spindler K.-L.G., Christensen P. Management of late adverse effects after chemoradiation for anal cancer. Acta Oncol. 2021;60:1688–1701. doi: 10.1080/0284186X.2021.1983208. PubMed DOI
Xu S.H., Tang J.S., Shen X.Y., Niu Z.X., Xiao J.L. Osteoradionecrosis of the Hip, a Troublesome Complication of Radiation Therapy: Case Series and Systematic Review. Front. Med. 2022;9:858929. doi: 10.3389/fmed.2022.858929. PubMed DOI PMC
Yarnold J., Brotons M.C. Pathogenetic mechanisms in radiation fibrosis. Radiother. Oncol. 2010;97:149–161. doi: 10.1016/j.radonc.2010.09.002. PubMed DOI
Jereczek-Fossa B.A., Orecchia R. Radiotherapy-induced mandibular bone complications. Cancer Treat. Rev. 2002;28:65–74. doi: 10.1053/ctrv.2002.0254. PubMed DOI
Hellmann D.B., Imboden J.B. Update in rheumatology: Evidence published in 2014. Ann. Intern. Med. 2015;162:W122-6. doi: 10.7326/M15-0273. PubMed DOI
Straub J.M., New J., Hamilton C.D., Lominska C., Shnayder Y., Thomas S.M. Radiation-induced fibrosis: Mechanisms and implications for therapy. J. Cancer Res. Clin. Oncol. 2015;141:1985–1994. doi: 10.1007/s00432-015-1974-6. PubMed DOI PMC
Bilimoria K.Y., Bentrem D.J., Rock C.E., Stewart A.K., Ko C.Y., Halverson A. Outcomes and prognostic factors for squamous-cell carcinoma of the anal canal: Analysis of patients from the National Cancer Data Base. Dis. Colon Rectum. 2009;52:624–631. doi: 10.1007/DCR.0b013e31819eb7f0. PubMed DOI
Ali F., Ghareeb A.E., Jha A., Van der Voet H., Garg D., Jha M. Anal cancer survival: A socioeconomic analysis. Ann. R. Coll. Surg. Engl. 2021;103:191–196. doi: 10.1308/rcsann.2020.7019. PubMed DOI PMC
Martin D., Rödel C., Fokas E. Chemoradiotherapy for anal cancer: Are we as good as we think? Strahlenther. Onkologie. 2019;195:369–373. doi: 10.1007/s00066-019-01444-7. (In English) PubMed DOI
Kachnic L.A., Winter K., Myerson R.J., Goodyear M.D., Willins J., Esthappan J., Haddock M.G., Rotman M., Parikh P.J., Safran H., 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. doi: 10.1016/j.ijrobp.2012.09.023. PubMed DOI PMC
Ng M., Ho H., Skelton J., Guerrieri M., Guiney M., Chao M., Blakey D., Macleod C., Amor H., Subramanian B., et al. Intensity-modulated Radiotherapy for Anal Cancer: Dose-Volume Relationship of Acute Gastrointestinal Toxicity and Disease Outcomes. Clin. Oncol. 2018;30:634–641. doi: 10.1016/j.clon.2018.07.020. PubMed DOI
Ortholan C., Ramaioli A., Peiffert D., Lusinchi A., Romestaing P., Chauveinc L., Touboul E., Peignaux K., Bruna A., de La Roche G., et al. Anal canal carcinoma: Early-stage tumors < or =10 mm (T1 or Tis): Therapeutic options and original pattern of local failure after radiotherapy. Int. J. Radiat. Oncol. Biol. Phys. 2005;62:479–485. doi: 10.1016/j.ijrobp.2004.09.060. PubMed DOI
Engineer R., Mallik S., Mahantshetty U., Shrivastava S. Impact of radiation dose on locoregional control and survival on squamous cell carcinoma of anal canal. Radiother. Oncol. 2010;95:283–287. doi: 10.1016/j.radonc.2010.04.013. PubMed DOI
Wo J.Y., Plastaras J.P., Metz J.M., Jiang W., Yeap B.Y., Drapek L.C., Adams J., Baglini C., Ryan D.P., Murphy J.E., et al. Pencil Beam Scanning Proton Beam Chemoradiation Therapy with 5-Fluorouracil and Mitomycin-C for Definitive Treatment of Carcinoma of the Anal Canal: A Multi-institutional Pilot Feasibility Study. Int. J. Radiat. Oncol. Biol. Phys. 2019;105:90–95. doi: 10.1016/j.ijrobp.2019.04.040. PubMed DOI
Ojerholm E., Kirk M.L., Thompson R.F., Zhai H., Metz J.M., Both S., Ben-Josef E., Plastaras J.P. Pencil-beam scanning proton therapy for anal cancer: A dosimetric comparison with intensity-modulated radiotherapy. Acta Oncol. 2015;54:1209–1217. doi: 10.3109/0284186X.2014.1002570. PubMed DOI
Dittmann K.H., Mayer C., Ohneseit P.A., Raju U., Andratschke N.H., Milas L., Rodemann H.P. Celecoxib induced tumor cell radiosensitization by inhibiting radiation induced nuclear EGFR transport and DNA-repair: A COX-2 independent mechanism. Int. J. Radiat. Oncol. Biol. Phys. 2008;70:203–212. doi: 10.1016/j.ijrobp.2007.08.065. PubMed DOI
Delanian S. Striking regression of radiation-induced fibrosis by a combination of pentoxifylline and tocopherol. Br. J. Radiol. 1998;71:892–894. doi: 10.1259/bjr.71.848.9828807. PubMed DOI
Flechsig P., Dadrich M., Bickelhaupt S., Jenne J., Hauser K., Timke C., Peschke P., Hahn E.W., Gröne H.-J., Yingling J., et al. LY2109761 attenuates radiation-induced pulmonary murine fibrosis via reversal of TGF-beta and BMP-associated proinflammatory and proangiogenic signals. Clin. Cancer Res. 2012;18:3616–3627. doi: 10.1158/1078-0432.CCR-11-2855. PubMed DOI
Bueno L., de Alwis D.P., Pitou C., Yingling J., Lahn M., Glatt S., Trocóniz I.F. Semi-mechanistic modelling of the tumour growth inhibitory ef fects of LY2157299, a new type I receptor TGF-beta kinase antagonist, in mice. Eur. J. Cancer. 2008;44:142–150. doi: 10.1016/j.ejca.2007.10.008. PubMed DOI
Bonner J.C. Regulation of PDGF and its receptors in fibrotic diseases. Cytokine Growth Factor Rev. 2004;15:255–273. doi: 10.1016/j.cytogfr.2004.03.006. PubMed DOI
Nishioka Y., Azuma M., Kishi M., Aono Y. Targeting platelet-derived growth factor as a therapeutic approach in pulmonary fibrosis. J. Med. Investig. 2013;60:175–183. doi: 10.2152/jmi.60.175. PubMed DOI
Frenette P.S., Pinho S., Lucas D., Scheiermann C. Mesenchymal stem cell: Keystone of the hematopoietic stem cell niche and a stepping-stone for regenerative medicine. Annu. Rev. Immunol. 2013;31:285–316. doi: 10.1146/annurev-immunol-032712-095919. PubMed DOI
Eke I., Makinde A.Y., Aryankalayil M.J., Sandfort V., Palayoor S.T., Rath B.H., Liotta L., Pierobon M., Petricoin E.F., Brown M.F., et al. Exploiting radiation-induced signaling to increase the susceptibility of resistant Cancer cells to targeted drugs: AKT and mTOR inhibitors as an ex ample. Mol. Cancer Ther. 2018;17:355–367. doi: 10.1158/1535-7163.MCT-17-0262. PubMed DOI PMC
Vera-Rosas A., Aguiar D., Domínguez A., Cabrera-Vicente A., Martín-Barrientos P., Cabrera R., Salas-Salas B.G., Ferrera-Alayón L., Ribeiro I., Chicas-Sett R., et al. Prospective Pilot study of Quality of Life in patients with severe late-radiation-toxicity treated by Low hyperbaric-oxygen-therapy. Clin. Transl. Radiat. Oncol. 2023;40:100620. doi: 10.1016/j.ctro.2023.100620. PubMed DOI PMC
Bennett M.H., Feldmeier J., Hampson N.B., Smee R., Milross C. Hyperbaric oxygen therapy for late radiation tissue injury. Cochrane Database Syst. Rev. 2016;4:Cd005005. doi: 10.1002/14651858.CD005005.pub4. PubMed DOI
Wang B., Wei J., Meng L., Wang H., Qu C., Chen X., Xin Y., Jiang X. Advances in pathogenic mechanisms and management of radiation-induced fibrosis. Biomed. Pharmacother. 2020;121:109560. doi: 10.1016/j.biopha.2019.109560. PubMed DOI
Wolff H.A., Raus I., Jung K., Schüler P., Herrmann M.K., Hennies S., Vorwerk H., Hille A., Hess C.F., Christiansen H. High-grade acute organ toxicity as a positive prognostic factor in primary radiochemotherapy for anal carcinoma. Int. J. Radiat. Oncol. Biol. Phys. 2011;79:1467–1478. doi: 10.1016/j.ijrobp.2010.01.010. PubMed DOI
Oblak I., Petric P., Anderluh F., Velenik V., Fras P. Long term outcome after combined modality treatment for anal cancer. Radiol. Oncol. 2012;46:145–152. doi: 10.2478/v10019-012-0022-2. PubMed DOI PMC
Eng C., Chang G.J., You Y.N., Das P., Xing Y., Delclos M., Wolff R.A., Rodriguez-Bigas M.A., Skibber J., Ohinata A., et al. Long-term results of weekly/daily cisplatin-based chemoradiation for locally advanced squamous cell carcinoma of the anal canal. Cancer. 2013;119:3769–3775. doi: 10.1002/cncr.28296. PubMed DOI
Wexler A., Berson A.M., Goldstone S.E., Waltzman R., Penzer J., Maisonet O.G., McDermott B., Rescigno J. Invasive anal squamous-cell carcinoma in the HIV-positive patient: Outcome in the era of highly active antiretroviral therapy. Dis. Colon Rectum. 2008;51:73–81. doi: 10.1007/s10350-007-9154-7. PubMed DOI
Fraunholz I., Weiss C., Eberlein K., Haberl A., Rödel C. Concurrent chemoradiotherapy with 5-fluorouracil and mitomycin C for invasive anal carcinoma in human immunodeficiency virus-positive patients receiving highly active antiretroviral therapy. Int. J. Radiat. Oncol. Biol. Phys. 2010;76:1425–1432. doi: 10.1016/j.ijrobp.2009.03.060. PubMed DOI
Peiffert D., Tournier-Rangeard L., Gérard J.P., Lemanski C., François E., Giovannini M., Cvitkovic F., Mirabel X., Bouché O., Luporsi E., 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. doi: 10.1200/JCO.2011.35.4837. Erratum in J. Clin. Oncol. 2012, 30, 3903. PubMed DOI
Young S.C., Solomon M.J., Hruby G., Frizelle F.A. Review of 120 anal cancer patients. Color. Dis. 2009;11:909–914. doi: 10.1111/j.1463-1318.2008.01723.x. PubMed DOI
Johansson M., Axelsson A., Haglind E., Bock D., Angenete E. Long-term survival after treatment for primary anal cancer- results from the Swedish national ANCA cohort study. Acta Oncol. 2022;61:478–483. doi: 10.1080/0284186X.2022.2033314. PubMed DOI
Gerard J.P., Ayzac L., Hun D., Romestaing P., Coquard R., Ardiet J.M., Mornex F. 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. doi: 10.1016/S0167-8140(97)00192-8. PubMed DOI
Madhu J., Marshall F., Palma N. Ten-year results of chemoradiation for anal cancer: Focus on late morbidity. Int. J. Radiat. Oncol. Biol. Phys. 1996;34:65–69. PubMed
Delanian S., Lefaix J.L. The radiation-induced fibroatrophic process: Therapeutic perspective via the antioxidant pathway. Radiother. Oncol. 2004;73:119–131. doi: 10.1016/j.radonc.2004.08.021. PubMed DOI
van Geel A.N., Lans T.E., Haen R., Tjong Joe Wai R., Menke-Pluijmers M.B. Partial mastectomy and m. latissimus dorsi reconstruction for radiation-induced fibrosis after breast-conservin cancer therapy World. J. Surg. 2011;355:568–572. PubMed PMC
Johansson S., Svensson H., Denekamp J. Dose response and latency for radiation-induced fibrosis, edema, and neuropathy in breast cancer patients. Int. J. Radiat. Oncol. Biol. Phys. 2002;52:1207–1219. doi: 10.1016/S0360-3016(01)02743-2. PubMed DOI
Chronopoulos A., Zarra T., Ehrenfeld M., Otto S. Osteoradionecrosis of the jaws: Definition, epidemiology, staging and clinical and radiological findings. A concise review. Int. Dent. J. 2018;68:22–30. doi: 10.1111/idj.12318. (In English) PubMed DOI PMC
Musbah T.M., Mupparapu M. Diagnosis and management of late onset osteoradionecrosis of the mandible. J. Orofac. Sci. 2013;5:71–73. doi: 10.4103/0975-8844.113711. DOI
Eschwege F., Lasser P., Chavy A., Wibault P., Kac J., Rougier P., Bognel C. Squamous cell carcinoma of the anal canal: Treatment by external beam irradiation. Radiother. Oncol. 1985;3:145–150. doi: 10.1016/S0167-8140(85)80019-0. PubMed DOI
Papillon J., Montbarbon J.F. Epidermoid carcinoma of the anal canal. A series of 276 cases. Dis. Colon Rectum. 1987;30:324–333. doi: 10.1007/BF02555448. PubMed DOI
Slørdahl K.S., Klotz D., Olsen J.Å., Skovlund E., Undseth C., Abildgaard H.L., Brændengen M., Nesbakken A., Larsen S.G., Hanekamp B.A., et al. Treatment outcomes and prognostic factors after chemoradiotherapy for anal cancer. Acta Oncol. 2021;60:921–930. doi: 10.1080/0284186X.2021.1918763. PubMed DOI
Leon O., Guren M., Hagberg O., Glimelius B., Dahl O., Havsteen H., Naucler G., Svensson C., Tveit K.M., Jakobsen A., et al. Anal carcinoma—Survival and recurrence in a large cohort of patients treated according to Nordic guidelines. Radiother. Oncol. 2014;113:352–358. doi: 10.1016/j.radonc.2014.10.002. PubMed DOI
Lim D.R., Hur H., Min B.S., Baik S.H., Lee K.Y., Kim N.K. Oncologic outcomes of squamous cell carcinoma of the anal canal after chemoradiation therapy. Korean J. Clin. Oncol. 2016;12:41–47. doi: 10.14216/kjco.16007. pISSN: 1738-8082, eISSN: 2288-4084. DOI
Delanian S., Lefaix J.L. Current management for late normal tissue injury: Radiation-induced fibrosis and necrosis. Semin. Radiat. Oncol. 2007;17:99–107. doi: 10.1016/j.semradonc.2006.11.006. PubMed DOI