Top

Journal of Cancer Research and Clinical Oncology

Published in:

01-11-2015 | Review – Clinical Oncology

Radiation-induced fibrosis: mechanisms and implications for therapy

Authors: Jeffrey M. Straub, Jacob New, Chase D. Hamilton, Chris Lominska, Yelizaveta Shnayder, Sufi M. Thomas

Published in: Journal of Cancer Research and Clinical Oncology | Issue 11/2015

Abstract

Purpose

Radiation-induced fibrosis (RIF) is a long-term side effect of external beam radiation therapy for the treatment of cancer. It results in a multitude of symptoms that significantly impact quality of life. Understanding the mechanisms of RIF-induced changes is essential to developing effective strategies to prevent long-term disability and discomfort following radiation therapy. In this review, we describe the current understanding of the etiology, clinical presentation, pathogenesis, treatment, and directions of future therapy for this condition.

Methods

A literature review of publications describing mechanisms or treatments of RIF was performed. Specific databases utilized included PubMed and clinicaltrials.gov, using keywords “Radiation-Induced Fibrosis,” “Radiotherapy Complications,” “Fibrosis Therapy,” and other closely related terms.

Results

RIF is the result of a misguided wound healing response. In addition to causing direct DNA damage, ionizing radiation generates reactive oxygen and nitrogen species that lead to localized inflammation. This inflammatory process ultimately evolves into a fibrotic one characterized by increased collagen deposition, poor vascularity, and scarring. Tumor growth factor beta serves as the primary mediator in this response along with a host of other cytokines and growth factors. Current therapies have largely been directed toward these molecular targets and their associated signaling pathways.

Conclusion

Although RIF is widely prevalent among patients undergoing radiation therapy and significantly impacts quality of life, there is still much to learn about its pathogenesis and mechanisms. Current treatments have stemmed from this understanding, and it is anticipated that further elucidation will be essential for the development of more effective therapies.

Abratt RP, Morgan GW, Silvestri G, Willcox P (2004) Pulmonary complications of radiation therapy. Clin Chest Med 25:167–177. doi:10.1016/s0272-5231(03)00126-6 PubMedCrossRef

Abreu MT, Fukata M, Arditi M (2005) TLR signaling in the gut in health and disease. J Immunol 174:4453–4460PubMedCrossRef

Andreassen CN et al (2006) ATM sequence variants and risk of radiation-induced subcutaneous fibrosis after postmastectomy radiotherapy. Int J Radiat Oncol Biol Phys 64:776–783. doi:10.1016/j.ijrobp.2005.09.014 PubMedCrossRef

Ao X, Zhao L, Davis MA, Lubman DM, Lawrence TS, Kong FM (2009) Radiation produces differential changes in cytokine profiles in radiation lung fibrosis sensitive and resistant mice. J Hematol Oncol 2:6. doi:10.1186/1756-8722-2-6 PubMedCentralPubMedCrossRef

Azria D et al (2004) Concomitant use of tamoxifen with radiotherapy enhances subcutaneous breast fibrosis in hypersensitive patients. Br J Cancer 91:1251–1260. doi:10.1038/sj.bjc.6602146 PubMedCentralPubMedCrossRef

Azria D et al (2008) Single nucleotide polymorphisms, apoptosis, and the development of severe late adverse effects after radiotherapy. Clin Cancer Res 14:6284–6288. doi:10.1158/1078-0432.CCR-08-0700 PubMedCentralPubMedCrossRef

Baranano CF, Rosenthal EL, Morgan BA, McColloch NL, Magnuson JS (2011) Dynasplint for the management of trismus after treatment of upper aerodigestive tract cancer: a retrospective study. Ear Nose Throat J 90:584–590PubMed

Barnett GC et al (2012) Randomized controlled trial of forward-planned intensity modulated radiotherapy for early breast cancer: interim results at 2 years. Int J Radiat Oncol Biol Phys 82:715–723. doi:10.1016/j.ijrobp.2010.10.068 PubMedCrossRef

Bentzen SM, Overgaard M (1991) Relationship between early and late normal-tissue injury after postmastectomy radiotherapy. Radiother Oncol J Eur Soc Ther Radiol Oncol 20:159–165CrossRef

Bentzen SM, Overgaard M, Thames HD, Christensen JJ, Overgaard J (1989) Early and late normal-tissue injury after postmastectomy radiotherapy alone or combined with chemotherapy. Int J Radiat Biol 56:711–715PubMedCrossRef

Bentzen SM, Overgaard M, Overgaard J (1993) Clinical correlations between late normal tissue endpoints after radiotherapy: implications for predictive assays of radiosensitivity. Eur J Cancer 29A:1373–1376PubMedCrossRef

Bhrany AD, Izzard M, Wood AJ, Futran ND (2007) Coronoidectomy for the treatment of trismus in head and neck cancer patients. Laryngoscope 117:1952–1956. doi:10.1097/MLG.0b013e31812eee13 PubMedCrossRef

Boerma M, Hauer-Jensen M (2010) Potential targets for intervention in radiation-induced heart disease. Curr Drug Targets 11:1405–1412PubMedCentralPubMedCrossRef

Borger JH, Kemperman H, Smitt HS, Hart A, van Dongen J, Lebesque J, Bartelink H (1994) Dose and volume effects on fibrosis after breast conservation therapy. Int J Radiat Oncol Biol Phys 30:1073–1081PubMedCrossRef

Bourgeois JF, Gourgou S, Kramar A, Lagarde JM, Guillot B (2008) A randomized, prospective study using the LPG technique in treating radiation-induced skin fibrosis: clinical and profilometric analysis. Skin Res Technol 14:71–76. doi:10.1111/j.1600-0846.2007.00263.x PubMed

Bourgier C et al (2005) Inhibition of Rho kinase modulates radiation induced fibrogenic phenotype in intestinal smooth muscle cells through alteration of the cytoskeleton and connective tissue growth factor expression. Gut 54:336–343. doi:10.1136/gut.2004.051169 PubMedCentralPubMedCrossRef

Bourhis J et al (2006) Phase III randomized trial of very accelerated radiation therapy compared with conventional radiation therapy in squamous cell head and neck cancer: a GORTEC trial. Clin Oncol 24:2873–2878. doi:10.1200/JCO.2006.08.057 CrossRef

Box RC, Reul-Hirche HM, Bullock-Saxton JE, Furnival CM (2002) Shoulder movement after breast cancer surgery: results of a randomised controlled study of postoperative physiotherapy. Breast Cancer Res Treat 75:35–50PubMedCrossRef

Burger A, Loffler H, Bamberg M, Rodemann HP (1998) Molecular and cellular basis of radiation fibrosis. Int J Radiat Biol 73:401–408PubMedCrossRef

Calveley VL, Khan MA, Yeung IW, Vandyk J, Hill RP (2005) Partial volume rat lung irradiation: temporal fluctuations of in-field and out-of-field DNA damage and inflammatory cytokines following irradiation. Int J Radiat Biol 81:887–899. doi:10.1080/09553000600568002 PubMedCrossRef

Campana F et al (2004) Topical superoxide dismutase reduces post-irradiation breast cancer fibrosis. J Cell Mol Med 8:109–116PubMedCrossRef

Camphausen K (2013) Pirfenidone in treating patients with fibrosis caused by radiation therapy for cancer. https://clinicaltrials.gov/ct2/show/NCT00020631. Accessed 23 Oct 2014

Chaudiere J, Ferrari-Iliou R (1999) Intracellular antioxidants: from chemical to biochemical mechanisms. Food Chem Toxicol 37:949–962PubMedCrossRef

Cheuk IW, Yip SP, Kwong DL, Wu VW (2014) Association of and gene haplotypes with the development of radiation-induced fibrosis in patients with nasopharyngeal carcinoma. Mol Clin Oncol 2:553–558. doi:10.3892/mco.2014.276 PubMedCentralPubMed

Chithra P, Sajithlal GB, Chandrakasan G (1998) Influence of Aloe vera on the glycosaminoglycans in the matrix of healing dermal wounds in rats. J Ethnopharmacol 59:179–186PubMedCrossRef

Chua DT, Lo C, Yuen J, Foo YC (2001) A pilot study of pentoxifylline in the treatment of radiation-induced trismus. Am J Clin Oncol 24:366–369PubMedCrossRef

Chung YL, Wang AJ, Yao LF (2004) Antitumor histone deacetylase inhibitors suppress cutaneous radiation syndrome: implications for increasing therapeutic gain in cancer radiotherapy. Mol Cancer Ther 3:317–325PubMedCrossRef

Coia LR, Myerson RJ, Tepper JE (1995) Late effects of radiation therapy on the gastrointestinal tract. Int J Radiat Oncol Biol Phys 31:1213–1236. doi:10.1016/0360-3016(94)00419-l PubMedCrossRef

Darby IA, Hewitson TD (2007) Fibroblast differentiation in wound healing and fibrosis. Int Rev Cytol 257:143–179. doi:10.1016/S0074-7696(07)57004-X PubMedCrossRef

Darley-Usmar V, Halliwell B (1996) Blood radicals: reactive nitrogen species, reactive oxygen species, transition metal ions, and the vascular system. Pharm Res 13:649–662PubMedCrossRef

Davis AM et al (2005) Late radiation morbidity following randomization to preoperative versus postoperative radiotherapy in extremity soft tissue sarcoma. Radiother Oncol J Eur Soc Ther Radiol Oncol 75:48–53CrossRef

Delanian S, Lefaix JL (2002) Complete healing of severe osteoradionecrosis with treatment combining pentoxifylline, tocopherol and clodronate. Br J Radiol 75:467–469PubMedCrossRef

Delanian S, Martin M, Bravard A, Luccioni C, Lefaix JL (1998) Abnormal phenotype of cultured fibroblasts in human skin with chronic radiotherapy damage. Radiother Oncol J Eur Soc Ther Radiol Oncol 47:255–261CrossRef

Delanian S, Balla-Mekias S, Lefaix JL (1999) Striking regression of chronic radiotherapy damage in a clinical trial of combined pentoxifylline and tocopherol. J Clin Oncol 17:3283–3290PubMed

Delanian S, Martin M, Bravard A, Luccioni C, Lefaix JL (2001) Cu/Zn superoxide dismutase modulates phenotypic changes in cultured fibroblasts from human skin with chronic radiotherapy damage. Radiother Oncol J Eur Soc Ther Radiol Oncol 58:325–331CrossRef

Delanian S, Depondt J, Lefaix JL (2005) Major healing of refractory mandible osteoradionecrosis after treatment combining pentoxifylline and tocopherol: a phase II trial. Head Neck 27:114–123. doi:10.1002/hed.20121 PubMedCrossRef

Deng J, Ridner SH, Wells N, Dietrich MS, Murphy BA (2014) Development and preliminary testing of head and neck cancer related external lymphedema and fibrosis assessment criteria. Eur J Oncol Nurs. doi:10.1016/j.ejon.2014.07.006 PubMed

Denham JW, Hauer-Jensen M (2002) The radiotherapeutic injury—a complex ‘wound’. Radiother Oncol J Eur Soc Ther Radiol Oncol 63:129–145CrossRef

Dijkstra PU, Kalk WW, Roodenburg JL (2004) Trismus in head and neck oncology: a systematic review. Oral Oncol 40:879–889. doi:10.1016/j.oraloncology.2004.04.003 PubMedCrossRef

Donovan E et al (2007) Randomised trial of standard 2D radiotherapy (RT) versus intensity modulated radiotherapy (IMRT) in patients prescribed breast radiotherapy. Radiother Oncol J Eur Soc Ther Radiol Oncol 82:254–264. doi:10.1016/j.radonc.2006.12.008 CrossRef

Dorr W, Hendry JH (2001) Consequential late effects in normal tissues. Radiother Oncol J Eur Soc Ther Radiol Oncol 61:223–231CrossRef

Edvardsen H et al (2007) Linkage disequilibrium pattern of the ATM gene in breast cancer patients and controls; association of SNPs and haplotypes to radio-sensitivity and post-lumpectomy local recurrence. Radiat Oncol 2:25. doi:10.1186/1748-717X-2-25 PubMedCentralPubMedCrossRef

Edvardsen H et al (2013) SNP in TXNRD2 associated with radiation-induced fibrosis: a study of genetic variation in reactive oxygen species metabolism and signaling. Int J Radiat Oncol Biol Phys 86:791–799. doi:10.1016/j.ijrobp.2013.02.025 PubMedCrossRef

Eisbruch A et al (2003) Salivary gland sparing and improved target irradiation by conformal and intensity modulated irradiation of head and neck cancer. World J Surg 27:832–837PubMedCrossRef

Evans P, Halliwell B (1999) Free radicals and hearing. Cause, consequence, and criteria. Ann N Y Acad Sci 884:19–40PubMedCrossRef

Evans ML, Graham MM, Mahler PA, Rasey JS (1987) Use of steroids to suppress vascular response to radiation. Int J Radiat Oncol Biol Phys 13:563–567PubMedCrossRef

Finkelstein JN, Johnston C, Barrett T, Oberdorster G (1997) Particulate-cell interactions and pulmonary cytokine expression. Environ Health Perspect 105(Suppl 5):1179–1182PubMedCentralPubMedCrossRef

Finlay GA, Thannickal VJ, Fanburg BL, Paulson KE (2000) Transforming growth factor-beta 1-induced activation of the ERK pathway/activator protein-1 in human lung fibroblasts requires the autocrine induction of basic fibroblast growth factor. J Biol Chem 275:27650–27656. doi:10.1074/jbc.M000893200 PubMed

Flechsig P et al (2012) LY2109761 attenuates radiation-induced pulmonary murine fibrosis via reversal of TGF-beta and BMP-associated proinflammatory and proangiogenic signals. Clin Cancer Res 18:3616–3627. doi:10.1158/1078-0432.CCR-11-2855 PubMedCrossRef

Ford AQ, Dasgupta P, Mikhailenko I, Smith EM, Noben-Trauth N, Keegan AD (2012) Adoptive transfer of IL-4Ralpha + macrophages is sufficient to enhance eosinophilic inflammation in a mouse model of allergic lung inflammation. BMC Immunol 13:6. doi:10.1186/1471-2172-13-6 PubMedCentralPubMedCrossRef

Gao F, Fish BL, Moulder JE, Jacobs ER, Medhora M (2013) Enalapril mitigates radiation-induced pneumonitis and pulmonary fibrosis if started 35 days after whole-thorax irradiation. Radiat Res 180:546–552. doi:10.1667/RR13350.1 PubMedCentralPubMedCrossRef

Geara FB, Komaki R, Tucker SL, Travis EL, Cox JD (1998) Factors influencing the development of lung fibrosis after chemoradiation for small cell carcinoma of the lung: evidence for inherent interindividual variation. Int J Radiat Oncol Biol Phys 41:279–286PubMedCrossRef

Gold DG, Miller RC, Petersen IA, Osborn TG (2007) Radiotherapy for malignancy in patients with scleroderma: the Mayo Clinic experience. Int J Radiat Oncol Biol Phys 67:559–567. doi:10.1016/j.ijrobp.2006.09.003 PubMedCrossRef

Gordon S, Martinez FO (2010) Alternative activation of macrophages: mechanism and functions. Immunity 32:593–604. doi:10.1016/j.immuni.2010.05.007 PubMedCrossRef

Gorshkova I et al (2012) Inhibition of serine palmitoyltransferase delays the onset of radiation-induced pulmonary fibrosis through the negative regulation of sphingosine kinase-1 expression. J Lipid Res 53:1553–1568. doi:10.1194/jlr.M026039 PubMedCentralPubMedCrossRef

Gorshkova IA et al (2013) Inhibition of sphingosine-1-phosphate lyase rescues sphingosine kinase-1-knockout phenotype following murine cardiac arrest. Life Sci 93:359–366. doi:10.1016/j.lfs.2013.07.017 PubMedCrossRef

Graham MV, Purdy JA, Emami B, Harms W, Bosch W, Lockett MA, Perez CA (1999) Clinical dose-volume histogram analysis for pneumonitis after 3D treatment for non-small cell lung cancer (NSCLC). Int J Radiat Oncol Biol Phys 45:323–329PubMedCrossRef

Grandi G, Silva ML, Streit C, Wagner JC (2007) A mobilization regimen to prevent mandibular hypomobility in irradiated patients: an analysis and comparison of two techniques. Med Oral Patol Oral Cir Bucal 12:E105–E109PubMed

Greenberger JS, Epperly MW (2007) Review. Antioxidant gene therapeutic approaches to normal tissue radioprotection and tumor radiosensitization In vivo 21:141–146PubMed

Gross NJ (1977) Pulmonary effects of radiation therapy. Ann Intern Med 86:81–92PubMedCrossRef

Gupta T et al (2012) Three-dimensional conformal radiotherapy (3D-CRT) versus intensity modulated radiation therapy (IMRT) in squamous cell carcinoma of the head and neck: a randomized controlled trial. Radiother Oncol J Eur Soc Ther Radiol Oncol 104:343–348. doi:10.1016/j.radonc.2012.07.001 CrossRef

Hallahan DE, Geng L, Shyr Y (2002) Effects of intercellular adhesion molecule 1 (ICAM-1) null mutation on radiation-induced pulmonary fibrosis and respiratory insufficiency in mice. J Natl Cancer Inst 94:733–741PubMedCrossRef

Harrison JD, Stather JW (1996) The assessment of doses and effects from intakes of radioactive particles. J Anat 189(Pt 3):521–530PubMedCentralPubMed

Hartl DM, Cohen M, Julieron M, Marandas P, Janot F, Bourhis J (2008) Botulinum toxin for radiation-induced facial pain and trismus. Otolaryngol Head Neck Surg 138:459–463. doi:10.1016/j.otohns.2007.12.021 PubMedCrossRef

Haston CK, Travis EL (1997) Murine susceptibility to radiation-induced pulmonary fibrosis is influenced by a genetic factor implicated in susceptibility to bleomycin-induced pulmonary fibrosis. Cancer Res 57:5286–5291PubMed

Haston CK et al (2002) Universal and radiation-specific loci influence murine susceptibility to radiation-induced pulmonary fibrosis. Cancer Res 62:3782–3788PubMed

Haston CK, Begin M, Dorion G, Cory SM (2007) Distinct loci influence radiation-induced alveolitis from fibrosing alveolitis in the mouse. Cancer Res 67:10796–10803. doi:10.1158/0008-5472.CAN-07-2733 PubMedCrossRef

Holscher T, Bentzen SM, Baumann M (2006) Influence of connective tissue diseases on the expression of radiation side effects: a systematic review. Radiother Oncol J Eur Soc Ther Radiol Oncol 78:123–130. doi:10.1016/j.radonc.2005.12.013 CrossRef

Horton JA et al (2013a) Inhibition of radiation-induced skin fibrosis with imatinib. Int J Radiat Biol 89:162–170. doi:10.3109/09553002.2013.741281 PubMedCrossRef

Horton JA, Hudak KE, Chung EJ, White AO, Scroggins BT, Burkeen JF, Citrin DE (2013b) Mesenchymal stem cells inhibit cutaneous radiation-induced fibrosis by suppressing chronic inflammation. Stem Cells 31:2231–2241. doi:10.1002/stem.1483 PubMedCrossRef

Horton JA et al (2013c) Quercetin inhibits radiation-induced skin fibrosis. Radiat Res 180:205–215. doi:10.1667/RR3237.1 PubMedCentralPubMedCrossRef

Iwakawa M et al (2004) Strain dependent differences in a histological study of CD44 and collagen fibers with an expression analysis of inflammatory response-related genes in irradiated murine lung. J Radiat Res 45:423–433PubMedCrossRef

Jacobson G, Bhatia S, Smith BJ, Button AM, Bodeker K, Buatti J (2013) Randomized trial of pentoxifylline and vitamin E vs standard follow-up after breast irradiation to prevent breast fibrosis, evaluated by tissue compliance meter. Int J Radiat Oncol Biol Phys 85:604–608. doi:10.1016/j.ijrobp.2012.06.042 PubMedCrossRef

Ji Y (2013) Efficiency study for acute radiation-induced and chemotherapy-induced pulmonary fibrosis with bevasizumab. https://clinicaltrials.gov/ct2/show/NCT01917877. Accessed 23 Oct 2014

Jiang ZQ et al (2012) Long-term clinical outcome of intensity-modulated radiotherapy for inoperable non-small cell lung cancer: the MD Anderson experience. Int J Radiat Oncol Biol Phys 83:332–339. doi:10.1016/j.ijrobp.2011.06.1963 PubMedCrossRef

Johansson S, Svensson H, Denekamp J (2002) Dose response and latency for radiation-induced fibrosis, edema, and neuropathy in breast cancer patients. Int J Radiat Oncol Biol Phys 52:1207–1219PubMedCrossRef

Jones HA et al (2006) Preliminary investigation of symptom distress in the head and neck patient population: validation of a measurement instrument. Am J Clin Oncol 29:158–162. doi:10.1097/01.coc.0000207424.62275.9d PubMedCrossRef

Kamstra JI, Roodenburg JL, Beurskens CH, Reintsema H, Dijkstra PU (2013) TheraBite exercises to treat trismus secondary to head and neck cancer. Support Care Cancer 21:951–957. doi:10.1007/s00520-012-1610-9 PubMedCentralPubMedCrossRef

Khan MA, Van Dyk J, Yeung IW, Hill RP (2003) Partial volume rat lung irradiation; assessment of early DNA damage in different lung regions and effect of radical scavengers. Radiother Oncol J Eur Soc Ther Radiol Oncol 66:95–102CrossRef

Kirwan JM, Symonds P, Green JA, Tierney J, Collingwood M, Williams CJ (2003) A systematic review of acute and late toxicity of concomitant chemoradiation for cervical cancer. Radiother Oncol J Eur Soc Ther Radiol Oncol 68:217–226CrossRef

Lee JW et al (2010) Inhibition of Smad3 expression in radiation-induced fibrosis using a novel method for topical transcutaneous gene therapy. Arch Otolaryngol Head Neck Surg 136:714–719. doi:10.1001/archoto.2010.107 PubMedCrossRef

Lefaix JL, Daburon F (1998) Diagnosis of acute localized irradiation lesions: review of the French experimental experience. Health Phys 75:375–384PubMedCrossRef

Lemos QT, Andrade ZA (2010) Angiogenesis and experimental hepatic fibrosis. Mem Inst Oswaldo Cruz 105:611–614PubMedCrossRef

Leung SF, Zheng Y, Choi CY, Mak SS, Chiu SK, Zee B, Mak AF (2002) Quantitative measurement of post-irradiation neck fibrosis based on the young modulus: description of a new method and clinical results. Cancer 95:656–662. doi:10.1002/cncr.10700 PubMedCrossRef

Li MO, Wan YY, Sanjabi S, Robertson AK, Flavell RA (2006) Transforming growth factor-beta regulation of immune responses. Annu Rev Immunol 24:99–146. doi:10.1146/annurev.immunol.24.021605.090737 PubMedCrossRef

Li M, Jendrossek V, Belka C (2007) The role of PDGF in radiation oncology. Radiat Oncol 2:5. doi:10.1186/1748-717X-2-5 PubMedCentralPubMedCrossRef

Machtay M et al (2008) Factors associated with severe late toxicity after concurrent chemoradiation for locally advanced head and neck cancer: an RTOG analysis. J Clin Oncol 26:3582–3589. doi:10.1200/JCO.2007.14.8841 PubMedCrossRef

Madani I, De Ruyck K, Goeminne H, De Neve W, Thierens H, Van Meerbeeck J (2007) Predicting risk of radiation-induced lung injury. J Thorac Oncol 2:864–874. doi:10.1097/JTO.0b013e318145b2c6 PubMedCrossRef

Marks LB, Carroll PR, Dugan TC, Anscher MS (1995) The response of the urinary bladder, urethra, and ureter to radiation and chemotherapy. Int J Radiat Oncol Biol Phys 31:1257–1280. doi:10.1016/0360-3016(94)00431-j PubMedCrossRef

Martin M, Lefaix J, Delanian S (2000) TGF-beta1 and radiation fibrosis: a master switch and a specific therapeutic target? Int J Radiat Oncol Biol Phys 47:277–290PubMedCrossRef

Mathew M, Thomas SM (2012) The cellular microenvironment of head and neck squamous cell carcinoma. In: Li X (ed) Squamous cell carcinoma. InTech, pp 163–174. doi:10.5772/25652

Mathew B et al (2011) Simvastatin attenuates radiation-induced murine lung injury and dysregulated lung gene expression. Am J Respir Cell Mol Biol 44:415–422. doi:10.1165/rcmb.2010-0122OC PubMedCentralPubMedCrossRef

Melchers LJ, Van Weert E, Beurskens CH, Reintsema H, Slagter AP, Roodenburg JL, Dijkstra PU (2009) Exercise adherence in patients with trismus due to head and neck oncology: a qualitative study into the use of the Therabite. Int J Oral Maxillofac Surg 38:947–954. doi:10.1016/j.ijom.2009.04.003 PubMedCrossRef

Olman MA, White KE, Ware LB, Cross MT, Zhu S, Matthay MA (2002) Microarray analysis indicates that pulmonary edema fluid from patients with acute lung injury mediates inflammation, mitogen gene expression, and fibroblast proliferation through bioactive interleukin-1. Chest 121:69S–70SPubMedCrossRef

Otón C (2013) Treatment of Radiation-induced Fibrosis in the Upper Aerodigestive Tract Cancer by a Combination of Pentoxifylline-tocopherol and Hyperbaric Oxygen (ORT-OXI-2009). https://clinicaltrials.gov/ct2/show/NCT01822405. Accessed 23 Oct 2014

Pardo A, Selman M (2006) Matrix metalloproteases in aberrant fibrotic tissue remodeling. Proceedings of the American Thoracic Society 3:383–388. doi:10.1513/pats.200601-012TK PubMedCrossRef

Porter DW et al (2002) Time course of pulmonary response of rats to inhalation of crystalline silica: NF-kappa B activation, inflammation, cytokine production, and damage. Inhalation Toxicol 14:349–367. doi:10.1080/08958370252870998 CrossRef

Potter R, Knocke TH, Fellner C, Baldass M, Reinthaller A, Kucera H (2000) Definitive radiotherapy based on HDR brachytherapy with iridium 192 in uterine cervix carcinoma: report on the Vienna University Hospital findings (1993-1997) compared to the preceding period in the context of ICRU 38 recommendations. Cancer Radiother 4:159–172. doi:10.1016/s1278-3218(00)88900-3 PubMedCrossRef

Puthawala K et al (2008) Inhibition of integrin alpha(v)beta6, an activator of latent transforming growth factor-beta, prevents radiation-induced lung fibrosis. Am J Respir Crit Care Med 177:82–90. doi:10.1164/rccm.200706-806OC PubMedCentralPubMedCrossRef

Quarmby S, Kumar P, Wang J, Macro JA, Hutchinson JJ, Hunter RD, Kumar S (1999) Irradiation induces upregulation of CD31 in human endothelial cells. Arterioscler Thromb Vasc Biol 19:588–597PubMedCrossRef

Radiation Therapy Oncology Group (2014) Cooperative group common toxicity criteria. http://www.rtog.org/ResearchAssociates/AdverseEventReporting/CooperativeGroupCommonToxicityCriteria.aspx. Accessed 23 Oct 2014

Rodemann HP, Bamberg M (1995) Cellular basis of radiation-induced fibrosis. Radiother Oncol J Eur Soc Ther Radiol Oncol 35:83–90CrossRef

Rosenthal DI, Lewin JS, Eisbruch A (2006) Prevention and treatment of dysphagia and aspiration after chemoradiation for head and neck cancer. J Clin Oncol 24:2636–2643. doi:10.1200/JCO.2006.06.0079 PubMedCrossRef

Rudolph R, Vande Berg J, Schneider JA, Fisher JC, Poolman WL (1988) Slowed growth of cultured fibroblasts from human radiation wounds. Plast Reconstr Surg 82:669–677PubMedCrossRef

Sciubba JJ, Goldenberg D (2006) Oral complications of radiotherapy. Lancet Oncol 7:175–183. doi:10.1016/S1470-2045(06)70580-0 PubMedCrossRef

Sedgwick JB, Menon I, Gern JE, Busse WW (2002) Effects of inflammatory cytokines on the permeability of human lung microvascular endothelial cell monolayers and differential eosinophil transmigration. J Allergy Clin Immunol 110:752–756PubMedCrossRef

Sharplin J, Franko AJ (1989) A quantitative histological study of strain-dependent differences in the effects of irradiation on mouse lung during the early phase. Radiat Res 119:1–14PubMedCrossRef

Shu HK et al (2013) Inhibition of the CXCL12/CXCR4-axis as preventive therapy for radiation-induced pulmonary fibrosis. PLoS ONE 8:e79768. doi:10.1371/journal.pone.0079768 PubMedCentralPubMedCrossRef

Shulman DH, Shipman B, Willis FB (2008) Treating trismus with dynamic splinting: a cohort, case series. Adv Ther 25:9–16. doi:10.1007/s12325-008-0007-0 PubMedCrossRef

Sica A, Mantovani A (2012) Macrophage plasticity and polarization: in vivo veritas. J Clin Investig 122:787–795. doi:10.1172/JCI59643 PubMedCentralPubMedCrossRef

Sonis ST, Fey EG (2002) Oral complications of cancer therapy Oncology (Williston Park, NY) 16:680–686; discussion 686, 691–682, 695

Spanos W (2013) Study of topical superoxide dismutase to treat radiation induced fibrosis (Sodermix). https://clinicaltrials.gov/show/NCT01771991. Accessed 23 Oct 2014

Stubblefield MD, Manfield L, Riedel ER (2010) A preliminary report on the efficacy of a dynamic jaw opening device (dynasplint trismus system) as part of the multimodal treatment of trismus in patients with head and neck cancer. Arch Phys Med Rehabil 91:1278–1282. doi:10.1016/j.apmr.2010.05.010 PubMedCrossRef

Suarez EM, Knackstedt RJ, Jenrette JM (2014) Significant fibrosis after radiation therapy in a patient with Marfan syndrome. Radiat Oncol J 32:208–212. doi:10.3857/roj.2014.32.3.208 PubMedCentralPubMedCrossRef

Tak JK, Park JW (2009) The use of ebselen for radioprotection in cultured cells and mice. Free Radic Biol Med 46:1177–1185. doi:10.1016/j.freeradbiomed.2009.01.023 PubMedCrossRef

Terasaki Y et al (2011) Hydrogen therapy attenuates irradiation-induced lung damage by reducing oxidative stress. Am J Physiol Lung Cell Mol Physiol 301:L415–L426. doi:10.1152/ajplung.00008.2011 PubMedCrossRef

Toledano A et al (2006) Concurrent administration of adjuvant chemotherapy and radiotherapy after breast-conserving surgery enhances late toxicities: long-term results of the ARCOSEIN multicenter randomized study. Int J Radiat Oncol Biol Phys 65:324–332. doi:10.1016/j.ijrobp.2005.12.020 PubMedCrossRef

Tomasek JJ, Gabbiani G, Hinz B, Chaponnier C, Brown RA (2002) Myofibroblasts and mechano-regulation of connective tissue remodelling. Nat Rev Mol Cell Biol 3:349–363. doi:10.1038/nrm809 PubMedCrossRef

Toussaint O, Remacle J, Dierick JF, Pascal T, Frippiat C, Royer V, Chainiaux F (2002) Approach of evolutionary theories of ageing, stress, senescence-like phenotypes, calorie restriction and hormesis from the view point of far-from-equilibrium thermodynamics. Mech Ageing Dev 123:937–946PubMedCrossRef

Travis EL (2001) Organizational response of normal tissues to irradiation. Seminars in radiation oncology 11:184–196PubMedCrossRef

Vainshtein JM, Griffith KA, Feng FY, Vineberg KA, Chepeha DB, Eisbruch A (2014) Patient-reported voice and speech outcomes after whole-neck intensity modulated radiation therapy and chemotherapy for oropharyngeal cancer: prospective longitudinal study. Int J Radiat Oncol Biol Phys 89:973–980. doi:10.1016/j.ijrobp.2014.03.013 PubMedCrossRef

Varin A, Gordon S (2009) Alternative activation of macrophages: immune function and cellular biology. Immunobiology 214:630–641. doi:10.1016/j.imbio.2008.11.009 PubMedCrossRef

Weigel C, Schmezer P, Plass C, Popanda O (2014) Epigenetics in radiation-induced fibrosis. Oncogene. doi:10.1038/onc.2014.145 PubMedCentral

Williams JP, Johnston CJ, Finkelstein JN (2010) Treatment for radiation-induced pulmonary late effects: spoiled for choice or looking in the wrong direction? Curr Drug Targets 11:1386–1394PubMedCentralPubMedCrossRef

Xavier S et al (2004) Amelioration of radiation-induced fibrosis: inhibition of transforming growth factor-beta signaling by halofuginone. J Biol Chem 279:15167–15176. doi:10.1074/jbc.M309798200 PubMedCrossRef

Yarnold J, Brotons MC (2010) Pathogenetic mechanisms in radiation fibrosis. Radiother Oncol J Eur Soc Ther Radiol Oncol 97:149–161. doi:10.1016/j.radonc.2010.09.002 CrossRef

Zhang H et al (2011) The development of classically and alternatively activated macrophages has different effects on the varied stages of radiation-induced pulmonary injury in mice. J Radiat Res 52:717–726PubMedCrossRef

Zhao W, Robbins ME (2009) Inflammation and chronic oxidative stress in radiation-induced late normal tissue injury: therapeutic implications. Curr Med Chem 16:130–143PubMedCrossRef

Title: Radiation-induced fibrosis: mechanisms and implications for therapy
Authors: Jeffrey M. Straub
Jacob New
Chase D. Hamilton
Chris Lominska
Yelizaveta Shnayder
Sufi M. Thomas
Publication date: 01-11-2015
Publisher: Springer Berlin Heidelberg
Published in: Journal of Cancer Research and Clinical Oncology / Issue 11/2015
Print ISSN: 0171-5216
Electronic ISSN: 1432-1335
DOI: https://doi.org/10.1007/s00432-015-1974-6

Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin

Prof. Florian Limbourg

Prof. Anoop Chauhan

Developed by: Springer Medicine

Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Pediatric Cardiology Video

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

Cardiopulmonary Comorbidity Video

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Valvular Heart Disease Video

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

Watch now

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits

Illustration of figure on mountain summit/© Orapun / Stock.adobe.com, STEP AAG HeroTeaserCollection image/© Tarek / Generated with AI / Stock.adobe.com, ACC 2024 Pediatric and Congenital Heart Disease: Year in Review/© 2024 American College of Cardiology, ACC 2024 Pulmonary Vascular Disease: Year in Review/© 2024 American College of Cardiology, ACC 2024 Valvular Heart Disease: Year in Review/© 2024 American College of Cardiology, ACC 2024 HF and Cardiomyopathies: Year in Review/© 2024 American College of Cardiology, Woman out walking/© Seventyfour / stock.adobe.com (symbolic image with model), Woman checking smartwatch /© saltdium / stock.adobe.com (symbolic image with model), Cardiac catheterization/© Damian / stock.adobe.com

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Purpose

Methods

Results

Conclusion

Please log in to get access to this content

Other articles of this Issue 11/2015

Nilotinib in patients with systemic mastocytosis: analysis of the phase 2, open-label, single-arm nilotinib registration study

Cervical cancer stem cells: opportunities and challenges

Retraction Note to: siRNA-participated chemotherapy: an efficient and specific therapeutic against gastric cancer

The use of targeted MR-guided prostate biopsy reduces the risk of Gleason upgrading on radical prostatectomy

Evaluation of a bacteriochlorin-based photosensitizer’s anti-tumor effect in vitro and in vivo

A bispecific antibody directly induces lymphoma cell death by simultaneously targeting CD20 and HLA-DR

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

Highlights from the ACC 2024 Congress

ACC 2024 Congress Coverage