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Originally published as JCO Early Release 10.1200/JCO.2005.03.6194 on October 31 2005 © 2005 American Society of Clinical Oncology.
The Irreversibility of Radiation-Induced Fibrosis: Fact or Folklore?Department of Radiation Oncology, Duke University Medical Center, Durham, NC As the number of long-term cancer survivors increases, late complications of therapy will become an increasingly important concern to both patients and physicians. In administering radiation therapy, the physician typically has attempted to prevent complications primarily by limiting the irradiated dose and volume.1 Unfortunately, the relationship between radiation dose, volume of tissue irradiated, development of complications, and tumor control is complex and not precisely defined for most normal tissues and malignancies.1,2 Unlike medical oncology, there are few formal prospective studies in radiation oncology designed to establish the maximum-tolerated dose for a particular tumor or normal tissue. Commonly accepted normal tissue tolerance doses of radiation, for the most part, have been derived empirically, often with little supporting data.2 Although these estimates may be reasonably generalized, there remains considerable individual variation in radiation sensitivity. Recently, however, much progress has been made toward better elucidating the molecular mechanisms underlying radiation injury.3-10 Late radiation damage in most tissues is characterized by loss of parenchymal cells and excessive formation of fibrous tissue.11 For years, it was taught that radiation fibrosis is a permanent irreversible condition, but its underlying mechanism remained uncertain. It has been known for decades that the biologic effects of ionizing radiation begin almost instantaneously with the generation of reactive oxygen species.12 More recently, however, we are beginning to learn that these immediate biochemical events lead to clinically and histologically recognizable injury through a series of genetic and molecular responses.7,13-23 This process is dynamic and involves a number of proinflammatory cytokines, profibrotic cytokines, and chemokines produced by a variety of cell types, including macrophages, epithelial cells, and fibroblasts. Furthermore, these events seem to be sustained for months or even years after therapy is completed.8 For example, the presence of progressive hypoxia has been noted after radiation of the lung and spinal cord.16,24 Because hypoxia itself is known to generate reactive oxygen species, promote inflammation and vascular damage, activate profibrotic cytokines, and promote collagen formation,25-27 it has been suggested that postradiation hypoxia may be an important contributor to maintenance of the injured phenotype.28 These findings have also suggested that, because the process is dynamic, it may not be irreversible. In this issue, Delanian et al29 contribute significantly to the growing body of knowledge that indicates that, indeed, radiation-induced fibrosis is at least partially reversible. They also demonstrate for the first time that long-term antifibrotic therapy will be needed to sustain benefit. The authors report on a retrospective series of 44 patients with 55 distinct superficial progressive fibrotic lesions induced by radiation therapy for breast cancer. The patients were administered the combination of pentoxifylline and vitamin E twice daily for either 6 to 12 months or 24 to 48 months. Both drugs have antioxidant properties, and pentoxifylline may also have antifibrotic effects, although neither agent is clearly effective as a single agent in reversing radiation-induced fibrosis. The main end points were reduction in the size of the fibrotic region and reduction in the global score of late injury. Delanian et al29 demonstrated the following: both treatment regimens produced significant improvements in both outcome measures; the maximum regression to be expected is approximately 69%; improvement occurred sooner in younger lesions (< 6 years since radiotherapy); and stopping the drugs resulted in a rebound effect that was more severe in the patients treated for a short duration. Tolerance of the regimen was good, and no patient discontinued therapy as a result of toxicity. Although oncologists should be encouraged by the mounting evidence that radiation-induced fibrosis may be reversible, many questions remain unanswered. First, because this was not a randomized trial, the results need to be confirmed. Second, fibrosis occurs in many different organs and tissues after radiation. Is it equally reversible in all of them? Third, the results of this study suggest that patients may need to be on antifibrotic therapy indefinitely. Is this, in fact, the case, or could treatment be discontinued after some finite interval? Finally, as the authors point out, the safety of long-term high-dose vitamin E remains in doubt. How does this drug combination impact on that issue? Delanian et al29 are to be congratulated on their pioneering work. The future continues to look brighter for cancer survivors who may be troubled by the long-term complications of treatment for their malignancy. Author's Disclosures of Potential Conflicts of Interest The author indicated no potential conflicts of interest. REFERENCES 1. Vujaskovic Z, Marks L, Anscher M: The physical parameters and molecular events associated with radiation-induced lung toxicity. Semin Radiat Oncol 10: 296-307, 2000[CrossRef][Medline] 2. Emami B, Lyman J, Brown A, et al: Tolerance of normal tissue to therapeutic irradiation. Int J Radiat Oncol Biol Phys 21: 109-122, 1991[Medline] 3. Stone HB, McBride WH, Coleman CN: Modifying normal tissue damage postirradiation: Report of a workshop sponsored by the Radiation Research Program, National Cancer Institute, Bethesda, Maryland, September 6-8, 2000. Radiat Res 157: 204-223, 2002[CrossRef][Medline] 4. Dent P, Yacoub A, Contessa J, et al: Stress and radiation-induced activation of multiple intracellular signaling pathways. Radiat Res 159: 283-300, 2003[Medline] 5. Chen Y, Williams J, Ding I, et al: Radiation pneumonitis and early circulatory cytokine markers. Semin Radiat Oncol 12: 26-33, 2002[CrossRef][Medline] 6. Rubin P, Finkelstein JN, Shapiro D: Molecular biology mechanisms in the radiation induction of pulmonary injury syndromes: Interrelationship between the alveolar macrophage and the septal fibroblast. Int J Radiat Oncol Biol Phys 24: 93-101, 1992[Medline]
7. Hallahan DE, Geng L, Shyr Y: 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: 733-741, 2002 8. Fu X, Huang H, Bentel G, et al: Predicting the risk of symptomatic radiation-induced lung injury using both the physical and biologic parameters V(30) and transforming growth factor beta. Int J Radiat Oncol Biol Phys 50: 899-908, 2001[CrossRef][Medline]
9. Paris F, Fuks Z, Kang A, et al: Endothelial apoptosis as the primary lesion initiating intestinal radiation damage in mice. Science 293: 293-297, 2001 10. Barcellos-Hoff MH, Brooks AL: Extracellular signaling through the microenvironment: A hypothesis relating carcinogenesis, bystander effects, and genomic instability. Radiat Res 156: 618-627, 2001[CrossRef][Medline] 11. Fajardo LF: Morphology of radiation effects on normal tissues, in Perez CA, Brady LW (eds): Principles and Practice of Radiation Oncology (ed 2). Philadelphia, PA, J.B. Lippincott Company, 1992, pp 114-123 12. Riley PA: Free radicals in biology: Oxidative stress and the effects of ionizing radiation. Int J Radiat Biol 65: 27-33, 1994[Medline] 13. Rubin P, Johnston CJ, Williams JP, et al: A perpetual cascade of cytokines post irradiation leads to pulmonary fibrosis. Int J Radiat Oncol Biol Phys 33: 99-109, 1995[CrossRef][Medline] 14. Barcellos-Hoff M: How do tissues respond to damage at the cellular level? The role of cytokines in irradiated tissues. Radiat Res 150: S109-S120, 1998[Medline] 15. Hauer-Jensen M, Kong FM, Fink LM, et al: Circulating thrombomodulin during radiation therapy of lung cancer. Radiat Oncol Investig 7: 238-242, 1999[CrossRef][Medline] 16. Vujaskovic Z, Anscher M, Feng Q-F, et al: Radiation-induced hypoxia may perpetuate late normal tissue injury. Int J Radiat Oncol Biol Phys 50: 851-855, 2001[CrossRef][Medline] 17. Hong JH, Chiang CS, Campbell IL, et al: Induction of acute phase gene expression by brain irradiation. Int J Radiat Oncol Biol Phys 33: 619-626, 1995[CrossRef][Medline]
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20. Kharbanda S, Bharti A, Pei D, et al: The stress response to ionizing radiation involves c-Abl-dependent phosphorylation of SHPTP1. Proc Natl Acad Sci U S A 93: 6898-6901, 1996
21. Kharbanda S, Saleem A, Yuan ZM, et al: Nuclear signaling induced by ionizing radiation involves colocalization of the activated p56/p53lyn tyrosine kinase with p34cdc2. Cancer Res 56: 3617-3621, 1996 22. Brach MA, Hass R, Sherman ML, et al: Ionizing radiation induces expression and binding activity of the nuclear factor kappa B. J Clin Invest 88: 691-695, 1991 23. Johnston C, Piedboeuf B, Baggs R, et al: Differences in correlation of mRNA gene expression in mice sensitive and resistant to radiation-induced pulmonary fibrosis. Radiat Res 142: 197-203, 1995[CrossRef][Medline]
24. Li YQ, Ballinger JR, Nordal RA, et al: Hypoxia in radiation-induced blood-spinal cord barrier breakdown. Cancer Res 61: 3348-3354, 2001 25. Shweiki D, Itin A, Soffer D, et al: Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis. Nature 359: 843-845, 1992[CrossRef][Medline] 26. Haroon ZA, Raleigh JA, Greenberg CS, et al: Early wound healing exhibits cytokine surge without evidence of hypoxia. Ann Surg 231: 137-147, 2000[CrossRef][Medline] 27. Zhong Z, Arteel GE, Connor HD, et al: Cyclosporin A increases hypoxia and free radical production in rat kidneys: Prevention by dietary glycine. Am J Physiol 275: F595-F604, 1998 28. Anscher MS, Chen L, Rabbani Z, et al: Recent progress in defining mechanisms and potential targets for prevention of normal tissue injury after radiation therapy. Int J Radiat Oncol Biol Phys 62: 255-259, 2005[CrossRef][Medline]
29. Delanian S, Porcher R, Rudant J, et al: Kinetics of response to long-term treatment combining pentoxifylline and tocopherol in patients with superficial radiation-induced fibrosis. J Clin Oncol 23: 8570-8579, 2005
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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