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Journal of Clinical Oncology, Vol 25, No 36 (December 20), 2007: pp. 5841-5843 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.14.6035
Enhanced Local Control by Radiation Boost in Breast Cancer: Back Side of the Coin?Institut Gustave Roussy, Villejuif, France
Institut Gustave Roussy, Villejuif; and Institut de Radioprotection et de Sûreté Nucléaire, Fontenay aux Roses, France
Institut Gustave Roussy, Villejuif, France; and Karolinska Institutet, Stockholm, Sweden To The Editor: Update of the large European Organisation for Research and Treatment of Cancer trial testing the effect of an additional (boost) 16-Gy dose in patients with breast cancer has been reported recently by Bartelink et al1 and Antonini et al2 These reports confirm the expected benefit of the boost that reduced local recurrence by half in terms of relative risk and showed a significant absolute gain with a smaller effect in older patients for whom the baseline risk is low.3 More than 20 years ago, by using a multivariate analysis performed on 463 patients with locally advanced breast cancer, we showed a linear dose-tumor control relationship in which local recurrence relative risk was equal to 18.36 x e–0.04746 x D(Gy) (where D is tumor dose).4 This model predicted that an additional dose of 15 Gy in conventional fractionation would decrease by two-fold the relative local recurrence risk in patients with subclinical disease. This effect on relative risk was shown to be independent from other clinical factors, such as tumor size, nodal involvement, and age. The recent results of the European Organisation for Research and Treatment of Cancer trial showing a reduction equal to 0.552 confirms the value of our predictive model and demonstrates further the larger absolute therapeutic benefit of the additional dose in younger patients. However, in this subpopulation, the high baseline risk level of local recurrence is a matter of concern. The additional 16-Gy dose decreased the recurrence rate to approximately 10% at 5 years, but the risk still might reach 15% to 20% at 10 to 15 years,5 justifying the recent ongoing trials investigating the potential benefit of an additional 10-Gy dose. In this context and using our predictive model, the additional relative risk reduction will reach approximately 30%, but will probably be associated with a higher risk of delayed adverse effects (mainly breast fibrosis). These adverse effects are likely to influence the long-term quality of life of these younger patients and emphasize the need for development of efficient antifibrotic strategies. One of the challenges of modern radiation oncology is to develop treatments able to mitigate or reverse undesirable adverse effects. Radiation-induced fibrosis is characterized by the excessive deposition of extracellular matrix, which is a highly dynamic process and results from a wound-healing defect.6,7 Although transforming growth factor β1 and its associated pathway that depend on the smad proteins are currently recognized as the main fibrogenic cascade,8,9 the downstream effector, the connective tissue growth factor (CTGF), might be more attractive therapeutically because of a more specific effect during the chronic phase of the pathology. Recently, the activation of the pathway depending on the small guanosine triphosphatase Rho and their downstream effectors Rho kinases (ROCKS) has been proposed.10,11 The relevance of this pathway to radiation fibrosis is expected to be high, given that it is involved in the control of vascular activation, inflammation, and fibrogenic response.12 The use of clinically relevant pharmacologic inhibitors of Rho and ROCK, including statins (well-known inhibitors of β-hydroxy-β-methylglutaryl-coenzyme A reductase12,13) would allow a quick transfer into the clinics. Preclinical studies with statins (lovastatin, simvastatin, and pravastatin) in lung and gut have shown a significant mitigating action on normal tissues and raised the question of a concomitant tumor protection effect.14-16 However, preliminary experiments conducted on tumor cell lines and xenograft models ruled out the latter hypothesis.16 Furthermore, Katz et al17 suggested that statin use was associated with an increased pathologic complete response rate after neoadjuvant chemoradiotherapy for rectal cancer.
In addition to fibrosis mitigation, strategies allowing fibrosis reversion are required; one of the most promising applications for statins in radiation oncology is their antifibrotic action, which would not interfere with previous anticancer treatments. Preclinical studies conducted in human samples and rodents showed a significant improvement of radiation-induced intestinal fibrosis after pravastatin treatment.18 The molecular mechanisms associated with this reversion rely on the Rho/ROCK inhibition, which lead in cascade to CTGF and extracellular matrix-related genes inhibition. Other antifibrotic therapeutic agents have been proposed to patients (reviewed by Delanian and Lefaix19), such as exogenous superoxide dismutase administration, and the combination of pentoxifylline with In summary, additional improvement of treatment modalities will require a careful evaluation of quality of life, especially for younger patients with a potential longer follow-up time. The ongoing clinical trial investigating an additional dose of 26 Gy on the tumor bed in this category of patients may provide a unique opportunity to investigate the molecular mechanisms involved in the development and maintenance of subcutaneous radiation fibrosis, and to evaluate the validity of targeted antifibrotic therapies, such as Rho/ROCK/CTGF, in an attempt to provide a long-term treatment benefit. AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. REFERENCES
1. Bartelink H, Horiot JC, Poortmans PM, et al: Impact of a higher radiation dose on local control and survival in breast-conserving therapy of early breast cancer: 10-year results of the randomized boost versus no boost EORTC 22881-10882 trial. J Clin Oncol 25:3259-3265, 2007 2. Antonini N, Jones H, Horiot JC, et al: Effect of age and radiation dose on local control after breast conserving treatment: EORTC trial 22881-10882. Radiother Oncol 82:265-271, 2007[CrossRef][Medline] 3. Bartelink H, Horiot JC, Poortmans P, et al: Recurrence rates after treatment of breast cancer with standard radiotherapy with or without additional radiation. N Engl J Med 345:1378-1387, 2001 4. Arriagada R, Mouriesse H, Sarrazin D, et al: Radiotherapy alone in breast cancer: I. Analysis of tumor parameters, tumor dose and local control—The experience of the Gustave-Roussy Institute and the Princess Margaret Hospital. Int J Radiat Oncol Biol Phys 11:1751-1757, 1985[Medline] 5. Arriagada R, Le MG, Guinebretiere JM, et al: Late local recurrences in a randomised trial comparing conservative treatment with total mastectomy in early breast cancer patients. Ann Oncol 14:1617-1622, 2003 6. Strup-Perrot C, Mathe D, Linard C, et al: Global gene expression profiles reveal an increase in mRNA levels of collagens, MMPs, and TIMPs in late radiation enteritis. Am J Physiol Gastrointest Liver Physiol 287:G875-G885, 2004 7. Denham JW, Hauer-Jensen M: The radiotherapeutic injury: A complex ‘wound’. Radiother Oncol 63:129-145, 2002[CrossRef][Medline] 8. Delanian S, Lefaix JL: Reversibility of radiation-induced fibroatrophy [in French]. Rev Med Interne 23:164-174, 2002[Medline] 9. Martin M, Lefaix J, Delanian S: TGF-beta1 and radiation fibrosis: A master switch and a specific therapeutic target? Int J Radiat Oncol Biol Phys 47:277-290, 2000[CrossRef][Medline] 10. Bourgier C, Haydont V, Milliat F, et al: 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, 2005 11. Vozenin-Brotons MC, Milliat F, Linard C, et al: Gene expression profile in human late radiation enteritis obtained by high-density cDNA array hybridization. Radiat Res 161:299-311, 2004[CrossRef][Medline] 12. Haydont V, Bourgier C, Vozenin-Brotons MC: Rho/ROCK pathway as a molecular target for modulation of intestinal radiation-induced toxicity. Br J Radiol 80:S32-S40, 2007 (Spec No. 1) 13. Haydont V, Mathe D, Bourgier C, et al: Induction of CTGF by TGF-beta1 in normal and radiation enteritis human smooth muscle cells: Smad/Rho balance and therapeutic perspectives. Radiother Oncol 76:219-225, 2005[CrossRef][Medline] 14. Williams JP, Hernady E, Johnston CJ, et al: Effect of administration of lovastatin on the development of late pulmonary effects after whole-lung irradiation in a murine model. Radiat Res 161:560-567, 2004[CrossRef][Medline] 15. Wang J, Boerma M, Fu Q, et al: Simvastatin ameliorates radiation enteropathy development after localized, fractionated irradiation by a protein C-independent mechanism. Int J Radiat Oncol Biol Phys 68:1483-1490, 2007[Medline] 16. Haydont V, Gilliot O, Rivera S, et al: Successful mitigation of delayed intestinal radiation injury using pravastatin is not associated with acute injury improvement or tumor protection. Int J Radiat Oncol Biol Phys 68:1471-1482, 2007[Medline] 17. Katz MS, Minsky BD, Saltz LB, et al: Association of statin use with a pathologic complete response to neoadjuvant chemoradiation for rectal cancer. Int J Radiat Oncol Biol Phys 62:1363-1370, 2005[CrossRef][Medline] 18. Haydont V, Bourgier C, Pocard M, et al: Pravastatin inhibits the Rho/CCN2/extracellular matrix cascade in human fibrosis explants and improves radiation-induced intestinal fibrosis in rats. Clin Cancer Res 13:5331-5340, 2007 19. Delanian S, Lefaix JL: Current management for late normal tissue injury: Radiation-induced fibrosis and necrosis. Semin Radiat Oncol 17:99-107, 2007[CrossRef][Medline] 20. 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 21. Delanian S, Porcher R, Balla-Mekias S, et al: Randomized, placebo-controlled trial of combined pentoxifylline and tocopherol for regression of superficial radiation-induced fibrosis. J Clin Oncol 21:2545-2550, 2003 22. Okunieff P, Augustine E, Hicks JE, et al: Pentoxifylline in the treatment of radiation-induced fibrosis. J Clin Oncol 22:2207-2213, 2004 23. Gothard L, Cornes P, Earl J, et al: Double-blind placebo-controlled randomised trial of vitamin E and pentoxifylline in patients with chronic arm lymphoedema and fibrosis after surgery and radiotherapy for breast cancer. Radiother Oncol 73:133-139, 2004[CrossRef][Medline] 24. Ozturk B, Egehan I, Atavci S, et al: Pentoxifylline in prevention of radiation-induced lung toxicity in patients with breast and lung cancer: A double-blind randomized trial. Int J Radiat Oncol Biol Phys 58:213-219, 2004[CrossRef][Medline] 25. Anscher MS: The irreversibility of radiation-induced fibrosis: Fact or folklore? J Clin Oncol 23:8551-8552, 2005
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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