Concomitant use of tamoxifen with radiotherapy enhances subcutaneous breast fibrosis in hypersensitive patients

D Azria, S Gourgou, W J Sozzi, A Zouhair, R O Mirimanoff, A Kramar, C Lemanski, J B Dubois, G Romieu, A Pelegrin, M Ozsahin, D Azria, S Gourgou, W J Sozzi, A Zouhair, R O Mirimanoff, A Kramar, C Lemanski, J B Dubois, G Romieu, A Pelegrin, M Ozsahin

Abstract

Concomitant use of adjuvant tamoxifen (TAM) and radiation therapy (RT) is not widely accepted. We aim to assess whether this treatment is associated with an increased risk of developing subcutaneous fibrosis after conservative or radical surgery in breast cancer patients. We analysed 147 women with breast cancer treated with adjuvant RT, and who were included in the KFS 00539-9-1997/SKL 00778-2-1999 prospective study aimed at evaluating the predictive value of CD4 and CD8 T-lymphocyte apoptosis for the development of radiation-induced late effects. TAM (20 mg day(-1)) with concomitant RT was prescribed in 90 hormone receptor-positive patients. There was a statistically significant difference in terms of complication-relapse-free survival (CRFS) rates at 3 years, 48% (95% CI 37.2-57.6%) vs 66% (95% CI 49.9-78.6%) and complication-free survival (CFS) rates at 2 years, 51% (95% CI 40-61%) vs 80% (95% CI 67-89%) in the TAM and no-TAM groups, respectively. In each of these groups, the CRFS rates were significantly lower for patients with low levels of CD8 radiation-induced apoptosis, 20% (95% CI 10-31.9%), 66% (95% CI 51.1-77.6%), and 79% (95% CI 55-90.9%) for CD8 </=16, 16-24, and >24%, respectively. Similar results were observed for the CFS rates. The concomitant use of TAM with RT is significantly associated with an increased incidence of grade 2 or greater subcutaneous fibrosis; therefore, caution is needed for radiosensitive patients.

Figures

Figure 1
Figure 1
Cumulative incidence of grade 2 or greater fibrosis curves according to CD8 radiation-induced apoptosis and concomitant tamoxifen with radiation therapy.

References

    1. Arriagada R, Rutqvist LE, Kramar A, Johansson H (1992) Competing risks determining event-free survival in early breast cancer. Br J Cancer 66: 951–957
    1. Azria D, Larbouret C, Cunat S, Romieu G, Evans D, Bastie A, Pujol P, Dubois JB, Pelegrin A (2003) Letrozole (Femara®) sensitises breast cancer cells to gamma irradiation. Int J Radiat Oncol Biol Phys 57: 255–256
    1. Barber JB, Burrill W, Spreadborough AR, Levine E, Warren C, Kiltie AE, Roberts SA, Scott D (2000) Relationship between in vitro chromosomal radiosensitivity of peripheral blood lymphocytes and the expression of normal tissue damage following radiotherapy for breast cancer. Radiother Oncol 55: 179–186
    1. Baum M, Budzar AU, Cuzick J, Forbes J, Houghton JH, Klijn JG, Sahmoud T (2002) Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early breast cancer: first results of the ATAC randomised trial. Lancet 359: 2131–2139
    1. Beadle GF, Silver B, Botnick L, Hellman S, Harris JR (1984) Cosmetic results following primary radiation therapy for early breast cancer. Cancer 54: 2911–2918
    1. Bentzen SM (1997) Potential clinical impact of normal-tissue intrinsic radiosensitivity testing. Radiother Oncol 43: 121–131
    1. 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 29: 1373–1376
    1. Bentzen SM, Skoczylas JZ, Overgaard M, Overgaard J (1996) Radiotherapy-related lung fibrosis enhanced by tamoxifen. J Natl Cancer Inst 88: 918–922
    1. Berthois Y, Katzenellenbogen JA, Katzenellenbogen BS (1986) Phenol red in tissue culture media is a weak estrogen: implications concerning the study of estrogen-responsive cells in culture. Proc Natl Acad Sci USA 83: 2496–2500
    1. Border WA, Noble NA (1994) Transforming growth factor beta in tissue fibrosis. N Engl J Med 331: 1286–1292
    1. Border WA, Okuda S, Languino LR, Sporn MB, Ruoslahti E (1990) Suppression of experimental glomerulonephritis by antiserum against transforming growth factor beta 1. Nature 346: 371–374
    1. Bostrom A, Sjolin-Forsberg G, Wilking N, Bergh J (1999) Radiation recall – another call with tamoxifen. Acta Oncol 38: 955–959
    1. Brock WA, Tucker SL, Geara FB, Turesson I, Wike J, Nyman J, Peters LJ (1995) Fibroblast radiosensitivity versus acute and late normal skin responses in patients treated for breast cancer. Int J Radiat Oncol Biol Phys 32: 1371–1379
    1. Burnet NG, Nyman J, Turesson I, Wurm R, Yarnold JR, Peacock JH (1992) Prediction of normal-tissue tolerance to radiotherapy from in-vitro cellular radiation sensitivity. Lancet 339: 1570–1581
    1. Butler WB, Kelsey WH, Goran N (1981) Effects of serum and insulin on the sensitivity of the human breast cancer cell line MCF-7 to estrogen and antiestrogens. Cancer Res 41: 82–88
    1. Butta A, MacLennan K, Flanders KC, Sacks NP, Smith I, McKinna A, Dowsett M, Wakefield LM, Sporn MB, Baum M (1992) Induction of transforming growth factor beta 1 in human breast cancer in vivo following tamoxifen treatment. Cancer Res 52: 4261–4264
    1. Canney PA, Dean S (1990) Transforming growth factor beta: a promotor of late connective tissue injury following radiotherapy? Br J Radiol 63: 620–633
    1. Christensen VJ, Harris E, Hwang WT, Fox K, Solin L (2003) The impact of concurrent versus sequential tamoxifen and radiation therapy in breast cancer patients undergoing breast conservation therapy. Proc Am Soc Clin Oncol 22: 11 (abstract 40)
    1. Colletta AA, Wakefield LM, Howell FV, van Roozendaal KE, Danielpour D, Ebbs SR, Sporn MB, Baum M (1990) Anti-oestrogens induce the secretion of active transforming growth factor beta from human fetal fibroblasts. Br J Cancer 62: 405–409
    1. Cormier EM, Jordan VC (1989) Contrasting ability of antiestrogens to inhibit MCF-7 growth stimulated by estradiol or epidermal growth factor. Eur J Cancer Clin Oncol 25: 57–63
    1. Cox JD, Stetz J, Pajak TF (1995) Toxicity criteria of the Radiation Therapy Oncology Group (RTOG) and the European Organization for Research and Treatment of Cancer (EORTC). Int J Radiat Oncol Biol Phys 31: 1341–1346
    1. Dalberg K, Johansson H, Johansson U, Rutqvist LE (1998) A randomized trial of long term adjuvant tamoxifen plus postoperative radiation therapy versus radiation therapy alone for patients with early stage breast carcinoma treated with breast-conserving surgery. Stockholm Breast Cancer Study Group. Cancer 82: 2204–2211
    1. 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: 3283–3290
    1. Delanian S, Porcher R, Balla-Mekias S, Lefaix JL (2003) Randomized, placebo-controlled trial of combined pentoxifylline and tocopherol for regression of superficial radiation-induced fibrosis. J Clin Oncol 21: 2545–2550
    1. Delozier T, Switsers O, Genot JY, Ollivier JM, Hery M, Namer M, Frenay M, Kerbrat P, Julien JP, Naja A, Janvier M, Mace-Lesec’h J (1997) [Tamoxifen adjuvant delays early breast cancer. Results of a cooperative randomized trial]. Bull Cancer 84: 25–30
    1. Early Breast Cancer Trialists’ Collaborative Group (1998) Tamoxifen for early breast cancer: an overview of the randomised trials. Lancet 351: 1451–1467
    1. Fertil B, Malaise EP (1981) Inherent cellular radiosensitivity as a basic concept for human tumor radiotherapy. Int J Radiat Oncol Biol Phys 7: 621–629
    1. Fisher B, Costantino J, Redmond C, Poisson R, Bowman D, Couture J, Dimitrov NV, Wolmark N, Wickerham DL, Fisher ER (1989) A randomized clinical trial evaluating tamoxifen in the treatment of patients with node-negative breast cancer who have estrogen-receptor-positive tumors. N Engl J Med 320: 479–484
    1. Fisher B, Dignam J, Wolmark N, Wickerham DL, Fisher ER, Mamounas E, Smith R, Begovic M, Dimitrov NV, Margolese RG, Kardinal CG, Kavanah MT, Fehrenbacher L, Oishi RH (1999) Tamoxifen in treatment of intraductal breast cancer: National Surgical Adjuvant Breast and Bowel Project B-24 randomised controlled trial. Lancet 353: 1993–2000
    1. Fowble B, Fein DA, Hanlon AL, Eisenberg BL, Hoffman JP, Sigurdson ER, Daly MB, Goldstein LJ (1996) The impact of tamoxifen on breast recurrence, cosmesis, complications, and survival in estrogen receptor-positive early-stage breast cancer. Int J Radiat Oncol Biol Phys 35: 669–677
    1. Germain P, Harbrioux G (1993) Modulation of the estradiol-17 beta mitogenic effect on human breast cancer MCF-7 cells by serum albumin in defined medium. Anticancer Res 13: 1581–1585
    1. Gould MN, Clifton KH (1978) The survival of rat mammary gland cells following irradiation in vivo under different endocrinological conditions. Int J Radiat Oncol Biol Phys 4: 629–632
    1. Houghton J, George WD, Cuzick J, Duggan C, Fentiman IS, Spittle M (2003) Radiotherapy and tamoxifen in women with completely excised ductal carcinoma in situ of the breast in the UK, Australia, and New Zealand: randomised controlled trial. Lancet 362: 95–102
    1. Huang EY, Wang CJ, Chen HC, Sun LM, Fang FM, Yeh SA, Hsu HC, Hsiung CY, Wu JM (2000) Multivariate analysis of pulmonary fibrosis after electron beam irradiation for postmastectomy chest wall and regional lymphatics: evidence for non-dosimetric factors. Radiother Oncol 57: 91–96
    1. Johansen J, Bentzen SM, Overgaard J, Overgaard M (1996) Relationship between the in vitro radiosensitivity of skin fibroblasts and the expression of subcutaneous fibrosis, telangiectasia, and skin erythema after radiotherapy. Radiother Oncol 40: 101–109
    1. Jones LA, Scott D, Cowan R, Roberts SA (1995) Abnormal radiosensitivity of lymphocytes from breast cancer patients with excessive normal tissue damage after radiotherapy: chromosome aberrations after low dose-rate irradiation. Int J Radiat Biol 67: 519–528
    1. Kantorowitz DA, Thompson HJ, Furmanski P (1993) Effect of conjoint administration of tamoxifen and high-dose radiation on the development of mammary carcinoma. Int J Radiat Oncol Biol Phys 26: 89–94
    1. Kiltie AE, Ryan AJ, Swindell R, Barber JB, West CM, Magee B, Hendry JH (1999) A correlation between residual radiation-induced DNA double-strand breaks in cultured fibroblasts and late radiotherapy reactions in breast cancer patients. Radiother Oncol 51: 55–65
    1. Koc M, Polat P, Suma S (2002) Effects of tamoxifen on pulmonary fibrosis after cobalt-60 radiotherapy in breast cancer patients. Radiother Oncol 64: 171–175
    1. Leborgne F, Leborgne JH, Ortega B, Doldan R, Zubizarreta E (1995) Breast conservation treatment of early stage breast cancer: patterns of failure. Int J Radiat Oncol Biol Phys 31: 765–775
    1. Lefaix JL, Delanian S, Vozenin MC, Leplat JJ, Tricaud Y, Martin M (1999) Striking regression of subcutaneous fibrosis induced by high doses of gamma rays using a combination of pentoxifylline and alpha-tocopherol: an experimental study. Int J Radiat Oncol Biol Phys 43: 839–847
    1. Mahler P (2002) Radiation, tamoxifen and pulmonary fibrosis. Proc Eur Soc Ther Radiat Oncol 64: 583 (abstract 249)
    1. Martin M, Lefaix JL, Pinton P, Crechet F, Daburon F (1993) Temporal modulation of TGF-beta 1 and beta-actin gene expression in pig skin and muscular fibrosis after ionizing radiation. Radiat Res 134: 63–70
    1. Olivotto IA, Rose MA, Osteen RT, Love S, Cady B, Silver B, Recht A, Harris JR (1989) Late cosmetic outcome after conservative surgery and radiotherapy: analysis of causes of cosmetic failure. Int J Radiat Oncol Biol Phys 17: 747–753
    1. Oppitz U, Baier K, Wulf J, Schakowski R, Flentje M (2001) The in vitro colony assay: a predictor of clinical outcome. Int J Radiat Biol 77: 105–110
    1. Osborne CK, Boldt DH, Clark GM, Trent JM (1983) Effects of tamoxifen on human breast cancer cell cycle kinetics: accumulation of cells in early G1 phase. Cancer Res 43: 3583–3585
    1. Overgaard M, Hansen PS, Overgaard J, Rose C, Andersson M, Bach F, Kjaer M, Gadeberg CC, Mouridsen HT, Jensen MB, Zedeler K (1997) Postoperative radiotherapy in high-risk premenopausal women with breast cancer who receive adjuvant chemotherapy. Danish Breast Cancer Cooperative Group 82b Trial. N Engl J Med 337: 949–955
    1. Overgaard M, Jensen MB, Overgaard J, Hansen PS, Rose C, Andersson M, Kamby C, Kjaer M, Gadeberg CC, Rasmussen BB, Blichert-Toft M, Mouridsen HT (1999) Postoperative radiotherapy in high-risk postmenopausal breast-cancer patients given adjuvant tamoxifen: Danish Breast Cancer Cooperative Group DBCG 82c randomised trial. Lancet 353: 1641–1648
    1. Ozsahin M, Li L, Crompton NE, Shi Y, Zouhair A, Coucke PA, Mirimanoff RO, Azria D (2003) Radiation-induced late toxicity can be predicted by CD4 and CD8 T-lymphocyte apoptosis: results of a prospective study in 399 individual consenting patients. Int J Radiat Oncol Biol Phys 57: 203–204
    1. Ozsahin M, Ozsahin H, Shi Y, Larsson B, Wurgler FE, Crompton NE (1997) Rapid assay of intrinsic radiosensitivity based on apoptosis in human CD4 and CD8 T-lymphocytes. Int J Radiat Oncol Biol Phys 38: 429–440
    1. Page MJ, Field JK, Everett NP, Green CD (1983) Serum regulation of the estrogen responsiveness of the human breast cancer cell line MCF-7. Cancer Res 43: 1244–1250
    1. Parry BR (1992) Radiation recall induced by tamoxifen. Lancet 340: 49
    1. Paulsen GH, Strickert T, Marthinsen AB, Lundgren S (1996) Changes in radiation sensitivity and steroid receptor content induced by hormonal agents and ionizing radiation in breast cancer cells in vitro. Acta Oncol 35: 1011–1019
    1. Peacock J, Ashton A, Bliss J, Bush C, Eady J, Jackson C, Owen R, Regan J, Yarnold J (2000) Cellular radiosensitivity and complication risk after curative radiotherapy. Radiother Oncol 55: 173–178
    1. Pierce LJ, Hutchins L, Green SJ, Lew D, Gralow J, Livingston RB, Osborne K, Albain KS (2003) Sequencing of tamoxifen and radiotherapy with breast conservation in early stage breast cancer. Proc Am Soc Clin Oncol 22: 10 (abstract 39)
    1. Rayan G, Dawson LA, Bezjak A, Lau A, Fyles AW, Yi QL, Merante P, Vallis KA (2003) Prospective comparison of breast pain in patients participating in a randomized trial of breast-conserving surgery and tamoxifen with or without radiotherapy. Int J Radiat Oncol Biol Phys 55: 154–161
    1. Russell NS, Grummels A, Hart AA, Smolders IJ, Borger J, Bartelink H, Begg AC (1998) Low predictive value of intrinsic fibroblast radiosensitivity for fibrosis development following radiotherapy for breast cancer. Int J Radiat Biol 73: 661–670
    1. Rutqvist LE, Cedermark B, Glas U, Johansson H, Rotstein S, Skoog L, Somell A, Theve T, Wilking N, Askergren J (1992) Randomized trial of adjuvant tamoxifen in node negative postmenopausal breast cancer. Stockholm Breast Cancer Study Group. Acta Oncol 31: 265–270
    1. Sarkaria JN, Miller EM, Parker CJ, Jordan VC, Mulcahy RT (1994) 4-Hydroxytamoxifen, an active metabolite of tamoxifen, does not alter the radiation sensitivity of MCF-7 breast carcinoma cells irradiated in vitro. Breast Cancer Res Treat 30: 159–165
    1. Shah M, Foreman DM, Ferguson MW (1992) Control of scarring in adult wounds by neutralising antibody to transforming growth factor beta. Lancet 339: 213–214
    1. Sinclair WK (1968) Cyclic x-ray responses in mammalian cells in vitro. Radiat Res 33: 620–643
    1. Singletary SE, Allred C, Ashley P, Bassett LW, Berry D, Bland KI, Borgen PI, Clark G, Edge SB, Hayes DF, Hughes LL, Hutter RV, Morrow M, Page DL, Recht A, Theriault RL, Thor A, Weaver DL, Wieand HS, Greene FL (2002) Revision of the American Joint Committee on Cancer staging system for breast cancer. J Clin Oncol 20: 3628–3636
    1. Taylor ME, Perez CA, Halverson KJ, Kuske RR, Philpott GW, Garcia DM, Mortimer JE, Myerson RJ, Radford D, Rush C (1995) Factors influencing cosmetic results after conservation therapy for breast cancer. Int J Radiat Oncol Biol Phys 31: 753–764
    1. Tucker SL, Turesson I, Thames HD (1992) Evidence for individual differences in the radiosensitivity of human skin. Eur J Cancer 28: 1783–1791
    1. Wazer DE, DiPetrillo T, Schmidt-Ullrich R, Weld L, Smith TJ, Marchant DJ, Robert NJ (1992) Factors influencing cosmetic outcome and complication risk after conservative surgery and radiotherapy for early-stage breast carcinoma. J Clin Oncol 10: 356–363
    1. Wazer DE, Morr J, Erban JK, Schmid CH, Ruthazer R, Schmidt-Ullrich RK (1997) The effects of postradiation treatment with tamoxifen on local control and cosmetic outcome in the conservatively treated breast. Cancer 80: 732–740
    1. Wazer DE, Tercilla OF, Lin PS, Schmidt-Ullrich R (1989) Modulation in the radiosensitivity of MCF-7 human breast carcinoma cells by 17B-estradiol and tamoxifen. Br J Radiol 62: 1079–1083

Source: PubMed

스폰서 및 공동 작업자

건강 상태

약물 개입

3
구독하다