Cardiovascular mortality in a randomized trial of adjuvant radiation therapy versus surgery alone in primary breast cancer

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      One concern with adjuvant radiation therapy for early breast cancer is the potential risk of increasing intercurrent mortality due to radiation-induced damage of the myocardium. The paper presents an analysis of long-term survival among 960 patients with primary breast cancer included in a randomized trial of pre- or postoperative radiation therapy (45 Gy/5 weeks) versus surgery alone. All patients were treated with a modified radical mastectomy. The mean follow-up was 16 years (range: 13–19 years). During the entire follow-up period there was an overall survival difference in favor of the irradiated patients that was of borderline significance (p = 0.09). There was no increase in intercurrent mortality due to any cause. However, when the results were analyzed according to estimated doses of radiation to the myocardium, the subset of patients who received the highest doses, that is, those treated with tangential 60Co fields for left-sided tumors, were found to have a significantly increased risk of death due to ischemic heart disease compared to the surgical controls (relative hazard: 3.2, p < 0.05). No such increase was observed among the patients who received less radiation to the myocardium, that is, whose chest wall and internal mammary nodes were treated with electrons or those with right-sided tumors, irrespective of the treatment technique. It is concluded that cardiovascular mortality associated with radiation therapy for early breast cancer is correlated with the biological dose of radiation to the heart and the irradiated volume. All of the following factors are thus important: laterality of the tumor, portal arrangements, radiation energy, fractionation, and total dose. The study illustrates that an increased cardiovascular mortality can be avoided by the use of appropriate techniques and avoidance of excessive treatment.


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        • Arriagada R.
        • Le M.G.
        • Mouriesse H.
        • Fontaine F.
        • Dewar J.
        • Rochard F.
        • Spielman M.
        • Lacour J.
        • Tubiana M.
        • Sarrazin D.
        Long-term effect of internal mammary chain treatment. Results of a multivariate analysis of 1204 patients with operable breast cancer and positive axillary nodes.
        Radiother. Oncol. 1988; 11: 213-222
        • Breslow N.E.
        Elementary methods of cohort analysis.
        Int. J. Epidemiol. 1984; 13: 112-115
        • Brinkley D.
        • Haybittle J.L.
        • Houghton J.
        The Cancer Research Campaign (King's/Cambridge) trial for early breast cancer: and analysis of the radiotherapy data.
        Br. J. Cancer. 1984; 57: 309-316
        • Cutler S.
        • Ederer F.
        Maximum utilization of the life table method in analyzing survival.
        J. Chron. Dis. 1958; 8: 699-710
        • Cuzick J.
        • Stewart H.
        • Peto R.
        • Baum M.
        • Fisher B.
        • Höst H.
        • Lythgoe J.P.
        • Ribeiro G.
        • Scheurlen H.
        • Wallgren A.
        Over-view of randomised trials of post-operative adjuvant radiotherapy in breast cancer.
        Cancer Treat. Rep. 1987; 71: 15-19
        • Cuzick J.
        • Stewart H.
        • Peto R.
        • Fisher B.
        • Kaae S.
        • Johansen H.
        • Lythgoe J.P.
        • Prescott R.J.
        Over-view of randomised trials comparing radical mastectomy against simple mastectomy with radiotherapy in breast cancer.
        Cancer Treat. Rep. 1987; 71: 7-14
        • Early Breast Cancer Trialists' Collaborative Group (EBCTCG)
        Treatment of early breast cancer: worldwide evidence in 1985–1990.
        in: A systematic overview of all available randomized trials in early breast cancer of adjuvant endocrine and cytotoxic therapy. Oxford University Press, Oxford1990
        • Fisher B.
        • Redmond C.
        • Poisson R.
        • Margolese R.
        • Wolmark N.
        • Wickerham L.
        • Fisher E.
        • Deutsch M.
        • Caplan R.
        • Pilch Y.
        • Glass A.
        • Shibata H.
        • Lerner H.
        • Terz J.
        • Sidorovich L.
        Eight-year results of a randomized clinical trial comparing total mastectomy and lumpectomy with or without irradiation in the treatment of breast cancer.
        N. Engl. J. Med. 1989; 320: 822-828
        • Griem K.L.
        • Henderson I.C.
        • Gelman R.
        • Ascoli D.
        • Silver B.
        • Recht A.
        • Goodman R.
        • Hellman S.
        • Harris J.R.
        The five-year results of a randomized trial of adjuvant irradiation therapy after chemotherapy in breast cancer patients treated with mastectomy.
        J. Clin. Oncol. 1987; 5: 1546-1555
        • Gustavsson A.
        • Eskilsson J.
        • Landsberg T.
        • Svahn-Tapper G.
        • White T.
        • Wollmer P.
        • Åkerman M.
        Late cardiac effects after mantle radiotherapy in patients with Hodgkin's disease.
        Ann. Oncol. 1990; 1: 355-363
        • Handley R.S.
        A surgeon's view of the spread of breast cancer.
        Cancer. 1969; 24: 1231-1234
        • Haybittle J.L.
        The reporting of non-significant results in clinical trials.
        in: Scheurlen H.R. Weckesser G. Armbruster I. Clinical trials in “early” breast cancer (lecture notes in medical informatics). Springer-Verlag, Berlin1979: 28-39
        • Haybittle J.L.
        • Brinkley D.
        • Houghton J.
        • A'Hern R.P.
        • Baum M.
        Postoperative radiotherapy and late mortality: evidence from the Cancer Research Campaign trial for early breast cancer.
        Br. Med. J. 1989; 298: 1611-1614
        • Höst H.
        • Brennhovd I.O.
        The effect of postoperative radiotherapy in breast cancer.
        Int. J. Radiat. Oncol. Biol. Phys. 1977; 2: 1061-1067
        • Höst H.
        • Brennhovd I.
        • Loeb M.
        Postoperative radiotherapy in breast cancer-long-term results from the Oslo study.
        Int. J. Radiat. Oncol. Biol. Phys. 1986; 12: 727-732
        • Jones J.M.
        • Ribeiro G.G.
        Mortality pattern over 34 years of breast cancer patients in a clinical trial of post-operative radiotherapy.
        Clin. Radiol. 1989; 40: 204-208
        • Kirk J.
        • Gray W.M.
        • Watson E.R.
        Cumulative radiation effect. Part I: fractionated treatment regimes.
        Clin. Radiol. 1971; 22: 145-155
        • Lacour J.
        • Bucalossi P.
        • Cacers E.
        • Jacobelli G.
        • Koszarowski T.
        • Le M.
        • Rumeau-Rouquette C.
        • Veronesi U.
        Radical mastectomy versus radical mastectomy plus internal mammary node dissection.
        Cancer. 1976; 37: 206-214
        • Lax I.
        Development of a generalized Gaussian model for absorbed dose calculation and dose planning in therapeutic electron beams.
        in: 1st edition. Thesis. University of Stockholm, Stockholm1986
        • Levitt S.H.
        Is there a role for post-operative adjuvant radiation in breast cancer? Beautiful hypothesis versus ugly facts: 1987 Gilbert H Fletcher lecture.
        Int. J. Radiat. Oncol. Biol. Phys. 1988; 14: 787-796
        • Levitt S.
        The role of radiation therapy as an adjuvant in the treatment of breast cancer.
        Int. J. Radiat. Oncol. Biol. Phys. 1986; 12: 843-844
        • Lindahl J.
        • Strender L.E.
        • Larsson L.E.
        • Unsgaard A.
        Electrocardiographic changes after radiation therapy for carcinoma of the breast. Incidence and functional significance.
        Acta Radiol. Oncol. 1983; 22: 433-440
        • Mouridsen H.
        • Rose C.
        • Overgaard M.
        • Dombernowsky P.
        • Panduro J.
        • Thorpe S.
        • Bruun Rasmussen B.
        • BlichertToft M.
        • West Andersen K.
        Adjuvant treatment of post menopausal patients with high risk primary breast cancer. Results from the Danish DBCG 77 C and DBCG 82 C.
        Acta Oncol. 1988; 27: 699-705
        • Overgaard M.
        • Juul Christensen J.
        • Johansen H.
        • NyboRasmussen A.
        • Brincker H.
        • van der Kooy P.
        • Frederiksen P.L.
        • Laursen F.
        • Panduro J.
        • Sörensen N.E.
        • Gadeberg C.C.
        • Hjelm-Hansen M.
        • Overgaard J.
        • West Andersen K.
        • Zedeler K.
        Postmastectomy irradiation in high-risk breast cancer patients. Present status of the Danish Breast Cancer Cooperative Group trials.
        Acta Oncol. 1988; 27: 707-714
        • Overgaard M.
        • Bentzen S.M.
        • Christensen J.J.
        • Madsen E.H.
        The value of the NSD formula in equation of acute and late radiation complications in normal tissue following 2 and 4 fractions per week in breast cancer patients treated with postmastectomy irradiation.
        Radiother. Oncol. 1987; 9: 1-12
        • Peto R.
        • Pike M.C.
        • Armitage P.
        • Breslow N.E.
        • Cox D.R.
        • Howard S.v.
        • Mantel N.
        • McPherson K.
        • Peto J.
        • Smith P.G.
        Design and analysis of randomized clinical trials requiring prolonged observation of each patient. I: introduction and design.
        Br. J. Cancer. 1976; 34: 585-612
        • Peto R.
        • Pike M.C.
        • Armitage P.
        • Breslow N.E.
        • Cox D.R.
        • Howard S.v.
        • Mantel N.
        • McPherson K.
        • Peto J.
        • Smith P.G.
        Design and analysis of randomized clinical trials requiring prolonged observation of each patient. II: analysis and examples.
        Br. J. Cancer. 1977; 35: 1-39
        • Rutqvist L.E.
        • Johansson H.
        Mortality by laterality of the primary tumour among 55,000 breast cancer patients from the Swedish cancer registry.
        Br. J. Cancer. 1990; 61: 866-868
        • Rutqvist L.E.
        • Cedermark B.
        • Glas U.
        • et al.
        Radiotherapy chemotherapy and tamoxifen as adjuncts to surgery in early breast cancer: a summary of three randomized trials.
        Int. J. Radiat. Oncol. Biol. Phys. 1989; 16: 629-639
        • de Schryver A.
        The Stockholm breast cancer trial: preliminary report of a randomized study concerning the value of pre-operative or post-operative radiotherapy in operable disease.
        Int. J. Radiat. Oncol. Biol. Phys. 1976; 1: 601-609
        • Stewart J.R.
        • Fajardo L.F.
        Radiation-induced heart disease: an update.
        Prog. Cardiovasc. Dis. 1984; 27: 173-194
        • Stewart J.R.
        Normal tissue tolerance to irradiation of the cardiovascular system.
        in: 1st edition. Frontiers in Radiation Therapy and Oncology. Vol. 23. Karger, Basel1989: 302-309
        • Strender L.-E.
        • Wallgren A.
        • Arndt J.
        • Amer O.
        • Berström J.
        • Blomstedt B.
        • Granberg P.-O.
        • Nilsson B.
        • Räf L.
        • Silfversward C.
        Adjuvant radiotherapy in operable breast cancer. Correlation between dose in internal mammary nodes and prognosis.
        Int. J. Radiat. Oncol. Biol. Phys. 1981; 7: 1319-1326
        • Uppsala-Örebro Breast Cancer Study Group
        Sector resection with or without postoperative radiotherapy for stage I breast cancer: a randomized trial.
        JNCI. 1990; 82: 277-282
        • Wallgren A.
        • Arner O.
        • Bergström J.
        • Blomstedt B.
        • Granberg P.-O.
        • Karnström L.
        • Räf L.
        • Silfversward C.
        Preoperative radiotherapy in operable breast cancer. Results in the Stockholm breast cancer trial.
        Cancer. 1978; 42: 1120-1125
        • Wallgren A.
        • Arner O.
        • Bergström J.
        • Blomstedt B.
        • Granberg P.-O.
        • Räf L.
        • Silfversward C.
        • Einhorn J.
        Radiation therapy in operable breast cancer: results from the Stockholm trial on adjuvant radiotherapy.
        Int. J. Radiat. Oncol. Biol. Phys. 1986; 12: 533-537
        • World Health Organization
        International classification of diseases.
        in: 1st edition. Manual of the international statistical classification of diseases injuries and causes of death. WHO, Geneva1969 (8th revision)


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