Inl. J. Radrarmn Oncolo~)’ Biol PhJj.7..Vol. 19. PP. 1121-l 124 Printed in the U.S.A All nghts reserved.

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??Original Contribution

EVALUATION

OF RADIOTHERAPY IN HIGH-RISK BREAST CANCER REPORT FROM THE DANISH BREAST CANCER COOPERATIVE GROUP (DBCG 82) TRIAL

M. OVERGAARD, A. NYBO-RASMUSSEN, F. LAURSEN,

PATIENTS:

M.D.,’ J. JUUL CHRISTENSEN, PH.D.,~ H. JOHANSEN, M.D.,3 C. ROSE,M.D.,5 P. VAN DER KOOY, PH.D.,~ J. PANDURO,

PH.D.,~

PH.D.,~

M.

M. HJELM-HANSEN,

KJER, PH.D.,‘*

M.D.,9

N. E. SORENSEN,

J. OVERGAARD,

PH.D.,”

M.D.,13

AND K. ZEDELER,

C. C. GADEBERG,

K. WEST

ANDERSEN,

M.D.,’ M.D.,”

PH.D.‘~

PH.D.‘~

‘Department of Oncology, ‘Department of Radiophysics, and 13Danish Cancer Society, Department of Experimental Clinical Oncology, Radiumstationen, 8000 Aarhus C; 3Department of Oncology ONA, 4Department of Radiophysics, and 14Danish Breast Cancer Cooperative Group Secretariat, Finseninstitutet, Rigshospitalet, 2 100 Copenhagen; ‘Department of Oncology and 6Department of Radiophysics, Odense University Hospital, 5000 Odense; ‘Department of Oncology and ‘Department of Radiophysics, Copenhagen University Hospital, 2730 Herlev; ‘Department of Oncology and “Department of Radiophysics, County Hospital, 9000 Aalborg; and “Department of Oncology and 12Department of Radiophysics, County Hospital, 7 100 Vejle The role of postmastectomy irradiation together with systemic treatment was evaluated in high-risk patients included in the Danish Breast Cancer Cooperative Group (DBCG) protocol 82. As of June 1989, a total of 1473 pre- and menopausal patients were randomized to postmastectomy irradiation + CMF versus CMF alone (protocol 82-b). A total of 1202 postmenopausal patients were randomized to postmastectomy irradiation + Tamoxifen versus Tamoxifen alone (protocol 82-c). At 5 years the actuarial loco-regional recurrence rate was significantly lower in the irradiated patients (82-b: 9% vs 28%, 82-c: 6% vs 36%). Further, disease-free survival was significantly improved in both pre- and postmenopausal irradiated patients compared with those who had only systemic treatment (82-b: 54% vs 47%, 82-c: 52% vs 38%). At present, overall survival is significantly different in 82-b patients (68% vs 63%) but not in post-menopausal 82-c patients (62% vs 61%). Thus, adjuvant systemic treatment alone (chemotherapy or tamoxifen) did not prevent loco-regional recurrences in high-risk patients after mastectomy and axillary lymph node sampling. However, a longer observation time is necessary to evaluate the consequence of primary optimal loco-regional tumor control in high-risk breast cancer patients with respect to overall survival. Postmastectomy

radiotherapy, High-risk breast cancer, CMF, Tamoxifen,

METHODS

INTRODUCTION

Reprint requests to: Marie Overgaard, M.D., Department Radiumstationen,

DK-8000

AND MATERIALS

Patients In the DBCG

of operable breast cancer comprises two major components: management of local and regional disease and eradication of occult systemic metastases. The Danish Breast Cancer Cooperative Group (DBCG) protocol 82 trial was designed to evaluate the efficacy of postmastectomy radiotherapy combined with adjuvant systemic therapy against adjuvant systemic therapy alone with respect to loco-regional tumor control, disease-free survival, overall survival, and toxicity. The aim of the present study was to analyze the influence of radiotherapy in high-risk patients treated with chemotherapy after mastectomy and axillary node sampling. Thus, only directly comparable patient groups will be described. A detailed description of the trial design and various protocols has previously been given (5, 9, 10).

The treatment

Oncology,

Loco-regional control.

82 b + c protocols, all pre- and postmenopausal high-risk (T3-4 and/or N+) breast cancer patients were included. Only patients less than 70 years of age were eligible. The criteria for entry were as follows: no evidence of advanced disease as estimated by physical examination, biochemical tests, chest X ray, bone scin-

tigraphy, or X rays of bones and no previous or concomitant other malignant disease. Orally informed consent was also mandatory (2). Protocol design Protocol DBCG 82 (b and c) recruited patients from November 1982 and is still open for patient entry. After mastectomy, pre- and menopausal women (82 b) were Accepted

of

Aarhus C, Denmark. 1121

for publication

24 May 1990.

I.J.

1122

Radiation Oncology 0 Biology 0 Physics

randomized to RT + CMF versus CMF alone versus CMF + TAM for 9 months, (CMF: Cyclophosphamide (600 mg/m* I.V.), Methotrexate (40 mg/m2 I.V.), 5-Fluorouracil(600 mg/m2 I.V.; TAM: Tamoxifen (30 mg daily)). Similarly, postmenopausal women (82 c) were randomized to RT plus TAM versus TAM alone or CMF + TAM. CMF was given every 4 weeks to a total of 9 cycles and TAM for 12 months. Only the comparison between RT + CMF and CMF and RT + TAM and TAM will be described in the present paper.

November 1990, Volume 19, Number 5 419

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Surgery

The primary surgical treatment was total mastectomy and partial axillary dissection. A mean of 6.3 lymph nodes 524

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1

0

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3

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AFTER TREATMENT

Fig. 2. Loco-regional control (upper panel), disease-free survival (middle panel), and overall survival (lower panel) in high risk, postmenopausal patients (DBCG 82 c) given adjuvant treatment with RT + TAM or TAM alone.

100

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4

were available for examination. The aim of the surgery was to make a macro-radical removal of the primary tumor and grossly involved axillary lymph nodes and at the same time to make a pathological staging.

5

AFTER TREATMENT

Fig. 1. Loco-regional control (upper panel), disease-free survival (middle panel), and overall survival (lower panel) in high risk, pre- and menopausal patients (DBCG 82 b) given adjuvant treatment with RT + CMF or CMF alone.

The aim of the radiation therapy was to deliver a tumor dose sufficient for eradication of subclinical disease in peripheral lymph nodes and chest wall, including the surgical scar. The target volume included the axillary, supraclavicular/infmclavicular, and the internal mammary nodes. The intended dose was either a median absorbed dose in the target volume (DT_mdian ) = 50.00 Gy in 25 fractions

Evaluationof radiotherapy in high-risk breast cancer patients 0 M. in 5 weeks, or DT_median = 48.00 Gy in 22 fractions in 5$ weeks, according to ICRU-29. Details of the technique have previously been published ( 10). Adjuvant systemic treatment CMF and radiotherapy in this protocol were given sequentially, with an interval of a few days from the first cycle of CMF and the start of RT and an interval of l-2 weeks after the completion of RT. Thus, patients who were randomized to RT + CMF got only a total of 8 CMF cycles, whereas patients randomized to CMF got a total of 9 CMF cycles. TAM was continued for 12 months. A more detailed description of the systemic treatment has been given before (5, 9). Evaluation and statistical methods All diagnostic, therapeutic, and follow-up data were validated and processed by the DBCG data center (12, 13). The frequency of loco-regional recurrences, diseasefree survival, and overall survival were evaluated by the life-table method and compared using the log-rank test ( 13). The p-values given are those for a two-tailed test. The definition of the endpoint loco-regional recurrence was the first site of recurrence either alone or together with distant metastases. Loco-regional recurrences occurring after first relapse are not included. RESULTS As of June 1989 a total of 1473 pre- and menopausal patients were randomized to postmastectomy irradiation + CMF versus CMF alone (protocol 82-b). A total of 1202 postmenopausal patients were randomized to postmastectomy irradiation + Tamoxifen versus Tamoxifen alone (protocol 82-c). An overview of the whole patient population and the distribution according to known prognostic parameters has previously been published ( 12). The results of DBCG 82 b are seen in Figure 1. A statistically significant improvement in loco-regional tumor control was found in irradiated patients compared to patients who were only given systemic adjuvant therapy. Among patients with loco-regional recurrences, 49% had recurrences in the chest wall, 17% in the supraclavicular/ infraclavicular region, and 45% in the axilla. Also, the disease-free survival showed a significant difference in fa-

OVERGAARD er al.

1123

vor of the group who received both radiotherapy and CMF compared to CMF alone. This difference has now been reflected in the overall survival (Fig. 1). The survival benefit was most prominent in younger women (45 years) who had four positive nodes in the axilla. In the postmenopausal group (82 c) a similar improvement in loco-regional tumor control was observed in all irradiated patients (Fig. 2). The site of loco-regional recurrences in the postmenopausal patients reveals a similar pattern as in the former group, with 54% in the chest wall, 12% in the supra-infraclavicular region, and 40% in the axilla. The reduced local-regional failure rate resulted in a significant difference in disease-free survival between the RT + TAM and TAM alone group. However, at present this difference is not reflected in the overall survival (Fig. 2). DISCUSSION The efficacy of radiation after non-radical mastectomy is in agreement with several other studies (see 4, 10). Whether this has a major impact on overall survival cannot yet be evaluated in this preliminary analysis due to a median observation time of only approximately 3 years. The problems of obtaining optimal loco-regional tumor control in patients who are also treated with adjuvant chemotherapy or hormonal therapy has only been addressed in a few recent trials ( 1, 7). The main conclusion in these studies as well as in the present study is that systemic adjuvant therapy after non-radical mastectomy does not prevent loco-regional recurrences. Although the observation time is fairly short, there are data that indicate that insufficient loco-regional tumor control may have had an influence on survival (3,6,8). Furthermore, there is an indication that patients with inner quadrant breast tumors show significant improvement in survival by additional treatment of internal mammary nodes either by surgery or radiotherapy ( 11). However, the temporary and persistent toxicity following each treatment modality (local or systemic) and the possible interaction by combining two or three modalities have to be weighed against the outcome of obtaining an optimum quality of life. A further search to identify favorable prognostic subgroups is important to avoid unnecessary adjuvant systemic or local treatments.

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November 1990, Volume 19, Number 5 9. Mouridsen, H. T.; Rose, C.; Overgaard, M.; Dombemowsky, P.; Panduro, J.; Thorpe, S.; Bruun Rasmussen, B.; BlichertToft, M.; West Andersen, K. Adjuvant treatment of postmenopausal patients with high-risk primary breast cancerresults from the Danish adjuvant trials DBCG 77-C and DBCG 82-C. Acta Oncol. 27:699-705; 1988. 10. Overgaard, M.; Christensen, J. J.; Johansen, H.; Nybo-Rasmussen, A.; Frederiksen, P.; Laursen, F.; Brincker, H.; van der Kooy, P.; Gadeberg, C. C.; Hjelm-Hansen, M.; Panduro, J.; Sorensen, N. E.; 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. 27:707-714; 1988. 11. Tubiana, M.; Arriagada, R.; Sarrazin, D. Human cancer natural history, radiation induced immunodepression and post-operative radiotherapy. Int. J. Radiat. Oncol. Biol. Phys. 12:477-485; 1986. 12. West Andersen, K.; Mouridsen, H. T. Danish breast cancer cooperative group (DBCG). A description of the register of the nation-wide programme for primary breast cancer. Acta Oncol. 27:627-647; 1988. 13. Zedeler, K. Assessment and presentation of survival experience in the Danish breast cancer cooperative group. Acta Oncol. 27:649-662; 1988.