[en] Purpose: To determine the effects of different sequences of CT and RT following CS for pts with clinical Stage I or II breast carcinoma. Methods and Materials: From 6/84-12/92, 244 pts were randomized following CS to receive CT (4 cycles of CAMFP at 3-wk intervals) either before or after RT. Median pt age was 45 yrs (range, 20-68). 164 pts were pre-, 18 pts peri-, and 62 pts were postmenopausal. 209 pts were node-positive (61 had 4 or more positive nodes); after 6/88, 35 selected node-negative pts were also included. 45 Gy was prescribed to the entire breast, followed by a boost of 16 Gy; nodal RT was optional. The medians ( and ranges) of the surgery-radiotherapy interval (SRI) according to assigned arm were: RT-first, 36 days (14-234); CT-first, 126 days (98-185). Drug doses were based on ideal body weight. Doses (per square meter) and schedule were: methotrexate, 200 mg, d.1 and 15; leucovorin, 10 mg, q6H x 12, start d.2 and 16; 5-fluorouracil, 500 mg, d.1; cyclophosphamide, 500 mg, d.1; prednisone, 40 mg/day x 5d, start d.1; and doxorubicin, 45 mg, d.3. All except leucovorin and prednisone were given by IV bolus. Dose reductions were based on the granulocyte nadir from the previous cycle, with an attempt to reescalate doses in subsequent cycles. Tamoxifen 10 mg BID was prescribed to postmenopausal pts with ER+ tumors following both RT and CT. 4 pts were ineligible due to prior malignancies, 2 pts on the RT-first arm refused their assigned sequence and received CT first, 2 pts on the RT-first arm and 1 pt on the CT-first arm refused to start or complete CT, 1 pt on the CT-arm underwent elective mastectomy prior to starting RT, and 1 pt on each arm received nonprotocol CT. Possible prognostic factors including age, menopausal status, ERP status, nodal status, and lymphatic vessel invasion were distributed nearly uniformly between the 2 arms. There was an excess of pts with EIC-positive tumors on the RT-first arm (25%) compared to the CT-first arm (11%) (p-bar=0.03). Overall outcome and patterns of failure were analyzed by intent-to-treat; all enrolled pts were included. Median FU in surviving pts was 58 mo (range, 10-124 mo). Results: 5-yr actuarial failure rates (i.e., failure at any site) and overall survival (OS) rates were not statistically different between the arms, but the 5-yr actuarial total risk of developing distant metastases (DM) (i.e, at any time during observation) was significantly greater in the RT-first arm. The first sites of failure in the RT-first and CT-first arms were: local failure (LF) with or without simultaneous DM or regional nodal failure (RNF) - 9 vs. 14; RNF without other failure - 0 vs. 2; and DM (with or without simultaneous RNF) - 36 vs. 18. Of note, 1 LF in the RT-first arm was among the 2 pts who refused their assigned sequence. Because of differing lengths of potential observation for each pt, the 5-yr crude failure rates were used to assess the difference in patterns of failure. The difference was of borderline significance. The proportions of pts receiving at least 85% of the planned drug doses were lower in the RT-first arm than the CT-first arm for cyclophosphamide (46% v. 64%, p-bar=0.006), doxorubicin (43% vs. 64%, p-bar=0.002), and d.15 methotrexate (22% vs. 46%, p-bar=0.0002). There were no differences between the arms in the d.1 methotrexate or 5FU doses. Conclusions: The overall risk of distant failure was higher in the RT-first arm in this study. This may reflect both the longer interval to initiating CT and the lower drug doses given in pts first receiving RT. The risk of local failure was higher in the CT-first arm, consistent with prior studies suggesting that the SRI has an impact on the effectiveness of RT. Further study is needed of other factors that may affect these results. Alternative ways of combining RT and CT which do not sacrifice their effectiveness while minimizing treatment toxicity should be explored