O-019Distant-relapse analysis of STAR-01, a randomized phase III trial comparing preoperative chemoradiation with or without oxaliplatin in locally advanced rectal cancer

Background: STAR-01 is a randomized phase III trial investigating the effect of adding oxaliplatin (OXA) to preoperative (preop) 5-fluorouracil (FU)-based pelvic chemoradiation (CRT) in patients (pts) with resectable locally advanced rectal cancer (LARC).Methods: Eligibility required a resectable, biopsy-proven rectal adenocarcinoma within 12 cm from the anal verge with radiological evidence of perirectal fat or nodal involvement. Randomization was between infused FU (225 mg/msq/day) concomitant to external-beam pelvic radiation (50.4 Gy in 28 daily fractions) (arm A) or the same regimen + weekly OXA (60 mg/msq x 6) (Arm B). Surgery was scheduled 6-8 weeks after completing CRT and 4 months of adjuvant FU monotherapy were advised in both arms. Overall survival (OS) was the primary endpoint. The cumulative incidence of distant metastases was a protocol-planned secondary end-point, particularly relevant to directly test the study hypothesis of a systemic effect of weekly oxaliplatin added to preoperative FU-based chemoradiation.Results: From November 2003 through August 2008, 739 (arm A: 377, arm B: 362) eligible patients were enrolled at 41 Italian institutions. We previously reported safety and tumor response results showing a higher rate of moderate to severe acute toxicity in patients receiving OXA without any difference in pCR. However, a significant reduction in early distant metastases was observed in patients receiving preoperative OXA combined to FP-based standard CRT (6-month incidence of distant relapse: 6.2 vs 2.2% in arm A vs B). With a median follow up of 8.9 years (IQR 8.1-9.9), 162 treatment failures (80 local and 189 at distant sites) and 248 deaths were observed. Rates of metastases at distant sites were 8% vs 5% at 1-y, 22% vs 19% at 3-y, 26 % vs 23 % at 5-y and 28% vs 24 % at 7-y. Overall, the relative risk of developing metastases at distant sites in patients receiving preoperative OXA was 0.86, 95% CI 0.65-1.14. There were 136 deaths in Arm A vs 112 in arm B (HR 0.82, CI 0.64-1.05, p = 0.114). The corresponding 5- and 10-year OS rates were 77.6 vs 80.4 % and 62.3 vs 67.4 % (Arm A vs B).Conclusions: Although statistical significance is not reached, these results suggest a small, but sustained, impact on the development of distant metastases supporting the study hypothesis of a systemic effect of weekly OXA concomitant to preoperative chemoradiation. This difference is paralleled by a smaller than planned reduction in the relative risk of death with a 3-6% absolute long-term benefit. Further investigation with pooled analyses of similar studies testing OXA in combination with FP-based preop CRT is warranted and planned. Background: STAR-01 is a randomized phase III trial investigating the effect of adding oxaliplatin (OXA) to preoperative (preop) 5-fluorouracil (FU)-based pelvic chemoradiation (CRT) in patients (pts) with resectable locally advanced rectal cancer (LARC). Methods: Eligibility required a resectable, biopsy-proven rectal adenocarcinoma within 12 cm from the anal verge with radiological evidence of perirectal fat or nodal involvement. Randomization was between infused FU (225 mg/msq/day) concomitant to external-beam pelvic radiation (50.4 Gy in 28 daily fractions) (arm A) or the same regimen + weekly OXA (60 mg/msq x 6) (Arm B). Surgery was scheduled 6-8 weeks after completing CRT and 4 months of adjuvant FU monotherapy were advised in both arms. Overall survival (OS) was the primary endpoint. The cumulative incidence of distant metastases was a protocol-planned secondary end-point, particularly relevant to directly test the study hypothesis of a systemic effect of weekly oxaliplatin added to preoperative FU-based chemoradiation. Results: From November 2003 through August 2008, 739 (arm A: 377, arm B: 362) eligible patients were enrolled at 41 Italian institutions. We previously reported safety and tumor response results showing a higher rate of moderate to severe acute toxicity in patients receiving OXA without any difference in pCR. However, a significant reduction in early distant metastases was observed in patients receiving preoperative OXA combined to FP-based standard CRT (6-month incidence of distant relapse: 6.2 vs 2.2% in arm A vs B). With a median follow up of 8.9 years (IQR 8.1-9.9), 162 treatment failures (80 local and 189 at distant sites) and 248 deaths were observed. Rates of metastases at distant sites were 8% vs 5% at 1-y, 22% vs 19% at 3-y, 26 % vs 23 % at 5-y and 28% vs 24 % at 7-y. Overall, the relative risk of developing metastases at distant sites in patients receiving preoperative OXA was 0.86, 95% CI 0.65-1.14. There were 136 deaths in Arm A vs 112 in arm B (HR 0.82, CI 0.64-1.05, p = 0.114). The corresponding 5- and 10-year OS rates were 77.6 vs 80.4 % and 62.3 vs 67.4 % (Arm A vs B). Conclusions: Although statistical significance is not reached, these results suggest a small, but sustained, impact on the development of distant metastases supporting the study hypothesis of a systemic effect of weekly OXA concomitant to preoperative chemoradiation. This difference is paralleled by a smaller than planned reduction in the relative risk of death with a 3-6% absolute long-term benefit. Further investigation with pooled analyses of similar studies testing OXA in combination with FP-based preop CRT is warranted and planned.