Clinical Data Do Not Support the Hypothesis That Irradiation Promotes Biologically Aggressive Local Recurrences through Stromal Activation.
Authors: Woodward W. , Truong P. , Yu T. , Tereffe W. , Oh J. , Perkins G. , Strom E. , Meric-Bernstam F. , Gonzalez-Angulo A. , Ragaz J. , Buchholz T. 
Published: December 2010

Abstract
Objective: Recent data in select pre-clinical models suggest that radiation can activate normal stroma to promote tumor metastases and aggressiveness. We hypothesized that if these were occurring clinically, there would be a lower survival after locoregional recurrence (LRR) in patients after post-mastectomy radiation therapy (PMRT) compared to mastectomy (Mx) alone. This study used two independent datasets to compare survival after LRR in women treated with versus without PMRT.Methods: Data from 229 of 1,505 patients who experienced LRR after treatment on sequential non-randomized institutional prospective trials at the MD Anderson Cancer Center (MDA) and 66 of 318 patients enrolled in the British Columbia (BC) PMRT randomized trial who experienced LRR were analyzed. All patients underwent Mx and level I/II axillary dissection. In both data sets analysis was based on treatment received. Patients from MDA received doxorubicin based chemotherapy +/- PMRT, with 45 LRR after PMRT and 184 LRR after Mx alone). Patients treated on the BC trial received CMF chemotherapy +/- PMRT, with LRR in 14/160 after PMRT versus 52/158 after Mx alone. Survival was calculated from time of LRR to death using Kaplan-Meier and log rank statistics.Results:MDA Data: Median follow up of living patients was 192 months. Analyzing data from all patients with LRR regardless of distant metastasis (DM), patients with LRR after PMRT were younger (47 vs. 51 y, p = 0.033) and had shorter time to first LRR (40mo vs. 51 mo, p = 0.018). 5-yr/10-yr OS were 31%/16% without PMRT and 20%/7% after PMRT (p = 0.008). However, PMRT-treated patients had increased risk factors for DM (advanced T and N stage) and more PMRT-treated patients developed DM prior to LRR (58% vs. 36% p = 0.009). Analyzing only patients without DM there was no difference in OS between groups (p = 0.67), and a separate analysis of all patients who developed metastatic disease (N = 385 no PMRT, 233 after PMRT) revealed no difference in 5 or 10-yr OS after DR (15%/4% without PMRT vs. 13%/6% after PMRT, p = 0.5).BC Data: Median follow up of living patients was 235 months. The distributions of age, T stage, N stage, grade, LVI, ER status, excised nodes and nodal ratio were similar between patients with LRR after Mx alone vs. Mx plus PMRT. (all p &gt; 0.05). The mean time to first LRR was 39 mo in patients treated with Mx alone and 57 mo in patients treated with PMRT, p= 0.27). The rate of DM was similar in patients with LRR after Mx with vs without PMRT (93% vs. 96%, p=0.60). Distant relapse free survival after LRR was similar in Mx alone vs. PMRT-treated patients (log rank p=0.75). Overall survival was also similar in the two groups (5-yr/10-yr OS 21%/8% without PMRT vs. 23%/12% with PMRT, log rank p=0.93).Conclusions: Decades of randomized data have demonstrated that PMRT reduces LRR and improves overall survival. In the non-randomized dataset, removing the competing risk of DM which is higher in patients selected for PMRT by studying patients with isolated LRR, we find no difference in survival after LRR in the PMRT setting. Analysis of the randomized PMRT trial dataset confirmed the finding of similar survival among women with LRR irrespective of PMRT use.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 4101.