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The increasing use of targeted therapy (TT) has resulted in prolonged disease control and survival in many metastatic cancers. In parallel, stereotactic radiotherapy (SRT) is increasingly performed in patients receiving TT to obtain a durable control of resistant metastases, and thereby to prolong the time to disseminated disease progression and switch of systemic therapy. The aims of this study were to analyze the safety and efficacy of SRT combined with TT in metastatic cancer patients and to assess the influence of continuous vs. interrupted TT during metastasis-directed SRT. The data of 454 SRTs in 158 patients from the international multicenter database (TOaSTT) on metastatic cancer patients treated with SRT and concurrent TT (within 30 days) were analyzed using Kaplan–Meier and log rank testing. Toxicity was defined by the CTCAE v4.03 criteria. The median FU was 19.9 mo (range 1–102 mo); 1y OS, PFS and LC were 59%, 24% and 84%, respectively. Median TTS was 25.5 mo (95% CI 11–40). TT was started before SRT in 77% of patients. TT was interrupted during SRT in 44% of patients, with a median interruption of 7 (range 1–42) days. There was no significant difference in OS or PFS whether TT was temporarily interrupted during SRT or not. Any-grade acute and late SRT-related toxicity occurred in 63 (40%) and 52 (33%) patients, respectively. The highest toxicity rates were observed for the combination of SRT and EGFRi or BRAF/MEKi, and any-grade toxicity was significantly increased when EGFRi (p = 0.016) or BRAF/MEKi (p = 0.009) were continued during SRT. Severe (≥grade 3) acute and late SRT-related toxicity were observed in 5 (3%) and 7 (4%) patients, respectively, most frequently in patients treated with EGFRi or BRAF/MEKi and in the intracranial cohort. There was no significant difference in severe toxicity whether TT was interrupted before and after SRT or not. In conclusion, SRT and continuous vs. interrupted TT in metastatic cancer patients did not influence OS or PFS. Overall, severe toxicity of combined treatment was rare; a potentially increased toxicity after SRT and continuous treatment with EGFR inhibitors or BRAF(±MEK) inhibitors requires further evaluation.
Men and women differ substantially regarding height, weight, and body fat. Interestingly, previous work detecting genetic effects for waist-to-hip ratio, to assess body fat distribution, has found that many of these showed sex-differences. However, systematic searches for sex-differences in genetic effects have not yet been conducted. Therefore, we undertook a genome-wide search for sexually dimorphic genetic effects for anthropometric traits including 133,723 individuals in a large meta-analysis and followed promising variants in further 137,052 individuals, including a total of 94 studies. We identified seven loci with significant sex-difference including four previously established (near GRB14/COBLL1, LYPLAL1/SLC30A10, VEGFA, ADAMTS9) and three novel anthropometric trait loci (near MAP3K1, HSD17B4, PPARG), all of which were significant in women, but not in men. Of interest is that sex-difference was only observed for waist phenotypes, but not for height or body-mass-index. We found no evidence for sex-differences with opposite effect direction for men and women. The PPARG locus is of specific interest due to its link to diabetes genetics and therapy. Our findings demonstrate the importance of investigating sex differences, which may lead to a better understanding of disease mechanisms with a potential relevance to treatment options.