Abstract
BackgroundThe optimal procedure for combining radiotherapy (RT) with tamoxifen treatment is controversial as RT may alter the pharmacokinetics and biotransformation of tamoxifen. The present study investigated this potential interaction by assessing the pharmacokinetics of tamoxifen during concurrent and sequential RT.MethodPlasma tamoxifen concentration was measured in rats with or without RT 2.0 Gy (RT2.0Gy) or 0.5 Gy (RT0.5Gy) with ultra-high-performance liquid chromatography-tandem mass spectrometry after tamoxifen administration (10 mg/kg, p.o., n = 6). Tamoxifen was either administered 1 h after RT (concurrent condition) or 24 h after RT (sequential condition).ResultsPharmacokinetic data analysis demonstrated that the area under the curve (AUC) and half-life of tamoxifen were 2,004 ± 241 h ng/ml and 6.23 ± 1.21 h, respectively, after tamoxifen administration (10 mg/kg, p.o.). The respective conversion rate of 4-hydroxytamoxifen, N-desmethytamoxifen, and endoxifen for tamoxifen metabolism was 20%, 16%, and 5%. The AUC value of tamoxifen in the RT0.5Gy group was 1.5- to 1.7-fold higher than in the sham and RT2.0Gy groups. The relative bioavailability of tamoxifen at concurrent RT0.5Gy and RT2.0Gy groups ranged from 127% to 202% and from 71% to 152%, respectively. The magnitude of endoxifen, which converted from 4-hydroxytamoxifen and N-desmethyltamoxifen, increased 3- to 5-fold in the concurrent RT groups. By contrast, the AUC of tamoxifen decreased by roughly 24% in the sequential RT2.0Gy group. The conversion ratio of endoxifen was four times higher than that in the sequential RT2.0Gy group compared with rats not exposed to RT.ConclusionThe current study provides advanced pharmacokinetic data to confirm the interaction between RT and hormone therapy. Our findings indicate that RT facilitates the metabolism of tamoxifen to active metabolites and thus imply that combination RT-tamoxifen has potential benefits for the treatment of hormone-dependent breast cancer.
Highlights
Breast cancer is one of the top 10 diagnosed cancers for women, accounting for 11.7% of total new cases [1]
The National Surgical Adjuvant Breast and Bowel Project (NSABP)-B14 trial suggested that tamoxifen and RT may have a synergistic interaction since patients receiving both therapies experienced better outcomes in terms of local control [9]
There were no significant differences in the recurrence, disease-free survival, or overall survival of breast cancer patients treated with tamoxifen concurrent or sequential with RT [13]
Summary
Breast cancer is one of the top 10 diagnosed cancers for women, accounting for 11.7% of total new cases [1]. Current treatment strategies for breast cancer include surgery, chemotherapy, endocrine therapy, radiotherapy (RT), immunotherapy, and combinations of these options. The National Surgical Adjuvant Breast and Bowel Project (NSABP) B-06 study demonstrated that the rate of local recurrence after a 20-year follow-up was 39% for patients treated with lumpectomy alone or 14% for patients treated with both lumpectomy and RT [2]. The relative risk was reduced by 34%–50% for patients who received 5year adjuvant tamoxifen therapy [5, 7, 9]. The NSABP-B14 trial suggested that tamoxifen and RT may have a synergistic interaction since patients receiving both therapies experienced better outcomes in terms of local control [9]. There were no significant differences in the recurrence, disease-free survival, or overall survival of breast cancer patients treated with tamoxifen concurrent or sequential with RT [13].
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