Head and neck irradiation modulates pharmacokinetics of 5-fluorouracil and cisplatin

Chen-Hsi Hsieh, Mei-Ling Hou, Meng-Hsuan Chiang, Hung-Chi Tai, Hui-Ju Tien, Li-Ying Wang, Tung-Hu Tsai, Yu-Jen Chen, Chen-Hsi Hsieh, Mei-Ling Hou, Meng-Hsuan Chiang, Hung-Chi Tai, Hui-Ju Tien, Li-Ying Wang, Tung-Hu Tsai, Yu-Jen Chen

Abstract

Background: 5-fluorouracil (5-FU) and cisplatin (CDDP) are used to enhance radiotherapy (RT) effect for head and neck (HN) cancers. However, the effect of local RT on systemic chemotherapeutics remains unclear. Here, we evaluated the influence of HN irradiation on the pharmacokinetics (PK) of 5-FU and CDDP in rats as experimental model.

Methods: The radiation dose distributions of HN cancer patients were determined for the low dose areas, which are generously deposited around the target volume. Two Gy and 0.5 Gy RT were selected. Single-fraction radiation was delivered to the HN of Sprague-Dawley rats. 5-FU at 100 mg/kg or CDDP at 5 mg/kg was intravenously infused 24 hours after radiation.

Results: Radiation at 2 Gy reduced the area under the plasma concentration vs. time curve (AUC) of 5-FU and CDDP by 16% and 29% compared to non-irradiated controls, respectively. This was accompanied by incremental total plasma clearance values. Intriguingly, low dose radiation at 0.5 Gy resulted in a similar pharmacokinetic profile, with a 17% and 33% reduction in the AUC of 5-FU and CDDP, respectively. The changes in AUC of bile, which increases with RT, were opposite to AUC of plasma for both drugs.

Conclusions: The local HN RT could modulate systemic PK of 5-FU and CDDP in rats. This unexpected RT-PK phenomena may provide a reference for adjustment of drug administration and is worthy of further investigation.

Trial registration: ClinicalTrials.gov ID NCT01755585 and NCT01609114.

Figures

Figure 1
Figure 1
Computed tomography was used for simulation of the head and neck field. The cranial margin was set at 5 mm above the head and the caudal margin was set above the head of humerus. Conventional radiotherapy was used to deliver the radiation dose via the anterior-posterior (AP) and PA portals.
Figure 2
Figure 2
An example of isodose distribution using different irradiation techniques delivering 2 Gy to the tumor bed for one nasopharyngeal carcinoma patient with transverse, coronal and sagittal view. A) The conventional radiation therapy (2DRT). B) Three-dimensional conformal radiotherapy (3DCRT). C) Intensive modulated radiotherapy (IMRT). D) Helical tomotherapy (HT).
Figure 3
Figure 3
The area under the plasma concentration vs. time curve (AUC) of (A) 5-FU 100 mg/kg (B) Cisplatin 5 mg/kg to rats in the control, 0.5 and 2 Gy groups with head and neck irradiation.
Figure 4
Figure 4
The area under the bile concentration vs. time curve (AUC) of (A) 5-FU 100 mg/kg (B) Cisplatin 5 mg/kg to rats in the control, 0.5 and 2 Gy groups with head and neck irradiation.

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