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Kinetically Guided Neoadjuvant Chemoradiotherapy Based on 5-Fluorouracil in Patients with Locally Advanced Rectal Cancer

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An Erratum to this article was published on 20 March 2015

Abstract

Background and Purpose

This study estimated patients’ early response following neoadjuvant chemoradiotherapy (CHRT) of locally advanced rectal cancer based on 5-fluorouracil (5-FU). The target was to achieve pathological complete response (pCR; residual disease-free stage) and toxicities of grade ≤2, using individual dosing predicted according to the steady-state plasma concentration (C ss) and pharmacokinetic parameters of 5-FU: the area under the time–concentration curve at steady state (AUC) and clearance (CL).

Patients and Methods

This open-label prospective study enrolled 33 adult patients treated with 5-FU administered as a continuous intravenous infusion over 4–5 weeks, as follows: in Group 1a (N = 6), the patients received a standard dose of 300 mg/m2/24 h. In Group 1b (N = 7), the patients were treated with an escalated dose of 400–1,000 mg/m2/24 h. In Group 2 (N = 20), the patients were given dosing kinetically guided in order to reach the target range of 5-FU C ss 50–100 µg/L. Tolerability was tested according to Common Terminology Criteria for Adverse Events v3.0 (CTCAE). Radiotherapy was delivered with 10–15 MV photon beams at 1.8 Gy/fraction up to 50.4 Gy in 28 daily fractions for 5 days a week. Surgery followed 4–6 weeks after the completion of CHRT and clinical restaging. The pCR and residual tumour stage were evaluated using preoperative tumour downstaging in magnetic resonance, postoperative histopathological staging and tumour regression rate (residual disease).

Results and Conclusion

The cumulative AUC of 5-FU (total exposure to the drug) correlated with cumulative 5-FU dose (r = 0.61; p < 0.001) and residual disease (r s  = −0.53; p < 0.005). A higher target pCR rate was reached in patients individually treated (Group 2) who finished the whole 5-week CHRT. The individual daily dose needed to reach the target C ss should be >350 mg/m2 (up to 600 mg/m2) provided that 5-FU metabolic ratio is within the range of 2.5–6 and the cumulative AUC5wks is within 50–100 mg·h/L.

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Acknowledgments

We thank Hana Krupičková for excellent technical assistance. This work was supported by a grant from the Ministry of Health (IGA MZ 9357), Czech Republic.

Conflicts of interest of all authors

The authors have no conflicts of interest that are directly relevant to the content of this manuscript.

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Authors and Affiliations

  1. Department of Oncology and Radiotherapy, University Hospital, Sokolská Street, 500 05, Hradec Králové, Czech Republic

    Jiří Grim & Petera Jiří

  2. Department of Medical Biochemistry, Faculty of Medicine in Hradec Králové, Charles University in Prague, Prague, Czech Republic

    Hroch Miloš

  3. Department of Pharmacology, Faculty of Medicine in Hradec Králové, Charles University in Prague, Prague, Czech Republic

    Chládek Jaroslav & Martínková Jiřina

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  1. Jiří Grim
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Correspondence to Jiří Grim.

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Grim, J., Miloš, H., Jaroslav, C. et al. Kinetically Guided Neoadjuvant Chemoradiotherapy Based on 5-Fluorouracil in Patients with Locally Advanced Rectal Cancer. Clin Pharmacokinet 54, 503–515 (2015). https://doi.org/10.1007/s40262-014-0216-4

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