5-Fluorouracil-Spiegelbestimmung unter neoadjuvanter Radiochemotherapie und adjuvanter Chemotherapie beim lokal fortgeschrittenen Rektumkarzinom

Effects of a body surface area based 5-fluoruracil dosing under the neoadjuvant radiochemotherapy and adjuvant chemotherapy in locally advanced rectal cancer

by Henriette Quack
Doctoral thesis
Date of Examination:2015-05-19
Date of issue:2015-05-06
Advisor:Prof. Dr. Torsten Liersch
Referee:Prof. Dr. Torsten Liersch
Referee:PD Dr. Hendrik Wolff
Persistent Address: http://dx.doi.org/10.53846/goediss-5049

 

 

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Abstract

English

5-fluoruracil (5-FU) still remains the backbone of chemotherapy in colorectal cancer and effects as a radiosensitizer for radiotherapy. During the last decades several clinical trials have demonstrated that neoadjuvant 5-FU based chemoradiotherapy (CRT) significantly improves locoregional control of rectal cancer. The standard administration based on body surface area (bsa) results in highly variable drug plasma levels. With the Saladax immunoassay My5FU® a test was established to determine inter- and intraindividual dose variations. 5-FU plasma levels were correlated with early response parameters and treatment-associated toxicity and the influence of 5-FU plasma levels for local tumor. In a set of 82 consecutive patients a total of 524 peripheral blood samples were analyzed during multimodal neoadjuvant CRT for locally advanced rectal cancer (UICC stage II and III). Patients were treated either with 5-FU mono therapy (n=42) or with 5-FU in combination with Oxaliplatin (n=40). Samples were taken at standardized time points during the continuous infusion of 5-FU and plasma levels were determined by the nanoparticle immunoassay on a Roche cobas integra 800® analyzer. Overall only 13% (neoadjuvant) and 2 % (adjuvant) of patients were in the recommended range of 5-FU plasma levels. There was a significant correlation between gender and 5-FU level with higher doses in female patients (p=0.0235). Additionally, 5-FU doses were associated with body surface (p=0.034). While acute organ toxicity was not related to 5-FU plasma levels, hematologic toxicity was strongly correlated to the AUC of 5-FU (maximal hematologic toxicity p=0.0122, leucocytes P=0.0473, thrombocytes p=0.0039).After the neoadjuvant therapy 42% (n=32) of patients showed a near complete tumor regression with TRG4 and TRG3 pN-. Overall 11% (n=8) were histopathological non responders (TRG 0 and TRG1 pN+) to the preoperative treatment. During long-term mean follow-up for a median of 21 months (range 1 to 58 months) the “responders” after neoadjuvant therapy (TRG4 and TRG3 pN-) had significant prolonged disease free survival (DFS) (p= 0.003). Dose monitoring might in the future help to individualize dose adjustment for an optimal treatment of patients receiving 5-FU in order to reduce treatment-associated toxicity and to reach the best therapeutic efficacy. The influence of 5-FU dose under CRT on tumor response has to be revaluated when the 5-FU dose is adjusted into the optimal AUC range. The tumor response can be optimized under a dose adjusted neoadjuvant 5-FU treatment in locally advanced rectal cancer and has a significant influence on the DFS. The Immunoassay is a practicable and simple test for the drug monitoring of 5-FU.
Keywords: rectal cancer; immunoassay; 5-fluoruracil
Schlagwörter: 5-Fluorouracil; Rektumkarzinom; Immunoassay
 
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