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Multicenter Study
. 2023 Aug;149(10):6989-6998.
doi: 10.1007/s00432-023-04601-9. Epub 2023 Feb 28.

Individual hematotoxicity prediction of further chemotherapy cycles by dynamic mathematical models in patients with gastrointestinal tumors

Vivien Topf  1   2 , Yuri Kheifetz  3 , Severin Daum  4 , Alexej Ballhausen  5 , Andreas Schwarzer  6 , Kien Vu Trung  2 , Gertraud Stocker  1   2 , Achim Aigner  7 , Florian Lordick  1   2 , Markus Scholz  3 , Maren Knödler  8   9   10
Affiliations
Multicenter Study

Individual hematotoxicity prediction of further chemotherapy cycles by dynamic mathematical models in patients with gastrointestinal tumors

Vivien Topf et al. J Cancer Res Clin Oncol. 2023 Aug.

Abstract

Purpose: Hematotoxicity is a common side-effect of cytotoxic gastrointestinal (GI) cancer therapies. An unsolved problem is to predict the individual risk therefore to decide on treatment adaptions. We applied an established biomathematical prediction model and primarily evaluated its predictive value in patients undergoing chemotherapy for GI cancers in curative intent.

Methods: In a prospective, observational multicenter study on patients with gastro-esophageal or pancreatic cancer (n = 28) receiving myelosuppressive adjuvant or neoadjuvant chemotherapy (FLO(T) or FOLFIRINOX), individual model parameters were learned based on patients' observed laboratory values during the first chemotherapy cycle and further external data resources. Grades of hematotoxicity of subsequent cycles were predicted by model simulation and compared with observed data.

Results: The most common high-grade hematological toxicity was neutropenia [19/28 patients (68%)]. For the FLO(T) regimen, individual grades of thrombocytopenia and leukopenia could be well predicted for cycles 2-4, as well as grades of neutropenia for cycle 2. Prediction accuracy for neutropenia in the third and fourth cycle differed by one toxicity grade on average. For the FOLFIRINOX-regimen, thrombocytopenia predictions showed a maximum deviation of one toxicity grade up to the end of therapy (8 cycles). Deviations of predictions were less than one degree on average up to cycle 4 for neutropenia, and up to cycle 6 for leukopenia.

Conclusion: The biomathematical model showed excellent short-term and decent long-term prediction performance for all relevant hematological side effects associated with FLO(T)/FOLFIRINOX. Clinical utility of this precision-medicine approach needs to be further investigated in a larger cohort.

Keywords: Biomathematical model; Cytotoxic chemotherapy; Gastrointestinal cancer; Hematotoxicity; Pharmacodynamics; Precision medicine.

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Conflict of interest statement

The authors declare no competing interests.

The authors have no competing interests to declare.

Figures

Fig. 1
Fig. 1
Basic structure of our integrated biomathematical model of hematopoiesis under chemotherapy as described in (Kheifetz and Scholz 7/1/2022). CMP active common myeloid progenitor cells, CM megakaryocyte precursors, MKC megakaryocytes. Thin black lines display transitions between different cell types. Thick colored lines represent different feedback mechanisms. Arrows imply stimulations; perpendicular lines imply suppressions
Fig. 2
Fig. 2
Fitting results of three exemplary patients (no. 3, 13, and 19) treated by FLOT (3), FLOT (13), and FOLFIRINOX (19). Data points (blue dots) and model simulation (solid orange curves) are shown. Grades of respective adverse effects are provided by colored lines. Pt Platelets, ANC Absolute neutrophil count, Leuko Leukocyte count
Fig. 3
Fig. 3
Average deviation of predicted and observed toxicity grades per chemotherapy cycle. We present average values and their standard errors. Cycle 1 was fitted and is shown for comparison only
Fig. 4
Fig. 4
Average deviation of predicted and observed toxicity grades per therapy and treatment cycle. We present average values and their standard errors. Cycle 1 data were used for individual parameter fitting. Note that different ranges of the y-axes were implemented to improve readability of the figure. Predictions for the FLO/mFOLFOX regimen were good for all blood cell types (b). However, this treatment group did not develop high-grade hematological adverse events
See this image and copyright information in PMC

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