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Genetics and Genomics

A systematic review and meta-analysis of toxicity and treatment outcomes with pharmacogenetic-guided dosing compared to standard of care BSA-based fluoropyrimidine dosing

British Journal of Cancer volume 127, pages 126–136 (2022)Cite this article

Subjects

Abstract

Background

Serious and potentially life-threatening toxicities can occur following 5-fluorouracil/capecitabine exposure. Patients carrying Dihydropyrimidine Dehydrogenase (DPYD) variant alleles associated with decreased enzymatic function are at a greater risk of early/severe 5-fluorouracil/capecitabine toxicity. The objective of this systematic review/meta-analysis was to evaluate treatment outcomes between Pharmacogenetics Guided Dosing (PGD) versus non-PGD and within PGD (DPYD variant allele carriers versus wild type).

Methods

A systematic review/meta-analysis of original publications indexed in Ovid Medline, Ovid Embase, and the Cochrane CENTRAL (Wiley) library from inception to 7-Dec-2020. Eligible studies evaluated at least one pre-defined treatment outcome measures (toxicity/hospitalisations/survival/overall response/quality of life).

Results

Of 1090 identified publications, 17 met predefined eligibility criteria. The meta-analysis observed reduced incidence of grade 3/4 overall toxicity (Risk Ratio [RR] 0.32 [95% Cl 0.27–0.39], p < 0.00001) and grade 3/4 diarrhoea (RR 0.38 [95% Cl 0.24–0.61], p < 0.0001) among PGD versus non-PGD cohorts. Within PGD cohorts, there was no statistical differences for overall response rates (complete/partial) (RR 1.31 [95% Cl 0.93–1.85], p = 0.12). Similar results were found with stable disease (RR 1.27 [95% Cl 0.66–2.44], p = 0.47).

Conclusion

PGD improves patient outcomes in terms of grade 3/4 toxicity, in particular overall toxicity and diarrhoea, without impacting on treatment response.

Registration number

The study is registered with PROSPERO, registration number CRD42020223768.

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Fig. 1: PRISMA flow diagram.
Fig. 2: Forest plots for grade 3/4 overall toxicity, grade 3/4 diarrhoea, and hospitalisations.
Fig. 3: Forest plots for overall response.

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Data availability

All data generated or analysed during this study are included in this published article [and its Supplementary information files].

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Acknowledgements

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Funding

The authors received no specific funding for this work.

Author information

Authors and Affiliations

  1. Department of Pharmacy, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia

    Sarah Glewis, Marliese Alexander & Senthil Lingaratnam

  2. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Australia

    Sarah Glewis, Marliese Alexander, Jeanne Tie & Michael Michael

  3. School of Biomedical Sciences, The University of Melbourne, Parkville, VIC, Australia

    Muhammad N. H. Khabib & Annabelle Brennan

  4. Health Sciences Library, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia

    Smaro Lazarakis

  5. School of Medicine and Public Health, University of Newcastle, Callaghan, NSW, Australia

    Jennifer Martin

  6. Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia

    Jeanne Tie & Michael Michael

  7. Personalised Oncology Division, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia

    Jeanne Tie

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Contributions

SG: conducted data screening, extractions, reviewing of articles, assessing risk of bias, methodology, writing original draft preparation. MA: overseeing data screening, extractions, reviewing of articles, assessing risk of bias, writing, reviewing and editing. MNHK: conducted data screening, extractions, reviewing of articles, assessing risk of bias, writing parts of original draft. AB: conducted data screening, extractions, reviewing of articles, assessing risk of bias, writing parts of original draft. Smaro Lazarakis: data sourcing, developed search strategy, methodology. JM: writing, reviewing and editing. JT: writing, reviewing and editing. Senthil Lingaratnam: writing, reviewing and editing. MM: overseeing data screening, extractions, reviewing of articles, assessing risk of bias, writing, reviewing and editing.

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Correspondence to Sarah Glewis.

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Glewis, S., Alexander, M., Khabib, M.N.H. et al. A systematic review and meta-analysis of toxicity and treatment outcomes with pharmacogenetic-guided dosing compared to standard of care BSA-based fluoropyrimidine dosing. Br J Cancer 127, 126–136 (2022). https://doi.org/10.1038/s41416-022-01779-6

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