The ‘ESMO consensus guidelines for the management of patients with metastatic colorectal cancer’ [1] is a comprehensive and influ- ential document; however, because of its relevance for clinical prac- tice, we critically appraise the conclusions on the impact of dihydropyrimidine dehydrogenase (DPD) on fluoropyrimidine therapy. The statement that ‘DPD testing [. . ..] remains an option but is not routinely recommended’ is biased on the inappropriate choice of the method to assess levels of evidence and grades of rec- ommendation concerning DPD assessment. More importantly, the evaluation of scientific literature, which strongly associates DPD de- ficiency with preventable fluoropyrimidine toxicity, would have sug- gested a less negative opinion and a more differentiated conclusion. The statement that ‘DPD deficiency is generally not assessed in routine practice before 5-FU administration’ does not reflect the current awareness of the importance of testing for DPD defi- ciency by different methods. Indeed, the Royal Dutch Pharmacists Association, the French GPCO-Unicancer group and the Italian Association of Medical Oncology-Italian Society of Pharmacology working groups have issued recommendations on pre-emptive DPD analysis for rational dose adaptation. Moreover, the fact that ‘there is no recommended standar- dized assessment technique’ is not a limitation since CE-marked In Vitro Diagnostic Medical Devices (CE-IVD)-marked genetic diagnostics are available and internally validated phenotypic approaches also offer a reliable service. The statements that ‘none of the current strategies are adequate to mandate routine DPD testing’ and ‘in the case of [. . .] severe 5-FU toxicity, DPD levels should be tested before 5-FU is re-introduced’ are misleading. First, none of the current techniques assess DPD lev- els. Second, prevention of severe toxicity in DPD-deficient patients is the primary goal as hospitalization and/or supportive treatments may be required—not to mention possible deaths. With these premises, we are left puzzled about the opinion of ESMO, especially in colorectal cancer, where fluoropyrimidine- based regimens are aggressive in terms of dosing. The following issues should be considered in the ESMO guidelines: • DPD-based dose adaptation criteria [2] in case of DPD defi- ciency depending on patient’s individual DPYD genotype [3, 4] are well established to minimize fluoropyrimidine-associated toxicity and maintain treatment efficacy and • DPD analysis is cost-effective [5], thus justifying pre-emp- tive DPD testing. Finally, the literature in favour of pre-emptive DPD evaluation is extremely wide and scientifically sound and, for this reason, it is unclear why the authors of the ESMO consensus guidelines do not recommend routine clinical implementation of DPD testing before fluoropyrimidine administration to increase the safety of chemotherapy treatment. Therefore, to extend the concept of personalized medicine to preventable fluoropyrimidine toxicities—too often neglected— we consider it to be in the best interest of patients that ESMO re- visits its position with the contribution of experts in clinical pharmacogenomics.
Prevention of fluoropyrimidine toxicity: do we still have to try our patient's luck?
DANESI, ROMANO
Writing – Original Draft Preparation
;DEL RE, MARZIA;
2017-01-01
Abstract
The ‘ESMO consensus guidelines for the management of patients with metastatic colorectal cancer’ [1] is a comprehensive and influ- ential document; however, because of its relevance for clinical prac- tice, we critically appraise the conclusions on the impact of dihydropyrimidine dehydrogenase (DPD) on fluoropyrimidine therapy. The statement that ‘DPD testing [. . ..] remains an option but is not routinely recommended’ is biased on the inappropriate choice of the method to assess levels of evidence and grades of rec- ommendation concerning DPD assessment. More importantly, the evaluation of scientific literature, which strongly associates DPD de- ficiency with preventable fluoropyrimidine toxicity, would have sug- gested a less negative opinion and a more differentiated conclusion. The statement that ‘DPD deficiency is generally not assessed in routine practice before 5-FU administration’ does not reflect the current awareness of the importance of testing for DPD defi- ciency by different methods. Indeed, the Royal Dutch Pharmacists Association, the French GPCO-Unicancer group and the Italian Association of Medical Oncology-Italian Society of Pharmacology working groups have issued recommendations on pre-emptive DPD analysis for rational dose adaptation. Moreover, the fact that ‘there is no recommended standar- dized assessment technique’ is not a limitation since CE-marked In Vitro Diagnostic Medical Devices (CE-IVD)-marked genetic diagnostics are available and internally validated phenotypic approaches also offer a reliable service. The statements that ‘none of the current strategies are adequate to mandate routine DPD testing’ and ‘in the case of [. . .] severe 5-FU toxicity, DPD levels should be tested before 5-FU is re-introduced’ are misleading. First, none of the current techniques assess DPD lev- els. Second, prevention of severe toxicity in DPD-deficient patients is the primary goal as hospitalization and/or supportive treatments may be required—not to mention possible deaths. With these premises, we are left puzzled about the opinion of ESMO, especially in colorectal cancer, where fluoropyrimidine- based regimens are aggressive in terms of dosing. The following issues should be considered in the ESMO guidelines: • DPD-based dose adaptation criteria [2] in case of DPD defi- ciency depending on patient’s individual DPYD genotype [3, 4] are well established to minimize fluoropyrimidine-associated toxicity and maintain treatment efficacy and • DPD analysis is cost-effective [5], thus justifying pre-emp- tive DPD testing. Finally, the literature in favour of pre-emptive DPD evaluation is extremely wide and scientifically sound and, for this reason, it is unclear why the authors of the ESMO consensus guidelines do not recommend routine clinical implementation of DPD testing before fluoropyrimidine administration to increase the safety of chemotherapy treatment. Therefore, to extend the concept of personalized medicine to preventable fluoropyrimidine toxicities—too often neglected— we consider it to be in the best interest of patients that ESMO re- visits its position with the contribution of experts in clinical pharmacogenomics.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
