A multicenter phase II study of personalized FOLFIRI-cetuximab for safe dose intensification

Boisdron‐Celle, Michèle; Metges, Jean Philippe; Capitain, Olivier; Adenis, Antoine; Raoul, Jean‐Luc; Lecomte, Thierry; Lam, You-Heng; Faroux, Roger; Masliah, Claude; Poirier, A; Berger, Virginie; Morel, Alain; Gamelin, Érick

doi:10.1053/j.seminoncol.2017.02.007

Cited by 14 publications

(12 citation statements)

References 41 publications

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“…Despite a very large increase in drug dosages, a low incidence of severe ADR was shown in patients who used a guiding dosing approach. However, also in this case, it was not possible to conclude if this phenotyping analysis enhanced the predictability of DPYD genotyping because of the low sample size of the study [32]. Etienne et al failed to demonstrate a correlation between DPYD variants and the plasmatic UH2/U ratio values.…”

Section: Systematic Reviewmentioning

confidence: 86%

“…Indeed, to perform daily careful, clinical monitoring during all patients' treatment cycles is very arduous. In fact, among these studies, three out of eight reported ADR only for two cycles [22,25,33], one out of eight monitored the toxicity until the third cycle [30] and two out of eight made clinical monitoring for two-to-three months [20,32].…”

Section: Discussionmentioning

confidence: 99%

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A Genotyping/Phenotyping Approach with Careful Clinical Monitoring to Manage the Fluoropyrimidines-Based Therapy: Clinical Cases and Systematic Review of the Literature

Conti

Bellis

Manzo

et al. 2020

JPM

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Fluoropyrimidines (FP) are mainly metabolised by dihydropyrimidine dehydrogenase (DPD), encoded by the DPYD gene. FP pharmacogenetics, including four DPYD polymorphisms (DPYD-PGx), is recommended to tailor the FP-based chemotherapy. These polymorphisms increase the risk of severe toxicity; thus, the DPYD-PGx should be performed prior to starting FP. Other factors influence FP safety, therefore phenotyping methods, such as the measurement of 5-fluorouracil (5-FU) clearance and DPD activity, could complement the DPYD-PGx. We describe a case series of patients in whom we performed DPYD-PGx (by real-time PCR), 5-FU clearance and a dihydrouracil/uracil ratio (as the phenotyping analysis) and a continuous clinical monitoring. Patients who had already experienced severe toxicity were then identified as carriers of DPYD variants. The plasmatic dihydrouracil/uracil ratio (by high-performance liquid chromatography (HPLC)) ranged between 1.77 and 7.38. 5-FU clearance (by ultra-HPLC with tandem mass spectrometry) was measured in 3/11 patients. In one of them, it reduced after the 5-FU dosage was halved; in the other case, it remained high despite a drastic dosage reduction. Moreover, we performed a systematic review on genotyping/phenotyping combinations used as predictive factors of FP safety. Measuring the plasmatic 5-FU clearance and/or dihydrouracil/uracil (UH2/U) ratio could improve the predictive potential of DPYD-PGx. The upfront DPYD-PGx combined with clinical monitoring and feasible phenotyping method is essential to optimising FP-based chemotherapy.

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Section: Systematic Reviewmentioning

confidence: 86%

Section: Discussionmentioning

confidence: 99%

A Genotyping/Phenotyping Approach with Careful Clinical Monitoring to Manage the Fluoropyrimidines-Based Therapy: Clinical Cases and Systematic Review of the Literature

Conti

Bellis

Manzo

et al. 2020

JPM

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“…66 UGT1A1 genotype can be used next to customize irinotecan dosing, either to reduce dosing in patients bearing homozygous variant or conversely to increase dosing in wild-type patients. 67 With fluoropyrimidine drugs, the Clinical Pharmacogenetics Implementation Consortium (CPIC) has repeatedly issued guidelines based upon the screening of four allelic variants (i.e., c.1905 + 1G>A, c.1679T> G, c.2846A> T, and c.1129-5923C> G likely to predict life-threatening toxicities upon 5-FU or oral capecitabine intake. 68 Of note, a genetic score has been built to help transpose genotyping into functional status, thus paving the way for up-front adaptive dosing.…”

Section: Genotype-guided Dosingmentioning

confidence: 99%

Towards Rational Cancer Therapeutics: Optimizing Dosing, Delivery, Scheduling, and Combinations

Ferrer

Fanciullino

Milano

et al. 2020

Clin Pharma and Therapeutics

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The current trend to personalize anticancer therapies mostly relies on selecting the best drug or combination of drugs to achieve optimal efficacy in patients. In addition to the comprehensive genetic and molecular knowledge of each tumor before choosing the drugs to be given, there is probably much room left for improvement by further personalizing the very modes by which the drugs are given, once they have been carefully selected. In particular, shifting from standard dosing to tailored dosing should help in maintaining drug exposure levels in the right therapeutic window, thus ensuring that the efficacy/toxicity balance is optimal. This paper covers the current knowledge regarding pharmacokinetic/pharmacodynamic relationships of anticancer agents, from decades‐old cytotoxics to the latest immune checkpoint inhibitors, the most frequent sources for long‐neglected interpatient variability impacting on drug exposure levels, and what could be done to achieve real personalized medicine in oncology such as implementing therapeutic drug monitoring with adaptive dosing strategies or using model‐driven modalities for personalized dosing and scheduling.

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“…5-FU and capecitabine, an oral prodrug of 5-FU, are the backbone of the therapeutic scheme for CRC and many other solid tumors including monotherapy and combined with other chemotherapy drugs. Common combination regimens include FOLFOX [1]: (oxaliplatin combined with bolus/infusional 5-FU, and leucovorin); XELOX [2]: (capecitabine plus oxaliplatin); and FOLFIRI [3]: ( uorouracil, leucovorin, and irinotecan). Unfortunately, approximately 10% to 30% of patients display varying degrees of adverse effects [4], most frequent manifestations include anemia, neutropenia, nausea, vomiting, diarrhea, and neurological toxicities.…”

Section: Introductionmentioning

confidence: 99%

Predictive value of clinical toxicities of chemotherapy with fluoropyrimidines and oxaliplatin in colorectal cancer by DPYD and GSTP1 gene polymorphisms

Deng

Hou

Deng

et al. 2020

Preprint

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Background: Fluoropyrimidines and platinum are still widely used for colorectal cancer (CRC) management. Several studies have reported that mutations of dihydropyrimidine dehydrogenase (DPYD) and glutathione S-transferase pi-1 (GSTP1) polymorphisms are related to Chemotherapy-related adverse events. In the present study, we purposed to assess the impact of DPYD and GSTP1 variants on toxicity of chemotherapy risk among the Hakka population, minimize adverse events, and to maximize therapy outcome for individualized treatment.Methods: Genotyping was examined in 104 patients diagnosed with CRC cases and receiving fluoropyrimidine and platinum drugs based chemotherapy regimen by direct sequencing of DPYD and GSTP1 polymorphisms. Three DPYD variants including *2A, *5A, *9A, and GSTP1 c.313A>G were analyzed and clinical outcomes were assessed. Results: The data suggest that the incidence of DPYD*5A, DPYD*9A, and GSTP1 c.313A>G variants were 37.5%, 24%, and 31.7%, respectively. DPYD*2A variant was not found. A total of 38 patients (36.5%) suffered severe neutropenia and 23 patients (22.1%) suffered severe vomiting. DPYD*5A polymorphism was found significantly associated with grade 3/4 ulceration (p = 0.001). GSTP1 was determined to be an independent risk factor for severe neutropenia and ulceration (p = 0.010 and p = 0.034, respectively). Patients with GSTP1 c. 313A>G wild type contributed to a higher risk for grade severe toxicity compared with A/G + G/G genotype (p = 0.024). Nevertheless, no significant difference was found between patients with DPYD*9A T/T and T/C + C/C genotype for chemotherapeutic toxicity.Conclusions: The results demonstrated that DPYD*5A and GSTP1 polymorphisms were useful predictors of severe events. Screening of single nucleotide polymorphisms of DPYD and GSTP1 in colorectal cancer patients prior to chemotherapy may help to realize personalized therapy.

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A multicenter phase II study of personalized FOLFIRI-cetuximab for safe dose intensification

Cited by 14 publications

References 41 publications

A Genotyping/Phenotyping Approach with Careful Clinical Monitoring to Manage the Fluoropyrimidines-Based Therapy: Clinical Cases and Systematic Review of the Literature

A Genotyping/Phenotyping Approach with Careful Clinical Monitoring to Manage the Fluoropyrimidines-Based Therapy: Clinical Cases and Systematic Review of the Literature

Towards Rational Cancer Therapeutics: Optimizing Dosing, Delivery, Scheduling, and Combinations

Predictive value of clinical toxicities of chemotherapy with fluoropyrimidines and oxaliplatin in colorectal cancer by DPYD and GSTP1 gene polymorphisms

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