13C-uracil breath test to predict 5-fluorouracil toxicity in gastrointestinal cancer patients.

e13008 Background: Up to 30% of patients on 5-fluorouracil (5FU) experience severe toxicity. Dihydropyrimidine-dehydrogenase (DPD) deficiency explains 36-61% of cases. Predicting toxicity is an unmet challenge. Uracil breath test (UraBT) consists of measuring 13CO2 in exhaled breath after ingestion of 2-13C-uracil to evaluate pyrimidine (and 5FU) catabolism. Methods: We studied 33 gastrointestinal cancer patients previously exposed to 5FU: thirteen had grade 3-4 and 20, grade 0-1 toxicity. Groups were well-balanced regarding: age (median, 57 years); gender (males, 35%); primary (colorectal, 90%); ethnicity (Caucasians, 55%); chemotherapy (Mayo clinic regimen, 75%). Main toxicities were febrile neutropenia, diarrhea and stomatitis. Tests used to evaluate pyrimidine catabolism: (1) sequencing of three exons of DPYD; (2) plasma dihydrouracil/uracil ratio (UH2/U); (3) UraBT. We tested the performance of UraBT to discriminate patients who had grade 0-1 toxicity versus grade 3-4 toxicity and patients with and without proven DPD-deficiency. DPD-deficients were defined as having had grade 3-4 toxicity plus either UH2/U < 1.8 or deleterious mutation. Results: 4/13 grade 3-4 toxicity patients proved to be DPD-deficient: three had deleterious mutations (IVS14+1G>A in one; SNP 2846A>T in two), and one had low UH2/U ratio. Mean delta over baseline in 50 minutes (DOB50) significantly differed between groups. DOB50 ≤ 161.4 discriminated individuals with grade 3-4 versus grade 0-1 toxicity (sensitivity= 61.5%; specificity= 85%) and DPD-deficient versus non DPD-deficient (sensitivity= 75%; specificity= 85%). Conclusions: UraBT is a non-invasive and easy to perform method with promising accuracy in discriminating individuals with severe toxicity to 5FU, comparing favorably to most tests available to predict 5FU toxicity. [Table: see text]

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13C-uracil breath test to predict 5-fluorouracil toxicity in gastrointestinal cancer patients

Cancer Chemotherapy and Pharmacology ◽

10.1007/s00280-013-2309-4 ◽

2013 ◽

Vol 72 (6) ◽

pp. 1273-1282 ◽

Cited By ~ 11

Author(s):

Geraldo Felício Cunha-Junior ◽

Luiz De Marco ◽

Luciana Bastos-Rodrigues ◽

Marina Borges Bolina ◽

Flavia Linhares Martins ◽

...

Keyword(s):

Cancer Patients ◽

Gastrointestinal Cancer ◽

Breath Test ◽

Fluorouracil Toxicity

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Tegafur–uracil is a safe alternative for the treatment of colorectal cancer in patients with partial dihydropyrimidine dehydrogenase deficiency: a proof of principle

Therapeutic Advances in Medical Oncology ◽

10.1177/1758834012441049 ◽

2012 ◽

Vol 4 (4) ◽

pp. 167-172 ◽

Cited By ~ 6

Author(s):

Daniel I.G. Cubero ◽

Felipe Melo Cruz ◽

Patrícia Santi ◽

Ismael Dale C.G. Silva ◽

Auro del Giglio

Keyword(s):

Colorectal Cancer ◽

Cancer Patients ◽

Dehydrogenase Deficiency ◽

Dihydropyrimidine Dehydrogenase ◽

Gene Sequencing ◽

Severe Toxicity ◽

Safe Alternative ◽

Grade 3 ◽

Colorectal Cancer Patients ◽

Proof Of Principle

Objective: The objective of this study was to evaluate the safety of using tegafur–uracil (UFT) in colorectal cancer patients with partial dihydropyrimidine dehydrogenase (DPD) deficiency. Patients and Methods: The study included five colorectal cancer patients who presented with acute toxicity (grades 3 and 4) after being given the first cycle of chemotherapy using 5-fluorouracil. The DPD deficiency was confirmed by gene sequencing. After a full recovery from all side effects, we changed the regimen to UFT (300 mg/m2/day) associated with leucovorin (90 mg/day) for 21 days, with an empirical dose reduction of at least 10% in the first cycle. Results: We prospectively analysed 22 UFT cycles in 5 patients. We did not observe any episodes of grade 3 or 4 toxicity. The predominant toxicities were of grades 1 and 2 (nausea, vomiting and diarrhoea). Conclusion: Here, we demonstrate a complete absence of severe toxicity in all patients and cycles analysed. We believe that UFT is a safe alternative for the treatment of patients with partial DPD deficiency.

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Cost Implications of Reactive Versus Prospective Testing for Dihydropyrimidine Dehydrogenase Deficiency in Patients With Colorectal Cancer: A Single-Institution Experience

Dose-Response ◽

10.1177/1559325818803042 ◽

2018 ◽

Vol 16 (4) ◽

pp. 155932581880304 ◽

Cited By ~ 8

Author(s):

Con Murphy ◽

Stephen Byrne ◽

Gul Ahmed ◽

Andrew Kenny ◽

James Gallagher ◽

...

Keyword(s):

Colorectal Cancer ◽

Dihydropyrimidine Dehydrogenase ◽

Cost Savings ◽

Cost Effective ◽

Public Hospitals ◽

Severe Toxicity ◽

Care Payer ◽

Input Variables ◽

Grade 3 ◽

The Cost

Background: Severe toxicity is experienced by a substantial minority of patients receiving fluoropyrimidine-based chemotherapy, with approximately 20% of these severe toxicities attributable to polymorphisms in the DPYD gene. The DPYD codes for the enzyme dihydropyrimidine dehydrogenase (DPD) important in the metabolism of fluoropyrimidine-based chemotherapy. We questioned whether prospective DPYD mutation analysis in all patients commencing such therapy would prove more cost-effective than reactive testing of patients experiencing severe toxicity. Methods: All patients experiencing severe toxicity from fluoropyrimidine-based chemotherapy for colorectal cancer in an Irish private hospital over a 3-year period were tested for 4 DPYD polymorphisms previously associated with toxicity. The costs associated with an index admission for toxicity in DPD-deficient patients were examined. A cost analysis was undertaken comparing the anticipated cost of implementing screening for DPYD mutations versus current usual care. One-way sensitivity analysis was conducted on known input variables. An alternative scenario analysis from the perspective of the Irish health-care payer (responsible for public hospitals) was also performed. Results: Of 134 patients commencing first-line fluoropyrimidine chemotherapy over 3 years, 30 (23%) patients developed grade 3/4 toxicity. Of these, 17% revealed heterozygote DPYD mutations. The cost of hospitalization for the DPYD-mutated patients was €232 061, while prospectively testing all 134 patients would have cost €23 718. Prospective testing would result in cost savings across all scenarios. Conclusions: The cost of hospital admission for severe chemotherapy-related toxicity is significantly higher than the cost of prospective DPYD testing of each patient commencing fluoropyrimidine chemotherapy.

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A phase II study on the efficacy and toxicity of cabozantinib in recurrent/metastatic salivary gland cancer patients.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.6529 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. 6529-6529

Author(s):

Wim van Boxtel ◽

Maike Uijen ◽

Chantal Driessen ◽

Sjoert Pegge ◽

Stefan M. Willems ◽

...

Keyword(s):

Salivary Gland ◽

Cancer Patients ◽

Phase Ii ◽

Phase Ii Study ◽

Objective Response ◽

Salivary Gland Cancer ◽

Severe Toxicity ◽

Duct Carcinoma ◽

Systemic Treatments ◽

Grade 3

6529 A phase II study on the efficacy and toxicity of cabozantinib in recurrent/metastatic salivary gland cancer patients. Background: Because c-MET and VEGFR are often overexpressed in salivary gland cancer (SGC), this study evaluated the efficacy and safety of cabozantinib in recurrent/metastatic (R/M) SGC pts. Methods: A single center, single arm, phase II study was conducted. Immunohistochemical c-MET positive (H-score ≥10) R/M SGC pts were included in 3 cohorts: adenoid cystic carcinoma (ACC), salivary duct carcinoma (SDC), and other SGCs. Objective growth or complaints due to the disease were required before inclusion in the ACC and other SGC cohort. No prior systemic treatments were required. Pts started 60 mg cabozantinib tablets OD. Primary endpoint was the objective response rate (ORR). A Simon two-stage design was used. In case of ≥1 objective response in the first 9 pts/cohort, 8 additional pts would be included in the cohort. Results: In total 25 pts were included from Sep. 2018 until premature closure due to severe toxicity in Nov. 2019. Median age was 56 years (range 49-72), prior treatments included: primary tumor resection ( n=19), radiotherapy ≥50Gy ( n=24), systemic therapy ( n=10; adjuvant in 2 pts, palliative in 8 pts). Six pts had grade 3 ( n=4), grade 4 ( n=1), or grade 5 ( n=1) wound/fistula complications, occurring at a median of 7.2 mths on cabozantinib (range 2.1-12.8). This resulted in a severe wound complication rate of 32% in 19 pts on treatment for ≥2 mths. Remarkably, 4 out of 6 pts developed this complication in the area exposed to high-dose Rx; 2/4 had a pre-existing fistula in this area. Median interval between Rx and start of cabozantinib was 71.3 mths (range 10.6-94.7). Other grade ≥3 adverse events in >1 pt were: hypertension (5 pts), diarrhoea (2 pts) and dehydration (2 pts). Current median follow-up is 6.8 mths. The ORR was 6% (1/17 pts) in the ACC cohort, 20% (1/5 pts) in the SDC cohort, and 0% (0/3 pts) in other SGC pts; median PFS is 12.6 mths (95% CI 6.8 – 18.4 mths), 9.0 mths (insufficient events for 95% CI), and 6.9 mths (95% CI 0 – 15.2 mths), respectively. Median OS is not reached in any cohort. Conclusions: This phase II study on cabozantinib in R/M SGC pts demonstrated severe wound and fistula complications in 32% of pts on treatment for ≥2 mths, mostly (4/6 pts) within the radiotherapy field. Because of this toxicity the study was closed prematurely. Furthermore, cabozantinib showed minimal clinical activity in SGC pts. Research funding: Ipsen Pharmaceuticals Clinical trial information: NCT03729297 .

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Predictive Value of Clinical Toxicities to Chemotherapy with Fluoropyrimidines and Oxaliplatin in Colorectal Cancer by DPYD and GSTP1 Genes Polymorphisms

10.21203/rs.3.rs-73108/v1 ◽

2020 ◽

Author(s):

Xunwei Deng ◽

Jingyuan Hou ◽

Qiaoting Deng ◽

Zhixiong Zhong

Keyword(s):

Colorectal Cancer ◽

Adverse Events ◽

Direct Sequencing ◽

Dihydropyrimidine Dehydrogenase ◽

Severe Neutropenia ◽

Severe Toxicity ◽

Nucleotide Polymorphisms ◽

Significant Difference ◽

Grade 3 ◽

Colorectal Cancer Patients

Abstract 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. The present study was aimed to determine the role of DPYD and GSTP1 variants on patient chemotherapy toxicity risk among the Hakka population, minimize adverse events and in order 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 higher risk for grade severe toxicity compared with A/G + G/G genotype (p = 0.024). However, there was no significant difference 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 for 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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Genetic polymorphisms of the adenosine triphosphate-binding cassette transporters (ABCC2, ABCG2) and irinotecan toxicity in cancer patients

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.13096 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 13096-13096

Author(s):

M. Usui ◽

M. Ando ◽

C. Kitagawa ◽

Y. Ando ◽

Y. Sekido ◽

...

Keyword(s):

Cancer Patients ◽

Adenosine Triphosphate ◽

Interindividual Variability ◽

Antitumor Drugs ◽

Severe Toxicity ◽

Reference Allele ◽

Reference Type ◽

Grade 3 ◽

Altered Sensitivity

13096 Background: Irinotecan is subject to substantial interindividual variability in pharmacokinetic and the occurrence of unpredictably severe toxicities of leukopenia or diarrhea. These toxicities have been reported to be associated with increased levels of SN-38, the active metabolite of irinotecan. ABCC2 and ABCG2, members of adenosine triphosphate-binding cassette transporters, are involved in mediating the elimination of anionic antitumor drugs, such as SN-38 and SN-38G. Recently, Innocenti et al. reported SN-38G AUC and SN-38G/SN-38 AUC ratios were correlated with ABCC2 3972T>C. The variant ABCG2 421C>A was associated with low ABCG2 expression levels and altered sensitivity to several drugs, including SN-38, in vitro as compared with the reference-type protein. Methods: We assessed whether the variants ABCC2 3972T>C and ABCG2 421C>A would be associated with severe toxicity (leucopenia of grade 4 and/or diarrhea of grade 3 or worse) in 120 Japanese cancer patients in which 27 patients experienced severe toxicity. Results: 74 patients (62%) were homozygotes for the reference allele of ABCC2 3972T>C, 39 heterozygous (33%), and 7 homozygous (6%) for the variant, whereas 62 patients (52%) were homozygous for the reference allele of ABCG2 421C>A, 48 heterozygous (40%) and 10 homozygous (8%) for the variant. Logistic regression analysis did not show any significant associations between the occurrence of severe toxicity and carrying these variants (see Table ). Conclusions: It suggests that genotyping of ABCC2 3972T>C and ABCG2 421C>A would not be useful for predicting severe toxicity caused by irinotecan. [Table: see text] No significant financial relationships to disclose.

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The 2-13C-5-fluorouracil breath test (FUBT) as a novel, rapid method for assessment of dihydropyrimidine dehydrogenase (DPD) activity in cancer patients: Initial characterization and comparison to the 2-13C-uracil breath test (UraBT)

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.2551 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 2551-2551

Author(s):

J. Fourie ◽

L. K. Mattison ◽

T. E. Wood ◽

J. A. Posey ◽

A. Modak ◽

...

Keyword(s):

Colorectal Cancer ◽

Single Dose ◽

Oral Dose ◽

Cancer Patients ◽

Drug Administration ◽

Breath Test ◽

Dihydropyrimidine Dehydrogenase ◽

Metabolite Formation ◽

Colorectal Cancer Patients ◽

Further Development

2551 Background: The UraBT is currently in development as a phenotypic test to screen for DPD deficiency. Following an oral dose of 2-13C-uracil, the UraBT shows a significant relationship between breath 13CO2 metabolite formation and plasma 2-13C-uracil and 2-13C-dihydrouracil pharmacokinetics. We herein describe a novel, potentially more clinically relevant test in which a small oral dose of 2-13C-5-fluorouracil (5-FU) is administered, followed by assessment of breath 13CO2 metabolite formation as previously described for the UraBT. We hypothesize that the FUBT can rapidly assess interindividual variability in 5-FU catabolism and predisposition to 5-FU toxicity. Methods: Over two sessions separated by a seven day washout, a single dose (6mg/kg, p.o.) of 2-13C-uracil or 2-13C-5-FU was administered to patients with stage III-IV colorectal cancer (n = 4). Subsequent to drug administration, in each session, 13CO2 catabolite formation was quantified in the breath over eight hours. In a separate investigation over two sessions separated by a seven day washout, a single dose (3mg/kg, p.o.) of 2-13C-uracil or 213C-5-FU was administered to colorectal cancer patients with previously documented severe (n=2) or moderate (n=2) 5-FU dose-related hematological/gastrointestinal toxicity. Following drug administration 13CO2 catabolite formation was quantified over eight hours. 13CO2 concentration was expressed as Delta Over Baseline (DOB) in all sessions. Results: Compared to the UraBT, the FUBT showed an increased Cmax (50.7 ± 6.6 DOB/mg vs. 36.8 ± 7.8 DOB/mg; mean ± SD) and decreased Tmax (25 ± 4 min vs. 45 ± 6 min) for 13CO2 formation (p<0.05). The FUBT was able to distinguish patients with previously reported severe and moderate 5- FU toxicity, with 13CO2 Cmax values of 35.5 ± 9.5 DOB/mg (mean ± SD) and 59.8 ± 7.3 DOB/mg, respectively. Importantly, FUBT Cmax values positively correlated with DPD activity (rs=1.00, p<0.01). Conclusions: These data lend support to further development of the FUBT as a rapid and informative test to assess DPD activity and to predict susceptibility to severe dose-related 5-FU toxicity. [CA116964] No significant financial relationships to disclose.

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Screening patients for fluoropyrimidine-related toxicity risk.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.3529 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 3529-3529

Author(s):

Olivier Capitain ◽

Valérie Seegers ◽

Jean-Philippe Metges ◽

Roger Faroux ◽

Claire Stampfli ◽

...

Keyword(s):

Dihydropyrimidine Dehydrogenase ◽

Public Health Problem ◽

Late Toxicity ◽

Screening Tests ◽

Screening Methods ◽

Severe Toxicity ◽

Risk Of Death ◽

The Usa ◽

Pre Treatment ◽

Grade 3

3529 Background: Severe, sometimes fatal, toxicity can occur during the 1st or 2nd course of chemotherapy using fluoropyrimidines (FPs), and poses a serious public health problem. FPs carry a 3-5% risk of grade ≥ 3 early toxicities and 0.2% risk of death linked to Dihydropyrimidine Dehydrogenase (DPD) deficiency. Methods: Of 29,000 patients screened since July 2000, 472 were referred to us due to severe toxicity during 1st round 5-FU, or because pre-screening was done too late. Toxicity evaluation was performed according to the NCI scale of adverse reactions to cancer drugs (0=none, 5=death). Patients were previously 5-FU naïve, had different cancers, and received various protocols, eg. 5FU or Capecitabine; bolus±continuous or per os. The reliability of the following 4 pre-treatment screening tests to predict grade≥ 4 toxicity was assessed: 1) DPYD genotype mutation (*2A,*2B,*7, 13, HapB3) 2) Plasma uracil (U) level, 3) Plasma dihydrouracil/uracil ratio (UH2/U) 4) a multiparametric approach with genotyping, UH2/U ratio and key patient factors (age, sex, etc.). McNemar’s test with Bonferroni correction was used for statistical analysis. Results: Of the 472 referred patients, 169 had grade 4 or 5 toxicity, of which 41 died from toxicity. 98 had one or plus DPYD mutation: 42(42.9%)*2A; 43(43.9%)*2B; 3(3%)*7; 4(4%)*13; 8(8.16%) HapB3; 1 was homozygous *2A. Data below compare the 4 screening methods for predicting grade 4-5 toxicity. Conclusions: The multiparametric approach is statistically (p<0.0001) the most efficient in terms of preventing grade 4 and 5 toxicity (death) due to 5-FU treatment. Around 290,000 patients are treated with 5-FU per year in the USA. Assuming a 0.2% mortality rate due to toxicity, around 580 lives could be saved per year using the multiparametric pre-treatment test. [Table: see text]

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