Impact of UGT1A1 Polymorphisms on Febrile Neutropenia in Pancreatic Cancer Patients Receiving FOLFIRINOX: A Single-Center Cohort Study
Abstract
:Simple Summary
Abstract
1. Introduction
2. Materials and Methods
2.1. Study Design
2.2. Chemotherapy Schedule and Response Evaluation
2.3. Assessment of Chemotherapy-Related Adverse Events
2.4. Febrile Neutropenia and Grade 4 Neutropenia
2.5. UGT1A1 Polymorphisms
2.6. Overall Survival and Progression-Free Survival
2.7. Statistical Analyses
3. Results
3.1. Patient Characteristics
3.2. Risk Factors for the Development of Febrile Neutropenia
3.3. Risk Factors for the Development of Grade 4 Neutropenia
3.4. Relationship between UGT1A1 Phenotypes and Hematologic Toxicities
3.5. Overall Survival and Progression-Free Survival
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Variable | All Patients (n = 154) | FN Group (n = 31) | Non-FN Group (n = 123) | p-Value | |
---|---|---|---|---|---|
Patient characteristics | |||||
Age, years | 62 (55–67) | 66 (62–70) | 60 (55–66) | <0.001 | |
Sex, no. (%) | |||||
Male | 95 (61.7) | 13 (41.9) | 82 (66.7) | 0.011 | |
Female | 59 (38.3) | 18 (58.1) | 41 (33.3) | ||
ECOG PS | |||||
0 | 130 (84.4) | 21 (67.7) | 109 (88.6) | 0.010 | |
1 | 24 (15.6) | 10 (32.3) | 14 (11.4) | ||
BMI, median (kg/m2) | 22.7 (21.2–25.0) | 23.6 (21.2–26.1) | 22.3 (21.2–24.9) | 0.499 | |
DM | 50 (32.5) | 13 (41.9) | 37 (30.1) | 0.208 | |
UGT1A1 | |||||
Extensive metabolizer | 71 (46.1) | 5 (16.1) | 66 (53.7) | <0.001 | |
Intermediate metabolizer | 66 (42.9) | 21 (67.7) | 45 (36.6) | ||
Poor metabolizer | 17 (11.0) | 5 (16.1) | 12 (9.8) | ||
Tumor characteristics | |||||
Location | |||||
Head | 83 (53.9) | 23 (74.2) | 60 (48.8) | 0.011 | |
Body/Tail | 71 (46.1) | 8 (25.8) | 63 (51.2) | ||
Stage | |||||
Resectable | 12 (7.8) | 3 (9.7) | 9 (7.3) | 0.449 | |
Borderline Resectable | 24 (15.6) | 2 (6.5) | 22 (17.9) | ||
Locally advanced | 55 (35.7) | 12 (38.7) | 43 (35.0) | ||
Metastatic | 63 (40.9) | 14 (45.2) | 49 (39.8) | ||
Laboratory characteristics | |||||
WBC per μL | 6860.0 (5565.0–8192.5) | 7590.0 (5590.0–8660.0) | 6810.0 (5550.0–7920.0) | 0.212 | |
Neutrophils per μL | 4200.0 (3172.5–5422.5) | 4600.0 (3390.0–6490.0) | 4030.0 (3150.0–5200.0) | 0.103 | |
Lymphocytes per μL | 1630.0 (1310.0–2040.0) | 1600.0 (1140.0–2030.0) | 1630.0 (1310.0–2060.0) | 0.442 | |
NLR | 2.4 (1.8–3.6) | 2.6 (2.0–4.3) | 2.3 (1.7–3.3) | 0.159 | |
Hemoglobin, g/dL | 12.6 (11.6–13.6) | 12.6 (11.2–13.2) | 12.5 (11.6–13.7) | 0.429 | |
Platelets, 103/μL | 242.5 (198.8–316.6) | 273.0 (220.0–346.0) | 228.0 (196.0–308.0) | 0.033 | |
Total bilirubin, mg/dL | 0.6 (0.5–1.0) | 0.8 (0.6–2.0) | 0.6 (0.4–0.9) | 0.002 | |
AST, IU/L | 20.0 (16.0–34.0) | 25.0 (15.0–46.0) | 20.0 (16.0–30.0) | 0.168 | |
ALT, IU/L | 21.0 (14.8–40.5) | 27.0 (17.0–48.0) | 19.0 (14.0–38.0) | 0.091 | |
CA 19-9, U/mL | 245.0 (28.5–1370.8) | 611.0 (135.0–2364.0) | 209.0 (20.8–1247.0) | 0.160 | |
Albumin, g/dL | 4.1 (3.7–4.4) | 4.0 (3.5–4.2) | 4.1 (3.7–4.5) | 0.151 |
Variables | All Patients (n = 154) | FN Group (n = 31) | Non-FN Group * (n = 123) | p-Value |
---|---|---|---|---|
Accumulation Dose, mg/m2 | ||||
5-FU | 10,400.0 (9645.0–11,200.0) | 8400.0 (5600.0–16,800.0) | 10,500.0 (10,000.0–11,200.0) | 0.237 |
Oxaliplatin | 340.0 (303.9–340.0) | 255.0 (170.0–510.0) | 340.0 (340.0–340.0) | 0.090 |
Irinotecan | 720.0 (630.0–720.0) | 540.0 (360.0–1080.0) | 720.0 (675.0–720.0) | 0.110 |
During All Cycles | |||||
---|---|---|---|---|---|
Variables | Univariate | Multivariate | |||
OR (95% CI) | p-Value | OR (95% CI) | p-Value | ||
Age, years | |||||
≥65 | 2.30 (1.03–5.11) | 0.042 | |||
Sex | |||||
Male | 1.0 | 0.013 | 1.0 | 0.021 | |
Female | 2.77 (1.24–6.20) | 2.87 (1.17–7.05) | |||
ECOG | |||||
0 | 1.0 | 0.006 | 1.0 | 0.015 | |
1 | 3.71 (1.45–9.46) | 3.86 (1.31–11.42) | |||
BMI | |||||
≥25 | 1.33 (0.55–3.20) | 0.530 | |||
Tumor location | |||||
Body/tail | 1.0 | 0.014 | 1.0 | 0.023 | |
Head | 3.02 (1.25–7.27) | 3.06 (1.16–8.02) | |||
Stage | |||||
Resectable | 1.0 | ||||
Borderline resectable | 0.27 (0.04–1.92) | 0.192 | |||
Locally advanced | 0.84 (0.20–3.59) | 0.811 | |||
Metastatic | 0.86 (0.20–3.60) | 0.833 | |||
NLR | <3 | 1.0 | 0.222 | ||
≥3 | 1.65 (0.74–3.67) | ||||
Hemoglobin, g/dL | ≥12 | 1.0 | 0.471 | ||
<12 | 1.34 (0.60–3.00) | ||||
Total bilirubin, mg/dL | ≤1.8 | 1.0 | 0.012 | ||
>1.8 | 3.46 (1.32–9.09) | ||||
CA 19-9, U/mL | <1000 | 1.0 | 0.151 | ||
≥1000 | 1.82 (0.81–4.10) | ||||
UGT1A1 phenotype | |||||
Extensive metabolizer | 1.0 | 1.0 | |||
Intermediate metabolizer | 6.16 (2.16–17.54) | 0.001 | 4.78 (1.61–14.21) | 0.005 | |
Poor metabolizer | 5.50 (1.38–21.95) | 0.016 | 4.86 (1.12–21.17) | 0.035 |
Variable | Febrile Neutropenia | ||||
---|---|---|---|---|---|
Unadjusted HR | p-Value | Adjusted HR | 95% CI | p-Value | |
Female sex | 2.40 | 0.016 | 2.20 | 1.07–4.51 | 0.031 |
ECOG PS = 1 | 3.29 | 0.002 | 2.83 | 1.32–6.10 | 0.008 |
UGT1A1 IM | 5.15 | 0.001 | 4.30 | 1.61–11.52 | 0.004 |
UGT1A1 PM | 4.49 | 0.018 | 4.03 | 1.16–14.01 | 0.028 |
Variable | During All Cycles | ||||
---|---|---|---|---|---|
Univariate | Multivariate | ||||
OR (95% CI) | p-Value | OR (95% CI) | p-Value | ||
Age, years | |||||
≥65 | 1.95 (0.96–3.94) | 0.063 | |||
Sex | |||||
Male | 1.0 | 0.001 | 1.0 | 0.001 | |
Female | 3.47 (1.66–7.23) | 3.44 (1.63–7.25) | |||
ECOG | |||||
0 | 1.0 | 0.767 | |||
1 | 0.88 (0.63–2.12) | ||||
BMI | |||||
≥25 | 0.76 (0.53–2.40) | 1.127 | |||
Tumor location | |||||
Body/tail | 1.0 | 0.152 | |||
Head | 1.61 (0.84–3.10) | ||||
Stage | |||||
Resectable | 1.0 | ||||
Borderline resectable | 1.66 (0.41–6.71) | 0.481 | |||
Locally advanced | 3.13 (0.87–11.28) | 0.081 | |||
Metastatic | 2.13 (0.61–7.46) | 0.238 | |||
NLR | <3 | 1.0 | 0.376 | ||
≥3 | 0.74 (0.38–1.45) | ||||
Hemoglobin, g/dL | ≥12 | 1.0 | 0.950 | ||
<12 | 0.98 (0.50–1.92) | ||||
Total bilirubin, mg/dL | ≤1.8 | 1.0 | 0.787 | ||
>1.8 | 1.14 (0.45–2.90) | ||||
CA 19-9, U/mL | <1000 | 1.0 | 0.188 | ||
≥1000 | 1.62 (0.79–3.34) | ||||
UGT1A1 phenotype | |||||
Extensive metabolizer | 1.0 | 1.0 | |||
Intermediate metabolizer | 1.52 (0.77–3.01) | 0.231 | 1.41 (0.69–2.88) | 0.343 | |
Poor metabolizer | 4.05 (1.07–15.34) | 0.039 | 4.06 (1.04–15.87) | 0.044 |
Variable | Grade 4 Neutropenia | ||||
---|---|---|---|---|---|
Unadjusted HR | p-Value | Adjusted HR | 95% CI | p-Value | |
Female sex | 2.06 | 0.001 | 1.98 | 1.31–2.98 | 0.001 |
UGT1A1 IM | 1.32 | 0.217 | 1.29 | 0.83–2.00 | 0.264 |
UGT1A1 PM | 2.01 | 0.026 | 1.79 | 0.96–3.33 | 0.066 |
Extensive Metabolizer (n = 71) | Intermediate Metabolizer (n = 66) | Poor Metabolizer (n = 17) | All Patients (n = 154) | p-Value | |
---|---|---|---|---|---|
Neutropenia | 57/71 (80.3) | 58/66 (87.9) | 15/17 (88.2) | 130/154 (84.4) | 0.411 |
Neutropenia (Grade IV) | 38/71 (53.5) | 42/66 (63.6) | 14/17 (82.4) | 94/154 (61.0) | 0.082 |
Febrile neutropenia | 5/71 (7.0) | 21/66 (31.8) | 5/17 (29.4) | 31/154 (20.1) | 0.001 |
Anemia | 3/71 (4.2) | 13/66 (19.7) | 4/17 (23.5) | 20/154 (13.0) | 0.011 |
Thrombocytopenia | 4/71 (5.6) | 10/66 (15.2) | 3/17 (17.6) | 17/154 (11.0) | 0.118 |
Extensive Metabolizer (n = 71) | Intermediate Metabolizer (n = 66) | Poor Metabolizer (n = 17) | All Patients (n = 154) | p-Value | |
---|---|---|---|---|---|
Diarrhea | 22/71 (31.0) | 21/66 (31.8) | 4/17 (23.5) | 47/154 (30.5) | 0.801 |
Diarrhea (Grade III/ IV) | 2/71 (2.8) | 5/66 (7.6) | 1/17 (5.9) | 8/154 (5.2) | 0.427 |
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Keum, J.; Lee, H.S.; Jo, J.H.; Chung, M.J.; Park, J.Y.; Park, S.W.; Song, S.Y.; Bang, S. Impact of UGT1A1 Polymorphisms on Febrile Neutropenia in Pancreatic Cancer Patients Receiving FOLFIRINOX: A Single-Center Cohort Study. Cancers 2022, 14, 1244. https://doi.org/10.3390/cancers14051244
Keum J, Lee HS, Jo JH, Chung MJ, Park JY, Park SW, Song SY, Bang S. Impact of UGT1A1 Polymorphisms on Febrile Neutropenia in Pancreatic Cancer Patients Receiving FOLFIRINOX: A Single-Center Cohort Study. Cancers. 2022; 14(5):1244. https://doi.org/10.3390/cancers14051244
Chicago/Turabian StyleKeum, Jiyoung, Hee Seung Lee, Jung Hyun Jo, Moon Jae Chung, Jeong Youp Park, Seung Woo Park, Si Young Song, and Seungmin Bang. 2022. "Impact of UGT1A1 Polymorphisms on Febrile Neutropenia in Pancreatic Cancer Patients Receiving FOLFIRINOX: A Single-Center Cohort Study" Cancers 14, no. 5: 1244. https://doi.org/10.3390/cancers14051244