1State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China
2School of Public Health, Sun Yat-sen University, Guangzhou, China
3Cancer Center of Guangzhou Medical University, Guangzhou, China
Copyright © 2021 by the Korean Cancer Association
This is an Open-Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Ethical Statement
This study was approved by the Human Ethics Approval Committee of SYSUCC. Consent has been obtained from each participant after full explanation of the purpose and nature of all procedures used. All participants provided a blood specimen for DNA.
Author Contributions
Conceived and designed the analysis: Dong SQ, Wang TM, Zhang JB, He YQ, Xue WQ, Jia WH.
Collected the data: Dong SQ, Wu ZY, Yang DW, Cao LJ, Huang JW, Li XZ, Zhang PF, Zheng XH.
Contributed data or analysis tools: Dong SQ, Wang TM, Zhang JB, Wu ZY, Jia WH.
Performed the analysis: Dong SQ, Wang TM, He YQ, Xue WQ, Yang DW, Jia WH.
Wrote the paper: Dong SQ, Wang TM, Jia WH.
Conflicts of Interest
Conflict of interest relevant to this article was not reported.
Characteristic | No. of patients (%) | ORa) (95% CI) | p-valuea) | ORb)adjusted (95% CI) | pb)adjusted | |
---|---|---|---|---|---|---|
Ex-case (n=144) | Ex-control (n=144) | |||||
Agec) | ||||||
≤ 40 | 13 (9.0) | 12 (8.3) | 1.00 (reference) | - | - | - |
41–50 | 22 (15.3) | 23 (16.0) | 0.88 (0.33–2.35) | 0.803 | - | - |
51–60 | 55 (38.2) | 48 (33.3) | 1.06 (0.44–2.54) | 0.900 | - | - |
> 60 | 54 (37.5) | 61 (42.4) | 0.82 (0.34–1.94) | 0.648 | - | - |
Sex | ||||||
Male | 90 (62.5) | 90 (62.5) | 1.00 (reference) | - | - | - |
Female | 54 (37.5) | 54 (37.5) | 1.00 (0.62–1.61) | 1.000 | - | - |
AJCC stage | ||||||
Stage I–II | 33 (22.9) | 41 (28.5) | 1.00 (reference) | - | - | - |
Stage III–IV | 111 (77.1) | 103 (71.5) | 1.34 (0.79–2.28) | 0.281 | - | - |
Primary cancer site | ||||||
Colon | 80 (55.6) | 84 (58.3) | 1.00 (reference) | - | - | - |
Rectal | 64 (44.4) | 60 (41.7) | 1.12 (0.70–1.79) | 0.634 | - | - |
BSAd) | ||||||
Median (range) | 1.65 (1.2–2.1) | 1.63 (1.2–2.2) | 0.683 | - | - | |
Histologic appearance | ||||||
Poorly differentiated | 35 (24.3) | 28 (19.4) | 1.00 (reference) | - | - | - |
Moderately differentiated | 99 (68.8) | 102 (70.8) | 0.78 (0.44–1.37) | 0.383 | - | - |
Well differentiated | 3 (2.1) | 1 (0.7) | 2.40 (0.24–24.35) | 0.459 | - | - |
Others | 7 (4.9) | 13 (9.0) | 0.43 (0.15–1.22) | 0.114 | - | - |
Primary tumor surgery | ||||||
None | 22 (15.3) | 5 (3.5) | 1.00 (reference) | - | 1.00 (reference) | - |
Yes | 122 (84.7) | 139 (96.5) | 0.20 (0.07–0.50) | 0.002 | 0.15 (0.04–0.40) | < 0.001 |
Starting capecitabine dose (mg/m2 twice daily) | ||||||
≤ 800 | 4 (2.8) | 6 (4.2) | 1.00 (reference) | - | 1.00 (reference) | - |
801–900 | 25 (17.4) | 18 (12.5) | 2.08 (0.51–8.47) | 0.305 | 1.64 (0.37–7.99) | 0.523 |
901–1,000 | 64 (44.4) | 92 (63.9) | 1.04 (0.28–3.85) | 0.949 | 0.82 (0.21–3.65) | 0.787 |
1,001–1,100 | 32 (22.2) | 23 (16.0) | 2.09 (0.53–8.25) | 0.294 | 1.40 (0.32–6.64) | 0.658 |
> 1,100 | 19 (13.2) | 5 (3.5) | 5.70 (1.15–28.33) | 0.033 | 2.10 (0.36–13.65) | 0.421 |
Chemotherapy regimens | ||||||
Capecitabine monotherapy | 63 (43.8) | 12 (8.3) | 1.00 (reference) | - | 1.00 (reference) | - |
XELOXe) | 81 (56.3) | 132 (91.7) | 0.12 (0.06–0.22) | < 0.001 | 0.13 (0.06–0.27) | < 0.001 |
Concurrent chemoradiotherapy | ||||||
None | 132 (91.7) | 127 (88.2) | 1.00 (reference) | - | - | - |
Yes | 12 (8.3) | 17 (11.8) | 1.78 (0.69–4.91) | 0.241 | - | - |
Previous fluorouracil-based chemotherapy | ||||||
None | 106 (73.6) | 127 (88.2) | 1.00 (reference) | - | 1.00 (reference) | - |
Yes | 38 (26.4) | 17 (11.8) | 2.68 (1.45–5.12) | 0.002 | 2.50 (1.22–5.23) | 0.013 |
HFS prevention strategy | ||||||
None | 92 (63.9) | 101 (70.1) | 1.00 (reference) | - | 1.00 (reference) | - |
Pyridoxine | 27 (18.8) | 27 (18.8) | 1.10 (0.60–2.01) | 0.762 | 0.75 (0.34–1.59) | 0.462 |
Celecoxib | 13 (9.0) | 5 (3.5) | 2.85 (0.98–8.32) | 0.055 | 1.94 (0.56–7.23) | 0.303 |
Pyridoxine plus celecoxib | 12 (8.3) | 11 (7.6) | 1.20 (0.50–2.85) | 0.683 | 1.30 (0.47–3.54) | 0.605 |
AJCC, American Joint Committee on Cancer; BSA, body surface area; CI, confidence interval; HFS, hand-foot syndrome; OR, odds ratio.
a) p-value and OR and 95% CI were calculated by univariate logistic model,
b) padjusted and ORadjusted and 95% CI were calculated by multivariate logistic model using variables including primary tumor surgery, starting capecitabine dose group, chemotherapy regimens, previous fluorouracil-based chemotherapy and HFS prevention strategy,
c) Age at capecitabine-based chemotherapy, years,
d) BSA was calculated by Wilcoxon-Mann-Whitney test,
e) Capecitabine plus oxaliplatin.
Demographics and clinical characteristics of patients
Characteristic | No. of patients (%) | OR |
p-value |
OR |
p | |
---|---|---|---|---|---|---|
Ex-case (n=144) | Ex-control (n=144) | |||||
Age |
||||||
≤ 40 | 13 (9.0) | 12 (8.3) | 1.00 (reference) | - | - | - |
41–50 | 22 (15.3) | 23 (16.0) | 0.88 (0.33–2.35) | 0.803 | - | - |
51–60 | 55 (38.2) | 48 (33.3) | 1.06 (0.44–2.54) | 0.900 | - | - |
> 60 | 54 (37.5) | 61 (42.4) | 0.82 (0.34–1.94) | 0.648 | - | - |
Sex | ||||||
Male | 90 (62.5) | 90 (62.5) | 1.00 (reference) | - | - | - |
Female | 54 (37.5) | 54 (37.5) | 1.00 (0.62–1.61) | 1.000 | - | - |
AJCC stage | ||||||
Stage I–II | 33 (22.9) | 41 (28.5) | 1.00 (reference) | - | - | - |
Stage III–IV | 111 (77.1) | 103 (71.5) | 1.34 (0.79–2.28) | 0.281 | - | - |
Primary cancer site | ||||||
Colon | 80 (55.6) | 84 (58.3) | 1.00 (reference) | - | - | - |
Rectal | 64 (44.4) | 60 (41.7) | 1.12 (0.70–1.79) | 0.634 | - | - |
BSA |
||||||
Median (range) | 1.65 (1.2–2.1) | 1.63 (1.2–2.2) | 0.683 | - | - | |
Histologic appearance | ||||||
Poorly differentiated | 35 (24.3) | 28 (19.4) | 1.00 (reference) | - | - | - |
Moderately differentiated | 99 (68.8) | 102 (70.8) | 0.78 (0.44–1.37) | 0.383 | - | - |
Well differentiated | 3 (2.1) | 1 (0.7) | 2.40 (0.24–24.35) | 0.459 | - | - |
Others | 7 (4.9) | 13 (9.0) | 0.43 (0.15–1.22) | 0.114 | - | - |
Primary tumor surgery | ||||||
None | 22 (15.3) | 5 (3.5) | 1.00 (reference) | - | 1.00 (reference) | - |
Yes | 122 (84.7) | 139 (96.5) | 0.20 (0.07–0.50) | 0.002 | 0.15 (0.04–0.40) | < 0.001 |
Starting capecitabine dose (mg/m2 twice daily) | ||||||
≤ 800 | 4 (2.8) | 6 (4.2) | 1.00 (reference) | - | 1.00 (reference) | - |
801–900 | 25 (17.4) | 18 (12.5) | 2.08 (0.51–8.47) | 0.305 | 1.64 (0.37–7.99) | 0.523 |
901–1,000 | 64 (44.4) | 92 (63.9) | 1.04 (0.28–3.85) | 0.949 | 0.82 (0.21–3.65) | 0.787 |
1,001–1,100 | 32 (22.2) | 23 (16.0) | 2.09 (0.53–8.25) | 0.294 | 1.40 (0.32–6.64) | 0.658 |
> 1,100 | 19 (13.2) | 5 (3.5) | 5.70 (1.15–28.33) | 0.033 | 2.10 (0.36–13.65) | 0.421 |
Chemotherapy regimens | ||||||
Capecitabine monotherapy | 63 (43.8) | 12 (8.3) | 1.00 (reference) | - | 1.00 (reference) | - |
XELOX |
81 (56.3) | 132 (91.7) | 0.12 (0.06–0.22) | < 0.001 | 0.13 (0.06–0.27) | < 0.001 |
Concurrent chemoradiotherapy | ||||||
None | 132 (91.7) | 127 (88.2) | 1.00 (reference) | - | - | - |
Yes | 12 (8.3) | 17 (11.8) | 1.78 (0.69–4.91) | 0.241 | - | - |
Previous fluorouracil-based chemotherapy | ||||||
None | 106 (73.6) | 127 (88.2) | 1.00 (reference) | - | 1.00 (reference) | - |
Yes | 38 (26.4) | 17 (11.8) | 2.68 (1.45–5.12) | 0.002 | 2.50 (1.22–5.23) | 0.013 |
HFS prevention strategy | ||||||
None | 92 (63.9) | 101 (70.1) | 1.00 (reference) | - | 1.00 (reference) | - |
Pyridoxine | 27 (18.8) | 27 (18.8) | 1.10 (0.60–2.01) | 0.762 | 0.75 (0.34–1.59) | 0.462 |
Celecoxib | 13 (9.0) | 5 (3.5) | 2.85 (0.98–8.32) | 0.055 | 1.94 (0.56–7.23) | 0.303 |
Pyridoxine plus celecoxib | 12 (8.3) | 11 (7.6) | 1.20 (0.50–2.85) | 0.683 | 1.30 (0.47–3.54) | 0.605 |
AJCC, American Joint Committee on Cancer; BSA, body surface area; CI, confidence interval; HFS, hand-foot syndrome; OR, odds ratio.
a)p-value and OR and 95% CI were calculated by univariate logistic model,
b)padjusted and ORadjusted and 95% CI were calculated by multivariate logistic model using variables including primary tumor surgery, starting capecitabine dose group, chemotherapy regimens, previous fluorouracil-based chemotherapy and HFS prevention strategy,
c)Age at capecitabine-based chemotherapy, years,
d)BSA was calculated by Wilcoxon-Mann-Whitney test,
e)Capecitabine plus oxaliplatin.
The significant variants in TYMS exons associated with CAP-HFS
SNP | Minor allele | MAF | Genotype | OR (95% CI) | p-value | |
---|---|---|---|---|---|---|
Ex-case (n=144) | Ex-control (n=144) | |||||
rs34743033 | 2R | 0.18 | 7/52/85 | 4/31/109 | 1.91 (1.16–3.16) | 1.12×10−2 |
rs3786362 | G | 0.14 | 1/29/114 | 3/47/94 | 0.38 (0.21–0.70) | 1.89×10−3 |
rs699517 | C | 0.31 | 19/71/54 | 10/48/86 | 2.12 (1.39–3.24) | 4.62×10−4 |
rs2790 | G | 0.34 | 10/61/73 | 23/64/57 | 0.58 (0.39–0.87) | 8.80×10−3 |
rs11280056 | 6-bp insertion | 0.31 | 19/71/54 | 10/48/86 | 2.12 (1.39–3.24) | 4.62×10−4 |
CAP-HFS, capecitabine-induced hand-foot syndrome; CI, confidence interval; Ex-case, extreme case; Ex-control, extreme control; MAF, minor allele frequency; OR, odds ratio; SNP, single-nucleotide polymorphism.
AJCC, American Joint Committee on Cancer; BSA, body surface area; CI, confidence interval; HFS, hand-foot syndrome; OR, odds ratio. p-value and OR and 95% CI were calculated by univariate logistic model, padjusted and ORadjusted and 95% CI were calculated by multivariate logistic model using variables including primary tumor surgery, starting capecitabine dose group, chemotherapy regimens, previous fluorouracil-based chemotherapy and HFS prevention strategy, Age at capecitabine-based chemotherapy, years, BSA was calculated by Wilcoxon-Mann-Whitney test, Capecitabine plus oxaliplatin.
CAP-HFS, capecitabine-induced hand-foot syndrome; CI, confidence interval; Ex-case, extreme case; Ex-control, extreme control; MAF, minor allele frequency; OR, odds ratio; SNP, single-nucleotide polymorphism.