Correlation Analysis of Organic Acid Comprehensive Profile Markers with Chemotherapy Induced Peripheral Neuropathy in Cancer Patients

Article information

J Korean Med. 2017;38(1):72-80
Publication date (electronic) : 2017 March 31
doi :
1East West Cancer Center, Dunsan Korean Medicine Hospital of Daejeon University
2SUNIN BIO, Chungnam National University Hospital
3Seoul Clinical Laboratories, Chungnam National University Hospital
4Department of surgery, Chungnam National University Hospital
Correspondence to:박영배(Young-Bae Park) 경희대학교 한의과대학 진단·생기능의학 교실 Tel:+82-2-958-9242, Fax:+82-2-958-9104, E-mail:, 대전광역시 중구 문화로 282 충남대학교병원, Tel: +82-42-280-8503, Fax: +82-42-257-8024, E-mail:
Received 2017 February 28; Revised 2017 March 20; Accepted 2017 March 24.



The purpose of this study is to evaluate the urinary organic acid comprehensive profile for chemotherapy induced peripheral neuropathy (CIPN).


Participants are 66 patients with CIPN who had symptom (Visual analog scale ≥ 30 mm, Eastern Cooperative Oncology Group ≤ 2). Participants were tested with organic acid comprehensive profile markers.


Positive Correlation was observed in the neurotransmitter metabolism markers, N-methyl-D-aspartate (NMDA) modulators markers, detoxification markers, energy production markers, amino acid metabolism markers, and intestinal dysbiosis markers. Especially, all the neurotransmitter metabolism markers were showed positive rate of 44%. In addition, neuro-endo-immune was associated with energy metabolism (mitochondrial dysfunction) in CIPN of cancer patient. especially detoxification, intestinal bacterial hyperplasia, vitamin deficiency (folate, complex B group, vitamin C).


Significant urinary organic acid comprehensive profile results were obtained in cancer patients who induced peripheral neuropathy by chemotherapy.

Organic Acid Comprehensive Profile Markers Associated with Chemotherapy Induced Peripheral Neuropathy

General Characteristics of Subjects

The Ranking of Cases in Organic Acid Comprehensive Profile


1. Choie MH, Jeong IS, Jeong TY, Kim KS, Yoo HS. Effects of reflexology foot massage to improve quality of life and reduce anxiety for hospitalized cancer patients undergoing chemotherapy or radioisotope therapy. J Korean Trad Oncol 2009;14:61–74.
2. Windebank AJ, Grisold W. Chemotherapy -induced neuropathy. J Peripher Nerv Syst 2008;13(1):27–46.
3. Wolf S, Barton D, Kottschade L, Grothey A, Loprinzi C. Chemotherapy-induced peripheral neuropathy: prevention and treatment strategies. European journal of cancer 2008;44(11):1507–15.
4. Housheer FH, Schilsky RL, Bain S, Berghorn EJ, Lieberman F. Diagnosis, management, and evaluation of chemotherapy-induced peripheral neuropathy. Emin Oncol 2006;33:15–49.
5. Ajani JA, Welch SR, Raber MN, Fields WS, Krakoff IH. Comprehensive criteria for assessing therapy-induced toxicity. Cancer Invest 1990;8:147–59.
6. Miller AB, Hoogstraten B, Staquet M, Winkler A. Reporting results of cancer treatment. Cancer 1981;47:207–14.
7. Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982;5:649–55.
8. Cavaletti G, Jann S, Pace A, Plasmati R, Siciliano G, Briani C, et al. Multi-center assessment of he Total Neuropathy Score for chemotherapy-induced peripheral eurotoxicity. J Peripher Nerv Syst 2006;11:135–41.
9. Kwak MK, Kim EJ, Lee ER, Kwon IG, Hwang MS. Characteristics and Quality of Life in Patients with Chemotherapy-Induced Peripheral Neuropathy. Journal of Korean oncology nursing 2010;10(2):231–9.
10. Berger T, Malayeri R, Doppelbauer A, Krajnik G, Huber H, Auff E, et al. Neurological monitoring of neurotoxicity induced by paclitaxel/cisplatin chemotherapy. Eur J Cancer 1997;33(9):1393–9.
11. Forsyth PA, Balmaceda C, Peterson K, Seidman AD, Brasher P, DeAngelis LM, et al. Prospective study of paclitaxel-induced peripheral neuropathy with quantitative sensory testing. J Neurooncol 1997;35(1):47–53.
12. Du Bois A, Schlaich M, Luck HJ, Mollenkopf A, Wechsel U, Rauchholz M, et al. Evaluation of neurotoxicity induced by paclitaxel second -line chemotherapy. Support Care Cancer 1999;7(5):354–61.
13. Kim JH, Choi KS, Kim TW, Hong YS. Quality of life in colorectal cancer patients with chemotherapy-induced peripheral neuropathy. Asian Oncology Nursing 2011;11(3):254–62.
14. Kim HY, Kang JH, Youn HJ, So HS, Song CE, Chae SY, et al. Reliability and validty of the Korean version of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire to assess chemotherapy -induced peripheral neuropathy. J Korean Acad Nurs 2014;44(6):735–42.
15. Tofthagen CS, McMillan SC, Kip KE. Development and psychometric evaluation of the chemotherapy-induced peripheral neuropathy assessment tool. Cancer Nurs 2011;34(4):E10–20.
16. Usha KM, Jayantee K, Pradeep PN. Diagnostic approach to peripheral neuropathy. Ann Indian Acad Neurol 2008;11(2):89–97.
18. Seyfried Thomas N, Flores Roberto E, Poff Angela M, D’Agostino Dominic P. Cancer as a Metabolic Disease. Carcinogenesis 2014;35(3):515–27.
19. Lord RS, Bralley JA. Laboratory evaluations for integrative and functional medicine Duluth. GA: Metametrix Institute; 2008.
20. Orgacka h, Zbytniewski Z. Excretion of vanillic acid and homovanillic acid and tissue distribution of catecholamines and their metabolites in mice with various levels of pigmentation. Endocrinol Pol 1991;42(3):471–9.

Article information Continued

Table 1

Organic Acid Comprehensive Profile Markers Associated with Chemotherapy Induced Peripheral Neuropathy

Cause of Neuropathy Markers
Energy production markers 3-Hydroxy-3-methylglutarate (HMG), a-Ketoglutarate(AKG), CIS-Aconitate, Citrate, Fumerate, Isocitrate, Malate, Succinate
Vitamin B-Complex markers a-Ketoisocaproate, a-Ketoisovalerate, a-Keto-β-methylvalerate, Methylcitric Acid, β-Hydroxyisovalerate, Xanthurenate, Ascorbate
Neurotransmitter Metabolism markers 5-Hydroxyindoleacetate (5-HIA), Homovanillate (HVA), Vanilmandelate (VMA)
Methylation cofactor markers Formiminoglutamate(FIGLU), Methylmalonate
NMDA Modulators markers Kynurenate, Picolinate, Quinolinate
Oxidative Damage and Antioxidant markers 8-Hydroxy-2-deoxyguanosine(8-OHdG), p-Hydroxyphenyllactate (HPLA)
Detoxification Indicators markers 2-Hydroxyhippuric Acid, 2-Methylhippurate, 2-Oxoglutaric Acid, a-Hydroxybutyrate (AHB), Glucarate (glucuronic acid), Orotate, Phthalate, Pyroglutamate, 4-Cresol
Ketone Body Metabolism markers Acetoacetic Acid, β-Hydroxybutyrate
Amino Acid Metabolism markers 2-Hydroxyisocaproic acid, 2-Hydroxyisovaleric acid, 3-Hydroxyglutaric acid, 3-Methylglutaric acid, 3-Methylglutaric acid, Homogentisic Acid, Mandelic Acid, Phenylpyruvic Acid
Intestinal dysbiosis markers 2-Hydroxyphenylacetate, 3,4-Dihydroxyphenylpropionate (DHPPA), 4-Cresol, 4-Hydroxyhippurate, 5-Hydroxy-methyl-furoate, Benzoate, Citramalic Acid, Furan-2,5-dicarboxylate, Furancarbonylglycine, Hippurate, Indoleacetate, Oxalate, Phenylacetate (PAA), Phenylpropionate (PPA), p-Hydroxybenzoate, p-Hydroxyphenylacetate, Tartarate, Tricarballylate, 4-Hydroxyphenylacetate, D-Lactate.

Table 2

General Characteristics of Subjects

n=66 n=66
Sex (n, %) VAS (M±SD)
 Male 2 (3.0%)  Hand 48.86 ± 13.89
 Female 64 (97.0%)  Feet 50.40 ± 16.56

Age (years/M±SD) 49.03 ± 7.85 ECOG (M±SD) 1.09 ± 0.29

Weight (kg/M±SD) 58.38 ± 8.16

Height (cm/M±SD) 158.80 ± 5.77  Moving impediment, Visit1 (M±SD) 2.63 ± 0.67

Vital sign, Visit 1 (M±SD)  Painful impediment, Visit1 (M±SD) 2.60 ± 0.63
 Systolic BP, mmHg 112.57 ± 17.39 Fixed impediment, Visit1 (M±SD) 2.73 ± 0.61
 Diastolic BP, mmHg 72.50 ± 11.23 Deficiency impediment, Visit1 (M±SD) 3.26 ± 0.55
 Heart(pulse) rate 77.27 ± 11.89
 Body temperature 36.66 ± 0.21

Vital sign, Visit 2 (M±SD)
 Systolic BP, mmHg 109.58 ± 14.09 Moving impediment, Visit2 (M±SD) 2.48 ± 0.70
 Diastolic BP, mmHg 72.11 ± 8.82 Painful impediment, Visit2 (M±SD) 2.52 ± 0.57
 Heart(pulse) rate 75.29 ± 9.08 Fixed impediment, Visit2 (M±SD) 2.57 ± 0.55
 Body temperature 36.56 ± 0.21 Deficiency impediment, Visit2 (M±SD) 3.18 ± 0.59

Smoking (n, %)
 No 66 (100.0%)

Alcohol (n, %) FACT-G Total (M±SD) 46.52 ± 7.77
 Yes 1 (1.5%)  PWB (M±SD) 17.48 ± 5.04
 No 65 (98.5%)  SWB (M±SD) 11.35 ± 4.81

CIPN (n, %)  EWB (M±SD) 5.36 ± 4.86
 Yes 66 (100.0%)  FWB (M±SD) 12.32 ± 4.79

CIPN (Hand) (n, %) CIPN-20 Total 39.03 ± 8.26
 Yes 65 (98.5%)
 No 1 (1.5%)

CIPN (Feet) (n, %)
 Yes 64 (97.0%)
 No 2 (3.0%)

Past History (n, %)
 Yes 66 (100.0%)

Taking a medication History (n, %)
 Yes 48 (72.7%)
 No 18 (27.3%)

Adverse Reactions (n, %)
 Yes 5 (7.6%)
 No 61 (92.4%)

Changes in concomitant medications (n, %)
 Yes 6 (9.1%)
 No 60 (90.9%)

CIPN: Chemotherapy Induced Peripheral Neuropathy; VAS: Visual Analog Scale; ECOG: Eastern Cooperative Oncology Group; FACT-G: Functional Assessment of Cancer Therapy-General

Table 3

The Ranking of Cases in Organic Acid Comprehensive Profile

Ranking Markers Reference Range (mmol/mol creatinine) Positive Rate

Abnormal Cases Rate Mean ± Standard Deviation
1 Hippurate 0.00–314.32 25 38% 694.12±444.99
2 Phenylpyruvate 0.00–0.06 20 30% 1.47±6.25
3 5-Hydroxyindoleacetate 0.00–5.31 16 24% 7.86±3.50
3 2-Hydroxyhippurate 0.00–0.91 16 24% 41.43±76.88
5 Citrate 9.82–210.55 15 23% 280.36±73.51
5 Vanilmandelate 0.11–0.82 15 23% 1.03±0.40
7 Homovanillate 0.00–2.07 13 20% 2.45±0.45
7 α-Hydroxybutyrate 0.00–0.42 13 20% 0.63±0.46
9 Tricarballylate 0.00–0.13 12 18% 0.19±0.05
10 Quinolinate 0.25–1.71 11 17% 2.13±0.38