Elsevier

Cancer Epidemiology

Volume 55, August 2018, Pages 170-175
Cancer Epidemiology

Domperidone use and risk of primary liver cancer in the Clinical Practice Research Datalink

https://doi.org/10.1016/j.canep.2018.06.009Get rights and content

Highlights

  • Overall, the study found no association between domperidone use and liver cancer.

  • Among women there was an elevated risk among those who received the greatest number of prescriptions.

  • These results do not support the hypothesis that increasing prolactin level via domperidone is likely to decrease the risk of liver cancer.

  • The indication of increased risk among women warrants further study.

Abstract

Background

Pronounced sex-disparity in liver cancer suggests a role for hormones, one of which could be prolactin. Stimulation of prolactin production in mice via domperidone has been reported to decrease hepatocarcinogenesis, thus may have chemopreventive potential. To study the effect of domperidone in humans, a large medical records study was conducted.

Methods

Based in the Clinical Practice Research Datalink, 1921 liver cancer cases and 7681 controls were identified. Conditional logistic regression was employed to estimate odds ratios (OR) and 95% confidence intervals (CI). Domperidone use was analyzed overall, and by number of prescriptions and cumulative dose.

Results

Comparing ever- versus never-use, there was no association between domperidone and liver cancer among men (OR = 1.06, 95% CI: 0.76–1.48) or women (OR = 1.21, 95% CI: 0.82–1.76). Among men, there was no association with dose or number of prescriptions, while among women who received the highest doses (OR2700 mg vs. 0 mg = 2.52, 95% CI: 1.18–5.41, p-trend = 0.02) and greatest number of prescriptions (OR≥11 Rx vs. 0 Rx = 3.17, 95% CI: 1.07–9.40, p-trend = 0.02) there was a significantly increased risk, although there was no evidence of heterogeneity in the results by gender.

Conclusion

Domperidone use was not associated with decreased liver cancer risk among all study participants. Among women, an increased risk at highest levels of exposure warrants further study.

Introduction

Liver cancer is the sixth most commonly occurring cancer in the world and the second leading cause of cancer mortality [1]. In almost all areas of the world, the incidence of liver cancer is three- to four-fold higher among men than women [2]. Men also have higher recurrence rates and poorer survival after diagnosis of liver cancer than do women [3,4]. Reasons for this gender disparity are not clear. While some major risk factors, such as infection with hepatitis B virus (HBV) or hepatitis C virus (HCV), excessive alcohol consumption, and cigarette smoking, are more common among men, these factors do not fully account for the gender differences in liver cancer incidence and survival [2].

A role for endogenous hormones in the gender discrepancy in liver cancer risk has been hypothesized, with most speculation focusing on testosterone or estradiol [[5], [6], [7], [8]]. However, the role of estrogenic exposures remains unclear, as studies have reported mixed results for parity [[9], [10], [11], [12], [13], [14], [15]], oral contraceptive use [16], and menopausal hormone therapy [15,17,18], although two studies have shown an increased liver cancer risk associated with bilateral oophorectomy [15,18]. Other hormones could also play a role in liver cancer development. Prolactin is an estrogen-responsive hormone secreted by the pituitary gland that is expressed at higher levels among women than among men [19]. While its role in reproduction, including lactation, menstruation, and sexual behavior, is well characterized, prolactin also plays extensive roles in numerous other processes including immune response regulation [20]. Prolactin exhibits immunostimulatory properties and protects against inflammation under severe stress, such as trauma [21].

Whether the higher levels of prolactin found in women could underlie the gender difference in liver cancer risk is not known. Prolactin secretion, however, can be increased by domperidone, a dopamine antagonist that is commonly prescribed for the amelioration of nausea and vomiting [22,23]. Experiments in mice, one of which employed domperidone, have reported that stimulation of prolactin production decreased liver tumorigenesis [24,25]. As liver cancer rates are rising and survival rates remain poor, identification of possible chemopreventive agents could provide an effective intervention in high-risk populations. Thus, to examine the hypothesis that domperidone use, and by extension higher prolactin levels, is associated with decreased liver cancer risk in humans, a large study in a medical records database was undertaken.

Section snippets

Study population

A nested case-control study was conducted within the Clinical Practice Research Datalink CPRD, a United Kingdom (UK) database of anonymized, population-based electronic medical records. In the UK, universal health coverage is provided by the National Health Service, and the age and gender distributions in the CPRD are representative of the general UK population [26,27]. The CPRD contains medical data on approximately 8.5% of the population. Data, including demographic information, medical

Results

Overall, the median length of enrollment in CPRD was 10.3 years (range 6.5–14.6 years), with the median being slightly longer among men (10.4 years) than among women (9.9 years). Characteristics of the cases and controls are shown in Table 1. Among both men and women, cases were more likely than controls to be current smokers, have chronic HBV and/or HCV infection, have diabetes, have an alcohol related-disorder and have a rare genetic disorder. Male cases, compared to female cases, were more

Discussion

This study comprehensively evaluated the association between domperidone use and liver cancer, utilizing medical data recorded by general practitioners. Overall, no association between use of domperidone and liver cancer risk was identified. There was, however, a significantly increased risk among women who received the greatest number of prescriptions. There was no evidence of heterogeneity in the gender specific results, however, suggesting that the results among women will need confirmation

Conflict of interest

The authors declare no potential conflicts of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. The research was approved by the Institutional Review Board of the National Cancer Institute. This study does not contain any animal experiments performed by any of the authors.

Submission declaration

This manuscript has not been published and is not under consideration for publication elsewhere.

Authorship contributions

Conception and design: Baiyu Yang, Barry I. Graubard, Katherine A. McGlynn

Financial and administrative support: Katherine A. McGlynn

Collection and assembly of data: Jake E. Thistle, Baiyu Yang, Jessica L. Petrick, Katherine A. McGlynn

Data analysis: Jake E. Thistle, Baiyu Yang, Katherine A. McGlynn

Data interpretation: All authors

Manuscript writing: Jake E. Thistle, Katherine A. McGlynn

Review and approval of manuscript: All authors

Grant support

NIH Intramural Research Program, National Cancer Institute

Acknowledgements

The authors wish to thank Drs. Michael B. Cook, Shahinaz Gadalla and Julia Gage of DCEG, NCI for participating in covariate creation. The authors wish to thank Emily Carver and David Ruggieri of Information Management Systems, Inc. for assistance with data curation and file preparation.

References (54)

  • I.O. Ng et al.

    Better survival in women with resected hepatocellular carcinoma is not related to tumor proliferation or expression of hormone receptors

    Am. J. Gastroenterol.

    (1997)
  • H. Kuper et al.

    Estrogens, testosterone and sex hormone binding globulin in relation to liver cancer in men

    Oncology

    (2001)
  • M.W. Yu et al.

    Elevated serum testosterone levels and risk of hepatocellular carcinoma

    Cancer Res.

    (1993)
  • J.M. Yuan et al.

    A cohort study of serum testosterone and hepatocellular carcinoma in Shanghai, China

    Int. J. Cancer.

    (1995)
  • M.W. Yu et al.

    Hormonal markers and hepatitis B virus-related hepatocellular carcinoma risk: a nested case-control study among men

    J. Natl. Cancer Inst.

    (2001)
  • C.W. Fwu et al.

    Hepatitis B virus infection and hepatocellular carcinoma among parous Taiwanese women: nationwide cohort study

    J. Natl. Cancer Inst.

    (2009)
  • M. Kanazir et al.

    Risk factors for hepatocellular carcinoma: a case-control study in Belgrade (Serbia)

    Tumori

    (2010)
  • C. La Vecchia et al.

    Reproductive factors and the risk of hepatocellular carcinoma in women

    Int. J. Cancer

    (1992)
  • I. Plesko et al.

    Parity and cancer risk in Slovakia

    Int. J. Cancer

    (1985)
  • J.L. Stanford et al.

    Reproductive factors in the etiology of hepatocellular carcinoma. The WHO collaborative study of neoplasia and steroid contraceptives

    Cancer Causes Control

    (1992)
  • C.H. Wu et al.

    Parity, age at first birth, and risk of death from liver cancer: evidence from a cohort in Taiwan

    J. Gastroenterol. Hepatol.

    (2011)
  • E. Fernandez et al.

    Hormone replacement therapy and cancer risk: a systematic analysis from a network of case-control studies

    Int. J. Cancer

    (2003)
  • K.A. McGlynn et al.

    Reproductive factors, exogenous hormone use and risk of hepatocellular carcinoma among US women: results from the liver cancer pooling project

    Br. J. Cancer

    (2015)
  • M. Vekemans et al.

    Influence of age on serum prolactin levels in women and men

    Br. Med. J.

    (1975)
  • M.E. Freeman et al.

    Prolactin: structure, function, and regulation of secretion

    Physiol. Rev.

    (2000)
  • L.Y. Yu-Lee

    Prolactin modulation of immune and inflammatory responses

    Recent Prog. Horm. Res.

    (2002)
  • J.A. Barone

    Domperidone: a peripherally acting dopamine2-receptor antagonist

    Ann. Pharmacother.

    (1999)
  • Cited by (3)

    • Quantifying bias in epidemiologic studies evaluating the association between acetaminophen use and cancer

      2021, Regulatory Toxicology and Pharmacology
      Citation Excerpt :

      Most primary liver cancers are coded as ‘Primary malignant neoplasm of liver’ (READ code B150.00). For this reason, we define our outcome of interest as ‘Primary liver cancer’, similar to what was done by other studies performed in CPRD (Hagberg et al., 2016; McGlynn et al., 2016; Thistle et al., 2018). For all cancers, we restrict consideration to the earliest event for each case, which determines the date of the outcome, which was then used as the index date for cases in the case-control studies.

    • Comparison of efficiency of TACE plus HIFU and TACE alone on patients with primary liver cancer

      2019, Journal of the College of Physicians and Surgeons Pakistan
    View full text