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Sodium Channel-Inhibiting Drugs and Cancer Survival: Protocol for a Cohort Study Using the CPRD Primary Care Database

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Sodium Channel-Inhibiting Drugs and Cancer Survival: Protocol for a Cohort Study Using the CPRD Primary Care Database Open Access Protocol BMJ Open: first published as 10.1136/bmjopen-2016-011661 on 6 September 2016. Downloaded from Sodium channel-inhibiting drugs and cancer survival: protocol for a cohort study using the CPRD primary care database Caroline Fairhurst,1 Fabiola Martin,2,3 Ian Watt,1,2 Tim Doran,1 Martin Bland,1 William J Brackenbury3 To cite: Fairhurst C, Martin F, ABSTRACT et al Strengths and limitations of this study Watt I, . Sodium channel- Introduction: Voltage-gated sodium channel (VGSC)- inhibiting drugs and cancer inhibiting drugs are commonly used to treat epilepsy ▪ survival: protocol for a cohort The data source is a large prospectively collected and cardiac arrhythmia. VGSCs are also widely study using the CPRD primary care database containing information on primary care database. BMJ expressed in various cancers, including those of the causes of death, comorbidities and drug expos- Open 2016;6:e011661. breast, bowel and prostate. A number of VGSC- ure based on prescription data. doi:10.1136/bmjopen-2016- inhibiting drugs have been shown to inhibit cancer cell ▪ Potential immortal time bias will be considered 011661 proliferation, invasion, tumour growth and metastasis and a person-time approach implemented. in preclinical models, suggesting that VGSCs may be ▪ Cancer stage and other confounding details of ▸ Prepublication history for novel molecular targets for cancer treatment. the cancer and secondary care treatments are this paper is available online. Surprisingly, we previously found that prior exposure not available. To view these files please to VGSC-inhibiting drugs may be associated with ▪ Data on severity of epilepsy are not available. visit the journal online reduced overall survival in patients with cancer, but we ▪ General practitioner records may be of variable (http://dx.doi.org/10.1136/ were unable to control for the cause of death or quality and invariably contain incomplete data. bmjopen-2016-011661). indication for prescription. The purpose of the present study is to interrogate a different database to further Received 24 February 2016 investigate the relationship between VGSC-inhibiting Revised 3 June 2016 – β drugs and cancer-specific survival. (Nav1.1 Nav1.9) and smaller auxiliary subu- Accepted 19 July 2016 β –β 1 Methods and analysis: A cohort study using nits ( 1 4). VGSCs regulate action poten- fi http://bmjopen.bmj.com/ primary care data from the Clinical Practice Research tial ring, growth and migration of Datalink database will include patients with diagnosis electrically excitable cells, including neurons 2–5 of breast, bowel and prostate cancer (13 000). The and myocytes. Abnormal VGSC function is primary outcome will be cancer-specific survival from frequently a contributing factor in a number the date of cancer diagnosis. Cox proportional hazards of excitability-related disorders, including regression will be used to compare survival of patients epilepsy, cardiac arrhythmias, depression and taking VGSC-inhibiting drugs (including antiepileptic neuropathic pain.67Thus, a number of com- drugs and class I antiarrhythmic agents) with patients monly prescribed antiepileptic drugs and with cancer not taking these drugs, adjusting for class Ib antiarrhythmic agents, including on October 2, 2021 by guest. Protected copyright. cancer type, age and sex. Drug exposure will be treated phenytoin, lamotrigine, carbamazepine and as a time-varying covariate to account for potential valproate, elicit their therapeutic effect by immortal time bias. Various sensitivity and secondary 8 analyses will be performed. inhibiting the conductance of VGSCs. Ethics and dissemination: The project has been VGSCs are widely expressed in a number reviewed and approved by the University of York of major cancers, including carcinomas of 9–11 Ethical Review Process. Results will be presented at an the breast, prostate and colon. A number 1Department of Health international conference and published in open access of studies have shown that VGSC activity pro- Sciences, University of York, peer-reviewed journals according to the STROBE and motes the migration and invasion of meta- York, UK RECORD guidelines. 12–23 2Hull York Medical School, static cancer cells in vitro. Silencing York, UK Nav1.5 expression in breast cancer cells with 3Department of Biology, shRNA inhibits tumour growth and metasta- University of York, York, UK sis in an orthotopic xenograft breast cancer model in mice.24 On the other hand, overex- Correspondence to INTRODUCTION pression of the β1 subunit increases metasta- Dr William J Brackenbury; 25 26 [email protected]. Voltage-gated sodium channels (VGSCs) are sis. Furthermore, the VGSC-inhibiting uk composed of large pore-forming α subunits antiepileptic drug phenytoin significantly Fairhurst C, et al. BMJ Open 2016;6:e011661. doi:10.1136/bmjopen-2016-011661 1 Open Access BMJ Open: first published as 10.1136/bmjopen-2016-011661 on 6 September 2016. Downloaded from reduces migration, invasion and metastasis of cancer (https://www.cprd.com/home/), a governmental, cells in preclinical models, suggesting that VGSCs may not-for-profit research service holding anonymised – be novel molecular targets for treating metastasis.27 29 primary care records drawn from participating general We recently conducted a systematic review of clinical (primary care) practices dating back to 1987, which can and preclinical studies testing the effects of be used for public health research. Records were VGSC-inhibiting drugs in cancer.30 Only two clinical sampled in two stages. First, 125 general practices were studies were identified that explored the effect of purposively selected to be nationally representative in VGSC-inhibiting drugs in patients with cancer, and their terms of area deprivation and list size. Second, up to effect on survival and metastatic relapse was not 2500 patients were randomly sampled from each prac- clear.31 32 However, we identified 22 preclinical studies tice. The final data set contains records for ∼289 000 collectively, suggesting that a number of VGSC-inhibiting patients. These data have been specifically selected to be drugs inhibit various aspects of cancer progression, a large, general and nationally representative data set including proliferation, angiogenesis and invasion, sug- for use by multiple research groups collaborating with gesting that further investigation in this area is urgently members of the Department of Health Sciences, – required.27 28 33 52 University of York, to test a range of hypotheses. We will Using data from the QResearch primary care database, use these data to investigate the mortality of patients we recently considered the hypothesis that exposure to with breast, bowel or prostate cancer stratified by VGSC-inhibiting drugs which started prior to cancer whether or not they have a recorded prescription of a diagnosis may lead to an increased time to metastasis VGSC-inhibiting drug. Data relating to patient character- and thus improved survival time in patients with breast, istics, general practice, medical codes, clinical/consult- bowel and prostate cancer.53 We selected all patients ation details, referrals, immunisations, tests and from the database with a diagnosis of breast, bowel or therapies (prescriptions and treatments) are available. prostate cancer and a prescription for a VGSC-inhibiting We will identify and extract the records for all patients drug prior to their cancer diagnosis. This group formed with a diagnosis of breast, bowel or prostate cancer the exposed group. The unexposed group consisted of a (hereafter referred to as the index cancers) received random sample of patients with a breast, bowel or pros- before 31 December 2014 to allow at least 1 year of tate cancer diagnosis who had never had a recorded pre- follow-up for all patients. In practice we will define a scription for a VGSC-inhibiting drug. Data on the cause cancer diagnosis as any recording of one of these of death were not available and so our primary outcome cancers as a Medical Code (medcode, CPRD unique was all-cause mortality. In contrast to our hypothesis, code for the medical term selected by the general practi- and the preclinical evidence, we found that patients with tioner (GP), linked to Read codes) in the clinical data cancer prescribed VGSC-inhibiting drugs prior to their set of GP consultations in the CPRD (code list available diagnosis had an increased all-cause mortality rate rela- at clinicalcodes.org). The date of first mention of the tive to the control group.54 However, we could not rule cancer in the records will be used as a proxy for the http://bmjopen.bmj.com/ out the possibility that the elevated mortality of the date of diagnosis, since the cancer is likely to have been exposed group was due to confounding by indication, diagnosed previously in a secondary care setting. The for example, epilepsy diagnosis, or differences in base- CPRD primary care data that we will use are not linked line frailty. to cancer registry data, such as staging and secondary The purpose of the present study is to use a different care therapy (eg, chemotherapy); therefore, these data data set from the Clinical Practice Research Datalink will not be available for this study. Patients aged younger (CPRD), in which we have access to data on causes of than 25 at the time of diagnosis will be excluded as it is death and life-limiting comorbidity diagnoses, in order unlikely a person of that age would have one of these on October 2, 2021 by guest. Protected copyright. to test the hypothesis that exposure to VGSC-inhibiting three cancers. Causes of death are available and include drugs may predict altered survival of patients with an underlying cause of death and, often several, con- cancer. The objectives are to investigate: tributory causes. ▸ the relationship between VGSC-inhibiting drug use and cancer-specific and overall survival, controlling Exposure for potential confounding factors, for example, epi- We will identify which patients with cancer have (ever lepsy and baseline frailty, had) a recorded prescription for a VGSC-inhibiting drug ▸ the relationship between timing of VGSC-inhibiting (table 1).
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