Chemotherapy Induced Peripheral Neuropathy
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Department of Molecular and Clinical Cancer Medicine and the Department of Molecular and Clinical Pharmacology Institute of Translational Medicine Chemotherapy Induced Peripheral Neuropathy: Clinical Aspects and Molecular Genetics Thesis submitted in accordance with the requirements of the University of Liverpool for the degree of Doctor in Medicine by Joanne Cliff October 2018 Supervisors: Dr Rosemary Lord and Professor Sir Munir Pirmohamed Disclaimer: The entirety of the work presented in this thesis, unless otherwise stated, is that of the author. ABSTRACT As the treatment of cancer evolves, complexity is increasing with the range of and number therapies now being offered to patients. Patients are living with or beyond cancer for longer periods of time. Cancer survivorship issues are therefore gaining greater importance, and long term toxicities from cancer therapies must be acknowledged and addressed. One such adverse effect is chemotherapy induced peripheral neuropathy (CIPN). Many widely used cytotoxic agents lead to peripheral neuropathy in a proportion of patients. For some, the neuropathy settles after completion of treatment but for a small, but not insignificant minority, the neuropathy persists. The aims of this project were to systematically explore the clinical and molecular genetic risk factors, and effect on quality of life, of this potentially debilitating toxicity. Chapter 1 comprises an introduction to the topic including a narrative review of clinical risk factors. Choice of agent, duration of infusion and cumulative dose affect the development of CIPN. Patient-related factors are less clear, but body mass index and race appear to be of particular interest as possible determinants. Chapter 2 includes systematic reviews of the impact of diabetes and alcohol intake on risk of CIPN which identified a number of studies but meta-analysis was not possible and no definitive conclusion on effect could be drawn as findings from the included studies were contradictory. Chapter 3 describes a comprehensive systematic review of pharmacogenetic studies related to the risk of developing CIPN. This identified 93 studies for inclusion with a median sample size of 118 patients. GSTP Ile105Val was the most commonly investigated SNP, with SNPs in the excision repair genes, ABC transporter genes and CYP 3A4, 3A5 and 2C8 genes also frequently investigated. Meta-analysis was carried out where possible, the majority of which showed no significant association. CYP3A4*22 did show significant association but this data was based on two cohorts within the same study. Many studies however were not eligible for inclusion in meta-analysis due to lack of sufficient data presented. Pharmacogenetic studies in this field are fraught with methodological flaws. Accurate phenotypic definition and recognising potential clinical confounding factors in research populations is key to improving the quality of research. Chapter 4 presents a candidate gene study in both a taxane- and an oxaliplatin-treated cohort of patients 187 taxane- treated patients were included for genotype analysis. Based on the systematic review, seven single nucleotide polymorphisms (SNPs) were identified for investigation. However, no significant associations were identified for CYP2C8*3, CYP3A4*22, EPHA4, EPHA5, EPHA6, FGD4, and XKR4. For the oxaliplatin cohort of 120 patients, three SNPs, ACYP2 rs843748, FARS2 rs17140129 and TAC1 rs10486003, were investigated based on previous GWAS results. Again, no significant effects were seen in this population. A strength of this pharmacogenetic study was use of both medical assessment of CIPN and patient reported outcome to support phenotypic definition. The quality of life study is presented in chapter 5 and confirmed a statistically significant correlation between patient reported neuropathy scores and both quality of life and functional measures. In the paclitaxel cohort, the sensory score was negatively correlated with a functional score at 6 months post- chemotherapy. In the oxaliplatin cohort, at the end of the treatment time point for those who received >6 cycles, there was a significant negative correlation between the sensory score and both functional and global QoL scores. More consistently over time, however, correlations with QoL and functional scores in those who scored more highly on the motor aspects of the CIPN20 module were seen. Persistent neuropathy leading to higher scores in the motor aspects of the CIPN20 showed a statistically significant difference in functional score (p=0.002) and global QoL score (p=0.026) at the 18 month time-point. Finally, chapter 6 comprises discussion of the work and concludes that future work needs to build a clinical and genetic model upon which to assess an individual’s risk for development of this toxicity which can impact quality of life and function many months and years after treatment. Improving assessment and standardising outcome measurements, potentially through the development of consortia to further the pharmacogenetic research aspect of cancer drug safety is key to improving the evidence base to build risk models which may start to improve individualisation of treatment and develop a more personalised assessment of risk of harm. i Abstract………………………………………………………………………….……………….…………… i List of tables……………………………………………………………………..……………….………… iv List of figures …………………………………………………………………...……………….………… vii Acknowledgements ……………………………………………………………..……………….……… x CHAPTER 1. Introduction …………………………………………………………………….………. 1 1.1 Presentation, pharmacology and pathophysiology of CIPN ……………………. 3 1.2 Incidence and risk factors for development of CIPN ……………………………….. 8 1.3 Assessment and grading of severity of CIPN ……………………………..……………. 19 1.4 Prophylaxis and treatment of CIPN …………………………………………………………. 25 1.5 Pharmacogenetics and its role in clinical practice ……………………….…………… 27 1.6 Aims of the thesis …………………………………………………………..……………….……… 28 CHAPTER 2. Clinical determinants of chemotherapy induced peripheral neuropathy 2.1 Chapter Introduction ……………………………………………………………………….……… 31 2.2 Methods ……………………………………………………………………..……………….………… 32 2.3 Results ……………………………………………………………………………………….…………… 37 2.4 Discussion …………………………………………………………………...……………….………… 78 2.5 Conclusion …………………………………………………………………..……………….………… 80 CHAPTER 3: The molecular genetics of chemotherapy induced peripheral neuropathy 3.1 Chapter Introduction ……………………………………………………………………….……… 83 3.2 Methods ……………………………………………………………………..……………….………… 83 3.3 Results ……………………………………………………………………………………….…………… 86 3.4 Discussion …………………………………………………………………...……………….………… 140 3.5 Conclusion …………………………………………………………………..……………….………… 143 CHAPTER 4. Pharmacogenetic study: A candidate gene study to investigate putative associations with CIPN 4.1 Chapter Introduction ……………………………………………………………………….……… 145 4.2 Methods ……………………………………………………………………..……………….………… 153 ii 4.3 Results ……………………………………………………………………………………….…………… 159 4.4 Discussion …………………………………………………………………...……………….………… 168 4.5 Conclusion …………………………………………………………………..……………….………… 170 CHAPTER 5. Impact of CIPN on quality of life: clinical cohort study 5.1 Chapter introduction ……………………………………………………………………….……… 173 5.2 Methods ……………………………………………………………………..……………….………… 179 5.3 Results ……………………………………………………………………………………….…………… 183 5.4 Discussion …………………………………………………………………...……………….………… 198 5.5 Conclusion …………………………………………………………………..……………….………… 201 CHAPTER 6. DISCUSSION AND FUTURE DIRECTIONS……………….……………….……. 202 BIBLIOGRAPHY ……………………………………………………………...……………….…………… 206 iii LIST OF TABLES Table 1.1 A summary of the different grading scales in use for CIPN ………………… 22 Table 1.2 Different forms of the Total Neuropathy Score……………………………….…. 23 Table 2.1 Search strategy for systematic review of diabetes and risk of CIPN……………………………………………………………………………….…………….……. 34 Table 2.2 Search strategy for systematic review of alcohol consumption and risk of CIPN………………………………………………………………………………………… 35 Table 2.3 Search strategy for systematic review for scheduling of drug and risk of CIPN………………………………………………………………………….…………….. 36 Table 2.4 Summary of included papers for systematic review of effect of concurrent diabetes on risk of developing CIPN…………………………………. 41 Table 2.5 Table of included studies for the systematic review of association between alcohol consumption and CIPN……………………………………………. 46 Table 2.6 Included docetaxel studies for systematic review of dose dense versus less dose dense schedules and effect on risk of CIPN………………. 50 Table 2.7 Included paclitaxel studies for systematic review of dose dense versus less dose dense schedules and effect on risk of CIPN………..……. 59 Table 2.8 Included nab- paclitaxel studies for systematic review of dose dense versus less dose dense schedules and effect on risk of CIPN……. 67 Table 2.9 Included cisplatin studies for systematic review of dose dense versus less dose dense schedules and effect on risk of CIPN………………. 69 Table 2.10 Included oxaliplatin studies for systematic review of dose dense versus less dose dense schedules and effect on risk of CIPN………………. 73 Table 2.11 Included ixabepilone studies for systematic review of dose dense versus less dose dense schedules and effect on risk of CIPN………………. 76 Table 3.1 Details of search strategy…………………………………………………….…………….. 87 Table 3.2 Summary of drugs investigated…………………………………………….……………. 92 Table 3.3 Methods of assessment of CIPN………………………………………….……………… 95 Table 3.4 Included oxaliplatin-based studies for systematic review of pharmacogenetics of CIPN…………………………………………………….…………… 97 iv Table