Prevention of chemotherapy-induced peripheral neuropathy: a matter of personalized treatment?

Abstract

Peripheral neuropathy is a frequently occurring side-effect of neurotoxic chemotherapy, negatively influencing the quality of life of cancer patients [1.Markman M. Chemotherapy-induced peripheral neuropathy: an increasing concern for oncologists.Curr Oncol Rep. 2005; 7: 159-160Crossref PubMed Scopus (6) Google Scholar, 2.Argyriou A.A. Bruna J. Marmiroli P. et al.Chemotherapy-induced peripheral neuropathy (CIPN): an update.Crit Rev Oncol Hematol. 2012; 82: 51-77Crossref PubMed Scopus (371) Google Scholar, 3.Markman M. Clinical response versus clinical benefit in oncology: not necessarily equivalent terms.J Cancer Res Clin Oncol. 1997; 123: 363-364Crossref PubMed Scopus (3) Google Scholar]. Platinum analogues and antitubulins are among the most feared agents in this respect [4.Verstappen C.C. Heimans J.J. Hoekman K. et al.Neurotoxic complications of chemotherapy in patients with cancer: clinical signs and optimal management.Drugs. 2003; 63: 1549-1563Crossref PubMed Scopus (322) Google Scholar, 5.Grisold W. Cavaletti G. Windebank A.J. Peripheral neuropathies from chemotherapeutics and targeted agents: diagnosis, treatment, and prevention.Neuro Oncol. 2012; 14: 45-54Crossref Scopus (317) Google Scholar]. Development of chemotherapy-induced peripheral neuropathy (CIPN) also frequently has its impact on anticancer therapy, leading to dose reduction or discontinuation of neurotoxic treatment. Preventive measures to abolish or decrease CIPN are currently scarce, and not routinely used in clinical oncology practice, perhaps with the exception of Ca–Mg infusions before and after oxaliplatin treatment [6.Gamelin L. Boisdron-Celle M. Morel A. et al.Oxaliplatin-related neurotoxicity: interest of calcium-magnesium infusion and no impact on its efficacy.J Clin Oncol. 2008; 26: 1188-1190Crossref PubMed Scopus (87) Google Scholar, 7.Grothey A. Nikcevich D.A. Sloan J.A. et al.Intravenous calcium and magnesium for oxaliplatin-induced sensory neurotoxicity in adjuvant colon cancer: NCCTG N04C7.J Clin Oncol. 2011; 29: 421-427Crossref PubMed Scopus (166) Google Scholar]. Patient-related predisposing factors like higher age, pre-existing neuropathy and concomitant disease such as diabetes mellitus may contribute to the development of CIPN [8.Quasthoff S. Hartung H.P. Chemotherapy-induced peripheral neuropathy.J Neurol. 2002; 249: 9-17Crossref PubMed Scopus (731) Google Scholar]. Treatment-related factors such as cumulative dose, dose intensity and pharmacokinetics are influential as well [9.Mielke S. Sparreboom A. Mross K. Peripheral neuropathy: a persisting challenge in paclitaxel-based regimes.Eur J Cancer. 2006; 42: 24-30Abstract Full Text Full Text PDF PubMed Scopus (138) Google Scholar]. However, interindividual variability in toxicity and response to treatment is an important problem in clinical practice: in fact, we are not able to predict which of the patients are likely to develop CIPN. Genetic factors might be of importance in this respect [10.Mielke S. Individualized chemotherapy with paclitaxel.Curr Opin Oncol. 2007; 19: 585-589Crossref Scopus (27) Google Scholar]. However, literature data on the topic of pharmacogenomics in the development of CIPN are inconsistent so far [11.Cavaletti G. Alberta P. Marmiroli P. Chemotherapy-induced peripheral neurotoxicity in the era of pharmacogenomics.Lancet Oncol. 2011; 12: 1151-1161Abstract Full Text Full Text PDF PubMed Scopus (95) Google Scholar]. In this issue of Annals of Oncology, Hertz et al. describe a very interesting pharmacogenomic approach with the potential of CIPN prevention in breast cancer patients treated with paclitaxel (Taxol) [12.Hertz D.L. Roy S. Motsinger-Reif A.A. et al.CYP2C8*3 increases risk of neuropathy in breast cancer patients treated with paclitaxel.Ann Oncol. 2013; 24: 1472-1478Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar]. Paclitaxel is primarily metabolized by CYP2C8, and exposure to paclitaxel in cancer patients is correlated with CYP2C8 activity. Single-nucleotide polymorphisms in the CYP2C8, such as the *3(rs11572080 R139K and rs10509681 K339R) variant, influence paclitaxel metabolism, leading to increased drug exposure [12.Hertz D.L. Roy S. Motsinger-Reif A.A. et al.CYP2C8*3 increases risk of neuropathy in breast cancer patients treated with paclitaxel.Ann Oncol. 2013; 24: 1472-1478Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar]. In recent studies, the CYP2C8*3 variant was reported to lead to increased paclitaxel-induced peripheral neuropathy [13.Gréen H. Söderkvist P. Rosenberg P. et al.Pharmacogenetic studies of paclitaxel in the treatment of ovarian cancer.Basic Clin Pharmacol Toxicol. 2009; 104: 130-137Crossref PubMed Scopus (105) Google Scholar, 14.Leskelä S. Jara C. Leandro-Garcia L.J. et al.Polymorphisms in cytochromes P450 2C8 and 3A5 are associated with paclitaxel neurotoxicity.Pharmacogenomics. 2011; 112: 121-129Crossref Scopus (97) Google Scholar, 15.Hertz D.L. Motsinger-Reif A.A. Drobish A. et al.CYP2C8*3 predicts benefit/risk profile in breast cancer patients receiving neoadjuvant paclitaxel.Breast Cancer Res Treat. 2012; 134: 401-410Crossref PubMed Scopus (72) Google Scholar]. Breast cancer patients carrying the CYP2C8*3 variant were also more likely to achieve clinical complete response from neoadjuvant paclitaxel treatment [15.Hertz D.L. Motsinger-Reif A.A. Drobish A. et al.CYP2C8*3 predicts benefit/risk profile in breast cancer patients receiving neoadjuvant paclitaxel.Breast Cancer Res Treat. 2012; 134: 401-410Crossref PubMed Scopus (72) Google Scholar]. In the current, larger study, 411 paclitaxel-treated patients were eligible for CYP2C8*3 genotype analysis. As hypothesized, the risk of paclitaxel-induced peripheral neuropathy was highest in patients who were homogenous for the CYP2C8*3 variant, and lowest in patients homogenous for the wild-type allele (overall log-rank P = 0.006). Using the entire cohort, each CYP2C8*3 allele approximately doubled the risk for grade 2+ (NCI CTCAE criteria) neuropathy. Furthermore, non-European-American patients were at higher risk than European-American patients of a similar genotype (P = 0.030). The authors conclude that patients who are known to carry CYP2C8*3, and particularly those known to be homogenous, should be assumed to be at increased risk of paclitaxel-induced peripheral neuropathy. Furthermore, beyond CYP2C8 genotype, non-European individuals were at an increased risk of developing CIPN in this study [12.Hertz D.L. Roy S. Motsinger-Reif A.A. et al.CYP2C8*3 increases risk of neuropathy in breast cancer patients treated with paclitaxel.Ann Oncol. 2013; 24: 1472-1478Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar]. Important merits of the current study are the single genotype–phenotype association that was selected a priori, and the fact that almost all patients were treated with paclitaxel only. Most other studies in this field used patient populations treated with a combination of potential neurotoxic chemotherapies and/or a hypothesis-generating pharmacogenomic approach, potentially underestimating the role of single polymorphisms. For instance, Marsh et al. [16.Marsh S. Paul J. King C.R. et al.Pharmacogenetic assessment of toxicity and outcome after platinum plus taxane chemotherapy in ovarian cancer: the Scottish randomized trial in ovarian cancer.J Clin Oncol. 2007; 25: 4528-4535Crossref PubMed Scopus (217) Google Scholar] could not demonstrate reproducible significant associations between the genotype (27 selected polymorphisms) and the outcome or toxicity in a large study of ovarian cancer patients (n = 914) treated with platinum plus taxane chemotherapy. A limitation of the study by Hertz et al. [12.Hertz D.L. Roy S. Motsinger-Reif A.A. et al.CYP2C8*3 increases risk of neuropathy in breast cancer patients treated with paclitaxel.Ann Oncol. 2013; 24: 1472-1478Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar] is its retrospective nature, leading to differences in paclitaxel treatment and schedule, and potentially leading to non-uniform (neuro)toxicity data collection. Quite rightly, the authors propose to organize a prospective trial to substantiate their findings, and to demonstrate the clinical utility of individualizing paclitaxel therapy based on CYP2C8 genotype profiling [12.Hertz D.L. Roy S. Motsinger-Reif A.A. et al.CYP2C8*3 increases risk of neuropathy in breast cancer patients treated with paclitaxel.Ann Oncol. 2013; 24: 1472-1478Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar]. In general, a pharmacogenomic approach with the potential of identifying patients with a high risk of neurotoxicity development to a given chemotherapeutic agent is rather intriguing. Variants in genes relevant to drug disposition, metabolism and drug action can influence the patient's exposure and sensitivity to the drug [15.Hertz D.L. Motsinger-Reif A.A. Drobish A. et al.CYP2C8*3 predicts benefit/risk profile in breast cancer patients receiving neoadjuvant paclitaxel.Breast Cancer Res Treat. 2012; 134: 401-410Crossref PubMed Scopus (72) Google Scholar]. For paclitaxel, most studies focus on mutations in biologically relevant candidate genes such as CYP2C8, CYP3A4, CYP3A5 and ABCB1 [11.Cavaletti G. Alberta P. Marmiroli P. Chemotherapy-induced peripheral neurotoxicity in the era of pharmacogenomics.Lancet Oncol. 2011; 12: 1151-1161Abstract Full Text Full Text PDF PubMed Scopus (95) Google Scholar, 15.Hertz D.L. Motsinger-Reif A.A. Drobish A. et al.CYP2C8*3 predicts benefit/risk profile in breast cancer patients receiving neoadjuvant paclitaxel.Breast Cancer Res Treat. 2012; 134: 401-410Crossref PubMed Scopus (72) Google Scholar]. For several other neurotoxic agents (e.g. carboplatin, vincristine, thalidomide, oxaliplatin, cisplatin), positive associations have been found between CIPN development and genotype. However, other studies—partly with similar chemotherapeutic agents and genes tested—failed to show positive associations between the genotype and risk of CIPN development. As such, data are still inconclusive with regard to the potential role of pharmacogenomics in the risk management of CIPN [11.Cavaletti G. Alberta P. Marmiroli P. Chemotherapy-induced peripheral neurotoxicity in the era of pharmacogenomics.Lancet Oncol. 2011; 12: 1151-1161Abstract Full Text Full Text PDF PubMed Scopus (95) Google Scholar]. Also for non-neurological chemotherapy-induced toxicity, genotyping has been studied in terms of risk management. A recent study demonstrated the clinical value of prospective screening for dihydropyrimidine dehydrogenase deficiency, reducing the risk of severe toxicity (diarrhea) in advanced colorectal cancer patients treated with capecitabine [17.Deenen M.J. Tol J. Burylo A.M. et al.Relationship between single nucleotide polymorphisms and haplotypes in DPYD and toxicity and efficacy of capecitabine in advanced colorectal cancer.Clin Cancer Res. 2011; 17: 3455-3468Crossref PubMed Scopus (156) Google Scholar]. To further address the value of pharmacogenomic approaches for the optimization of patient care in terms of CIPN prevention in cancer therapy, several suggestions are proposed [11.Cavaletti G. Alberta P. Marmiroli P. Chemotherapy-induced peripheral neurotoxicity in the era of pharmacogenomics.Lancet Oncol. 2011; 12: 1151-1161Abstract Full Text Full Text PDF PubMed Scopus (95) Google Scholar, 12.Hertz D.L. Roy S. Motsinger-Reif A.A. et al.CYP2C8*3 increases risk of neuropathy in breast cancer patients treated with paclitaxel.Ann Oncol. 2013; 24: 1472-1478Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar]. First, only specific genes that have been associated with CIPN course and severity should be studied in such a clinical study. As such, candidate genes of interest are to be identified beforehand. Second, strict and well-defined inclusion criteria should be used in future studies. Ideally, only similar chemotherapeutic regimens for a specific indication/type of malignancy should be formulated. A combination of neurotoxic anticancer agents is potentially of less value in this respect than neurotoxic monochemotherapy. Third, such a study protocol should be strict with regard to the stratification for potential other CIPN risk factors, such as diabetes mellitus, age, alcohol intake, concurrent medication and symptomatic treatment. Lastly, the method leading to clinical assessment of CIPN severity is of pivotal importance, and should be described in detail beforehand. In everyday clinical practice, the assessment of CIPN is difficult, and differs among physicians in the field of oncology and neurology. The NCI-CTC criteria are used preferentially in oncology trials, whereas neurologists usually carry out neurological examinations, and score CIPN according to (sub)clinical neuropathy scales such as the total neuropathy score [18.Cornblath D.R. Chaudhry V. Carter K. et al.Total neuropathy score: validation and reliability study.Neurology. 1999; 53: 1660-1664Crossref PubMed Google Scholar, 19.Frigeni B. Piatti M. Lanzani F. et al.Chemotherapy-induced peripheral neurotoxicity can be misdiagnosed by the National Cancer Institute Common Toxicity scale.J Peripher Nerv Syst. 2011; 16: 228-236Crossref PubMed Scopus (56) Google Scholar]. Furthermore, interobserver variability is a potential pitfall in grading of CIPN severity [20.Postma T.J. Heimans J.J. Muller M.J. et al.Pitfalls in grading severity of chemotherapy-induced peripheral neuropathy.Ann Oncol. 1998; 9: 739-744Abstract Full Text PDF PubMed Scopus (169) Google Scholar]. Currently, the optimal way of sufficiently describing the clinical burden of CIPN is still a matter of debate: e.g. inclusion of clinical versus subclinical measures, and inclusion and choice of physician versus patient reported outcome measures [21.Griffith K.A. Merkies I.S. Hill E.E. et al.Measures of chemotherapy-induced peripheral neuropathy: a systematic review of psychometric properties.J Peripher Nerv Syst. 2010; 15: 314-325Crossref PubMed Scopus (70) Google Scholar, 22.Calhoun E.A. Welshman E.E. Chang C.H. et al.Psychometric evaluation of the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (Fact/GOG-Ntx) questionnaire for patients receiving systemic chemotherapy.Int J Gynecol Cancer. 2003; 13: 741-748Crossref PubMed Scopus (242) Google Scholar, 23.Postma T.J. Aaronson N.K. Heimans J.J. et al.The development of an EORTC quality of life questionnaire to assess chemotherapy-induced peripheral neuropathy: the QLQ-CIPN20.Eur J Cancer. 2005; 41: 1135-1139Abstract Full Text Full Text PDF PubMed Scopus (304) Google Scholar]. Recently, a unique multidisciplinary, multicenter collaboration has been achieved in order to study and optimize outcome measures in CIPN: the CI-PERINOMS study group [24.The CI-PERINOMS study group CI-PERINOMS: chemotherapy-induced peripheral neuropathy outcome measures study.J Peripher Nerv Syst. 2009; 14: 69-71Crossref PubMed Scopus (21) Google Scholar]. The CI-PERINOMS group studies and compares several outcome measures in CIPN, in order to facilitate CIPN assessment. The first step towards this goal has been published recently [25.Cavaletti G. Cornblath D.R. Merkies I.S. et al.The chemotherapy-induced peripheral neuropathy outcome measures standardization study: from consensus to the first validity and reliability findings.Ann Oncol. 2013; 24: 454-462Abstract Full Text Full Text PDF PubMed Scopus (209) Google Scholar]. Additional studies are foreseen shortly. As for now, a combination of clinical, physician-driven and patient reported outcome measures is potentially the most optimal way to assess CIPN [25.Cavaletti G. Cornblath D.R. Merkies I.S. et al.The chemotherapy-induced peripheral neuropathy outcome measures standardization study: from consensus to the first validity and reliability findings.Ann Oncol. 2013; 24: 454-462Abstract Full Text Full Text PDF PubMed Scopus (209) Google Scholar]. The combination of the use of sound, validated outcome measures for CIPN in future prospective, clinical trials with optimal inclusion criteria for chemotherapy, cancer population and pharmacogenomic approach will surely increase our knowledge of the genetic role in CIPN development. As such, a step forward towards personalized treatment could be achieved, ultimately leading to the prevention of CIPN. The authors have declared no conflicts of interest.