The presence of elevated systemic inflammation in people with advanced non-small cell lung cancer (NSCLC) is associated with significantly shorter survival following carboplatin-based chemotherapy.
This study investigated whether novel factors, such as systemic inflammation [platelet–lymphocyte ratio (PLR) and neutrophil–lymphocyte ratio (NLR)], impact carboplatin pharmacokinetics and drug utilisation. The study also examined the ability of current and alternate dosing regimens to meet therapeutic targets.
Seventy-two people with advanced NSCLC treated with carboplatin-based (460–1050 mg) doublet chemotherapy were recruited and pharmacokinetic data (n = 61) were analysed using non-linear mixed modelling. Covariate analysis was performed to investigate the impact of standard and novel patient characteristics of carboplatin pharmacokinetics. A Monte Carlo simulation of 100,000 representative NSCLC patients evaluated the ability of the Calvert formula and novel dosing strategies to achieve the targeted therapeutic range. The associations between systemic inflammation and chemotherapy drug utilisation (cycles received, relative dose intensity (RDI) and second-line uptake) and clinical endpoints were also investigated in the pharmacokinetic cohort, and two independent cohorts of people with advanced NSCLC from the Chemotherapy Dosing in Cancer-Related Inflammation (CDCRI) database that were administered carboplatin–paclitaxel (n = 37) or carboplatin–gemcitabine (n = 358).
In all cohorts, 25–53% of people had elevated systemic inflammation (NLR > 5 or PLR > 300). In the pharmacokinetic cohort, no patients achieved the desired therapeutic target of carboplatin. Carboplatin exposure was related to renal function, as estimated using the Cockcroft–Gault formula, albumin and inflammation (NLR). In the pharmacokinetic cohort, increasing carboplatin area under the curve (AUC) correlated with greater reductions in red blood cells and haemoglobin. In this cohort, the average measured AUC of partial responders was 2.4 mg·min/mL. Also in the pharmacokinetic cohort, only 12% of people with an NLR > 5 received four or more cycles of chemotherapy, compared with 62% of patients with an NLR ≤ 5 (p < 0.001). For people in the CDCRI cohort receiving carboplatin–gemcitabine, those with an NLR > 5 also received less cycles (four or more cycles, 41% vs. 60%; p < 0.01) as well as less second-line chemotherapy (46% vs. 60%; p = 0.02) compared with patients without inflammation. People in the pharmacokinetic cohort with an NLR > 5 had 12 months less median survival compared with people with an NLR ≤ 5 (6.5 vs. 18 months; p = 0.08). Similarly, overall survival was significantly shortened in people in the CDCRI cohort receiving carboplatin–gemcitabine with an NLR > 5 compared with those with an NLR ≤ 5 (7 vs. 12 months; p < 0.001), and Cox regression analysis showed a 1.5-fold (1.3–2.1; p < 0.001) increased hazard of death associated with the increased systemic inflammation. Simulations of the newly developed model-based and Calvert dosing assessed the ability to reach this study’s proposed actual target AUC of 2.2–2.6 mg·min/mL. These showed current Calvert dosing was predicted to result in substantial overexposure in patients with high systemic inflammation. The newly developed model showed equivalent levels of carboplatin therapeutic target achievement across the spectrum of inflammation observed in the lung cancer population.
An alternate model-based dosing strategy for carboplatin was developed and is predicted to result in consistent drug exposure across the population and improve attainment of therapeutic targets. Further studies of this new model are warranted in people with advanced NSCLC.
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Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394–424.
Molina JR, Yang P, Cassivi SD, Schild SE, Adjei AA. Non-small cell lung cancer: epidemiology, risk factors, treatment, and survivorship. Mayo Clin Proc. 2008;83(5):584–94.
Hanna N, Johnson D, Temin S, Baker S Jr, Brahmer J, Ellis PM, et al. Systemic therapy for stage IV non-small-cell lung cancer: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol. 2017;35(30):3484–515.
Ettinger DS, Aisner DL, Wood DE, Akerley W, Bauman J, Chang JY, et al. NCCN guidelines insights: non-small cell lung cancer, version 5.2018. J Natl Compr Cancer Netw. 2018;16(7):807–21.
Planchard D, Popat S, Kerr K, Novello S, Smit EF, Faivre-Finn C, et al. Metastatic non-small cell lung cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2018;29(Suppl 4):iv192–237.
Calvert AH, Newell DR, Gumbrell LA, O’Reilly S, Burnell M, Boxall FE, et al. Carboplatin dosage: prospective evaluation of a simple formula based on renal function. J Clin Oncol. 1989;7(11):1748–56.
Duffull SB, Robinson BA. Clinical pharmacokinetics and dose optimisation of carboplatin. Clin Pharmacokinet. 1997;33(3):161–83.
Ekhart C, de Jonge ME, Huitema AD, Schellens JH, Rodenhuis S, Beijnen JH. Flat dosing of carboplatin is justified in adult patients with normal renal function. Clin Cancer Res. 2006;12(21):6502–8.
Joerger M, Huitema AD, Richel DJ, Dittrich C, Pavlidis N, Briasoulis E, et al. Population pharmacokinetics and pharmacodynamics of paclitaxel and carboplatin in ovarian cancer patients: a study by the European organization for research and treatment of cancer-pharmacology and molecular mechanisms group and new drug development group. Clin Cancer Res. 2007;13(21):6410–8.
Kearns CM, Belani CP, Erkmen K, Zuhowski M, Hiponia D, Zacharski D, et al. Pharmacokinetics of paclitaxel and carboplatin in combination. Semin Oncol. 1995;22(5 Suppl 12):1–4 (discussion 5–7).
Schmitt A, Gladieff L, Laffont CM, Evrard A, Boyer JC, Lansiaux A, et al. Factors for hematopoietic toxicity of carboplatin: refining the targeting of carboplatin systemic exposure. J Clin Oncol. 2010;28(30):4568–74.
Diakos CI, Charles KA, McMillan DC, Clarke SJ. Cancer-related inflammation and treatment effectiveness. Lancet Oncol. 2014;15(11):e493–503.
Dolan RD, McSorley ST, Horgan PG, Laird B, McMillan DC. The role of the systemic inflammatory response in predicting outcomes in patients with advanced inoperable cancer: systematic review and meta-analysis. Crit Rev Oncol Hematol. 2017;116:134–46.
Guthrie GJ, Charles KA, Roxburgh CS, Horgan PG, McMillan DC, Clarke SJ. The systemic inflammation-based neutrophil-lymphocyte ratio: experience in patients with cancer. Crit Rev Oncol Hematol. 2013;88(1):218–30.
McMillan DC. The systemic inflammation-based Glasgow Prognostic Score: a decade of experience in patients with cancer. Cancer Treat Rev. 2013;39(5):534–40.
Charles KA, Harris BD, Haddad CR, Clarke SJ, Guminski A, Stevens M, et al. Systemic inflammation is an independent predictive marker of clinical outcomes in mucosal squamous cell carcinoma of the head and neck in oropharyngeal and non-oropharyngeal patients. BMC Cancer. 2016;16:124.
Mantovani A, Allavena P, Sica A, Balkwill F. Cancer-related inflammation. Nature. 2008;454(7203):436–44.
Vinay DS, Ryan EP, Pawelec G, Talib WH, Stagg J, Elkord E, et al. Immune evasion in cancer: mechanistic basis and therapeutic strategies. Semin Cancer Biol. 2015;35(Suppl):S185–98.
Umansky V, Sevko A. Tumor microenvironment and myeloid-derived suppressor cells. Cancer Microenviron. 2013;6(2):169–77.
Landskron G, De la Fuente M, Thuwajit P, Thuwajit C, Hermoso MA. Chronic inflammation and cytokines in the tumor microenvironment. J Immunol Res. 2014;2014:149185.
Gioulbasanis I, Pallis A, Vlachostergios PJ, Xyrafas A, Giannousi Z, Perdikouri IE, et al. The Glasgow Prognostic Score (GPS) predicts toxicity and efficacy in platinum-based treated patients with metastatic lung cancer. Lung Cancer. 2012;77(2):383–8.
Scott HR, McMillan DC, Forrest LM, Brown DJF, McArdle CS, Milroy R. The systemic inflammatory response, weight loss, performance status and survival in patients with inoperable non-small cell lung cancer. Br J Cancer. 2002;87(3):264–7.
Yao YW, Yuan DM, Liu HB, Gu XL, Song Y. Pretreatment neutrophil to lymphocyte ratio is associated with response to therapy and prognosis of advanced non-small cell lung cancer patients treated with first-line platinum-based chemotherapy. Cancer Immunol Immunother. 2013;62(3):471–9.
Gu X, Sun S, Gao XS, Xiong W, Qin S, Qi X, et al. Prognostic value of platelet to lymphocyte ratio in non-small cell lung cancer: evidence from 3,430 patients. Sci Rep. 2016;6:23893.
Gu XB, Tian T, Tian XJ, Zhang XJ. Prognostic significance of neutrophil-to-lymphocyte ratio in non-small cell lung cancer: a meta-analysis. Sci Rep. 2015;5:12493.
Shinko D, Diakos CI, Clarke SJ, Charles KA. Cancer-related systemic inflammation: the challenges and therapeutic opportunities for personalized medicine. Clin Pharmacol Ther. 2017;102(4):599–610.
Kim NH, Kim SK, Kim DS, Zhang D, Park JA, Yi H, et al. Anti-proliferative action of IL-6R-targeted antibody tocilizumab for non-small cell lung cancer cells. Oncol Lett. 2015;9(5):2283–8.
Roxburgh CS, McMillan DC. Cancer and systemic inflammation: treat the tumour and treat the host. Br J Cancer. 2014;110(6):1409–12.
Derman BA, Macklis JN, Azeem MS, Sayidine S, Basu S, Batus M, et al. Relationships between longitudinal neutrophil to lymphocyte ratios, body weight changes, and overall survival in patients with non-small cell lung cancer. BMC Cancer. 2017;17(1):141.
Christensen H, Hermann M. Immunological response as a source to variability in drug metabolism and transport. Front Pharmacol. 2012;3:8.
Slaviero KA, Clarke SJ, Rivory LP. Inflammatory response: an unrecognised source of variability in the pharmacokinetics and pharmacodynamics of cancer chemotherapy. Lancet Oncol. 2003;4(4):224–32.
Kacevska M, Robertson GR, Clarke SJ, Liddle C. Inflammation and CYP3A4-mediated drug metabolism in advanced cancer: impact and implications for chemotherapeutic drug dosing. Expert Opin Drug Metab Toxicol. 2008;4(2):137–49.
Charles KA, Rivory LP, Stockler MR, Beale P, Beith J, Boyer M, et al. Predicting the toxicity of weekly docetaxel in advanced cancer. Clin Pharmacokinet. 2006;45(6):611–22.
Cancer Institute of New South Wales. eviQ Cancer Treatments Online [cited Jan 2019]. https://www.eviq.org.au/.
CHARM heatlh. CHARM™ [cited Jan 2019]. https://www.charmhealth.com.au/charm-products/charm/.
Screnci D, Er HM, Hambley TW, Galettis P, Brouwer W, McKeage MJ. Stereoselective peripheral sensory neurotoxicity of diaminocyclohexane platinum enantiomers related to ormaplatin and oxaliplatin. Br J Cancer. 1997;76(4):502–10.
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228–47.
Hryniuk W, Bush H. The importance of dose intensity in chemotherapy of metastatic breast cancer. J Clin Oncol. 1984;2(11):1281–8.
Newell DR, Eeles RA, Gumbrell LA, Boxall FE, Horwich A, Calvert AH. Carboplatin and etoposide pharmacokinetics in patients with testicular teratoma. Cancer Chemother Pharm. 1989;23(6):367–72.
Belani CP, Kearns CM, Zuhowski EG, Erkmen K, Hiponia D, Zacharski D, et al. Phase I trial, including pharmacokinetic and pharmacodynamic correlations, of combination paclitaxel and carboplatin in patients with metastatic non-small-cell lung cancer. J Clin Oncol. 1999;17(2):676–84.
Craig AJ, Samol J, Heenan SD, Irwin AG, Britten A. Overestimation of carboplatin doses is avoided by radionuclide GFR measurement. Br J Cancer. 2012;107(8):1310–6.
Kuan IHS, Duffull SB, Putt TL, Schollum JBW, Walker RJ, Wright DFB. A population pharmacokinetic model for 51Cr EDTA to estimate renal function. Clin Pharmacokinet. 2017;56(6):671–8.
Okamoto H, Nagatomo A, Kunitoh H, Kunikane H, Watanabe K. Prediction of carboplatin clearance calculated by patient characteristics or 24-hour creatinine clearance: a comparison of the performance of three formulae. Cancer Chemother Pharmacol. 1998;42(4):307–12.
Burger H, Loos WJ, Eechoute K, Verweij J, Mathijssen RHJ, Wiemer EAC. Drug transporters of platinum-based anticancer agents and their clinical significance. Drug Resist Updat. 2011;14(1):22–34.
Jong NN, McKeage MJ. Emerging roles of metal solute carriers in cancer mechanisms and treatment. Biopharm Drug Dispos. 2014;35(8):450–62.
Aversa Z, Costelli P, Muscaritoli M. Cancer-induced muscle wasting: latest findings in prevention and treatment. Ther Adv Med Oncol. 2017;9(5):369–82.
McMillan DC. Systemic inflammation, nutritional status and survival in patients with cancer. Curr Opin Clin Nutr Metab Care. 2009;12(3):223–6.
The authors thank all patients who participated in this study. The authors acknowledge the clinical trials team at Concord Repatriation General Hospital, especially the assistance of Ms Cathy Xu, and acknowledge the support of additional investigator Associate Professor Phillip Beale for assistance, patient recruitment and clinical data. The authors also acknowledge the technical support of Danqing Zhu and the Molecular Medicine Laboratory at Concord Repatriation General Hospital, as well as technical support from Dan McKavanagh, Ian Fraser and Jacob Darch from Princess Alexandra Hospital and Gold Coast University Hospital. Finally, the authors acknowledge Dr Hongmei Xu who developed the initial base models for pharmacokinetic analysis, and Professor Sallie A. Pearson for advice and support, particularly with the use of electronic medical records.
This study was supported by funding from a National Health and Medical Research Council project grant (No. 512533). KAC was supported by a Cancer Institute NSW Career Development Fellowship; EW, JHM and KAC were supported by Sydney Catalyst Seed Funding; and VH and BDWH were supported by Australian Government postgraduate scholarships.
Conflict of interest
Vidya Perera is an employee and shareholder of Bristol Myers Squibb, but not at the time of data analysis for this manuscript. Benjamin D.W. Harris, Viet Phan, Anneliese Szyc, Peter Galettis, Jennifer H. Martin, Euan Walpole, Andrew J. McLachlan, Stephen J Clarke, Stephanie E. Reuter and Kellie A. Charles declare no conflicts of interest.
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. This article does not contain any studies with animals performed by any of the authors.
Informed consent was obtained from all individual participants included in the study. A waiver of consent was issued via a Public Health Act for retrospectively collected data.
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Harris, B.D.W., Phan, V., Perera, V. et al. Inability of Current Dosing to Achieve Carboplatin Therapeutic Targets in People with Advanced Non-Small Cell Lung Cancer: Impact of Systemic Inflammation on Carboplatin Exposure and Clinical Outcomes. Clin Pharmacokinet (2020). https://doi.org/10.1007/s40262-020-00870-6