Abstract
Chemotherapy-induced neutropenia (CIN) is one of the most common side effects seen in cancer patients. As an adverse event, it is deemed undesirable since it often constitutes a dose-limiting toxicity for cytotoxic agents leading to treatment delays and/or dose reductions. It is also associated with a financial cost component from diagnostic work-up and treatment of patients with chemotherapy-induced febrile neutropenia (CIFN). Neutropenia is commonly accompanied by a decrease in other hematopoietic lineages (anemia and/or thrombocytopenia). Dosing of chemotherapeutic agents is based on the severity of adverse effects seen. Depending on the degree of neutropenia, chemotherapeutic agents may be put on hold until count recovery and growth factor support might be added to allow for dosing as scheduled. However, neutropenia appears to be more than just an adverse event. While CIFN by itself constitutes an adverse event, the appearance of just CIN is not necessarily a marker of poor outcome. In fact, it rather appears to be a surrogate marker of response and/or survival in patients treated with cytotoxic regimens. Here we present evidence in different tumor types treated with different regimens on the role CIN plays as a marker for improved outcomes. If CIN is a surrogate prognostic and/or potentially predictive marker of response, chemotherapy doses may need to be escalated to achieve neutropenia. In addition, instead of reducing treatment doses for safety concerns, the addition of growth factor support and alternative dosing schemes may be strategies to consider.
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References
Jacobs VR, Mayer SC, Paessens B, Anker G, Schwarz-Boeger U, Paepke S, et al. Prospective study comparing hospital costs and DRG reimbursement of inpatient treatment of febrile neutropenia during adjuvant anthracycline-based CTX for primary breast cancer. J Clin Oncol. 2009;27(15_suppl):e11570.
Bottsford-Miller J, Choi HJ, Dalton HJ, Stone RL, Cho MS, Haemmerle M, et al. Differential platelet levels affect response to taxane-based therapy in ovarian cancer. Clin Cancer Res. 2015;21(3):602–10.
Mayer RJ, Van Cutsem E, Falcone A, Yoshino T, Garcia-Carbonero R, Mizunuma N, et al. Randomized trial of TAS-102 for refractory metastatic colorectal cancer. N Engl J Med. 2015;372(20):1909–19.
Kasi PM, Kotani D, Cecchini M, Shitara K, Ohtsu A, Ramanathan RK, et al. Chemotherapy induced neutropenia at 1-month mark is a predictor of overall survival in patients receiving TAS-102 for refractory metastatic colorectal cancer: a cohort study. BMC Cancer. 2016;16:467.
Hamauchi S, Yamazaki K, Masuishi T, Kito Y, Komori A, Tsushima T, et al. Neutropenia as a predictive factor in metastatic colorectal cancer treated with TAS-102. Clin Colorectal Cancer. 2017;16(1):51–7. https://doi.org/10.1016/j.clcc.2016.07.005.
Sunaga T, Suzuki S, Kogo M, Kurihara T, Kaji S, Koike N, et al. The association between neutropenia and prognosis in stage III colorectal cancer patients receiving adjuvant chemotherapy. Eur J Cancer Care (Engl). 2014;23(3):394–400.
Innominato PF, Giacchetti S, Moreau T, Smaaland R, Focan C, Bjarnason GA, et al. Prediction of survival by neutropenia according to delivery schedule of oxaliplatin-5-fluorouracil-leucovorin for metastatic colorectal cancer in a randomized international trial (EORTC 05963). Chronobiol Int. 2011;28(7):586–600.
Innominato PF, Giacchetti S, Smaaland R, Focan CN, Garufi C, Bjarnason GA, et al. Chemotherapy-induced neutropenia association with survival in metastatic colorectal cancer (MCC): schedule dependency. J Clin Oncol. 2011;29(4_suppl):454.
Shitara K, Matsuo K, Takahari D, Yokota T, Ura T, Muro K. Neutropenia as a prognostic factor in metastatic colorectal cancer patients undergoing chemotherapy with first-line FOLFOX. J Clin Oncol. 2009;27(15_suppl):4115.
Shitara K, Yuki S, Tahahari D, Nakamura M, Kondo C, Tsuda T, et al. Randomised phase II study comparing dose-escalated weekly paclitaxel vs standard-dose weekly paclitaxel for patients with previously treated advanced gastric cancer. Br J Cancer. 2014;110(2):271–7.
Chen Z, Chen W, Wang J, Zhu M, Zhuang Z. Pretreated baseline neutrophil count and chemotherapy-induced neutropenia may be conveniently available as prognostic biomarkers in advanced gastric cancer. Intern Med J. 2015;45(8):854–9.
Ikagawa M, Kimura M, Iwai M, Usami E, Yoshimura T, Yasuda K. Neutropenia as a prognostic factor and safety of second-line therapy with S-1 for advanced or recurrent pancreatic cancer. Mol Clin Oncol. 2016;5(3):283–8.
Kurihara T, Kogo M, Ishii M, Shimada K, Yoneyama K, Kitamura K, et al. Chemotherapy-induced neutropenia as a prognostic factor in patients with unresectable pancreatic cancer. Cancer Chemother Pharmacol. 2015;76(6):1217–24.
Okuyama H, Mitsunaga S, Nakachi K, Ohno I, Shimizu S, Takahashi H, et al. Association of interleukin-6 levels and neutropenia during gemcitabine monotherapy for advanced pancreatic cancer. J Clin Oncol. 2011;29(4):178.
Liu R, Huang M, Zhao X, Peng W, Sun S, Cao J, et al. Neutropenia predicts better prognosis in patients with metastatic gastric cancer on a combined epirubicin, oxaliplatin and 5-fluorouracil regimen. Oncotarget. 2015;6(36):39018–27.
Shitara K, Matsuo K, Takahari D, Yokota T, Shibata T, Ura T, et al. Neutropenia as a prognostic factor in advanced gastric cancer patients undergoing second-line chemotherapy with weekly paclitaxel. Ann Oncol Off J Eur Soc Med Oncol. 2010;21(12):2403–9.
Konishi H, Fujiwara H, Shiozaki A, Hiramoto H, Kosuga T, Komatsu S, et al. Effects of neutropenia and histological responses in esophageal squamous cell carcinoma with neo-adjuvant chemotherapy. Int J Clin Oncol. 2016;21(1):95–101.
Ma RM, Chen CZ, Zhang W, You J, Huang DP, Guo GL. Prognostic value of chemotherapy-induced neutropenia at the first cycle in invasive breast cancer. Medicine (Baltim). 2016;95(13):e3240.
Han Y, Yu Z, Wen S, Zhang B, Cao X, Wang X. Prognostic value of chemotherapy-induced neutropenia in early-stage breast cancer. Breast Cancer Res Treat. 2012;131(2):483–90.
Mitchell S, Li X, Woods M, Garcia J, Hebard-Massey K, Barron R, et al. Comparative effectiveness of granulocyte colony-stimulating factors to prevent febrile neutropenia and related complications in cancer patients in clinical practice: a systematic review. J Oncol Pharm Pract. 2016;22(5):702–16.
Tewari KS, Java JJ, Gatcliffe TA, Bookman MA, Monk BJ. Chemotherapy-induced neutropenia as a biomarker of survival in advanced ovarian carcinoma: an exploratory study of the gynecologic oncology group. Gynecol Oncol. 2014;133(3):439–45.
Lee CY, Park SY, Shin TR, Park YB, Kim CH, Jang SH, et al. Early-onset neutropenia during perioperative chemotherapy is predictive of increased survival in patients with completely resected non-small cell lung cancer: a retrospective analysis. Anticancer Res. 2013;33(6):2755–61.
Jang SH, Kim SY, Kim JH, Park S, Hwang YI, Kim DG, et al. Timing of chemotherapy-induced neutropenia is a prognostic factor in patients with metastatic non-small-cell lung cancer: a retrospective analysis in gemcitabine-plus-platinum-treated patients. J Cancer Res Clin Oncol. 2013;139(3):409–17.
Iranzo V, Sirera R, Bremnes RM, Blasco A, Jantus-Lewintre E, Taron M, et al. Chemotherapy-induced neutropenia does not correlate with DNA repair gene polymorphisms and treatment efficacy in advanced non-small-cell lung cancer patients. Clin Lung Cancer. 2011;12(4):224–30.
Di Maio M, Gridelli C, Gallo C, Shepherd F, Piantedosi FV, Cigolari S, et al. Chemotherapy-induced neutropenia and treatment efficacy in advanced non-small-cell lung cancer: a pooled analysis of three randomised trials. Lancet Oncol. 2005;6(9):669–77.
Pond GR, Berry WR, Galsky MD, Wood BA, Leopold LH, Sonpavde G. Neutropenia as a potential pharmacodynamic marker for docetaxel-based chemotherapy in men with metastatic castration-resistant prostate cancer (mCRPC). J Clin Oncol. 2012;30(5_suppl):51.
Pond GR, Berry WR, Galsky MD, Wood BA, Leopold L, Sonpavde G. Neutropenia as a potential pharmacodynamic marker for docetaxel-based chemotherapy in men with metastatic castration-resistant prostate cancer. Clin Genitourin Cancer. 2012;10(4):239–45.
Meisel A, von Felten S, Vogt DR, Liewen H, de Wit R, de Bono J, et al. Severe neutropenia during cabazitaxel treatment is associated with survival benefit in men with metastatic castration-resistant prostate cancer (mCRPC): a post-hoc analysis of the TROPIC phase III trial. Eur J Cancer. 2016;56:93–100.
Donskov F, Michaelson MD, Puzanov I, Davis MP, Bjarnason GA, Motzer RJ, et al. Sunitinib-associated hypertension and neutropenia as efficacy biomarkers in metastatic renal cell carcinoma patients. Br J Cancer. 2015;113(11):1571–80.
Hashiguchi Y, Kasai M, Fukuda T, Ichimura T, Yasui T, Sumi T. Chemotherapy-induced neutropenia and febrile neutropenia in patients with gynecologic malignancy. Anticancer Drugs. 2015;26(10):1054–60.
Kuboki Y, Mizunuma N, Ozaka M, Ogura M, Suenaga M, Shinozaki E, et al. Grade 3/4 neutropenia is a limiting factor in second-line FOLFIRI following FOLFOX4 failure in elderly patients with metastatic colorectal cancer. Oncol Lett. 2011;2(3):493–8.
Lee YM, Lang D, Lockwood C. Prognostic factors for risk stratification of adult cancer patients with chemotherapy-induced febrile neutropenia: a systematic review and meta-analysis. JBI Libr Syst Rev. 2012;10(40):2593–657.
Weycker D, Li X, Edelsberg J, Barron R, Kartashov A, Xu H, et al. Risk and consequences of chemotherapy-induced febrile neutropenia in patients with metastatic solid tumors. J Oncol Pract. 2015;11(1):47–54.
Kalinka-Warzocha E, Plazas JG, Mineur L, Salek T, Hendlisz A, DeCosta L, et al. Chemotherapy treatment patterns and neutropenia management in gastric cancer. Gastric Cancer. 2015;18(2):360–7.
Watanabe H, Ikesue H, Oshiro M, Nagata K, Mishima K, Takada A, et al. Risk factors for predicting severe neutropenia induced by amrubicin in patients with advanced lung cancer. Chemotherapy. 2012;58(6):419–25.
Cortejoso L, Garcia-Gonzalez X, Garcia MI, Garcia-Alfonso P, Sanjurjo M, Lopez-Fernandez LA. Cost-effectiveness of screening for DPYD polymorphisms to prevent neutropenia in cancer patients treated with fluoropyrimidines. Pharmacogenomics. 2016;17(9):979–84.
Patel SM, Chan J, Hui RL, Spence MM. Evaluation of the role of UGT1A1 genotype testing in colorectal cancer patients administered irinotecan and the occurence of grade 3 and 4 neutropenia. J Clin Oncol. 2012;30(4_suppl):412.
Hazama S, Okuyama Y, Kato T, Okayama N, Hinoda Y, Sakamoto J, et al. Use of genotype subset selections of multi-UGT1As polymorphisms to predict severe neutropenia and tumor responses of metastatic CRC patients received FOLFIRI regimen. J Clin Oncol. 2009;27(15_suppl):e15038.
Atasilp C, Chansriwong P, Sirachainan E, Reungwetwattana T, Chamnanphon M, Puangpetch A, et al. Correlation of UGT1A1(*)28 and (*)6 polymorphisms with irinotecan-induced neutropenia in Thai colorectal cancer patients. Drug Metab Pharmacokinet. 2016;31(1):90–4.
Li M, Seiser EL, Baldwin RM, Ramirez J, Ratain MJ, Innocenti F, et al. ABC transporter polymorphisms are associated with irinotecan pharmacokinetics and neutropenia. Pharmacogenomics J. 2018;18(1):35–42. https://doi.org/10.1038/tpj.2016.75.
Uchiyama T, Kanno H, Ishitani K, Fujii H, Ohta H, Matsui H, et al. An SNP in CYP39A1 is associated with severe neutropenia induced by docetaxel. Cancer Chemother Pharmacol. 2012;69(6):1617–24.
Nieuweboer AJ, Smid M, de Graan AJ, Elbouazzaoui S, de Bruijn P, Martens JW, et al. Predicting paclitaxel-induced neutropenia using the DMET platform. Pharmacogenomics. 2015;16(11):1231–41.
Ichikawa W, Uehara K, Minamimura K, Tanaka C, Takii Y, Miyauchi H, et al. An internally and externally validated nomogram for predicting the risk of irinotecan-induced severe neutropenia in advanced colorectal cancer patients. Br J Cancer. 2015;112(10):1709–16.
Lewis LD, Miller AA, Owzar K, Bies RR, Markova S, Jiang C, et al. The relationship of polymorphisms in ABCC2 and SLCO1B3 with docetaxel pharmacokinetics and neutropenia: CALGB 60805 (Alliance). Pharmacogenet Genom. 2013;23(1):29–33.
Tang NL, Liao CD, Wang X, Mo FK, Chan VT, Ng R, et al. Role of pharmacogenetics on adjuvant chemotherapy-induced neutropenia in Chinese breast cancer patients. J Cancer Res Clin Oncol. 2013;139(3):419–27.
Tsuji D, Ikeda M, Yamamoto K, Nakamori H, Kim YI, Kawasaki Y, et al. Drug-related genetic polymorphisms affecting severe chemotherapy-induced neutropenia in breast cancer patients: a hospital-based observational study. Medicine (Baltim). 2016;95(44):e5151.
Laskey RA, Poniewierski MS, Lopez MA, Hanna RK, Secord AA, Gehrig PA, et al. Predictors of severe and febrile neutropenia during primary chemotherapy for ovarian cancer. Gynecol Oncol. 2012;125(3):625–30.
Alenzi EO, Kelley GA. The association of hyperglycemia and diabetes mellitus and the risk of chemotherapy-induced neutropenia among cancer patients: a systematic review with meta-analysis. J Diabetes Complicat. 2017;31(1):267–72. https://doi.org/10.1016/j.jdiacomp.2016.09.006.
Ikesue H, Watanabe H, Hirano M, Chikamori A, Suetsugu K, Ryokai Y, et al. Risk factors for predicting severe neutropenia induced by pemetrexed plus carboplatin therapy in patients with advanced non-small cell lung cancer. Biol Pharm Bull. 2015;38(8):1192–8.
Yano R, Konno A, Watanabe K, Tsukamoto H, Kayano Y, Ohnaka H, et al. Pharmacoethnicity of docetaxel-induced severe neutropenia: integrated analysis of published phase II and III trials. Int J Clin Oncol. 2013;18(1):96–104.
Shigeta K, Kosaka T, Yazawa S, Yasumizu Y, Mizuno R, Nagata H, et al. Predictive factors for severe and febrile neutropenia during docetaxel chemotherapy for castration-resistant prostate cancer. Int J Clin Oncol. 2015;20(3):605–12.
Gupta V, Kumar V, Singh SK. Low vitamin D levels are associated with an adverse clinical outcome in febrile neutropenia. J Pediatr Hematol Oncol. 2016;38(3):202–4.
O’Malley M, Healy P, Daignault S, Ramnath N. Cigarette smoking and gemcitabine-induced neutropenia in advanced solid tumors. Oncology. 2013;85(4):216–22.
Sato I, Nakaya N, Shimasaki T, Nakajima H, Motoo Y. Prediction of docetaxel monotherapy-induced neutropenia based on the monocyte percentage. Oncol Lett. 2012;3(4):860–4.
Lyman GH, Abella E, Pettengell R. Risk factors for febrile neutropenia among patients with cancer receiving chemotherapy: a systematic review. Crit Rev Oncol Hematol. 2014;90(3):190–9.
Dinan MA, Hirsch BR, Lyman GH. Management of chemotherapy-induced neutropenia: measuring quality, cost, and value. J Natl Compr Canc Netw. 2015;13(1):e1–7.
Yoshida Y, Hoshino S, Aisu N, Mogi A, Yamada T, Kojima D, et al. Can grade 2 neutropenia predict the risk of grade 3 neutropenia in metastatic colorectal cancer patients treated with chemotherapy? Support Care Cancer. 2015;23(6):1623–7.
Chiarotto JA, Dranitsaris G. Full-dose chemotherapy in early stage breast cancer regardless of absolute neutrophil count and without G-CSF does not increase chemotherapy-induced febrile neutropenia. Support Care Cancer. 2013;21(10):2727–31.
Pinter T, Klippel Z, Cesas A, Croitoru A, Decaestecker J, Gibbs P, et al. A phase III, randomized, double-blind, placebo-controlled trial of pegfilgrastim in patients receiving first-line FOLFOX/bevacizumab or FOLFIRI/bevacizumab for locally advanced or metastatic colorectal cancer: final results of the pegfilgrastim and anti-VEGF evaluation study (PAVES). Clin Colorectal Cancer. 2017;16(2):103–114.e3. https://doi.org/10.1016/j.clcc.2016.08.008.
Barron R, Michels SL, Reynolds MW, Tomic K, Yu J, Lyman G. Risk of mortality in patients with cancer experiencing febrile neutropenia. J Clin Oncol. 2009;27(15_suppl):9561.
Lal A, Kumar P, Bhurgri Y, Rizvi N, Shaikh AJ, Adil S, et al. Factors influencing in-hospital length of stay and mortality in cancer patients suffering from febrile neutropenia. J Clin Oncol. 2009;27(15_suppl):e20716.
Bouteloup M, Perinel S, Bourmaud A, Azoulay E, Mokart D, Darmon M. Outcomes in adult critically Ill cancer patients with and without neutropenia: a systematic review and meta-analysis of the Groupe de Recherche en Reanimation Respiratoire du patient d’Onco-Hematologie (GRRR-OH). Oncotarget. 2017;8(1):1860–70. https://doi.org/10.18632/oncotarget.12165.
Aapro M, Bokemeyer C, Ludwig H, Gascon P, Boccadoro M, Denhaerynck K, et al. Chemotherapy-induced (febrile) neutropenia prophylaxis with biosimilar filgrastim in elderly versus non-elderly cancer patients: patterns, outcomes, and determinants (MONITOR-GCSF study). J Geriatr Oncol. 2017;8(2):86–95. https://doi.org/10.1016/j.jgo.2016.09.006.
Chohan K, Lai D, McNamara M, Grogan L, Breathnach OS. The frequency of febrile neutropenia in oncology patients receiving chemotherapy. J Clin Oncol. 2009;27(15_suppl):e20691.
Chia VM, Page JH, Rodriguez R, Yang SJ, Huynh J, Chao C. Chronic comorbid conditions associated with risk of febrile neutropenia in breast cancer patients treated with chemotherapy. Breast Cancer Res Treat. 2013;138(2):621–31.
Chan A, Lee CP, Chiang J, Ng R. Breakthrough febrile neutropenia and associated complications among elderly cancer patients receiving myelosuppressive chemotherapy for solid tumors and lymphomas. Support Care Cancer. 2013;21(8):2137–43.
Li X, Luthra R, Morrow PK, Fisher MD, Reiner M, Barron RL, et al. Comorbidities among patients with cancer who do and do not develop febrile neutropenia during the first chemotherapy cycle. J Oncol Pharm Pract. 2016;22(5):679–89.
Ozguroglu M, Oudard S, Sartor AO, Hansen S, Machiels JH, Shen L, et al. Effect of G-CSF prophylaxis on the occurrence of neutropenia in men receiving cabazitaxel plus prednisone for the treatment of metastatic castration-resistant prostate cancer (mCRPC) in the TROPIC study. J Clin Oncol. 2011;29(7):144.
Dienstmann R, Brana I, Rodon J, Tabernero J. Toxicity as a biomarker of efficacy of molecular targeted therapies: focus on EGFR and VEGF inhibiting anticancer drugs. Oncologist. 2011;16(12):1729–40.
Fukae M, Shiraishi Y, Hirota T, Sasaki Y, Yamahashi M, Takayama K, et al. Population pharmacokinetic-pharmacodynamic modeling and model-based prediction of docetaxel-induced neutropenia in Japanese patients with non-small cell lung cancer. Cancer Chemother Pharmacol. 2016;78(5):1013–23.
Pawloski PA, Thomas AJ, Kane S, Vazquez-Benitez G, Shapiro GR, Lyman GH. Predicting neutropenia risk in patients with cancer using electronic data. J Am Med Inform Assoc. 2017;24(e1):e129–35. https://doi.org/10.1093/jamia/ocw131.
Huang K, Luo A, Li X, Li S, Wang S. Chemotherapy-induced neutropenia during adjuvant treatment for cervical cancer patients: development and validation of a prediction model. Int J Clin Exp Med. 2015;8(7):10835–44.
Lyman GH, Lyman CH, Agboola O. Risk models for predicting chemotherapy-induced neutropenia. Oncologist. 2005;10(6):427–37.
Nieuweboer AJ, Smid M, de Graan AM, Elbouazzaoui S, de Bruijn P, Eskens FA, et al. Role of genetic variation in docetaxel-induced neutropenia and pharmacokinetics. Pharmacogenom J. 2016;16(6):519–24.
Charehbili A, de Groot S, van der Straaten T, Swen JJ, Pijl H, Gelderblom H, et al. Exploratory analysis of candidate germline gene polymorphisms in breast cancer patients treated with neoadjuvant anthracycline-containing chemotherapy and associations with febrile neutropenia. Pharmacogenomics. 2015;16(11):1267–76.
Wang L, Chen YZ, Shi D, Shi XY, Zou Z, Zhao JH. Incidence and risk of severe neutropenia in advanced cancer patients treated with cetuximab: a meta-analysis. Drugs R D. 2011;11(4):317–26.
Patel M, Palani S, Chakravarty A, Yang J, Shyu WC, Mettetal JT. Dose schedule optimization and the pharmacokinetic driver of neutropenia. PLoS One. 2014;9(10):e109892.
Kouranos V, Dimopoulos G, Vassias A, Syrigos KN. Chemotherapy-induced neutropenia in lung cancer patients: the role of antibiotic prophylaxis. Cancer Lett. 2011;313(1):9–14.
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Axel Grothey has no conflicts of interest to disclose. Author Pashtoon Murtaza Kasi institution received consulting fees for Pashtoon Murtaza Kasi to participate in an advisory board meeting in 2016 by Taiho Oncology. The authors have no other conflicts of interest to declare.
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Kasi, P.M., Grothey, A. Chemotherapy-Induced Neutropenia as a Prognostic and Predictive Marker of Outcomes in Solid-Tumor Patients. Drugs 78, 737–745 (2018). https://doi.org/10.1007/s40265-018-0909-3
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DOI: https://doi.org/10.1007/s40265-018-0909-3