Background. Chemotherapy with platinum agent and etoposide for small-cell lung cancer (SCLC) is supposed to be associated with intermediate risk (10-20%) of febrile neutropenia. Primary prophylaxis with granulocyte colonystimulating factors (G-CSFs) is not routinely recommended by the treatment guidelines. However, in clinical practice febrile neutropenia is often observed with standard etoposide/platinum regimen. The aim of this analysis was to evaluate the frequency of neutropenia and febrile neutropenia in advanced SCLC patients in the first cycle of standard chemotherapy. Furthermore, we explored the association between severe neutropenia and etoposide peak plasma levels in the same patients.
Methods. The case series based analysis of 17 patients with advanced SCLC treated with standard platinum/etoposide chemotherapy, already included in the pharmacokinetics study with etoposide, was performed. Grade 3/4 neutropenia and febrile neutropenia, observed after the first cycle are reported. The neutrophil counts were determined on day one of the second cycle unless symptoms potentially related to neutropenia occurred. Adverse events were classified according to Common Toxicity Criteria 4.0. Additionally, association between severe neutropenia and etoposide peak plasma concentrations, which were measured in the scope of pharmacokinetic study, was explored.
Results. Two out of 17 patients received primary GCS-F prophylaxis. In 15 patient who did not receive primary prophylaxis the rates of both grade 3/4 neutropenia and febrile neutropenia were high (8/15 (53.3%) and 2/15 (13.3%), respectively), already in the first cycle of chemotherapy. One patient died due to febrile neutropenia related pneumonia. Neutropenic events are assumed to be related to increased etoposide plasma concentrations after a standard etoposide and cisplatin dose. While the mean etoposide peak plasma concentration in the first cycle of chemotherapy was 17.6 mg/l, the highest levels of 27.07 and 27.49 mg/l were determined in two patients with febrile neutropenia.
Conclusions. Our study indicates that there is a need to reduce the risk of neutropenic events in chemotherapy treated advanced SCLC, starting in the first cycle. Mandatory use of primary G-CSF prophylaxis might be considered. Alternatively, use of improved risk models for identification of patients with increased risk for neutropenia and individualization of primary prophylaxis based on not only clinical characteristics but also on etoposide plasma concentration measurement, could be a new, promising options that deserves further evaluation.
1 . Califano R, Abidin AZ, Peck R, Faivre-Finn C, Lorigan P. Management of Small Cell Lung Cancer. Recent developments for optimal care. Drugs 2012; 72: 471-90.
2 . Crawford J, Dale DC, Lyman GH. Chemotherapy-induced neutropenia. Risks, consequences, and new directions for its management. Cancer 2004; 100: 228-37.
3 . de Naurois J, Novitzky-Basso I, Gill MJ, Marti Marti F, Cullen MH, Roila F, et al. Management of febrile neutropenia: ESMO clinical practice guidelines. Ann Oncol 2010; 21(Suppl 5): v252-6.
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: 190-9.
5 . Cooper KL, Madan J, Whyte S, Stevenson MD, Akehurst RL. Granulocyte colony-stimulating factors for febrile neutropenia prophylaxis following chemotherapy: systematic review and meta-analysis. BMC Cancer 2011; 11: 1471-2407.
6 . Aapro MS, Bohlius J, Cameron DA, Dal Lago L, Donnely JP, Kearney N, et al. 2010 update of EORTC guidelines for the use of granulocyte-colony stimulating factor to reduce the incidence of chemotherapy-induced febrile neutropenia in adult patients with lymphoproliferative disorders and solid tumors. Eur J Cancer 2011; 47: 8-32.
7 . Smith TJ, Khatcheressian J, Lyman GH, Ozer H, Armitage JO, Balducci L, et al. 2006 Update of recommendations for the use of white blood cell growth factors: An evidence-based clinical practice guideline. J Clin Oncol 2006; 24: 3187-205.
8 . National Comprehensive Cancer Network. NCCN Guidelines Version 2.2013. Available from: http://www.nccn.org/professionals/physician_gls/f_guidelines.asp#myeloid_growthMyeloid growth factors. Accessed 11 September 2013.
9 . Crawford J, Caserta C, Roila F. Haematopoietic growth factors: ESMO clinical practice guidelines for the applications. Ann Oncol 2010; 21(Suppl 5): v248-51.
10. Krogh-Madsen M, Honoré Hansen S, Hartvig Honoré P. Simultaneous determination of cytosine arabinoside, daunorubicin and etoposide in human plasma. J Chromatogr B 2010; 878: 1967-72.
11. Roth BJ, Johnson DH, Einhorn LH, Schacter LP, Cherng NC, Cohen HJ, et al. Randomized study of cyclophosphamide, doxorubicin, and vincristine versus etoposide and cisplatin versus alternation of these two regimens in extensive small-cell lung cancer: a phase III trial of the Southeastern Cancer Study Group. J Clin Oncol 1992; 10: 282-91.
12. Skarlos DV, Samantas E, Kosmidis P, Fountzilas G, Angelidou M, Palamidas Ph, et al. Randomized comparison of etoposide-cisplatin vs. etoposidecarboplatin and irradiation in small-cell lung cancer. A Hellenic Co-operative Oncology Group Study. Ann Oncol 1994; 5: 601-7.
13. Kosmidis PA, Samantas E, Fountzilas G, Pavlidis N, Apostolopoulou F, Skarlos D. Cisplatin/etoposide versus carboplatin/ etoposide chemotherapy and irradiation in small cell lung cancer randomized phase II study. Hellenic Cooperative Oncology Group for Lung Cancer Trials. Semin Oncol 1994; 21(Suppl 6): 23-30.
14. Miller AA, Herndon JE 2nd, Hollis DR, Ellerton J, Langleben A, Richards F 2nd, et al. Schedule dependency of 21-day oral versus 3-day intravenous etoposide in combination with intravenous cisplatin in extensive-stage small-cell lung cancer: a randomized phase III study of the Cancer and Leukemia Group B. J Clin Oncol 1995; 13: 1871-9.
15. Pujol JL, Daurès JP, Rivière A, Quoix E, Westeel V, Quantin X, et al. Etoposide plus cisplatin with or without the combination of 4’-epidoxorubicin plus cyclophosphamide in treatment of extensive small-cell lung cancer: a French Federation of Cancer Institutes multicenter phase III randomized study. J Natl Cancer Inst 2001; 93: 300-8.
16. Quo ix E, Breton JL, Daniel C, Jacoulet P, Debieuvre D, Paillot N, et al. Etoposide phosphate with carboplatin in the treatment of elderly patients with small-cell lung cancer: a phase II study. Ann Oncol 2001; 12: 957-62.
17. Schiller JH, Adak S, Cella D, DeVore RF 3rd, Johnson DH. Topotecan versus observation after cisplatin plus etoposide in extensive-stage small-cell lung cancer: E7593-a phase III trial of the Eastern Cooperative Oncology Group. J Clin Oncol 2001; 19: 2114-22.
18. Hanna N, Bunn Jr. PA, Langer C, Einhorn L, Guthrie T Jr, Beck T, et al. Randomized phase III trial comparing irinotekan/cisplatin with etoposide/ cisplatin in patients with previously untreated extensive stage disease smallcell lung cancer. J Clin Oncol 20 06; 24: 2038-43.
19. Sch mittel A, Fischer von Weikersthal L, Sebastian M, Martus P, Schulze K, Hortig P, et al. A randomized phase II trial of irinotekan plus carboplatin versus etoposide plus carboplatin treatment in patients with extended disease small-cell lung cancer. Ann Oncol 2006; 17: 663-7.
20. Heigener DF, Manegold C, Jäger E, Saal JG, Zuna I, Gatzemeier U. Multicenter randomized open-label phase III study comparing efficacy, safety, and tolerability of conventional carboplatin plus etoposide versus dose-intensified carboplatin plus etoposide plus lenograstim in small-cell lung cancer in “extensive disease” stage. Am J Clin Oncol 2009; 32: 61-4.
21. Lara PN Jr, Natale R, Crowley J, Lenz HJ, Redman MW, Carleton JE, et al. Phase III trial of irinotecan/cisplatin compared with etoposide/cisplatin in extensive-stage small-cell lung cancer: clinical and pharmacogenomic results from SWOG S0124. J Clin Oncol 2009; 27: 2530-5.
22. Zatloukal P, Cardenal F, Szczesna A, Gorbunova V, Moiseyenko V, Zhang X, et al. A multicenter international randomized phase III study comparing cisplatin in combination with irinotecan or etoposide in previously untreated small-cell lung cancer patients with extensive disease. Ann Oncol 2010; 21: 1810-6.
23. Maas HAAM, Janssen-Heijnen MLG, Olde Rikkert MGM, Machteld Wymenga AN. Comprehensive Geriatric assessment and its clinical impact in oncology. Eur J Cancer 2007; 43: 2161-9.
24. Craw ford J, Glaspy JA, Stoller RG, Tomita DK, Vincent ME, McGuire BW, et al. Final results of a placebo-controlled study of filgrastim in small-cell lung cancer: exploration of risk factors for febrile neutropenia. Support Cancer Ther 2005; 3: 36-46.
25. Clarke’s analysis of drugs and poisons. Moffat AC, Osselton MD, Widdop B, Watts J, editors. Available from: http://www.medicinescomplete.com/mc/clarke/current/CLK0691.htm?q=etoposide&t=search&ss=text&p=1#_hit. Accessed 19 September 2013.
26. López-Pousa A, Rifà J, Casas de Tejerina A, González-Larriba JL, Iglesias C, Gasquet JA, et al. Risk assessment model for first-cycle chemotherapyinduced neutropenia in patients with solid tumors. Eur J Cancer Care 2010; 19: 648-55.
27. Lyman GH , Lyman CH, Agboola O. Risk models for predicting chemotherapyinduced neutropenia. Oncologist 2005; 10: 427-37.
28. Režonja R, Knez L, Čufer T, Mrhar A. Oral treatment with etoposide in small cell lung cancer - dilemmas and solutions. Radiol Oncol 2013; 47: 1-13.