. Pharmacokinetic optimisation of treatment with oral etoposide. Clin Pharmacokinet 2004; 43: 441-6. 13. Montecucco A, Biamonti G. Cellular response to etoposide treatment. Cancer Lett 2007; 252: 9-18. 14. Hande KR. The importance of drug scheduling in cancer chemotherapy: etoposide as an example. Oncologist 1996; 1: 234-9. 15. Greco FA, Johnson DH, Hande KR, Porter LL, Hainsworth JD, Wolff SN. High-dose etoposide (VP-16) in small-cell lung cancer. Semin Oncol 1985; 12(Suppl 2): 42-4. 16. Slevin ML
Renata Rezonja, Lea Knez, Tanja Cufer and Aleš Mrhar
Renata Rezonja Kukec, Iztok Grabnar, Tomaz Vovk, Ales Mrhar, Viljem Kovac and Tanja Cufer
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.
Nina Erculj, Barbara Faganel Kotnik, Marusa Debeljak, Janez Jazbec and Vita Dolzan
. Association of genetic polymorphism in the folate metabolic pathway with methotrexate pharmacokinetics and toxicity in childhood acute lymphoblastic leukaemia and malignant lymphoma. Eur J Clin Pharmacol 2011; 67: 993-1006. 4. Erculj N, Kotnik BF, Debeljak M, Jazbec J, Dolzan V. Influence of folate pathway polymorphisms on high-dose methotrexate-related toxicity and survival in childhood acute lymphoblastic leukemia. Leuk Lymphoma 2012; 53: 1096-104. 5. Jazbec J, Kitanovski L, Aplenc R, Debeljak M, Dolzan V. No evidence of association of
Robert Königsberg, Julia Maierhofer, Tanja Steininger, Gabriele Kienzer and Christian Dittrich
chemotherapy plus trastuzumab plus bevacizumab. Available at http://clinicaltrials.gov/ct2/show/NCT00625898?term=BETH&rank=1 16. Lu JF, Bruno R, Eppler S, Novotny W, Lum B, Gaudreault J. Clinical pharmacokinetics of bevacizumab in patients with solid tumors. Cancer Chemother Pharmacol 2008; 62: 779-86. 17. Kabbinavar F, Hurwitz HI, Fehrenbacher L, Meropol NJ, Novotny WF, Lieberman G, et al. Phase II, randomized trial comparing bevacizumab plus fluorouracil (FU)/leucovorin (LV) with FU/LV alone in patients with metastatic colorectal cancer. J
Janja Ocvirk and Martina Rebersek
-602. Ciardiello F, Cervantes A, Vega-Villegas ME, Casado E, Rodriguez-Braun E, Martinelli E., et al. Optimal dose for an every 2 week (q2w) cetuximab (C) regimen in patients (pts) metastatic colorectal cancer (mCRC): a phase I safety, pharmacokinetics(PK) and pharmacodynamics (PD) study of weekly (q1w) add q2w schedules. [Abstract]. Eur J Cancer 2007; 5(4): 247. Pfeiffer P, Bjerregaard JK, Qvortrup C, Jensen BV, Yilmaz M, Nielsen D. Simplification of cetuximab (Cet) administration: double dose of every second week as a 60 minute infusion. J Clin
Nobuyuki Toshikuni, Hisakazu Shiroeda, Kazuaki Ozaki, Yasuhiro Matsue, Takahiro Minato, Tomoe Nomura, Nobuhiko Hayashi, Tomiyasu Arisawa and Mikihiro Tsutsumi
ablation of hepatocellular carcinoma. J Clin Ultrasound 2010; 38: 138-44. 20. Landmark KE, Johansen PW, Johnson JA, Johansen B, Uran SSkotland T. Pharmacokinetics of perfluorobutane following intravenous bolus injection and continuous infusion of sonazoid in healthy volunteers and in patients with reduced pulmonary diffusing capacity. Ultrasound Med Biol 2008; 34: 494-501. 21. Hiraoka A, Hirooka M, Koizumi Y, Hidaka S, Uehara T, Ichikawa S, et al. Modified technique for determining therapeutic response to radiofrequency ablation
Branka Strazisar and Nikola Besic
-42. 36. Stratford AF, Zoutman DE, Davidson JS. Effect of lidocaine and epinephrine on Staphylococcus aureus in a guinea pig model of surgical wound infection. Plast Reconstr Surg 2002; 110: 1275-9. 37. Parr AM, Zoutman DE, Davidson JS. Antimicrobial activity of lidocaine against bacteria associated with nosocomial wound infection. Ann Plast Surg 1999; 43: 239-45. 38. Mather LE, Copeland SE, Ladd LA. Acute toxicity of local anesthetics: underlying pharmacokinetic and pharmacodynamic concepts. Reg Anesth Pain Med 2005; 30: 553-66.
Barbara Jezersek Novakovic
M, et al. Methotrexate area under the curve is an important outcome predictor in patients with primary CNS lymphoma: A pharmacokinetic-pharmacodynamic analysis from the IELSG no. 20 trial. Br J Cancer 2010; 102: 673-7. 28. Abrey LE, Batchelor TT, Ferreri AJ, Gospodarowicz MJ, Pulczynski EJ, Zucca E, et al. Report of an international workshop to standardize baseline evaluation and response criteria for primary CNS lymphoma. J Clin Oncol 2005; 23: 5034-43. 29. Uhm JE, Kim KH, Yi SY, Chang MH, Park KW, Kong DS, et al. A
Barbara Mali, Damijan Miklavcic, Luca G. Campana, Maja Cemazar, Gregor Sersa, Marko Snoj and Tomaz Jarm
; 9: 22-25. 31. Alberts DS, Chen HS, Liu R, Himmelstein KJ, Mayersohn M, Perrier D, et al. Bleomycin pharmacokinetics in man. I. Intravenous administration. Cancer Chemother Pharmacol 1978; 1: 177-181. 32. Sersa G, Jarm T, Kotnik T, Coer A, Podkrajsek M, Sentjurc M, et al. Vascular disrupting action of electroporation and electrochemotherapy with bleomycin in murine sarcoma. Br J Cancer 2008; 98: 388-398. 33. Sersa G, Krzic M, Sentjurc M, Ivanusa T, Beravs K, Kotnik V, et al. Reduced blood flow and oxygenation
Barbara Faganel Kotnik, Janez Jazbec, Petra Bohanec Grabar, Cristina Rodriguez-Antona and Vita Dolzan
haplotype for SLC19A1 rs7499, rs1051266, rs2838956 and rs3788200 with MTX gastrointestinal toxicity was established. 38 The results of the haplotype based analysis indicate, that other polymorphisms that are in linkage disequilibrium with rs1051266 and rs1131596, may impact the functioning of SLC19A1 via, for example, alterations in SLC19A1 splicing. 39 , 40 As well, other genes coding for proteins that are involved in the transport and metabolism of MTX can also impact pharmacokinetics and the occurrence of MTX-induced AE, such as SLCO1B1 SNPs that are