Treating febrile neutropenia
A life-threatening complication for patients undergoing chemotherapy is febrile neutropenia, involving a loss of neutrophils (white blood cells) and fever. G‑CSFs are growth factors which are used to restore neutrophil production. The most commonly used recombinant G-CSFs are filgrastim (Neupogen) and its pegylated form pegfilgrastim (Neulasta), both from Amgen, and biosimilar filgrastim (Zarzio, from Sandoz/Novartis). Filgrastim and biosimilar filgrastim are administered daily for up to a maximum of 14 days, either subcutaneously or intravenously, until the patient’s neutrophil counts are restored to the target absolute neutrophil count (ANC) of greater than or equal to 10,000/mm3. In contrast, pegfilgrastim is given as a single subcutaneous dose per 14-day chemotherapy cycle .
Fixed versus variable costs
The study assumes, for the purpose of the cost comparison, that the three treatments have comparable efficacy, safety and tolerance. They define cost as the actual outlay of cash required to purchase or reimburse G-CSF treatment. Key to the cost comparison is the number of doses required for treating each patient. The cost of pegfilgrastim treatment is fixed at a single injection per 14-day cycle. In contrast, the cost of treatment with either originator or biosimilar filgrastim varies, depending on the number of daily injections. Likewise, the cumulative savings with biosimilar filgrastim can vary according to the number of doses over a 14-day cycle.
Previous studies have found pegfilgrastim to be more cost-effective than filgrastim for treatment periods of either six or 11 days, based on local prices in France, Germany, UK and USA, and for a 6-day treatment time in Italy [3, 4]. As Professor Aapro and co-authors stress, however, these do not necessarily reflect typical treatment times, which can vary from 1 to 13 days and which tend to cluster at around 4 to 7 days.
Which G-CSF provides the most cost-efficiency savings?
The current study by Professor Aapro and co-authors attempts to determine, firstly, whether there is a time point at which pegfilgrastim provides a cost saving over the use of filgrastim and its biosimilar in reducing the incidence of febrile neutropenia. Secondly, the study aims to see whether biosimilar filgrastim (Zarzio) provides a cost saving over the use of originator filgrastim (Neupogen). The study takes into account the duration of treatment time in order to estimate the cumulative cost savings.
The authors focused on the EU G5 countries: France, Germany, Italy, Spain and UK, and considered the direct costs a buyer or payer would incur when purchasing or covering any of the three agents Neupogen, Neulasta and Zarzio for the treatment of one patient during one chemotherapy cycle. The authors excluded costs associated with the administration of the treatment or any other expenses related to the management of febrile neutropenia.
Current clinical guidelines assume that there is no significant difference in efficacy or safety between the three products [5, 6]. On this basis, the authors compared the fixed cost of a single treatment with Neulasta (6 mg) (based on 11 days of standard filgrastim treatment) to the cumulative (variable) cost of treatment with Neupogen or Zarzio (300 mg per day) per 14-day chemotherapy cycle, to determine which product provides the most cost saving.
To provide a cross-G5 comparison, the authors calculated the weighted average cost of one dose of each product using the public pack prices for each G5 country, weighted according to its relative population size. Thus the weighted EU G5 unit dose prices were Euros 128.16 for Neupogen, Euros 1,414.96 for Neulasta, and Euros 95.46 for Zarzio. The study found the cumulative cost of Neupogen treatment to range from Euros 128.16 (for 1 day) to Euros 1,794.30 (for a full 14-day course). This compared with a unit dose cost of Euros 95.46 to Euros 1,336.46 for Zarzio. Choosing Zarzio over Neupogen, therefore, would provide a cost saving ranging from Euros 32.70 (for 1 day) to Euros 457.84 (for a 14-day regimen).
A single-dose treatment with pegfilgrastim therefore becomes cost saving at day 12 of Neupogen treatment, providing a cost saving of Euros 379.34 compared to the cost of 14 days of Neupogen treatment. However, there is no time point when pegfilgrastim yields a savings benefit over treatment with biosimilar filgrastim (Zarzio), according to the study. Even over 14 days, Zarzio provides a saving of Euros 78.50, and at a single dose of the biosimilar the saving compared to Neulasta is Euros 1,319.50.
The authors conclude that, ‘Zarzio provides the best value (defined as quality over cost) for the prophylaxis and treatment of febrile neutropenia’.
Their conclusion holds true across key tumour types. For example, in the case of non-Hodgkins lymphoma, Professor Aapro and co-authors estimate that choosing Zarzio over Neupogen achieves a cost saving of Euros 212.57 per patient per chemotherapy cycle for primary prophylaxis and a cost saving of Euros 794.46 by using Zarzio instead of Neulasta. For the treatment of breast cancer, the savings are Euros 199.49 and Euros 832.65 respectively, and for lung cancer treatment, Euros 140.62 and Euros 1,004.48 respectively.
This, of course, is a theoretical exercise exploring potential savings across the G5 countries. As the authors emphasise, however, actual costs of these three products may vary, both within and between different countries, and so cost-efficiency analyses need to be repeated in individual markets in order to make decisions on purchasing and reimbursement.
The authors also acknowledge that a careful line needs to be drawn between the desire to reduce costs and the need for best outcomes for patients. Shorter treatment regimens with filgrastim, for example, have been associated with an increased risk of hospitalisation . They conclude that ‘what is most needed to support decision-making by all stakeholders is an integrated, comprehensive assessment of the total cost of care of febrile neutropenia that considers health resource consumption, cost-effectiveness (including comparison of different outcomes, e.g. neutropenia-related chemotherapy dose delays and reductions, hospitalisations) and cost-efficiency’.
In summary, in a cross-G5 country comparison, the use of biosimilar filgrastim provides the most cost savings compared to originator filgrastim and pegfilgrastim for the treatment of febrile neutropenia. But when comparing just pegfilgrastim with filgrastim, the former becomes cost saving if treatment is required for 12 days or more over a 14-day treatment regimen.
Conflict of Interest
The study  was supported by an unrestricted grant from Sandoz Biopharmaceuticals (Sandoz International GmbH).
If you are interested in contributing a research article in a similar area to GaBI Journal, please send us your submission here.
Is pegfilgrastim superior to filgrastim for the treatment of febrile neutropenia?
The cost-effectiveness of biosimilars
1. Aapro M, Cornes P, Abraham I. Comparative cost-efficiency across the European G5 countries of various regimens of filgrastim, biosimilar filgrastim and pegfilgrastim to reduce the incidence of chemotherapy-induced febrile neutropenia. J Oncol Pharm Pract. 2011.doi: 10.1177/1078155211407367.
2. Kuderer N, Dale D, Crawford J, Cosler L, Lyman G. Impact of primary prophylaxis with granulocyte colony-stimulating factor or febrile neutropenia and mortality in adult cancer patients receiving chemotherapy: a systematic review. J Clin Oncol. 2007;25(21):3158-67.
3. Liu Z, Doan QV, Malin J and Leonard R. The economic value of primary prophylaxis using pegfilgrastim compared with filgrastim in patients with breast cancer in the UK. Appl Health Econ Health Policy. 2009;7(3):193-205.
4. Lyman GH, Lalla A, Barron RL, Dubois RW. Cost-effectiveness of pegfilgrastim versus filgrastim primary prophylaxis in women with early-stage breast cancer receiving chemotherapy in the United States. Clin Ther. 2009;31(5):1092-104.
5. Aapro MS, Cameron DA, Pettengell R, et al. EORTC guidelines for the use of granulocyte-colony stimulating factor to reduce the incidence of chemotherapy-induced febrile neutropenia in adult patients with lymphomas and solid tumours. Eur J Cancer. 2006;42(15):2433-53.
6. National Comprehensive Cancer Network. Myeloid growth factors. Practice guidelines in oncology v.1.2010 [monograph on the Internet]. c2012 [cited 2012 April 17]. Available from: www.nccn.org/professionals/physician_gls/pdf/myeloid_growth.pdf
7. Weycker D, Hackett J, Edelsberg J, et al. Are shorter courses of filgrastim prophylaxis associated with increased risk of hospitalization? Ann Pharmacother. 2006;40(3):402-7.