Critical Reviews in Oncology/Hematology 78 (2011) Jean Klastersky, Ahmad Awada

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1 Critical Reviews in Oncology/Hematology 78 (2011) Prevention of febrile neutropenia in chemotherapy-treated cancer patients: Pegylated versus standard myeloid colony stimulating factors. Do we have a choice? Jean Klastersky, Ahmad Awada Department of Medicine, Jules Bordet Institute, Centre des Tumeurs de l Université Libre de Bruxelles, Rue Héger Bordet 1, 1000 Bruxelles, Belgium Accepted 11 February 2010 Contents 1. Introduction pf versus F in breast cancer patients pf versus F in lymphoma patients pf versus F in patients with leukemia or blood stem-cell allogeneic or autologous transplantation pf versus F in large observational studies in patients with various solid tumors and/or lymphoma and meta-analyses Discussion of the literature review Conclusions Conflict of interest Reviewers References Biographies Abstract The pertinent literature on clinical studies comparing the respective value of myeloid colony stimulating factors to pegfilgrastim as a prevention of febrile neutropenia in chemotherapy-treated cancer patients has been reviewed. Pegfilgrastim is definitely not inferior to filgrastim or other myeloid colony stimulating agents with respect to duration of grade IV neutropenia and delivery of full chemotherapy dose on time; several comparative studies indicate a trend to less frequent febrile neutropenia with pegfilgrastim Elsevier Ireland Ltd. All rights reserved. Keywords: Myeloid colony stimulating factors; Pegfilgrastim; Febrile neutropenia; Propylaxis; Chemotherapy in cancer patients 1. Introduction Infectious complications remain a major cause of morbidity and mortality in chemotherapy-treated cancer patients, especially when dose-intensive schedules are used. These untoward effects lead to substantial decrease of quality of life and significantly increased costs. Therefore, strategies for Corresponding author. Tel.: ; fax: address: jean.klastersky@bordet.be (J. Klastersky). minimizing complications of neutropenia are needed. So far, two prophylaxis strategies have been evaluated to mitigate infectious complications associated with chemotherapyinduced neutropenia: antibiotics and myeloid growth factors. Overall, there are indications that a substantial benefit can be derived from the use of both these approaches in selected patients, each type of prophylaxis having advantages and disadvantages [1]. However, as many of the conclusions about the relative merits of antibiotics and growth factors, for preventing /$ see front matter 2010 Elsevier Ireland Ltd. All rights reserved. doi: /j.critrevonc

2 18 J. Klastersky, A. Awada / Critical Reviews in Oncology/Hematology 78 (2011) infectious complications during neutropenia induced by chemotherapy, were obtained through meta-analyses, there are inherent limitations to the conclusions about their efficacy, cost and safety. A series of unanswered questions thus remain and would be optimally resolved through prospective clinical trials; namely, whether one of these two approaches is superior to the other and should be recommended over the other, remains to be answered [2]. Recent ASCO recommendations justify the use of myeloid colony stimulating factors (mcsfs), regardless of impact of other factors, when this risk of febrile neutropenia (FN) is approximately 20% and no other equally effective regimen, that does not require CSF, is available. Moreover, primary prophylaxis is recommended for the prevention of FN in patients who are at high risk based on age, medical history and disease characteristics [3]. Whether the indications for the use of mcsfs should be extended, beyond these recommendations has been recently discussed [4]. One may indeed anticipate a broadening of the indications for these agents for multiple reasons; namely, because chemotherapy is given now more often to elderly patients, in whom there is sufficient evidence, based on efficacy and economic studies, to support the use of mcsfs, even when moderately intensive chemotherapy is given [5]. Another good reason for broadening the indication for mcsfs, in the future, might be the probable reduction of the cost of these factors, which becomes realistic through the introduction of bio-similars [6]; indeed, the cost has been, so far, a major consideration for defining policies for the use of mcsfs. The EORTC guidelines for the use of mcsfs to reduce the incidence of the chemotherapy-induced febrile neutropenia (FN) in adult patients with lymphoma and solid tumors support those made by ASCO [7]. The EORTC guidelines also clearly recognize that factors other than just the level of myelosuppression should be taken into account for deciding how to use the mcsfs for the prevention of FN. They also state that filgrastim, lenograstim and pegfilgrastim have clinical efficacy and we recommend the use of any of these agents to prevent febrile neutropenia and febrile neutropenia-related complications where indicated. Recommendation grade A. Since, during the last years, several studies comparing the efficacy, safety and/or cost-efficacy of filgrastim (F), lenograstim (L) and pegfilgrastim (pf) have been performed, we decided to review the pertinent literature to evaluate (only comparative studies are analysed here) the respective merits of these three agents in preventing FN and its complications. Safety and cost-efficacy will be also discussed, when indicated. 2. pf versus F in breast cancer patients The efficacy of pf in preventing FN in chemotherapytreated patients was clearly demonstrated in a placebocontrolled double-blind phase III study, conducted by Vogel et al. [8]. pf significantly decreased the incidence of FN, hospitalization and use of antibiotics; with a respective incidence of FN in the control arm of 17% versus 1% in the treatment group (p < 0.001). The need for hospitalization was reduced from 14% to 1% (p < 0.001). pf was generally well tolerated and safe, and adverse events reported were typical of this patient population. Cost-efficacy analysis was not performed but, in view of the dramatic decrease of the incidence of FN and its complications, it can be assumed that the savings on hospitalization and antibiotic costs probably balanced the expenses for pf. Two robust phase III multi-centre, double-blind, randomized studies, in breast cancer patients receiving epirubin and docetaxel, showed a lower incidence of FN in patients receiving pf in comparison with F [9,10]. The incidence of FN in patients receiving pf or F was, respectively 13% and 20% (not statistically significant) and 9% versus 18% (p = 0.029) in those two investigations. It should be stressed that the chemotherapy regimen given in those studies, which differed only by the dose of pf fixeddose: 6 mg [10] or body-weight-adjusted dose: 100 g/kg [9] had been previously associated with a 38% incidence of FN [11]. In both trials, the safety profile of pf, assessed by adverse events and changes in laboratory values, was similar to that of F; more adverse events were attributable to chemotherapy or the primary disease. A combined analysis of these two pivotal randomized trials of a single dose of pf per chemotherapy cycle and daily F, in patients with stages II IV breast cancer, has been subsequently published [12]; it indicated that a single dose of pf (6 mg or 100 g/kg on day 2) was as effective as daily F(5 g/kg started on day 2 and continued until the neutrophil count was > /L or for a total of 14 days) in reducing the duration of severe neutropenia and the risk of FN; actually, the occurrence of FN was significantly lower (11% versus 19%) in the patients receiving pf as compared to those treated with F. Trends towards lower need for hospitalization and intra-veinous anti-infectives use were also observed. These results were consistent irrespective of risk factors, including age, disease stage, performance status and prior treatment. A similar trend towards a superiority of pf over F was confirmed in a more recently published trial, also in breast cancer patients, receiving epirubicin plus docetaxel or paclitaxel, in a neoadjuvant and adjuvant setting [13]. FN occurred in 13 (2.7%) of 476 F or L supported chemotherapy cycles and in 2 (1.2%) of 172 cycles with pf support (p = 0.37). The frequency of chemotherapy delays and dose reductions were not different between the two treatment groups. A more recent study compared the efficacy of pf primary prophylaxis with or without ciprofloxacin in comparison with F, L or ciprofloxacin alone, for neutropenia management in breast cancer receiving TAC [14]. Primary prophylaxis consisted of: ciprofloxacin 500 mg orally twice daily on days

3 J. Klastersky, A. Awada / Critical Reviews in Oncology/Hematology 78 (2011) (253 patients and 1478 cycles), daily F or L 5 g/kg/day on days 5 10 (377 patients and 2400 cycles), pf 6 mg/kg on day 2 (305 patients, 1930 cycles) and pf plus ciprofloxacin (324 patients, 1890 cycles). In that comparative, non-randomized study, pf with or without ciprofloxacin was significantly more effective than daily F or L, for preventing FN (5 7% versus 18 22%, p < ), as well as grade IV neutropenia. pf plus ciprofloxacin completely prevented first-cycle FN (p < 0.01) versus pf alone as well as fatal neutropenic events. It was concluded that pf was significantly more efficacious than F or L, especially if given with ciprofloxacin. Another recently published study is discordant with the preceding reports. pf administered on the same day as dose dense adjuvant chemotherapy, for breast cancer, was found associated with a higher incidence of FN as compared to conventional support (F 5 g/kg/day, on days 2 10) [15]. Fourteen patients in the pf group (13%) developed FN as compared to 1 patient (1%) in the F group (p = 0.001). The authors speculated that the administration of pf on day 1 rather than on day 2 after chemotherapy might have been responsible for these negative results; however, very few studies have investigated the safety and efficacy of pf, when administered on the day of chemotherapy versus the next day and often led to contrasting or inconclusive results. The cost-effectiveness of pf versus 6 days of F for the prevention of FN has been recently evaluated in breast cancer patients [16]. Even when very low prices of F and high prices for pf were considered in that model, the resulting incremental cost-effectiveness ratio remained well within the acceptable cost-effectiveness limit of euros 50,000/qualityadjusted life year. Along the same lines, another recent study, evaluating the cost-effectiveness of pf versus F as primary prophylaxis in women with early-stage breast cancer receiving chemotherapy, reported that pf was clearly cost-saving compared to 11-day F and cost-effective compared to 6-day F, but only if one would be willing to pay >12,000 US dollars for preventing one episode of FN [17]. Finally, an integrated analysis in 2200 patients from various studies treated with a variety of chemotherapeutic regimens for breast cancer, and receiving either pf primary prophylaxis form cycle 1 or current practice for prophylaxis (no F or L, daily F or L and pf in any cycle) concluded that overall FN was less frequent with primary pf prophylaxis [18]. The odds ratio was 0.12 with a 95% confidence interval of 0.08 (p < ). Odds for FN during cycle 1, for dose reductions 15% of the scheduled regimen and FN-related hospitalizations were also significantly lower for primary prophylaxis with pf. 3. pf versus F in lymphoma patients In patients with lymphoid malignancy, aggressively treated with a dose-intensive chemotherapy regimen (hyper- CVAD), it was found that time to neutrophil recovery, incidence of FN, positive blood cultures and delays in subsequent chemotherapy were similar in patients receiving pf (6 mg) or F (5 g/kg/day); this was however a retrospective comparison of 43 patients receiving pf with 38 controls having received F for the first cycle of chemotherapy; the patients were matched for prior chemotherapy dose of cytarabine, age, histological diagnosis and bone narrow involvement [19]. Two earlier studies in patients with lymphoma had also shown equivalent effects of pf and F against FN-related endpoints [20,21]. Both studies were underpowered to detect a treatment advantage. More recently, the cost-effectiveness of pf versus 6-day F primary prophylaxis in patients with non-hodgkin s lymphoma receiving CHOP-21 was investigated [22]. The model considered direct medical costs and outcomes, related to reduced FN, and potential survival benefits due to reduced FN-related mortality. pf was found cost-effective as a primary prophylaxis compared to F given 6 days per cycle; however, the authors speculated that the results would have been more favorable for pf, if the comparison would have been done with a longer (10 11 days) administration of F, as the cost of F at days is more than the drug cost of pf. 4. pf versus F in patients with leukemia or blood stem-cell allogeneic or autologous transplantation A significant experience with pf as compared to F has been also accumulated in patients with acute leukemia and in patients receiving autologous or allogeneic peripheral blood stem-cell transplantations. In patients with acute myeloblastic leukemia and lowto-intermediate risk cytogenetics, a single dose of pf was compared to daily F for supporting neutrophil recovery [23]. No clinically meaningful difference between a single dose of PF and multiple daily doses of F for shortening the duration of severe neutropenia following chemotherapy was noticed. In another study, pf, administered on day 5 after allogeneic peripheral blood stem-cell transplantation from unrelated donors, in patients, most of whom presented with acute leukemia, was compared to daily administration of L until neutrophils were L [24]. There were no significant differences in the duration of neutropenia (p = 0.14) and frequency of FN (p = 0.25); differences were not observed in the treatment-related mortality or disease-free survival, and overall survival was not different between both study groups. Several other studies compared pf and F, after autologous peripheral stem-cell transplantation in patients with various hematological malignancies, lymphomas, multiple myeloma, and solid tumors [25 28]. Overall, in all studies, it was concluded to a similar safety and efficacy profiles of a fixed-dose single administration of pf and multiple daily doses of F. In one of these studies [25], it was found that the duration of FN, and the total days with fever, were significantly lower

4 20 J. Klastersky, A. Awada / Critical Reviews in Oncology/Hematology 78 (2011) in the pf arm. A higher incidence of documented infectious complications was observed in the F group (p = 0.02). In another of these studies [27], in patients with lymphoma or multiple myeloma, receiving autologous peripheral blood stem-cell transplantations, it was found that pf was possibly associated with a superior effect on cell counts after initial engraftment. 5. pf versus F in large observational studies in patients with various solid tumors and/or lymphoma and meta-analyses A large observational study of the prevalence of FN in patients receiving F or pf associated with 3 4-week chemotherapy regimens in community oncology practice was realized in the United States and published in 2007 [29]. Data were retrospectively collected from the medical records of a cohort of adult patients, aged 18 or older, who were treated in 99 community oncology practices, for breast, lung, ovary, colon cancers or lymphomas. Patients were treated with chemotherapy every 3 4 weeks and were users of F in 2001 (prior to the FDA approval of pf) or either F or pf or both in pf was initiated, on average, 2 days after chemotherapy, and F was started on average 6 days after onset of chemotherapy and its mean duration of administration was approximately 6 days. A total of 94 of 1451 patients (6.5%) who received F experienced FN compared to 67 of 1412 (4.7%) for pf. The odds ratio of developing FN among patients who received F versus pf was 1.41 (p = 0.040), after adjusting for patient and chemotherapy regimen characteristics. It should be stressed that, in that survey, patients who received F often initiated treatment later than recommended and received fever days per cycle that usually considered to be effective in randomized trials. Differences in the effectiveness of pf and F shown in that study might thus be related to how the drugs were actually used in clinical practice in contrast with their administration under optimal circumstances in clinical trials. The second similar study, LEARN, was conducted in Spain and consisted in a multi-centre, retrospective, observational review, comparing patterns of use of daily mcsf s (111 patients) and pf (75 patients) and chemotherapy-induced neutropenia-related outcomes in adults with non-myeloid malignancies [30]. In that study, the two types of mcsf s were used as primary or secondary prophylaxis and for treatment; in all cases, the administration of pf consisted of a single injection while the median number of injections of F or L was 6 for primary prophylaxis and 5 for secondary prophylaxis or treatment. Chemotherapy-induced neutropenia-related complications were less frequent in patients receiving pf than in those receiving other mcsf s; FN occurred, respectively in 11% versus 24%. Patients receiving pf had also numerically lower incidence of dose reductions due to neutropenia, hospitalizations due to FN, and antibiotic administrations. However, due to the descriptive nature of the analysis in that study, a conclusion of the significance could not been made. The risk of hospitalization for neutropenic complications of chemotherapy in patients with a variety of solid tumors or lymphoma, receiving pf or F prophylaxis, were also recently evaluated in a retrospective cohort study [31]. It was found that hospitalization for neutropenic complications occurred during 2.1% of F and 1.2% of pf cycles (p < 0.01) in this evaluation of 1193 unique chemotherapy cycles for F and 14,570 cycles for pf, among which 16% represented firstcycle use. These results confirm the numerically modest, although statistically significant, advantage of pf over F, already found in a similar type of study in breast cancer patients [18]. Finally, a meta-analysis of five randomized controlled trials, conducted to compare pf with F on FN, grade IV neutropenia and bone pain, has concluded that a single dose of pf performed better than a median days of F in reducing FN rates, for patients undergoing myelosuppresive chemotherapy [32]. Overall, the relative risk of FN was 0.64 for pf compared to F; it was 0.56 for the meta-analysis limited to the two large phase III trials (p < 0.001) and 0.96 (p < 0.92) for the three phase II trials. Grade IV neutropenia, time to normal neutrophil counts recovery and incidence of bone pain were similar between the two types of treatment. These results should be interpreted in the light of the usual limitations of meta-analyses. Here, only five controlled studies met the pre-specified inclusion criteria for the metaanalysis and, even those selected studies varied not only in design (phase II or III) but also in indications and chemotherapy regimens. 6. Discussion of the literature review It can be concluded, at this point, that pf is definitely not inferior (i.e. it is comparable) to F with respect to duration of grade IV neutropenia and delivery of full chemotherapy dose on time; the same applies to the frequency of FN, although several comparative studies indicate a trend to less frequent FN with pf, suggesting that prolonged serum levels of mcsf s may be clinically important. Although, it is recommended that F be administered until the recovery of a normal granulocyte count (which usually requires daily injections), many studies and current clinical practice [29], indicate the use of fewer injections, perhaps in an attempt to limit the cost. Actually, another way to limit the cost of mcsf s, while maintaining a full dosing, would be the use of more affordable bio-similars [6]. The cost-effectiveness of pf versus 6-day F, for primary prophylaxis, has been studied in patients with lymphoma [17]. Although pf has been found cost-effective in that evaluation, results would have been more favorable for PF if it

5 J. Klastersky, A. Awada / Critical Reviews in Oncology/Hematology 78 (2011) would have been compared to a longer course (10 11 days) with F, as commonly used in many trials and currently recommended. Another analysis, from Australia, confirms that if less than 12 injections of 300- g injections of F are anticipated to be required per cycle, then daily administration of F becomes more cost-effective that a single dose of pf [33]. On the other hand, as already discussed in patients with breast cancer, an Italian study [16] found that pf was more cost-effective than 6-day F, while another cost-effectiveness analysis [17] found that a 6-day F prophylaxis was costeffective, if the decision makers were willing to pay 12,000 US dollars to prevent one episode of FN; however pf was clearly cost-saving compared with 11-day F regimen. No clear conclusions can be derived from these data; clearly, at the present stage of cost, if the number of F or L administrations is limited, the cost-effectiveness compared to pf would be competitive. The introduction of more affordable mcsf s might bring new insights into that controversy. A recent review of the impact of primary prophylaxis with mcsf s on FN and mortality in adult cancer patients receiving chemotherapy suggests that a lower baseline FN risk may be associated with greater FN relative risk reduction by mcsf s [34]. This observation potentially explains why noncontinuous mcsf s therapy may be safe in patients at low FN risk as suggested by Papaldo et al. [35] in a non-randomized post hoc analysis of different interrupted G-CSF s strategies in patients treated with adjuvant EC for breast cancer and with a baseline risk of 7%. Five different schedules were tested in five consecutive cohorts of patients: 480 g/day on days 8 14; 480 g/day on days 8,10, 12 and 14; 300 g/day on days 8 14; 300 g/d on days 8, 10, 12 and 14; and 300 g/d on days 8 and 12. It was found that the less intense schedule (i.e. 300 g/d on days 8 and 12) was equivalent to all the other schedules with respect to incidence of grades III and IV neutropenia, incidence of FN, need of antibiotics and percentage of delayed cycles. If these results can be confirmed, a major progress would be achieved in terms of cost-effectiveness and facilitation of compliance for mcsf s use as a prophylaxis of FN. However, this trial was a non-randomized observational study and its results should be considered as hypothesis generating. Because of the uncertainty of benefit/harm of alternative treatment options, a high level of evidence, such as randomized clinical trial comparing standard versus alternative less intensive CSF dosing schedules is needed before accepting the results for current clinical practice [36]. In contrast to F, which is cleared via both renal and neutrophil mediated clearance mechanisms, pf is mostly cleared by neutrophil uptake and utilization; this self regulating clearance ensures that the plasma levels of pf remain elevated during chemotherapy-induced neutropenia and then decline as the neutrophil count recovers. These pharmacological properties probably justify the administration of pf as a single injection on day 2 after myelosuppression chemotherapy. Few studies have reported biological data regarding optimal timing of F administration, and controversy exists as to whether a schedule starting immediately after chemotherapy is better than a schedule starting later on [37]. Both approaches have been used in the studies comparing pf and F which were reviewed here, and it is very unlikely that further prospective comparisons of these two approaches would shed further light on the question. Actually, it seems that both immediate [12] or delayed [35] schedules of F administration are effective in terms of prevention of FN. Thus the question to be answered now is whether one could reduce the total dose of F to 2 3 administrations per cycle as suggested by Papaldo et al. [35], in comparison with a single dose of pf, to prevent effectively FN and preserve overall cost-effectiveness, in patients with a low to moderate risk of FN. 7. Conclusions To conclude, it appears that pf is definitely not inferior to classical F administration, in efficacy and cost-effectiveness. Whether it might be superior and more cost-effective cannot be derived from the presently available data, but it seems unlikely that major differences do exist between the two approaches. It is possible that the trend for superiority of pf, as compared to F, is influenced by the variations in doses and schedules used for F in current practice. On the other hand, there is some suggestion that a spaced administration of F might be effective in patients treated with a moderately intensive regimen. Consequently, it would be probably worthwhile to explore whether the type and dose of mcsf support should not be tailored to the aggressiveness of chemotherapy. In that context, the question whether primary prophylaxis with F could be made easier and more affordable by a reduction of the number of injections, is worth of being explored, at least in patients receiving relatively less aggressive myelosuppressive therapies. If shown effective, that approach would improve the compliance and the cost-efficacy of mcsf support in large numbers of patients. Conflict of interest Dr Klastersky has received consulting fees from TEVA and lecture fees from AMGEN. Dr Awada has no conflict of interest. Reviewers John R. Wingard, M.D., Professor of Medicine, University of Florida College of Medicine, 1600 SW Archer Rd, Gainesville, FL 32610, United States.

6 22 J. Klastersky, A. Awada / Critical Reviews in Oncology/Hematology 78 (2011) Paolo Pronzato, M.D., Istituto Nazionale per la Ricerca sul Cancero, Via Benedetto XV, 10, I Genova, Italy. References [1] Wingard JR, Elmongy M. Strategies for minimizing complications of neutropenia: prophylactic myeloid growth factors or antibiotics. Crit Rev Oncol Hematol 2009;72(2): [2] Herbst C, Naumann F, Kruse EB, et al. Prophylactic antibiotics or G-CSF for the prevention of infections and improvement of survival in cancer patients undergoing chemotherapy. Cochrane Libr 2009;(2) [Review]. [3] Smith TJ, Khatcheressian J, Lyman GH, et al. Update of recommendations for the use of white blood cell growth factors: an evidence-based clinical practice guideline. J Clin Oncol 2006;24: [4] Klastersky J, Awada A, Aoun M, et al. Should the indications for the use of myeloid growth factors for the prevention of febrile neutropenia in cancer patients be extended? Curr Opin Oncol 2009;21: [5] Lyman GH, Kuderer NM, Balducci L. Cost-benefit analysis of granulocyte colony-stimulating factor in the management of elderly cancer patients. Curr Opin Hematol 2002;9: [6] Del Giglio A, Eniu A, Ganea-Motan D, et al. XM02 is superior to placebo and equivalent to Neupogen in reducing the duration of severe neutropenia and the incidence of febrile neutropenia in cycle I in breast cancer patients receiving docetaxel/doxorubicin chemotherapy. BMC Cancer 2008;8: [7] 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: [8] Vogel CL, Wojtukiewicz MZ, Carroll RR, et al. First and subsequent cycle use of pegfilgrastim prevents febrile neutropenia in patients with breast cancer: a multicenter, double-blind, placebo-controlled phase III study. J Clin Oncol 2005;23: [9] Green MD, Koelbl H, Baselga J, et al. A randomised double-blind multicenter phase III study of fixed-dose single-administration pegfilgrastim versus daily filgrastim in patients receiving myelosuppressive chemotherapy. Ann Oncol 2003;14: [10] Holmes FA, O Shaughnessy JA, Vukelja S, et al. Blinded, randomised, multicenter study to evaluate single administration pegfilgrastim once per cycle versus daily filgrastim as an adjunct to chemotherapy in patients with high-risk stage II or stage III/IV breast cancer. J Clin Oncol 2002;20: [11] Misset JL, Dieras V, Gruia G, et al. Dose-finding study of docetaxel and doxorubicin in first-line treatment of patients with metastatic breast cancer. Ann Oncol 1999;10: [12] Siena S, Piccart M, Holmes FA, et al. A combined analysis of two pivotal randomized trials of a single dose of pegfilgrastim per chemotherapy cycle and daily filgrastim in patients with stage II-IV breast cancer. Oncol Rep 2003;10: [13] Schippinger W, Holub R, Dandachi N, et al. Frequency of febrile neutropenia in breast cancer patients receiving epirubicin and docetaxel/paclitaxel with colony-stimulating growth factors: a comparison of filgrastim or lenograstim with pegfilgrastim. Oncology 2006;70: [14] Von Minckwitz G, Kümmel S, du Bois A, et al. Pegfilgrastim ± ciprofloxacin for primary prophylaxis with TAC (docetaxel/doxorubicin/cyclophosphamide) chemotherapy for breast cancer. Results from the GEPARTRIO study. Ann Oncol 2008;19: [15] Skarlos DV, Timotheadou E, Galani E, et al. Pegfilgrastim administered on the same day with dose-dense adjuvant chemotherapy for breast cancer is associated with a higher incidence of febrile neutropenia as compared to conventional growth factor support: matched casecontrol study of the hellenic cooperative oncology group. Oncology 2009;77: [16] Danova M, Chiroli S, Rosti G, et al. Cost-effectiveness of pegfilgrastim versus six days of filgrastim for preventing febrile neutropenia in breast cancer patients. Tumori 2009;95: [17] Lyman GH, Lalla A, Barron RL, et al. 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: [18] Von Minckwitz G, Schwenkglenks M, Skacel T, et al. Febrile neutropenia and related complications in breast cancer patients receiving pegfilgrastim primary prophylaxis versus current practice neutropaenia management: results from an integrated analysis. Eur J Cancer 2009;45: [19] Lane SW, Crawford J, Kenealy M, et al. Safety and efficacy of pegfilgrastim compared to granulocyte colony stimulating factor (G-CSF) supporting a dose-intensive, rapidly cycling anti-metabolite containing chemotherapy regimen (Hyper-CVAD) for lymphoid malignancy. Leuk Lymphoma 2006;47: [20] Vose JM, Crump M, Lazarus H, et al. Randomized, multicenter, open-label study of pegfilgrastim compared with daily filgrastim after chemotherapy for lymphoma. J Clin Oncol 2003;21: [21] Grigg A, Solal-Celigny P, Hoskin P, et al. Open-label randomized study of pegfilgrastim vs. daily filgrastim as an adjunct to chemotherapy in elderly patients with non-hodgkin s lymphoma. Leuk Lymphoma 2003;44: [22] Lyman G, Lalla A, Barron T, et al. Cost-effectiveness of pegfilgrastim versus 6-day filgrastim primary prophylaxis in patients with non- Hodgkin s lymphoma receiving CHOP-21 in United States. Curr Med Res Opin 2009;25: [23] Sierra J, Szer J, Kassis J, et al. A single dose of pegfilgrastim compared with daily filgrastim for supporting neutrophil recovery in patients treated for low-to-intermediate risk acute myeloid leukemia: results from a randomized, double-blind, phase 2 trial. BMC Cancer 2008;8: [24] Ocheni S, Zabelina T, Bacher U, et al. Pegfilgrastim compared to lenograstim after allogeneic peripheral blood stem-cell transplantation from unrelated donors. Leuk Lymphoma 2009;50: [25] Staber PB, Holub R, Linkesch W, et al. Fixed-dose single administration of pegfilgrastim vs daily filgrastim in patients with haematological malignancies undergoing autologous peripheral blood stem cell transplantation. Bone Marrow Trans 2005;35: [26] Martino M, Pratico G, Messina G, et al. Pegfilgrastim compared with filgrastim after high-dose melphalan and autologous hematopoietic peripheral blood stem cell transplantation in multiple myeloma patients. Eur J Haematol 2006;77: [27] Vanstraelen G, Frère P, Ngirabacu MC, et al. Pegfilgrastim compared with filgrastim after autologous hematopoietic peripheral blood stem cell transplantation. Exp Hematol 2006;34: [28] Ballestrero A, Boy D, Gonella R, et al. Pegfilgrastim compared with filgrastim after autologous peripheral blood stem cell transplantation in patients with solid tumours and lymphomas. Ann Hematol 2008;87: [29] Morrison VA, Wong M, Hershman D, et al. Observational study of the prevalence of febrile neutropenia in patients who received filgrastim or pegfilgrastim associated with 3 4 week chemotherapy regimens in community oncology practices. J Manag Care Pharm 2007;13: [30] Almenar D, Mayans J, Juan O, et al. Pegfilgrastim and daily granulocyte colony-stimulating factor: patterns of use and neutropenia-related outcomes in cancer patients in spain results of the LEARN study. Eur J Cancer 2009;18: [31] Weycker D, Malin J, Kim J, et al. Risk of hospitalization for neutropenic complications of chemotherapy in patients with primary solid tumors receiving pegfilgrastim or filgrastim prophylaxis: a retrospective cohort study. Clin Ther 2009;31: [32] Pinto L, Liu Z, Doan Q, et al. Comparison of pegfilgrastim with filgrastim on febrile neutropenia, grade IV neutropenia and bone pain: a meta-analysis of randomized controlled trials. Curr Med Res Opin 2007;23:

7 J. Klastersky, A. Awada / Critical Reviews in Oncology/Hematology 78 (2011) [33] Grigg AP. A comparison of pegfilgrastim and filgrastim. Clin Adv Hemat Oncology 2005;3: [34] Kuderer NM, Dale DC, Crawford J, et al. Impact of primary prophylaxis with granulocyte colony-stimulating factor on febrile neutropenia and mortality in adult cancer patients receiving chemotherapy: a systematic review. J Clin Oncol 2007;21: [35] Papaldo P, Lopez M, Marolla P, et al. Impact of five prophylactic filgrastim schedules on hematologic toxicity in early breast cancer patients treated with epirubin and cyclophosphamide. J Clin Oncol 2005;28: [36] Djulbegovi B, Frohlich A, Bennett CL. Acting on imperfect evidence: how much regret are we ready to accept? J Clin Oncol 2005;28: [37] Crea F, Giovannetti E, Zinzani PL, et al. Pharmacologic rationale for early G-CSF prophylaxis in cancer patients and role of pharmacogenetics in treatment optimization. Crit Rev Oncol Hematol 2009;72(1): Biographies Klastersky has been Head of the Department of Medicine at the Institut Jules Bordet in Brussels and professor of Medicine, Medical Oncology and Physical Diagnosis at the Université Libre de Bruxelles since He retired from these positions in Currently, he is the coordinator of the Programme des Soins Oncologiques for the Public Hospitals in Brussels and consultant in Medical Oncology at the Institut Jules Bordet. He was a founder member of the European Lung cancer Working Party and has been his President since 1978 until He was President (and founder member) of the International EORTC Antimicrobial Therapy Project Group between 1979 and 1987 and the Group s Secretary General from 1987 to He was President (and founder member) of the Multinational Association for Supportive Care in Cancer (MASCC) from 1990 to He is visiting professor of Medical Oncology at the Charles University in Prague, since He is a member of the American Society of Clinical Oncology, the American Association of Cancer Research, the European Society of Medical Oncology, the American Society of Microbiology, the Infectious Diseases Society of America, the International Association for the Study of Lung Cancer, the Royale Académie de Médecine of Belgium and various other international and national medical and/or oncological societies. He is the author of over 500 original articles, nearly 400 review articles and 17 scientific books. He is the editor of Current Opinion in Oncology. Ahmad Awada was born in Lebanon and studied Medicine at the Free University in Brussels (ULB), Belgium. He did a specialisation in Internal Medicine and Medical Oncology at Jules Bordet Institute (under the supervision of Professor Jean Klastersky), in Brussels, until 1992 ( La plus grande distinction ). During his specialisation, he also followed trainings in the clinical development of new therapies and new anticancer drugs, under the supervision of Professor Martine Piccart. To deepen his training, he stayed in the Netherlands (New Drug Development Office, Free University, Amsterdam) and in San Antonio, USA (Institute for Drug Development, under the direction of Professor D. Von Hoff). He focused on the clinical development of new anticancer agents. Back from the USA at the beginning of 1994, he became Assistant Head of Medical Oncology Clinic, and Head of the New Drugs Development Unit at Jules Bordet Institute, Brussels. Since April 2005, he is the Head of the Medical Oncology Clinic. He has an important clinical activity in the treatment of solid tumors. He took an active part in the development of new drugs, some of them already widely used. Thanks to the recent progress in technology and computer sciences, and consequently in molecular biology, we can understand better now how a cancer cell works and how it becomes a cancer cell. Many drugs are now studied to block this process. Those are the molecular-targeted therapies, a subject studied extensively in clinical research by him and were the basis for this thesis obtained from the ULB, Brussels, in The aim of him, as far as research is concerned, is to look for new active anticancer drugs in solid tumors (new cytotoxics and molecular-targeted therapies), and to individualize the treatments according to the tumor characteristics. He is membership of several societies and responsible teacher at the Université Libre de Bruxelles. He received 2 awards, one from the Medecine Royal Academy. He published 24 book chapters, 154 articles in international publications