Description of the condition
According to the Norton-Simon-hypothesis, cancer resistance can result from a reduced sensitivity of tumour cells to chemotherapeutic agents (Norton 1982). Therefore, intensification of chemotherapy by increasing chemotherapy doses should result in higher cure rates. However, historically, in haematologic neoplastic diseases (cancers of the blood) specifically, until the development of autologous stem cell transplantation (ASCT) intensification with high dose chemotherapy (HDT) was precluded by chemotherapy-induced severe bone marrow toxicity (Gorin 1992). ASCT is the transplantation of a special type of marrow or peripheral cell, called stem cells, which are a source of self-renewing cells capable of differentiating into blood cells of all lineages and giving rise to erythrocytes (red blood cells), white blood cells and thrombocytes (cells involved in clotting). Following collection from a patient, stem cells can be safely cryopreserved (stored at a very low temperature) for subsequent use in the same patient (autologous transplantation) as a source of haematopoietic rescue (blood renewal) after high dose therapy (HDT). Haematopoietic stem cells for autologous transplantation can be collected from either the bone marrow (Gorin 1992; Philip 1995), or from peripheral blood following mobilisation from the bone marrow (Sheridan 1992). Autologous peripheral blood stem cell transplantation (ASCT) is currently preferred to autologous bone marrow stem cell transplantation (ABMT) because it achieves more rapid regrowth of red blood cells, white blood cells and platelets (Ottinger 1996; Vallenga 2001; Vose 2002).
HDT followed by ASCT has been successfully incorporated into the treatment of lymphoma (Yuen 1997; Sebban 2008; Le Gouill 2011), and multiple myeloma (MM) (Barlogie 2010). Lymphomas are a heterogeneous group of malignancies of the lymphatic system, classified into two categories: Hodgkin's lymphoma (HL) and non-Hodgkin's lymphoma (NHL) (Freedman 1999). HL accounts for approximately 10% of all lymphomas and approximately 0.6% of all cancers diagnosed annually in the developed world (Jemal 2009). This amounts to approximately 8830 new cases, and about 1300 deaths in the USA annually (Siegel 2011). The incidence of HL in Europe is approximately 2.4 cases per 100,000 persons (Sant 2010). Mortality from HL declined between the 1970s and 1990s in the USA and Western Europe, with resulting mortality rates of 0.5 per 100,000 in men and 0.3 per 100,000 in women (Levi 2002). The high success rates in HL treatment have been attributed to the development of multi-agent chemotherapy and the refinement of radiotherapy (Kennedy 1985). Relapse rates after first-line therapy range from 10% to 15% in favourable prognosis stage I-II disease (Specht 1998), to 30% to 40% in advanced disease (Somers 1994). HDT followed by ASCT is currently considered to be the treatment of choice for the following subsets of relapsed patients with HL: early relapse (i.e. within a year of treatment) and late relapse (i.e. more than 12 months after treatment), or after failure of initial chemotherapy; and second relapse after conventional treatment for first relapse (Brice 2008).
NHL is a heterogeneous (variable) group of lymphoproliferative disease variously derived from the clonal expansion of B-cell lymphocytes, T-cell lymphocytes, natural killer (NK)-cells or precursors of these cells. According to the World Health Organization (WHO) classification, NHL comprise the following subtypes: follicular lymphoma (FL); diffuse large B-cell lymphoma (DLBCL), Burkitt's lymphoma; mantle cell lymphoma; mucosa-associated lymphoid tissue (MALT) lymphoma; mature T-cell lymphoma; chronic lymphocytic lymphoma (CLL/SLL), mediastinal large B-cell lymphoma, anaplastic large-cell lymphoma; nodal marginal zone lymphoma, and precursor T-lymphoblastic lymphoma, lymphoplasmacytic lymphoma, and other types (Jaffe 2001). The most common subtypes of NHL are DLBCL and FL, accounting respectively for approximately 30% and 20% of patients with NHL (Glass 1997).The most relevant feature of NHL is its increase in incidence over the last 20 years in both the USA and Europe, with an overall annual incidence rate of 19.0 cases per 100,000 persons in 2001 (Ries 2004). It is estimated that between 1997 and 2001 the NHL mortality rate in the USA ran at 8.4 deaths per 100,000 (Ries 2004). However, survival rates differ according to histologic subtype (cell type), with high grade lymphomas - such as Burkitt's lymphoma, immunoblastic lymphoma and central nervous system lymphoma having the poorest survival rates (Sherr 1996; National Cancer Institute 2005).
HDT followed by ASCT has been incorporated into the treatment of NHL for both newly diagnosed and relapsing patients (Ketterer 1997), depending on histologic subtype. In patients with relapsed or refractory DLBCL that responds to a second course of chemotherapy, HDT followed by ABMT results in superior overall survival rates than chemotherapy alone (Philip 1995). In patients with FL, HDT followed by ASCT prolongs progression-free survival and overall survival rates in those who are in complete remission, or have minimal disease at the time of HDT (Sebban 2008). MM is characterised by the neoplastic (cancerous) proliferation of a single clone of plasma cells (i.e. monoclonal immunoglobulin). This clone of plasma cells proliferates in the bone marrow and often results in extensive skeletal destruction, reduced bone mass and pathologic fractures (Kyle 2003). The median age at diagnosis is 66 years; only 10% of patients are under 50 years of age and only 2% are under 40 years (Kyle 2003). MM accounts for approximately 1% of all cancers and slightly more than 10% percent of haematologic malignancies in the USA. The annual incidence in the USA is approximately four to five per 100,000. A similar incidence has been reported in the South Thames area of the United Kingdom and in Europe in general (Phekoo 2004). A high dose of the anti-cancer drug melphalan followed by ASCT, performed either at the time of initial diagnosis or at relapse, is considered to be the best treatment for younger patients (i.e. under 70 years of age) with newly diagnosed MM (Moreau 2002; Child 2003; Palumbo 2004).
Description of the intervention
Granulocytes are a type of white blood cell characterized by the presence of granules in their cytoplasm. The most abundant of the granulocytes are neutrophils. Granulocytes are derived from stem cells residing in the bone marrow and the differentiation of these stem cells from pluripotent (i.e. cells that can develop into many cell types) haematopoietic stem cells into granulocytes is termed granulopoiesis. Granulocyte colony-stimulating factor (G-CSF) is a glycoprotein, growth factor and cytokine produced by a number of different tissues to stimulate the bone marrow to produce granulocytes and stem cells. G-CSF also stimulates the survival, proliferation, differentiation, and function of neutrophil precursors and mature neutrophils (Kauschansky 2006). The artificially produced recombinant human G-CSF, synthesised in an Escherichia coli expression system, is called filgrastim. Filgrastim (Neupogen®) and PEG (polyethylene glycol)-filgrastim (Neulasta®) are two commercially available forms of recombinant human G-CSF (rhG-CSF). The PEG form is a recombinant methionyl form of human G-CSF, in which a 20 kDa polyethylene glycol molecule has been covalently bound to the N-terminal methionine residue. It has a much longer half-life (time during which the medicine can act within the body), reducing the necessity for daily injections. A single fixed dose of PEG-filgrastim can be given once during each chemotherapy cycle in conjunction with a variety of chemotherapy regimens (Yang 2011). The recent expiry of the patent for filgrastim allowed the marketing of generic versions, called bio-similars, which are drugs that are similar, but not identical, to the original drug (Zuniga 2010). Approved bio-similar G-CSFs include Biograstim®, Filgrastim ratiopharm/Ratiograstim® (this drug was withdrawn from use in 2011), Tevagrastim®, Zarzio® and Nivestim® (Gascon 2012). Another form of recombinant human G-CSF called lenograstim (Myelostim®, Granocyte®) is synthesised in Chinese hamster ovary cells. No clinical or therapeutic consequences of the differences between filgrastim and lenograstim have yet been identified, but there are no formal comparative studies. In adults, the recommended dose of rhG-CSF is 5 µg/kg/day. The usual route for drug administration is subcutaneous injection. G-CSFs are generally well tolerated, though bone pain, flu-like symptoms including fever, flushing, malaise, myalgia (muscle pain), arthralgia (joint pain), anorexia (lack of appetite), and headache, as well as mild elevation of aminotransferases and rashes have been reported. These side-effects are transitory and are alleviated by antipyretics drugs that reduce fever (Metcalf 2010).
How the intervention might work
Despite the faster repopulation of bone marrow obtained from reinfusion using peripheral stem cell transplantation(SCT), patients treated with HDT followed by ASCT are still susceptible to infections and sepsis because of a residual period of neutropenia - a condition that lasts seven to 10 days after peripheral SCT in which the neutrophil count falls below 1000/µl. The incidence of fever associated with neutropenia (i.e. febrile neutropenia) in this setting ranges from 60% to 100% of treated patients, with the majority of fevers classified as being of unknown origin (Reich 2005; Gil 2007). Moreover, the duration of severe neutropenia, in which the neutrophil count falls below 500/µl, following HDT and ASCT is correlated with the development of infectious complications that have a major impact on overall morbidity and mortality (Freifeld 2011). G-CSFs could be able to shorten the period of neutropenia following HDT and ASCT by stimulating production of neutrophils, and thus reduce the incidence of febrile neutropenia and infections. The faster speed of neutrophil recovery associated with G-CSF administration could eventually reduce the mortality associated with ASCT.
Why it is important to do this review
The prophylactic use of G-CSF in patients with malignant lymphoma undergoing conventional chemotherapy has been shown to reduce the risk of certain adverse events, including severe neutropenia, febrile neutropenia and infections. Despite this, the addition of G-CSF failed to improve overall survival (OS) or freedom from treatment failure (FFTF) in comparison with no prophylaxis (Bohlius 2008). Moreover, another recent Cochrane review investigating the role of colony-stimulating factors for the prevention and treatment of infectious episodes in patients with acute myelogenous leukaemia failed to demonstrate any advantage for infection-related outcomes (Gurion 2011). Contrary to its efficacy in the setting of ABMT (Advani 1992; Gorin 1992), the value of G-CSF following ASCT is less well defined and no overall consensus exists about its optimal use. However, despite the fact that the addition of G-CSF may accelerate neutrophil recovery in the setting of ASCT (Spitzer 1994; Demirer 2002), no clear demonstration of the related clinical benefit is available.This review will clarify the efficacy of G-CSFs in relation to various clinical issues following HDT and ASCT, and provide the basis of a more evidence-informed use of these growth factors.