DLBCL has an aggressive natural history but most patients have a relatively good response to chemotherapy at least initially. It is maintenance of achieved remissions that is the bigger therapeutic problem. Although overall response rate (ORR) with modern therapeutic regimens vary between 75% and 80%, only 40% - 50% of patients achieve long-term remission (Coiffier, 2001).
Chemotherapy with six – eight cycles of CHOP has been the mainstay of therapy since its development in the 1970s (McKelvey et al., 1976). The treatment outcome for patients with DLBCL varies considerably based on initial stage of disease. For patients with early-stage disease (stages I and II non-bulky), chemotherapy with “abbreviated CHOP”, 2 – 4 cycles plus involved field radiation therapy seems to be effective. 5-year
event free survival reaches 73% and overall survival is 84% (Horning et al., 2004). By contrast the outcome of patients with advanced disease treated with CHOP-like therapy is not satisfactory. This therapy can induce complete responses in only 44 % of patients, with three-year EFS and OS rates of 43% and 55%, respectively (Fisher et al., 1993).
In order to try and improve treatment outcomes new and more complex regimens were developed in the 1970s and 1980s. Some are based on dosage escalation, others are multidrug chemotherapies that include additional drugs. Initial results from single-institution studies using new multidrug regimens were promising and suggested that the number of patients cured with those regimens might be doubled compared with results achieved with CHOP-like regimens. However, these findings were not confirmed by multicentre prospective randomised trials carried out by the Southwest Oncology Group (SWOG) and the ECOG (Fisher et al., 1993). Results showed that the new regimens were more toxic and the achieved remissions rates and OS were not improved compared with those achieved using CHOP alone (Fisher et al., 1993).
The role of chemotherapy intensification was re-investigated in the late 1990s with the availability of granulocyte colony stimulating factors (G-CSF) or erythropoietin, which were supposed to reduce chemotherapy induced toxicities. The addition of etoposide to CHOP with or without time intensification improved complete remission (CR) and 5-year EFS for patients < 60 years but not for those > 60 years (Pfreundschuh et al., 2004a) (Pfreundschuh et al., 2004b).
High-dose chemotherapy (HDCT) with up-front autologous stem-cell transplantation (ASCT), was another therapy option investigated in order to try and improve treatment responses in patients with poor-prognosis DLBCL. A variety of regimens were used but conflicting results were reported. A recent meta-analysis analysing efficacy of HDCT compared to conventional therapy in DLBCL patients found no evidence that HDCT improved OS and EFS in good risk DLBCL patients and the evidence for poor risk patients was inconclusive (Greb et al., 2007). Inadequate selection of patients and use of inappropriate induction regimens were postulated as possible reasons for the results. Therefore, the role of ASCT as initial therapy for patients judged to be at high-risk of treatment failure with conventional therapy remains to be assessed in prospective clinical trials.
Further attempts to improve the outcome of CHOP treatment have been made by combining it with immune-factor-based therapy such as the infusion of B-cell specific monoclonal antibodies. The CD20 antigen is expressed on normal and malignant B-
lymphocytes and it is known to regulate the cell cycle and cell differentiation (Maloney et al., 1994). Activation of CD20 by binding to its antibodies induces apoptosis of CD20 expressing lymphocytes. Rituximab (MabThera, Rituxan Roche, Neuillyu-sur-Seine, France) is a chimeric human/murine immunoglobulin G1 monoclonal antibody that binds specifically to CD20. Activation of CD20 on lymphoma cells by rituximab results in complement mediated lysis of tumour cells, antibody dependent cell mediated cytotoxicity and induction of apoptosis (Golay et al., 2000) (Hofmeister et al., 2000) (Shan et al., 1998) (Cartron et al., 2004) (Eisenbeis et al., 2003). Recent clinical studies have shown that rituximab acts synergistically with chemotherapy in patients with B cell lymphoma. In phase II trials Rituximab demonstrated efficacy in patients with DLBCL either alone or in combination with CHOP (Sonkoly et al., 2007) (Vose et al., 2001a). In a randomized study carried out by the GELA on elderly untreated patients with DLBCL, the addition of rituximab to CHOP significantly increased the CR rate (76% vs. 63%, p=0.005), and prolonged EFS and OS without a significant increase in toxicity (Coiffier et al., 2002). The five-year follow-up study showed that EFS, PFS, disease free survival (DFS), and OS remained statistically significant in favour of the combination R-CHOP (p=0.00002, p<0.00001, p<0.00031 and p<0.0073, respectively) (Feugier et al., 2005). Since the publication of the GELA Study R-CHOP has become the new standard in the treatment of elderly patients with DLBCL. Similarly, a retrospective study from British Columbia showed that the addition of rituximab to CHOP-like treatment improved EFS and OS in a group of previously untreated patients with DLBCL of all ages (Sehn et al., 2005). Additionally the MInT revealed that patients receiving CHOP or CHOP-like therapy with rituximab had a significantly higher 3-year EFS and OS compared with those who received chemotherapy alone (79% vs. 59%, p<0.0001 and 93% vs. 84%, p=0.0001; respectively). Importantly, there were no differences between the patients treated with R-CHOP and those given the more-intensified regimen cyclophosphamide, doxorubicine, vincristine, etoposide, prednisolone (CHOEP) (Pfreundschuh et al., 2006). Furthermore, data analysis showed that R-CHOP was an effective treatment for the younger patients with good-prognosis DLBCL. Although the results of prospective multicentre clinical trials appear to be very promising, the experience of clinicians working with unselected populations of patients with DLBCL seems to be less optimistic. In particular the treatment results for patients with poor-prognosis disease remain unsatisfactory.
More recent trials have focussed on improving the treatment of DLBCL on the basis of time intensification of the R-CHOP regimen with the support of growth factors (Halaas et al., 2005). Initial results are not promising nor are the results of the studies on the role of intermediate positron emission tomography (PET) scanning to aid treatment decisions.
Another new approach in the therapy of DLBCL is the combination of R-CHOP with new less-toxic cytostatic agents, antibodies or small molecules (Zaja et al., 2006). To date findings of the first clinical trials which combine R-CHOP and antibodies to VEGF (bevacizumab), or anti-CD22 antibodies (epratuzumab) are very promising but require further study (Micallef et al., 2006) (Ganjoo et al., 2006). Targeting the affected pathways in GCB and ABC DLBCL with genasence and bortezomib is other new therapeutic option.
In conclusion, the treatment of patients with DLBCL, particularly those of high- risk, remains an important unresolved issue. New therapeutic concepts need to be developed particularly in the area of risk stratification. The above statements are of particularly high importance in view of the very disappointing results in relapsed/refractory patients with DLBCL. Patients with relapsed or progressive disease (PD) still have a very poor prognosis. High dose chemotherapy followed by ASCT is the treatment of choice for these patients (Verdonck et al., 1992) (Vose et al., 2001b) (Prince et al., 1996) (Saez et al., 1994) (Nademanee et al., 2000) (Kewalramani et al., 2000) (Philip et al., 1995). The most compelling evidence for the superiority of HDCT compared with conventional-dose salvage therapy in relapsed and progressive NHL is based on the randomized “Parma trial” (Philip et al., 1995). In this study all patients received two cycles of conventional chemotherapy. Responders were randomized to receive either four cycles of conventional chemotherapy or HDCT followed by ASCT. Analysis at five years revealed that patients treated with HDCT had superior outcomes as measured by freedom from treatment failure (FFTF) (12% vs. 46%) and by OS (32% and 53%). However, in the “Parma trial” more than 50% of patients treated in the HDCT-arm relapsed and most of them died. Recent published results of second-line treatments based on high-dose (HD) protocols and ASCT are very limited (Vellenga et al., 2008) (Sieniawski et al., 2007) (Josting et al., 2005).