At its most fundamental level, cancer has emerged as a disease of genes and DNA, and the entire message can now be interpreted with the aid of sophisticated techniques in molecular and cellular biology.
Aggressive chemotherapy may cure 50% of DLBCL cases; bone marrow transplantation might be able to rescue another 25%. Over the last eight years, the introduction of monoclonal antibodies—specifically the anti-CD20 monoclonal antibody rituximab (Rituxan, Genentech/Biogen Idec; MabThera, Roche)—has radically changed therapy for B-cell NHL
Rituximab, a genetically engineered chimeric mouse/human monoclonal antibody, binds to the transmembrane antigen, CD20, a non-glycosylated phosphoprotein, located on pre-B and mature B lymphocytes. This antigen is expressed on more than 95% of all B-cell NHLs and on normal B cells; however, it is not expressed on hematopoietic stem cells, normal cells, or malignant plasma cells. The Fc domain of rituximab recruits immune effector functions to mediate B-cell lysis.
Possible mechanisms include complement-dependent cytotoxicity (CDC), resulting from C1q binding, and antibody-dependent cellular cytotoxicity (ADCC), mediated by one or more of the Fc gamma receptors on the surface of granulo-cytes, macrophages, and natural killer cells. It is also possible that the binding of rituximab to the CD20 antigen on the cell surface directly induces apoptosis.
For patients with both follicular and diffuse large B-cell NHL, several large-scale, prospective randomized trials have demonstrated prolongation of remission when rituximab is incorporated into first-line treatment. For patients with fol-licular lymphoma, rituximab can be a component of salvage therapy.
An Italian study was conducted from June 2002 to June 2004 in 26 patients with stage III/IV DLBCL. The patients ranged in age from 60 to 76 years. They received a regimen of rituximab, followed on the next day by CHOP chemotherapy— cyclophosphamide, doxorubicin (Adriamycin), and vincristine (Oncovin)—accompanied by prednisone, given for five days.
The patients also received granulocyte-colony-stimulating factor (G-CSF) on days 7 to 11 of each treatment cycle to minimize treatment-induced reductions in neutrophil counts and the accompanying risk of infection. The regimen was repeated every two weeks, for a total of six full cycles.
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The intensity of this R-CHOP regimen, on the basis of its dose sizes and frequency of repetition at two-week intervals, was twice that originally reported for the regimen in 1984, when it had been used to treat metastatic breast cancer. As part of this study, patients in whom DLBCL had spread beyond the lymph nodes and patients with large or bulky sites of local disease were referred for radiotherapy when this was feasible.
Of the 26 patients in the study, 24 received all six planned cycles of treatment with the intensified R-CHOP regimen. Twenty of the 26 patients in the study (77%) achieved complete remissions, and six patients (23%) achieved partial remissions, for an overall response rate of 100%.
At a mean follow-up of 23 months, 79% of the patients were still alive. Despite the increase in treatment intensity from the original CHOP protocol, only one patient in the study died as the result of a stroke. Although a significant reduction in the cardiac left ventricular ejection fraction was among the potentially serious toxic effects of the intensified regimen, clinically evident heart failure developed in only one patient, and it was successfully managed with medication.
Six patients experienced severe grade 3/4 adverse hemato-logical effects from the treatment regimen in the form of neutropenia or anemia; three other patients developed severe infections or diarrhea. All patients in the study experienced alopecia.
Although a larger multicenter trial is needed to determine the effects of dose-intensive R-CHOP therapy for DLBCL, this study was an excellent example of the poor prognosis of the patients at the time of their diagnosis. The results with the intensified R-CHOP regimen were encouraging and confirmed the safety and efficacy of a dose-dense regimen of CHOP for treating older patients with an aggressive, high-risk NHL such as DLBCL. Furthermore, the addition of rituximab appeared to increase the rate of response from the regimen without increasing toxicity.
As a result of these and other studies, rituximab may be included for previously untreated patients with stage III/IV fol-licular lymphoma in combination with cyclophosphamide, vincristine, and prednisone (CVP) chemotherapy. cialis canadian pharmacy
For maintenance therapy, rituximab may be used in patients with relapsed follicular lymphoma who respond to induction therapy with chemotherapy or immunochemotherapy. Six courses of rituximab, perhaps as the gold standard, are effective in the treatment of patients with DLBCL in combination with CHOP chemotherapy.