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INTRODUCTION

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The introduction of targeted therapeutic approaches has revolutionised the field of cancer treatment over the last decade. In particular, the use of monoclonal antibodies has met with considerable success, firstly in the treatment of lymphoma and subsequently in other cancer types. Although engagement and direct interaction with selected surface proteins appear to be of therapeutic value, antibodies also constitute an excellent targeting system, marking selected cells for interaction with innate immune effector mechanisms, or by conjugation with moieties of therapeutic value. In contrast to the mixed results of the use of monoclonal antibodies as a means to deliver toxins, radioimmunotherapy (RIT) has been proven to be effective enough for the U.S. Food and Drug Administration to approve the first ever radioimmunoconjugate (RIC) for the treatment of a malignancy in February of 2002, when 90Y-ibritumomab tiuxetan (Zevalin, 90Y-IT) was licensed for the treatment of lymphoma. Nearly a year later, an earlier radioimmunotherapy product, 131I-tositumomab (Bexxar, 131IT) was also approved for rituximab-refractory indolent or transformed lymphoma. Both agents are considered comparable in terms of efficacy or toxicity. Thus, CD20-based RIT for non-Hodgkin’s lymphoma (NHL) follows the path first paved by the successful application of rituximab, an anti-CD20 monoclonal antibody widely used against B-cell malignancies. RIT has already been tested in a variety of tumour types, but its success in lymphoma is conferred by the relative radiosensitivity of the disease, and possibly by the therapeutic value of the direct engagement of CD20 by an antibody. RIT offers several advantages compared with external beam irradiation, because normal tissues overlying the tumour mass are prevented from significant radiation exposure; also, since the RIC is given intravenously, it provides systemic radiation treatment to known as well as unsuspected tumour cells. Obviously, the commercially available products are more advanced in clinical applications, although experimental agents for the treatment of lymphoma are under development as well.

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The launching of RIT is presumed to be the first step in the development of a therapeutic modality that complements current treatments of NHL and will evolve into a robust and well-defined strategy for the management of this disease. However, the optimal incorporation of RIT into the therapeutic algorithm of NHL remains to be proven. Monotherapy studies with RICs in indolent or follicular NHL have defined a relatively consistent response rate of 60–80%, with a duration of reponse (DR) of approximately one year [1–3]. Significant activity has been documented for patients with aggressive histologies such as diffuse large B-cell NHL and mantle cell lymphoma [4–6]. The activity of RIC is in general superior to what is observed with the naked anti-CD20 antibody rituximab, as shown in comparison studies or compared with historical controls. This is not surprising, given the fact that anti-CD20-based RIT combines the advantage of CD20 engagement with tumour irradiation. Given the successful incorporation of rituximab with standard chemotherapeutic treatments, it is only natural to try to define ways of combining ...

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