Special delivery: getting radiation to the target in diffuse large B-cell lymphoma

The term “early” or “limited” stage diffuse large B-cell lymphoma (DLBCL) embraces a diverse group of clinical presentations, broadly divisible into favorable and unfavorable categories. A highly selected group of patients with non-bulky, stage I nodal disease, and an International Prognostic Index (IPI) score of zero, are considered to have favorable disease. Such patients can anticipate a cure rate of approximately 90% with either six cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) or three cycles of R-CHOP plus involved field radiotherapy [1,2]. It is unknown which of these treatment strategies offers a higher freedom from progression rate, but any difference is likely to be too small to resolve in a feasible randomized trial. Research in this population is oriented toward defining minimal effective therapy, paralleling the evolution of management for favorable early stage Hodgkin lymphoma.

Unfavorable early stage DLBCL is much more heterogeneous. Disease may be unfavorable by virtue of “stage-modified” IPI > 1 (age, lactate dehydrogenase [LDH], performance status, stage I versus II), bulky disease (variously defined), special extranodal sites of origin, such as the testis or central nervous system, and an incomplete metabolic response on interim positron emission tomography (PET) scanning [3]. These risk factors predict a treatment failure rate of at least 25% with R-CHOP alone, and define a patient population suitable for treatment intensification or consolidation. In the routine management of unfavorable early stage DLBCL, alternatives to R-CHOP alone include the use of more intensive chemotherapy regimens and/or consolidation with ionizing radiation, traditionally in the form of external beam radiotherapy (EBRT) [4,5].

In this issue of Leukemia and Lymphoma, Yang et al. report a pilot trial which evaluated radioimmunotherapy (RIT) using ⁹⁰Y-ibritumomab as an alternative means of delivering consolidative radiation following R-CHOP chemotherapy for bulky, limited stage DLBCL [6]. Their data support previous studies which suggest that this approach is feasible and associated with some incremental responses beyond those achieved with R-CHOP [7]. The question arises, where does RIT stand in relation to the more traditional approach of EBRT in the first-line management of limited stage DLBCL, and what is the future potential of RIT for DLBCL?

Conventional EBRT allows the delivery of well-defined radiation doses to specified anatomical regions. Conceptually, consolidative locoregional irradiation can improve cure rates where systemic therapy is able to eradicate occult systemic disease, but fails to control disease in initial sites of involvement. With this perspective in mind, consolidative EBRT may be used in three settings: (1) to augment the results of maximal tolerable systemic therapy; (2) to allow the use of less than maximal systemic therapy while maintaining efficacy; and (3) to enhance treatment of chemotherapy sanctuary sites. A generation of randomized trials in the “CHOP era” supports the use of EBRT for all three applications, although the apparently conflicting results of these trials have led to uncertainty regarding the optimal use of EBRT for DLBCL. This uncertainty has increased in light of the greater efficacy of R-CHOP. However, extrapolation from CHOP-era trials, as well as more recent data from retrospective studies incorporating R-CHOP, suggest a continuing benefit for consolidative EBRT after R-CHOP for early stage DLBCL [2,5,8–10]. A further concern regarding the use of EBRT is the potential for late toxicity. However, modern involved field/node radiotherapy, coupled with improvements in tumor localization and response assessment with positron emission tomography (PET), facilitates the minimization of normal tissue exposure. For many patients in the typical demographic of DLBCL, the long-term risks of EBRT are likely to be small. The use of EBRT continues to form part of standard care for selected patients with limited stage DLBCL, particularly those with bulky locoregional disease [11].

In contrast to EBRT, radionuclide therapy exploits tumor biology to preferentially target malignant cells. In the classic case of thyroid cancer this is based on radioactive iodine uptake in tumor cells, whereas in the case of RIT it is based on targeting a specific antigen – for example the CD20 antigen – with a radioimmunoconjugate (RIC). In theory, RIT has two potential advantages over EBRT. First, it may allow irradiation of occult systemic disease, augmenting the systemic efficacy of chemotherapy, whereas EBRT is confined to initial known sites of disease. Second, by targeting at a cellular rather than anatomical level, RIT may reduce the dose of radiation to normal tissue, whereas even with optimal planning, EBRT exposes some normal tissue to therapeutic radiation doses.

In practice, RIT is currently subject to several limitations. First, it is difficult to quantify radiation dose delivery to target lesions, an aspect which is critical for optimizing RIT [12]. This is due to several factors that influence RIC biodistribution, such as the degree of antigen expression on tumor and normal cells, tumor vascularization and the clearance of the RIC. At present, the dosing of RICs is empirical, and based on patient weight, or the use of planar imaging to estimate marrow toxicity, rather than being based on precise target lesion dosimetry. Second, the two currently approved RICs, ⁹⁰Y-ibritumomab (Zevalin) and ¹³¹I-tositumomab (Bexxar), emit beta particles, which have an effective path length of around 5 mm and 1 mm, respectively. These relatively long path lengths result in damage to neighboring cells, rather than the site of radiotracer binding – the so called “bystander effect.” A positive aspect of this phenomenon is the potential to augment dose delivery to tumor cells that do not express the target antigen. This may be most pronounced where there are aggregations of cancer cells, i.e. in the presence of macroscopic disease. Conversely, when tumor cells are sparsely distributed, as in the setting of post-chemotherapy microscopic residual disease, the lack of bystander effect may make dosimetery even less certain.

How can lymphoma RIT be improved? Available radionuclides differ in the type and energy of radiation emitted, which in turn determine both the lesional dosimetry and the ability to image tumor uptake. There is growing interest in the potential use of alpha emitters and Auger electrons, which irradiate tissue volumes of cellular and subcellular dimensions. Alpha particles are considerably more damaging even in radioresistant cells, and their very short range allows sparing of normal tissue. Additonal areas for future research include the development of new antibodies, defining the optimal timing of RIT, and exploring the use of fractionated rather than single dose treatments [13].

New imaging techniques also have the potential to improve RIT dosimetry. Currently, gamma-emitting radionuclides, such as ¹³¹I, allow gamma camera imaging to estimate dose delivery within tumors and in dose limiting organs, at the cost of additional radiation protection requirements. Although pure beta emitters have not been amenable to imaging in the past, the decay of ⁹⁰Y produces low numbers of positrons, which allows imaging using PET. Recent reports describe the use of zirconium-89, a long half-life positron emitter, which allows better imaging of RIC biodistribution [14]. PET imaging allows three-dimensional quantification of uptake and may enable individualized patient dosimetry, and aid the selection of the most appropriate radionuclide for the burden of disease to be targeted.

The use of consolidative EBRT following chemotherapy for selected patients with limited stage DLBCL is supported by an extensive body of clinical data [5]. Although RIT offers the theoretical advantage of radiation dose delivery to both local and systemic disease, at present RIT remains an investigational intervention in the first-line management of limited stage DLBCL. It is tempting to speculate that EBRT and RIT may ultimately find application in different patient populations. Bulky limited-stage disease, the subject of the report from Yang et al., might best be consolidated with EBRT, whereas RIT may be of greatest utility for widespread, low volume stage II disease, and for advanced stage disease. The definition of the role of RIT in the first-line management of limited stage DLBCL awaits the conduct of well-designed, prospective randomized trials, in order to develop an evidence base comparable to that available for follicular lymphoma [15]. On the horizon are a range of emerging biological and targeted approaches for DLBCL, and the role of both EBRT and RIT will eventually need to be considered in this evolving therapeutic arena [16].

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