Introduction

Lymphomas represent the fifth most common malignancy in the western world in incidence, accounting for approximately 5% of new cancer diagnoses amounting to approximately 60,000 new diagnoses each year in the United States (1). Patients with this group of disorders typically present with symptoms related to lymphadenopathy, as well as constitutional symptoms such as fevers, night sweats, or weight loss. Diagnosis is ideally made by excisional biopsy of an involved lymph node. This is followed by the standard initial evaluation that includes staging by physical examination, computerized tomography and bone marrow studies to determine the extent of the disease, as these factors are important in determining the most appropriate therapy. The other major factor that influences the chosen therapy is the histological subtype. In general, patients with Hodgkin's disease are treated with curative intent. In contrast, patients with non-Hodgkin's lymphoma can be divided into two broad groups. The first group is the group of patients with "aggressive" histology with the prototypic subtype being diffuse large B-cell lymphoma, the most common non-Hodgkin's lymphoma (NHL) (2). Patients with aggressive histologies are also treated with curative intent, typically with combination chemotherapy for patients with advanced stage disease, and with short-course combination chemotherapy followed by involved field radiation therapy for patients with early-stage disease. With this approach, approximately 30% to 60% of patients can achieve long-term remissions (3). Unfortunately, the majority of patients with aggressive lymphomas will not be cured by primary therapy. For these patients, high-dose chemotherapy with hematopoietic stem cell transplantation has been shown to improve outcomes compared with further standard chemotherapy, though only 30% to 50% of such patients with responsive disease have the possibility of long-term remission with this approach (4). For such patients who have relapse following a hematopoietic stem cell transplant, the options for prolonged disease-free survival are limited to investigational therapies.

The second major clinical subgroup of non-Hodgkin's lymphoma is the cohort of patients with indolent lymphoid malignancy, with the prototypic subtype being follicular non-Hodgkin's lymphoma. Though patients with this group of malignancies generally experience a longer median survival, there appears to be no clear-cut evidence that these types of lymphoma can be cured with standard therapies (5). Typically, remission durations become shorter over time and tumors become resistant to any therapeutic venture, eventually resulting in death either from infectious complications, cytopenias, or direct lymphoma-tous progression. In addition, aggressive therapies in asymptomatic patients do not appear to impact the overall survival despite the fact that responses can be achieved (6). For this reason, many clinicians have opted to treat patients with indolent diseases that are asymptomatic with a "watch-and-wait" approach until they develop complications that can be attributed to their lymphoma (7). Once treatment is required, the specific choice of therapy can range from low tox-icity approaches such as oral alkylating agents to aggressive treatments such as high-dose therapy and stem cell transplantation. Despite the variety of therapeutic approaches for indolent NHL, the vast majority of patients will eventually succumb to their disease and proven approaches to prolong survival have yet to be developed.

The field of non-Hodgkin's lymphoma therapy, however, has achieved many advances in the last decade, particularly in the area of monoclonal antibody therapy. This has been possible, in part, owing to readily accessible tissue from lymph nodes and bone marrow biopsies, well-characterized lymphoma cell lines, as well as well defined and consistently expressed antigens. Unlabeled monoclonal antibodies are thought to kill target tumors via multiple mechanisms including induction of apoptosis, activation of complement, and recruitment of immune effector cells involved with antibody-dependent cellular cytotoxicity. A variety of antibodies and target antigens have been evaluated for this purpose as summarized in Table 1. The first monoclonal antibody to be approved for the treatment of cancer was rituximab, which targets the CD20 antigen. Initial studies demonstrated response rates approximately 50% with a minority of patients achieving complete response (8). CD20 has proven to be an ideal target owing to its only known expression on normal and malignant B-cells, its lack of modulation or internalization as well as its inability to be significantly shed from the cell surface. Despite the activity of agents such as rituximab, most patients treated with this agent alone do not attain complete responses. Limitations to the efficacy of unconjugated antibodies in lymphoma patients

Table 1 Summary of Selected Clinically Evaluated Anti-lymphoma Monoclonal Antibodies

Antibody

Target antigen

Target cell

1F5

CD20

B-cell NHL

Rituximab

CD20

B-cell NHL

Tositumomab

CD20

B-cell NHL

Ibritumomab

CD20

B-cell NHL

Campath 1H

CD52

CLL

Epratuzumab

CD22

B-cell NHL

Anti-idiotype

Surface Ig

B-cell NHL

Lym-1

HLA-DR

B-cell NHL

Denileukin-diftitox

IL-2 receptor

T-cell NHL

Anti-ferritin

Ferritin

Hodgkin's disease

Abbreviations: CLL, chronic lymphocytic leukemia; HLA, human leukocyte antigen; NHL, non-Hodgkin's lymphoma.

Abbreviations: CLL, chronic lymphocytic leukemia; HLA, human leukocyte antigen; NHL, non-Hodgkin's lymphoma.

include inherent apoptosis resistance mechanisms of malignant cells, the lack of adequate immune effector capability, and the requirement that each individual lymphoma cell must be targeted to be killed. The addition of a radionuclide payload to such antibodies can overcome some of these limitations.

Radioiummunotherapy (RIT) does not rely exclusively on immune effector mechanisms or direct induction of apotosis to effect target cells. RIT can also target unbound malignant cells that are within the path length of the emitted particle via the "crossfire" or "bystander effect" further enhancing the ability of this modality to fully eradicate tumor. The development of such lymphoma-specific monoclonal antibodies along with the known radiosensitivity of NHL made this an ideal system to evaluate the efficacy of RIT.

A variety of radioisotopes have been evaluated over the last two decades including iodine 131 (I-131), yttrium 90 (Y-90), copper 67 (Cu-67), rhenium 186 (Re-186), and bismuth 212 (Bi-212). Despite the variety of isotopes used, the vast majority of experience has been with isotopes with I-131 and Y-90. The properties of these isotopes are summarized in Table 2 (9). I-131 has both a high-energy gamma emission as well as beta emissions which

Table 2 Comparison of Iodine-131 (131I) and Yttrium-90 (90Y)

131I

90y

Emission

Beta, gamma

Beta

Average beta energy

0.192 MeV

0.934 MeV

Average path length

0.8 mm

5.3 mm

Nonspecific retention

Thyroid

Bone, liver

Half-life

8 days

2.7 days

allows I-131-based conjugates to be used both for imaging and dosimetry as well as therapy. In contrast, Y-90, which has only a beta emission requires a surrogate isotope, which is indium-111 (In-111) to be used for dosimetry and imaging purposes. The absence of a gamma emission with Y-90, however, does afford a potentially reduced risk of radiation exposure to family members and healthcare providers once the therapeutic dose is administered.

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