The Role of Conformal External Beam Radiotherapy in the Management of Patients With Bulky Disease Undergoing Y90-Ibritumomab Tiuxetan (Zevalin) Radio-immunotherapy for Indolent B-cell Non-Hodgkin's Lymphoma
Non-Hodgkin's lymphomas (NHL) are a heterogeneous group of lymphoid malignancies that
represent the 6th leading cause of cancer death and the 2nd fastest growing cancer in the
United States. NHLs can be divided into two prognostic groups: aggressive and indolent
lymphomas. Aggressive NHLs grow rapidly and present as disseminated disease in 70% of cases,
yet can be cured in a significant number of patients with intensive combination chemotherapy
regimens. Indolent (low-grade) NHLs are slow growing malignancies with long natural
histories that are incurable when disseminated. Early stage low-grade NHL (stage I and II)
has the potential for cure with radiotherapy, but only 10-20% of patients with low-grade NHL
present with early stage disease. The vast majority of patients with low-grade NHL present
with advanced disseminated disease. While indolent B-cell NHLs have initial sensitivity to
chemotherapy and radiotherapy, they frequently relapse and become increasingly resistant to
therapy with each successive relapse, eventually transforming to aggressive lymphomas in
most patients. Fifty percent of patients presenting with advanced indolent NHL die within 5
years of their first relapse. Only modest improvement has been made in the last 25 years in
increasing the survival of patients with indolent NHL with current median survival of 7-10
years.
Recent advances in the field of immunotherapy have proved to benefit patients with relapsed
or refractory B-cell NHL. In 1997, rituximab became the first FDA-approved monoclonal
antibody (mAb) for the treatment of cancer. Rituximab, a chimeric IgG1 kappa monoclonal
antibody, specifically recognizes and binds to the CD20 antigen found on the cell surface of
most normal B-cells and malignant B-cell lymphomas. Rituximab binds human complement and
lyses B-cell lines through complement dependent cytotoxicity and antibody dependent cellular
toxicity. A multi-center Phase II trial of 166 patients with relapsed indolent B-cell
lymphoma treated with rituximab found an overall response in 50% of patients with 6% having
a complete response and 44% having a partial response. Time to progression was a median of
13 months in patients who responded.
The introduction of radioimmunotherapy (RIT) has exploited the tumor cell targeting ability
of mAbs to deliver doses of radiation to the tumor and limited surrounding tissue. This is
especially useful in the treatment of NHL because lymphomas are highly sensitive to
radiotherapy. 90Yttrium-ibritumomab tiuxetan (Zevalin) is a unique compound composed of the
murine IgG1 anti-CD20 antibody ibritumomab, the linker chelator tiuxetan, and the
radioisotope 90Y chelated via the linker. 90Y-ibritumomab tiuxetan can be described as
providing a double hit therapeutic approach by having the CD20+ antibody properties of
rituximab combined with radiation therapy.
90Yttrium-ibritumomab tiuxetan appears to be effective in the treatment of patients
refractory to treatment with rituximab, but response rates decrease with increasing tumor
size. 90Y-ibritumomab tiuxetan was approved by the FDA in 2002 for the treatment of patients
with relapsed or refractory low-grade, follicular, or CD20+ transformed B-cell non-Hodgkin's
lymphoma (NHL), and rituximab-refractory follicular NHL.
A preliminary survey of 20 patients treated with 90Y-ibritumomab tiuxetan at the Cleveland
Clinic Foundation from 1998-2003 detailed patterns of NHL recurrence after treatment. The
results of this survey were presented in part by Dr. Macklis at the 2004 annual meeting of
the American Society of Therapeutic Radiation Oncology (ASTRO) in Atlanta and recently
accepted for publication in the International Journal of Radiation Oncology, Biology,
Physics. Based on preliminary data, a hypothesis can be made that some likely sites of
disease recurrence/progression after RIT can be predicted by the volume of disease at a
specific site prior to RIT. In short, pre-RIT bulky sites of disease are the most likely
locations of disease recurrence after RIT followed by gross, but non-bulky, pre-RIT sites
followed by entirely new sites. Based on this hypothesis, it might be beneficial to
pre-treat bulky sites of NHL with external beam radiotherapy prior to RIT in order to
promote a more durable response. Doses of external beam radiation required to consolidate
these bulky disease sites are unclear.
In this study, we plan to utilize a dose of EBRT of 2,400cGy to bulky sites of disease
followed by RIT. Though the combined effects of 2,400cGy of EBRT and RIT are likely to be
well tolerated, such a combination has not been sufficiently studied. Therefore, the
primary goal of this study is to determine if the combination of EBRT and RIT has an
acceptable toxicity profile with regard to long-term myelosuppression and other
non-hematological toxicities.
Interventional
Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
PET and CT (w/oral and IV contrast)
90 days after treatment
No
Roger Macklis, MD
Principal Investigator
The Cleveland Clinic
United States: Institutional Review Board
IRB 7883
NCT00271050
December 2005
June 2010
Name | Location |
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Cleveland Clinic | Cleveland, Ohio 44195 |