This review will focus on therapies and studies focusing on limited-stage DLBCL (Table 1), the inherent challenges and future considerations for this disease, and our recommended approach to these patients as diagnostics and therapeutics continue to evolve in the modern era.ĭLBCL is increasingly understood to be a highly heterogeneous neoplasm with many variations in morphology, gene expression, and biological regulation. The treatment of limited-stage DLBCL patients in the modern era has evolved to reconsider the role of RT, the optimal length of systemic therapy, and the emerging role of metabolic imaging via positron emission tomography (PET) in response-adapted management. This study helped establish the superiority of chemoimmunotherapy in younger patients with a good prognosis, limited-stage DLBCL. Notably, these survival benefits occurred without a significant increase in toxicity or rate of secondary hematologic malignancy in long-term follow-up.
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The MabThera International Trial (MInT) study found that non-bulky, limited-stage disease treated with R-CHOP had better 6-year event-free survival (EFS) at 84.3% and 6-year OS of 94.9% than CHOP alone. The anti-CD20 monoclonal antibody, rituximab, improves survival in limited-stage disease just as it does for advanced-stage DLBCL. In the rituximab era, outcomes in each IPI risk group have improved across both limited and advanced disease groups, and smIPI retains utility. This smIPI model was more powerful than an age-adjusted risk stratification alone. In the pre-rituximab era, those with no risk factors, and thus stage I disease, had the best outcomes with 5-year overall survival (OS) of 95% for those with one to two risk factors, 5-year OS dropped to 77%, and 50% for three or more risk factors.
This stage-modified IPI (smIPI) thus includes one point each for age > 60 years, stage II disease, elevated serum lactate dehydrogenase (LDH), and performance status of two or above. The International Prognostic Index (IPI) for DLBCL was adjusted to better stratify prognosis in limited-stage disease by removing the number of extranodal sites and dichotomizing stage as I versus II. SWOG S8736 also developed a risk stratification scoring system in limited-stage DLBCL that retains utility in the modern era.
This defined a new standard treatment length and inclusion of radiation for limited-stage patients which has continued to serve as the foundation for subsequent dedicated limited-stage disease trials. SWOG S8736 showed that three cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) with radiation therapy (RT) were non-inferior to eight cycles of CHOP alone.
This phase 3 trial, conducted in the pre-rituximab era (1988–1995), established combined modality therapy as a standard of care in the pre-rituximab era. The modern approach to the treatment of limited-stage DLBCL was influenced by SWOG 8736. There remains debate as to whether the delineation between limited and advanced stage reflects earlier identification of a disease or a biologically distinct entity with different risks and outcomes features. Large descriptive studies report that the median age of patients with the limited-stage disease is in the sixth decade of life, with a slight male predominance, the most common anatomic sites of disease are in cervical lymph nodes and/or head and neck region, including Waldeyer’s ring. Bulky disease, which is variably defined in the literature, is an important modifier to classical staging and is discussed further below. Currently, limited or early-stage disease is defined as stage I or II, and advanced-stage disease is defined as stage III or IV by Lugano criteria. It is biologically heterogeneous historically, limited-stage disease was defined as Ann Arbor stage I or II disease with sites that could be encompassed in a single radiation field. Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma (NHL), representing almost one-quarter of all new NHL cases per year in the United States.