About a quarter of patients with diffuse large B-cell lymphoma (DLBCL) present with limited stage (LS-DLBCL). LS-DLBCL is usually defined as Ann Arbor stages 1 to 2 disease (tumor is restricted to above or below the diaphragm) with largest mass size < 10 cm in diameter. However, no standard definition exists.

According to Rojek and Smith, from the Department of Medicine of the University of Chicago, “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.” Variations in the definition of LS-DLBCL compromise the overall understanding of the disease and the establishment of appropriate treatment guidelines.

Patients with LS-DLBCL have an excellent prognosis when treated adequately. The 10-year overall survival (OS) is at least 70% to 80% for patients treated with 4-6 cycles of  immunochemotherapy rituximab, cyclophosphamide, vincristine, doxorubicin, and prednisolone (R-CHOP) or combined modality therapy, including 3-4 cycles of systemic treatment and involved-site radiotherapy (RT).

“The favorable prognosis of the majority of cases of limited-stage DLBCL raises the question as to whether therapeutic algorithms could be response-adapted and treatment-minimized with the goal to retain disease control and minimize long-term toxicity,” explained Zhang et al.

For instance, the inclusion of RT in LS-DLBCL treatment regimen is still a matter of debate. Many argue that RT could be omitted in low-risk patients, thereby avoiding potential toxicity. But according to Zhang et al “current evidence cannot exclude a clinically meaningful benefit from RT even in low-risk patients and, given the low expected toxicity from modern RT techniques, a risk–benefit assessment should be individualized and considered in a multidisciplinary fashion.”

The introduction of positron-emission tomography (PET) scans has challenged treatment paradigms. It has revolutionized staging, end-of-treatment (EOT) assessment for prognosis, and response-adapted investigations in LS-DLBCL. Several studies have evaluated PET-based response-adapted strategies to limit both chemotherapy and RT in LS-DLBCL with promising results.

Treating Special Populations

Some cases require special attention when attempting the optimal treatment regimen. These include bulky disease, extranodal disease, and fully resected disease, as well as scenarios with adverse biologic features (eg, high-grade B-cell lymphoma with double/triple hit rearrangements and double-expressor lymphoma [DEL]).

Stage I bulky disease is relatively rare and stage II bulky disease is usually excluded from LS-DLBCL studies or considered similar to advanced-stage disease by several authors. Therefore, the conclusions of most studies may not reflect, at least entirely, the reality of bulky disease. A recent study showed that bulky disease has a poorer prognosis than nonbulky disease. It also suggested that RT may add value in cases of bulky LS-DLBCL, such as primary refractory disease, while corroborated the prognostic value of a negative iPET even in the presence of other risk factors.

Extranodal disease may be associated with inferior outcomes when compared to nodal disease, but conflicting results have been reported. A recent study suggested a positive role for consolidative RT in treating patients with extranodal disease. Furthermore, the implementation of EOT PET assessment may allow to better identify extranodal disease cases that would benefit from consolidative RT.

Some patients with extranodal disease may also benefit from central nervous system (CNS) prophylaxis, though no guidelines exist for its application in LS-DLBCL. Extranodal involvement or involvement at high-risk disease sites (eg, nasal sinuses, testes, breasts) are the features most associated with the risk of CNS relapse in LS-DLBCL.

Surgical resection of the entire tumor may be useful in specific cases of LS-DLBCL. Patients with fully resected disease are usually given the same duration of therapy as other limited-stage disease patients. However, abbreviated therapy may be sufficient, depending on the site of origin and other considerations.

The studies currently available suggest differences in prognosis for high-grade B-cell lymphoma with double hit rearrangements and DEL cases of limited-stage disease when compared to what is expected for advanced-stage disease. However, it is currently unknown wether these patients would benefit from intensified treatment.

Rojek and Smith’s Approach to Manage LS-DLBCL

Rojek and Smith proposed a pipeline to manage LS-DLBCL that takes into consideration initial clinicopathologic features, the stage-modified International Prognostic Index (smIPI), and results of interim PET (iPET) scanning. Recommendations are as follows:

  • Patients with a low smIPI or negative iPET, including fully resected disease, can be treated with a maximum of 4 cycles of R-CHOP without consolidative RT
  • Patients with positive iPET may benefit from additional RT and/or additional chemoimmunotherapy
  • RT may be considered for patients with bulky (> 7.5 cm) or extranodal disease, with additional guidance for individual cases
  • CNS prophylaxis should be considered in cases of involvement at high-risk disease sites
  • Abbreviated treatment courses may be considered for patients with fully resected disease at staging.

Reference

Rojek AE, Smith SM. Evolution of therapy for limited stage diffuse large B-cell lymphoma. Blood Cancer J. Published online February 24, 2022s. doi:10.1038/s41408-021-00596-z

Zhang X-Y, Collins GP, Cutter DJ, Eyre TA. Limited-stage diffuse large B-cell lymphoma: current management and challenges. Br J Haematol. Published online February 22, 2021. doi:https://doi.org/10.1111/bjh.17359

Hawkes EA, Barraclough A, Sehn LH. Limited-stage diffuse large B-cell lymphoma. Blood. Published online February 10, 2022. doi:10.1182/blood.2021013998