Limited-stage mantle cell lymphoma: not so different from advanced-stage

The National Comprehensive Cancer Network (NCCN) guidelines and treatment reviews support the use of radiation therapy for patients with limited-stage mantle cell lymphoma (MCL) [1,2]. In this issue of Leukemia and Lymphoma, Bernard and colleagues describe their experience with limited-stage MCL and contribute much-needed data to the discussion [3]. The hypothesis that radiation provides long-term local disease control of MCL is supported by the observation that radiation provides rapid and durable responses for symptomatic lesions in patients with systemic disease, and apparently longer time to progression in patients with localized disease [4,5].

An important consideration is the context in which the supporting data for existing publications were collected. The proportion of patients diagnosed with limited-stage MCL has been steadily decreasing over time [6,7]. According to Surveillance, Epidemiology and End Results (SEER) records, the proportion of patients diagnosed with limited-stage MCL from 2004 to 2007 was 5.8%, compared to 30.5% between 1992 and 1999. Over this same period of time, the number of patients diagnosed with advanced-stage disease, primarily stage 4, increased almost three-fold, suggesting a role for more sensitive assays of bone marrow and more frequent evaluation of the gastrointestinal tract, which is involved in > 90% of cases [8,9]. Moreover, despite the limited sensitivity of fluorodeoxyglucose-positron emission tomography (FDG-PET) imaging to detect bone marrow or gastrointestinal (GI) involvement [10,11], MCL is clearly an FDG-avid disease [12,13], and PET scanning almost certainly results in upstaging of some patients. Indeed, in the Bernard series, 2/8 patients with stage 1 disease and 7/13 patients with stage 2 disease experienced distant relapse (including three patients with GI tract relapse), suggesting the presence of undiagnosed disseminated disease prior to treatment. Interestingly, rather than detracting from the authors’ conclusions, these data support the concept that radiation may be more likely to benefit a more contemporary cohort of patients with truly localized disease.

Like others, Bernard and colleagues propose that patients with limited-stage MCL should receive combined modality chemotherapy and radiation therapy [5]. The suggestion is familiar to oncologists who treat limited-stage diffuse large B-cell lymphoma (DLBCL). The difference is that chemotherapy alone is curative in limited-stage DLBCL, and the addition of radiation improves local disease control while permitting patients to be treated with fewer cycles of chemotherapy. In MCL, despite our best intentions, cure remains elusive. In the Bernard series, the median progression-free survival of patients treated with curative intent was 3.2 years, despite a predominantly low-risk International Prognostic Index (IPI) score, and eight of 21 patients died of lymphoma within 6 years. It is, therefore, reasonable to challenge the “curative intent” rationale behind combined modality therapy in patients with limited-stage MCL.

Regardless of stage, the goal of therapy in patients with MCL is to provide durable remissions and to maximize quality of life, and choice of treatment is based on consideration of multiple factors. In patients with advanced-stage MCL, consolidation with autologous stem cell transplant significantly prolongs remissions but is associated with significant morbidity and mortality (a trade-off that may be worthwhile in many cases). The pros and cons of combined modality chemo-radiotherapy in limited-stage are equally foggy. The feasibility and toxicity of radiation can vary considerably depending on the site being irradiated. The choice of chemotherapy regimen and its associated toxicity may vary depending on the biology of the tumor (e.g. blastoid variant vs. classical MCL). A review of patients with limited-stage MCL treated at Weill Cornell Medical College and H. Lee Moffitt Cancer Center suggests a more individualized approach (unpublished observation). Endoscopy and PET staging were not used routinely, but appeared to be more common in cases where stage might impact choice of therapy. Treatment varied from observation to HyperCVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone), and radiation was used sporadically. Outcomes appeared promising in these patients, but interpretations are prone to multiple sources of bias [14].

The reports by Bernard and Leitch demonstrate the feasibility and efficacy of combined modality therapy in patients with limited-stage MCL, and serve as an important benchmark against which future reports may be compared. There does not appear to be any significant downside to local radiation in many cases: it successfully achieves local disease control and likely prolongs remission duration. The addition of chemotherapy also likely prolongs remission durations but is unlikely to increase the probability of cure. As is the case in patients diagnosed with advanced-stage disease, there is no standard of care, and treatment should be individualized to each patient and should be based on a clear definition of goals of therapy.

Potential conflict of interest:

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