Radiation Oncology/NHL/Mantle cell lymphoma

Overview

 * Rare subtype, comprises ~6% of NHL in US
 * Usually in older men
 * Only 5-15% present with Stage I-II
 * Most often Stage III or IV disease, extranodal involvement including spleen and liver and bone marrow common, frequent B symptoms (about 50%).
 * A variant can present as multiple polyps throughout the GI tract (lymphomatous polyposis)
 * Microscopically they have "angulated" nuclei, and resemble lymphocytes in mantle zone adjacent to the lymphoid follicles
 * Translocation t(11;14) rearranges the Bcl-1 gene (PRAD-1) which codes for Cyclin D1 (involved in cell cycle regulation) and puts it under the control of the immunoglobulin gene promoter.
 * Very poor survival. Aggressive and doesn't respond well to chemotherapy. Subset of elderly patients can present asymptomatic and have a very indolent course

Treatment

 * CHOP alone not very effective, early SWOG experience showed median OS 3 years
 * Addition of Rituximab (R-CHOP) did not improve PFS or OS
 * More intense chemotherapy regimens required
 * Stem cell transplant is being evaluated (e.g. R-CHOP-14 -> R-ICE -> ASCT)
 * Hyper-CVAD also appears promising
 * In asymptomatic elderly with limited disease, careful observation may be considered
 * RT has a potentially significant role in Stage I-II disease, as MCL is very radiosensitive

Radiotherapy
All Stages:
 * MSKCC; 2006 (1998-2004) PMID 16682133 -- "Highly effective local control and palliation of mantle cell lymphoma with involved-field radiation therapy (IFRT)." (Rosenbluth BD, Int J Radiat Oncol Biol Phys. 2006 Jul 15;65(4):1185-91.)
 * Retrospective. 21 pts treated to 38 sites. 81% were Stage IV or relapsed. Most pts had received prior chemotherapy. IFRT, mean dose 30 Gy (range: 10.5-45 Gy), dose per fraction 150-200 cGy. 2 pts received RT as consolidative therapy after CR to chemo.
 * Mean f/u 13 mo. For 36 sites with measurable disease, overall local response of 100% (CR 64%, PR 36%). 94% with pain relief. Local progression in 34% at a median of 10 months. No significant correlation between RT dose and control. 1-yr OS 55%
 * Conclusion: RT provided effective and lasting local responses in MCL patients and was associated with minimal toxicity. Radiation doses required for most lesions were relatively low and responses were noticed early in the course of treatment. Radiation therapy should be considered early in the course of relapsing, refractory, or localized MCL.

Limited Stage:
 * British Columbia; 2003 PMID 14504058 -- "Limited-stage mantle-cell lymphoma." (Leitch HA, Ann Oncol. 2003 Oct;14(10):1555-61.)
 * Retrospective. 26 patients. Initial therapy IFRT +/- chemo (n=17), observation or chemo (n=9)
 * 5-year outcome: PFS 46%, OS 70%
 * Predictors: age (PFS <60 83% vs. >60 39%, SS), RT (PFS RT 68% vs. no RT 11%; OS 71% vs. 25%, NS)
 * Conclusion: Limited-stage MCL had improved outcome with RT

Advanced Stage

 * GLSG (Germany)
 * Randomized. 122 untreated patients, advanced-stage MCL. Treated with Arm 1) CHOP vs. Arm 2) R-CHOP. Patients <=65 with CR/PR second randomization to ASCT vs. IFN-alpha. Patients >65 received IFN-alpha maintenance
 * 2005 PMID 15668467 -- "Immunochemotherapy with rituximab and cyclophosphamide, doxorubicin, vincristine, and prednisone significantly improves response and time to treatment failure, but not long-term outcome in patients with previously untreated mantle cell lymphoma: results of a prospective randomized trial of the German Low Grade Lymphoma Study Group (GLSG)." (Lenz G, J Clin Oncol. 2005 Mar 20;23(9):1984-92.)
 * Outcome: R-CHOP better for CR (34% vs. 7%, SS), and TTF (21 months vs. 14 months, SS), but no difference in PFS or OS
 * Conclusion: Better response rate, but no difference in PFS or OS


 * SWOG; 1995 -- PMID 7849295 -- "A clinical analysis of two indolent lymphoma entities: mantle cell lymphoma and marginal zone lymphoma (including the mucosa-associated lymphoid tissue and monocytoid B-cell subcategories): a Southwest Oncology Group study. (Fisher RI, Blood. 1995 Feb 15;85(4):1075-82.)
 * Retrospective. Treated with CHOP on SWOG-7204, SWOG-7426, SWOG-7713
 * Outcome: median FFS 1.7 years, median OS 3 years
 * Conclusion: MCL is not an indolent lymphoma, and requires innovative therapy

Reviews

 * Mayo; 2005 - PMID 16155027 &mdash; "Current Treatment Approaches for Mantle-Cell Lymphoma." Witzig TE et al. J Clin Oncol. Vol 23, No 26 (September 10), 2005: pp. 6409-6414.