Given ongoing demographic changes, when we care for the patient with non-Hodgkin's lymphoma (NHL), we are more than likely caring for the older person. Based on recent data from the National Cancer Institute's Surveillance Epidemiology and End Results (SEER) program, the incidence of NHL continues to increase, with a median age of 65 and over one-third of all patients older than 70 years. Furthermore, the increasing incidence is greatest in patients over 60 years of agea fact compounded by population predictions that the number of people living longer than 65 years will double over the next 50 years, with a near quadrupling of those over 80. Against this backdrop, the article by Dr. Morrison is both a timely and germane review of a problem all oncologists will face.
Age as a Prognostic Marker
Across histologies, age has repeatedly been one of the most important prognostic factors, figuring prominently in the international prognostic index (IPI), follicular lymphoma IPI (FLIPI), and, importantly, in Hodgkin's disease.[1-3] As oncologists have become more adept at designing trials specifically for the older patient with diffuse large B-cell lymphoma (DLBCL), they frequently find themselves evaluating a group of patients uniformly over 60. In these cases, the age-adjusted IPI (aaIPI) is an effective and important prognostic tool, but it reflects pre-rituximab (Rituxan) risk modeling.
More recently, prognostic models developed from modern era immunochemotherapy programs such as Eastern Cooperative Oncology Group (ECOG) 4494 and the German High-Grade Lymphoma Study Group (GHGLSG) studies have demonstrated that an age cutoff of 70 now functions as a dichotomous variable for prognosis.[4,5] Utilizing these modifications to the IPI will be essential as we assess and design prospective trials in the elderly and in the analysis of treatment populations from recent trials demonstrating improved outcomes over those achieved with CHOP-21 (cyclophosphamide, doxorubicin HCl, vincristine [Oncovin], prednisone).
Diffuse Large-Cell Lymphomas: Current Success in Context
Treatment of the older patient with DLBCL is frequently complicated by the presence of significant comorbidities, impaired organ function as a result of aging, and alterations in pharmacokinetics. Additionally, the patient generally has only a single chance at curative outcome. For these reasons, designing trials for the older patients is essential.
For the better part of 2 decades, CHOP chemotherapy remained the standard of care for patients of all ages with diffuse large-cell lymphoma (DLCL), proving to be superior in numerous randomized clinicals trials on the basis of greater or maintained efficacy with less toxicity. In the past, a litany of attempts to maintain or improve outcomes by decreasing toxicity with anthracycline substitutions, dose reductions, or omissions fell short of standard-dose CHOP (see Table 3 in part 1 of the Morrison article, August ONCOLOGY, page 1107). Thankfully, efforts to address the specific needs of the older DLCL patient did not cease. In fact, recent efforts have not only demonstrated the feasibility of carrying out well designed trials in the older patient, but have resulted in the first survival benefits over CHOP chemotherapy in roughly 20 yearsbenefits that have now been extended to the younger patient as well.
The recent randomized studies documenting improvements in overall survival have added the monoclonal antibody rituximab to CHOP (R-CHOP) and/or utilized more dose-intensive schedules (Table 1). R-CHOP chemotherapy administered every 21 days, as reported by the Groupe d'Etude des Lymphomes de l'Adulte (GELA) is the current standard of care for the patient over 60.[6,7] In the pre-rituximab era, the GELA also demonstrated an improvement in survival by employing a dose-intensive ACVBP program (doxorubicin [Adriamycin], cyclophosphamide, vindesine, bleomycin, prednisone) compared with CHOP in elderly patients with at least one risk factor. In a similar vein, the GHGLSG NHL-B2 study evaluated dose-dense (every 14 day) CHOP-14 vs standard schedule CHOP-21 (every 21 days), with and without etoposide. In this analysis, the dose-dense regimen was superior, but immunotherapy with rituximab was not included.
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2. Shipp M, Harrington D, Anderson J, et al: A predictive model for aggressive non-Hodgkin's lymphoma. The International Non-Hodgkin's Lymphoma Prognostic Factors Project. N Engl J Med 329:987-994, 1993.
3. Solal-Celigny P, Roy P, Colombat P, et al: Follicular lymphoma international prognostic index. Blood 104:1258-1265, 2004.
4. Advani RH, Chen H, Habermann TM, et al: Prognostic indices in older DLBCL patients receiving R-CHOP: An analysis of the US Intergroup study (E4494, CALGB 9793) (abstract 813). Blood 108, 2006.
5. Pfreundschuh M, Trumper L, Kloess M, et al: Two-weekly or 3-weekly CHOP chemotherapy with or without etoposide for the treatment of elderly patients with aggressive lymphomas: Results of the NHL-B2 trial of the DSHNHL. Blood 104:634-641, 2004.
6. Coiffier B, Lepage E, Briere J, et al: CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med 346:235-242, 2002.
7. Feugier P, Van Hoof A, Sebban C, et al: Long-term results of the R-CHOP study in the treatment of elderly patients with diffuse large B-cell lymphoma: A study by the Groupe d'Etude des Lymphomes de l'Adulte. J Clin Oncol 23:4117-4126, 2005.
8. Tilly H, Lepage E, Coiffier B, et al: Intensive conventional chemotherapy (ACVBP regimen) compared with standard CHOP for poor-prognosis aggressive non-Hodgkin lymphoma. Blood 102:4284-4289, 2003.
9. Pfreundschuh M, Kloess M, Zeynalova S, et al: Six vs eight cycles of bi-weekly CHOP-14 with or without rituximab for elderly patients with diffuse large B-Cell lymphoma (DLBCL): Results of the completed RICOVER-60 trial of the German High-Grade Non-Hodgkin Lymphoma Study Group (DSHNHL) (abstract 205). Blood 108:64a, 2006.
10. Sonneveld P, van Putten W, Biesma D, et al: Phase III trial of 2-weekly CHOP with rituximab for aggressive B-cell non-Hodgkin's lymphoma in elderly patients (abstract 210). Blood 108:66a, 2006.