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Non-Hodgkin's Lymphoma in the Elderly (Part 2: Treatment of Diffuse Aggressive Lymphomas)

Non-Hodgkin's Lymphoma in the Elderly (Part 2: Treatment of Diffuse Aggressive Lymphomas)

As noted in part 1 of this two-part article, non-Hodgkin's lymphoma is one of a few malignancies that have been increasing in incidence over the past several decades. Likewise, these disorders are more common in elderly patients, with a median age of occurrence of 65 years. Therapy in elderly patients may be affected by multiple factors, especially attendent comorbidities. The approaches to management of these patients, with either indolent or aggressive disease processes, have been based on prospective clinical trial results, many of which have included a younger patient population. Fortunately over the past decade, results of treatment trials that have targeted an older patient population have emerged. The disease incidence and treatment approaches for both follicular (part 1) and diffuse aggressive (part 2) histologies in elderly patients are reviewed, as well as the impact of aging on the care of these patients.

As noted in part 1 of this article, which appeared in the August issue of ONCOLOGY (21:1104-1110, 2007), non-Hodgkin's lymphoma (NHL) continues to increase in incidence and is more common in elderly patients. After examining the impact of aging on the disease and exploring prognostic factors in this setting, part 1 reviewed the treatment of patients with follicular lymphoma. Here, part 2 will address the treatment of diffuse aggressive lymphomas in older patients.

Therapy of Diffuse Aggressive Lymphomas

The diffuse aggressive lymphomas include a variety of histologic subtypes, among which the diffuse large-cell histology (DLCL) is the most common. In elderly patients, B-cell DLCL (DLBCL) is the most common subtype, accounting for 50% of all cases of NHL in these patients.[1,2] Among those aged 65 to 75 years, 50% will achieve a complete response (CR) with conventional therapies, with a 5-year disease-free survival (DFS) of about 33%. However, the CR rate drops to 40% for patients older than 75 years, with a 16-month median response duration (Table 1).[1]

Approach to Limited-Stage Disease

Approximately 30% of patients with diffuse aggressive NHL will have limited-stage disease. In an initial report of an Eastern Cooperative Oncology Group study of patients with limited-stage disease with 5-year follow-up, therapy with three cycles of CHOP (cyclophosphamide, doxorubicin HCl, vincristine [Oncovin], prednisone) followed by involved-field radiotherapy resulted in an improved progression-free (PFS) and overall survival (OS) and less cardiotoxicity, compared to treatment with eight cycles of CHOP.[3] However, in a later report of this study with a median follow-up of 10 years, the progression-free and overall survival curves for the two treatment arms appeared to come together between 7 and 9 years.[4] Using a similar approach, the Vancouver group found that the 10-year DFS was similar to that of younger patients.[2]

In another recent report, a series of 576 patients over 60 years old with localized stage I/II diffuse aggressive NHL were randomized to therapy with either CHOP alone or CHOP plus involved-field radiation therapy. With a median follow-up period of 7 years among the two groups, no difference was found in either event-free survival (EFS) or OS.[5]

Management of Advanced-Stage Disease

The majority of patients with diffuse aggressive NHL have advanced-stage disease, regardless of age. Therapy with CHOP for many years was the standard regimen for these patients, with cure rates of 25% to 30%, compared to 50% to 60% of younger patients, and a toxic death rate of 1%.[2,6,7] This was based on the results of an intergroup trial in which CHOP was compared to other combination regimens (m-BACOD [methotrexate, bleomycin, doxorubicin (Adriamycin), cyclophophamide, vincristine, dexamethasone], ProMACE-CytaBOM [prednisone, methotrexate, doxorubicin, cyclophosphamide, etoposide, cytarabine, bleomycin, vincristine, methotrexate], MACOP-B [methotrexate, doxorubicin, cyclophosphamide, vincristine, prednisone, bleomycin]), showing no significant difference in efficacy (CR, OS, or PFS) but fewer adverse events with CHOP.[8]

• Impact of Age—The impact of age on outcome has been examined in multiple series, albeit generally in a retrospective manner. In a series of patients aged ≥ 70 years treated with CHOP with no initial dose adjustment, the CR rate was comparable to that of younger patients, but more treatment-related complications were seen, including 30% treatment-related deaths (primarily sepsis).[9]

Vose et al reported the results of CAP/BOP therapy (cyclophophamide, doxorubicin, procarbazine, bleomycin, vincristine, prednisone) in 157 patients (112 > 60 years old), in which patients ≥ 70 years old had a 33% dose reduction in myelosuppressive drugs.[10] The response rate was similar in patients under or over age 60 (76% vs 61%, P = .18), as was the CR rate (76% vs 60%, P = .12), DFS, remission duration, and treatment toxicities. However, 5-year survival was shorter in patients over 60 compared to younger patients (34% vs 62%, P = .01), primarily related to intercurrent causes of death, especially late cardiovascular deaths.

In a series of 177 patients with DLCL treated with CHOP-based therapy, Gottlieb et al found a lower CR rate in patients over 70 than in younger patients (27% vs 53%, P = .01).[11] However, these older patients were less likely to receive full-dose therapy. Grogan found no correlation of age with outcome in a study in which 67 patients under age 65 and 60 patients at least 65 years of age received standard-dose CHOP or m-BACOD.[12] Response rates were comparable for older (95%/65% CR) and younger (92%/76% CR) patients, as were 3-year OS (59% vs 62%), DFS (74% vs 82%), and toxic death rate.

In a multivariate analysis of elderly patients treated with CHOP, Gomez et al found that poor performance status (PS) was the only risk factor for treatment-related death.[13] Age ≥ 60 years was prognostic for outcome in Solal-Celigny et al's series of 73 patients receiving anthracycline-based therapy, with a lower CR rate (24% vs 72%), shorter median survival (18 vs 48 months), and lower 5-year survival (18% vs 47%) in these older patients, compared to those < 60 years of age.[14] Lastly, Tirelli et al found that severe and lethal toxicities were more common in patients aged at least 70 years who were treated with more aggressive regimens.[15]

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