This population-based study is the first to describe the diffusion of rituximab usage in Medicare patients with diffuse large cell lymphoma, and confirms the low rate of ABC use in older subjects with this disease even after high-profile studies of R-ABC in the elderly were published. The survival of all elderly patients with DLBCL has improved substantially since 1998, coincident with the diffusion of rituximab into the population. However, undertreatment of the oldest old is of potential concern. The oldest old were very unlikely to receive any therapy, and, if they received therapy, were least likely to receive rituximab. Survival was worse with advancing age, and the age relationship with survival was in part mediated by receipt of treatment. The improvement in survival associated with rituximab use would be expected among those treated with ABC, consistent with prospective clinical trials and the British Columbia Cancer Registry experience. However, the improved survival associated with rituximab addition to non-ABC regimens—equivalent to patients receiving ABC only—has not been previously described.
Rituximab appeared to be used largely as an addition to whatever intensity of chemotherapy a patient might have received, had they been diagnosed in the pre-1999 era. Because rituximab has a minimal frequency of cardiac toxicities, cytopenias, or fatigue, we had anticipated that many elderly or frail patients not deemed candidates for any cytotoxic therapy might have been treated with rituximab alone. However, the rate of ‘no therapy’ remained constant at over 30% after the availability of rituximab. Similarly, we had anticipated an increase in anthracycline use because of studies demonstrating R-CHOP as feasible and optimal for selected patients aged over 60 with DLBCL. However, rituximab introduction did not affect the rate of anthracycline use. Rates of systemic therapy use in general (67%) and anthracycline use specifically (58%) were stable throughout the study period. Thus, a large segment of the elderly population with DLBCL do not receive the generally accepted most effective treatment for DLBCL.
Individuals over age 60 years constitute over half of all patients diagnosed with DLBCL. Randomized trials have shown that patients over 60 respond well to ABC, and efforts to establish chemotherapy regimens for elderly patients that eliminate or utilize less anthracycline result in poorer outcome [15
]. Anthracycline avoidance in this population is likely due to global concern for toxicity and tolerability in the elderly, with specific concerns for cardiac toxicity, cytopenias, fatigue, or generalized frailty. Cost–benefit studies utilizing phase III data have suggested that when combined with ABC, rituximab adds an acceptable $US20 000 or less per added year of life [16
]. Given the relatively low penetration of ABC chemotherapy in the elderly, it remains critical to investigate the impact of new therapies in patients who are not deemed candidates for standard treatment regimens. This population-based study demonstrates that survival in the non-ABC group who received rituximab was comparable to that for the ABC group without rituximab. Based on these findings, rituximab alone or in combination with non-ABC chemotherapy should be investigated for such patients.
In 2002, the Groupe d’Etude des Lymphomes de l’Adulte (GELA) reported a randomized trial comparing R-CHOP to CHOP alone in patients over age 60 with DLBCL. The 2-year OS for CHOP was 57%, while for R-CHOP it was 70%. In that study, patient selection was restricted to subjects without serious concomitant disease, resulting in a median age of enrollment of 69 years, and any application to the general population of elderly patients has remained speculative. Similarly, the BC Cancer Agency reported that 2-year survival rates for all adults with DLBCL increased from 52% to 78%. In spite of a relatively advanced median age (75 years), we observed very similar 2-year OS rates: 59% and 68% in patients treated with ABC and R-ABC, respectively. Although the present study is observational, it is strongly suggestive that improved survival was attributable to rituximab.
Analyses of treatment outcomes for cancer patients utilizing SEER–Medicare data are limited by changes in pathologic classification and staging, uncertainties in the measurement of disease-free survival, and the time it takes to observe outcomes related to newly introduced therapies. This study has addressed these weaknesses in three ways. First, we limited our analysis to DLBCL, a diagnosis that has not substantially changed in classification during the study period. Second, we limited analysis to overall survival, which is easily defined, reproducibly measured, and clinically meaningful. Last, we had at least 3 years of survival data for all study subjects, a meaningful endpoint in DLBCL. Due to its observational design and reliance on registry and administrative claims data, this study was not able to overcome other weaknesses such as the use of billing data to ascertain treatment, and limited data on delivered dose intensity, functional status, or quality of life outcomes. Furthermore, this analysis does not account for treatment selection biases or the role of any therapy, including rituximab, in the second-line or subsequent management of DBCL in this cohort.
In conclusion, we describe for the first time the patterns of utilization of rituximab in the initial therapy of patients with DLBCL over 66 years of age. Utilization started shortly after the presentation of phase II data at a 1998 American Society of Clinical Oncology meeting, and increased steadily such that in 2002 rituximab was added to over three-quarters of anthracycline and non-anthracycline regimens, well before the 2006 FDA approval for this indication. It does not appear that rituximab changed the utilization of ABC or the frequency of total therapy avoidance, which remains very high in those aged over 85. Survival of all US patients with DLBCL over age 66 improved substantially, coincident with the diffusion of rituximab into treatment regimens, and subset analysis suggests that rituximab-associated survival improvement occurred with non-anthracycline containing regimens as well as anthracycline containing regimens. The expectation of greater adverse events should not preclude the treatment of older patients with optimal regimens; rather, the focus should be on finding optimal dosing for older patients, preventing toxicity with available supportive measures, and prospectively evaluating the comparative effectiveness of non-anthracycline and anthracycline-based immunochemotherapy regimens in the oldest patients.