Fludarabine and the Older Patient

Abstract & Commentary

By William B. Ershler, MD, Editor, INOVA Fairfax Hospital Cancer Center, Fairfax, VA; Director, Institute for Advanced Studies in Aging, Washington, DC.

Synopsis: In a retrospective analysis from MacCallum Cancer Center in Melbourne, Australia, fludarabine-associated toxicities were examined in the context of patient age for those being treated for indolent lymphoma or chronic lymphocytic leukemia. Although there was slightly increased myelosuppression (neutropenia and thrombocytopenia), there was no difference in severe myelosuppression, infection rate, organ toxicity or drug-related mortality. The findings support the notion that this drug can be administered safely to good performance status elderly patients with these lymphoproliferative disorders.

Source: Polizzotto MN, et al. The influence of increasing age on the deliverability and toxicity of fludarabine-based combination regimens in patients with indolent lymphoproliferative disorders. Cancer. 2006 Jul 17; [Epub ahead of print].

Indolent lymphoproliferative disorders including chronic lymphocytic leukemia (CLL) and "low-grade" non-Hodgkin lymphoma are diseases primarily of the elderly with a median age approximating 70 years.1,2 Fludarabine-based combination chemotherapy regimens have proven effective treatment for these disorders but most clinical trials have an under representation of typical elderly patients. In the current research, Polizzotto examined the experience at the MacCallum Cancer Center in Melbourne, Australia with regard to age on the deliverability and toxicity of fludarabine-based regimens over an eleven year span (1994-2005). During this period three regimens were used but each included fludarabine administered at 25 mg/m2 per day for 3 days every 28 days. There were 180 patients arbitrarily split into two groups; < 60 years and > 60 years and multivariate analysis was undertaken to control for other differences between the groups. The authors also explored the impact of age > 70 years within the older cohort.

Older patients experienced non-severe hematologic and infectious toxicity to a greater extent than the younger cohort but there was no difference in the rate of severe toxicity. The rates of neutropenia (absolute neutrophil count [ANC] < 1.0 × 109/L) and severe neutropenia (ANC < 0.5 × 109/L) were 22% and 13%, respectively, in older patients vs 20% and 11%, respectively in younger patients (not statistically significant [NS]). The rates of thrombocytopenia (platelet count, < 100 × 109/L) and severe thrombocytopenia (platelet count, < 50 × 109/L) were 21% and 5% respectively in older patients vs 16% and 5% respectively, in the younger patients (NS). The rate of infection was 18% per cycle in the older patients compared to 15% in the younger patients (NS) and there was no difference in the severity of infection. Furthermore, other organ toxicities were uncommon and were not seen more frequently in the older patients. The treatment-related mortality was < 1% in both cohorts. In multivariate analysis, increasing age and performance status influenced the risk of hematologic toxicity, whereas only performance status influenced the rate of infection. The authors concluded that fludarabine regimens are well tolerated by older patients who have good performance status with only modestly increased myelosuppression but no increase in severe infectious complications or treatment-related mortality.

Commentary

This is a single-institution retrospective analysis with basically negative findings (minimal difference between young and old with regard to toxicity and deliverability). Yet, despite the reservations that one must consider with this type of analysis, the findings are both favorable and believable. Favorable, of course, because fludarabine is now widely appreciated as the cytotoxic drug of first choice for indolent lymphoma and CLL, and it is reassuring to know that no substantial increased toxicity is likely to occur on the basis of age. As is often the case, adverse events and organ toxicities are more closely associated with performance status than chronology. The physicians in Melbourne are to be commended for their inclusion of older and poor performance (ECOG 0-3) patients on standardized chemotherapy regimens, as well as well as for carefully capturing and cataloguing data, making possible assessments such as this. Yet, the age cut for "old" in this analysis was 60 years and the median age in the old group was 66 years. Thus, the great majority of patients in this analysis (including in the "old" group) were below the median age of the disease in the community. So, the question remains, what about chemotherapy for the truly elderly? Can we expect the same safety profile? My suspicion is that we won't know until we perform the study as a randomized clinical trial. We will not be able to extract this from retrospective review, for like the experience in Melbourne, and for whatever reason, the truly elderly are often not treated, or if they are, frequently not with standardized regimens. This might be appropriate, but it might not be. What is needed is an inclusive randomized clinical trial. The current report certainly helps to justify that approach.

References

1. Groves FD, et al. Cancer surveillance series: non-Hodgkin's lymphoma incidence by histologic subtype in the United States from 1978 through 1995. J Natl Cancer Inst. 2000;92:1240-1251.

2. Keating MJ, et al. Long-term follow-up of patients with chronic lymphocytic leukemia (CLL) receiving fludarabine regimens as initial therapy. Blood. 1998;92:1165-1171.