Therapy In The Older Patient

Age > 60 yr is the single most powerful predictor of shortened overall survival in patients with aggressive NHL (11). Possible reasons for decreased survival in this patient population may be related to the presence of comorbid illness, altered pharmacokinetics resulting in greater treatment-related toxicities, or a more aggressive tumor biology (5). Alternatively, it is possible that physicians, concerned about the potential for toxicity, treat older patients with less intensive chemotherapy and make significant dose reductions, resulting in inferior response rates (6,12). In a retrospective analysis, Kwak and colleagues (12) showed that the actual relative dose intensity (RDI) of chemotherapy, specifically doxorubicin, was an important prognostic factor for survival in diffuse large-cell lymphoma. Hence, dose reductions might compromise the outcome of potentially curative therapy. Whereas myelosuppression with its associated risk of infection remains a significant cause of treatment-related morbidity, the addition of HGFs in the older patient may reduce complication rates while allowing for maintenance of planned dose intensity.

Although the results of several small phase 2 studies suggest that the addition of HGFs improves the RDI of administered therapy, resulting in an improvement in response and survival (Table 1), this hypothesis has not been validated in three randomized trials (4,7,13-16). The Nordic Lymphoma Study Group randomized 458 patients over the age of 60 yr with aggressive NHL to receive either cyclophosphamide, dox-

orubicin, vincristine, and prednisone (CHOP) ± rHu granulocyte colony-stimulating factor (rHuG-CSF) or cyclophosphamide, mitoxantrone, vincristine, and prednisone (CNOP) ± rHuG-CSF in a bifactorial design (14). Decreased rates of neutropenia and infection were seen with the addition of HGFs, but there were no significant effects on rates of complete remission or overall survival. The median actual RDI for the anthra-cycline was the same whether or not the patient received rHuG-CSF.

The Dutch-Belgian Hemato-Oncology Cooperative Group had similar findings in their study of 303 patients 65 yr of age or older treated with CHOP ± rHuG-CSF (15). In yet another phase 3 trial, Zinzani and colleagues (16) evaluated 149 patients 60 yr or older with untreated aggressive NHL. Patients were randomly assigned to receive cyclophos-phamide, mitoxantrone, vincristine, etoposide, bleomycin, and prednisone ± rHuG-CSF (5 ^g/kg/d) for 5 d. A significant decrease was noted in the number of episodes of neu-tropenia and infection without a difference in overall response, complete response, and survival. A trend toward a higher RDI was noted in patients receiving rHuG-CSF, but the difference was not statistically significant. Together, these studies show that although there is a decline in myelosuppression-related toxicity with the addition of HGF in patients 60 yr or greater, there is no effect on response rates or overall survival.

The addition of HGFs to standard CHOP chemotherapy has been shown to result in fewer episodes of febrile neutropenia (FN) and a decreased risk of hospitalization with shorter lengths of stay (LOS) (17,18). A retrospective review of patients with NHL treated at a single institution found a potential cost savings through a reduction in neu-tropenic complications as well as an improvement in administered dose intensity of chemotherapy (17). When specifically studying patients aged 65 yr or greater, Chrischilles and colleagues (18) showed that those treated with HGFs were hospitalized for FN an average of 1.2 d less than those not receiving HGF. Consequently, despite the lack of impact on response and overall survival, possibly in part reflecting the presence of comorbid illnesses or alterations in tumor biology, there is a benefit to HGF administration in terms of decreased frequency of neutropenic complications and hospitalizations. Therefore, in accordance with the American Society of Clinical Oncology (ASCO) guidelines, it is appropriate to treat the older patient with lymphoma and a good performance status with conventional-dose chemotherapy supplemented with HGFs to reduce the risk of complications (19).

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