Vinorelbine and Prednisone in Frail Elderly Patients with Intermediate-High Grade Non-Hodgkin’s Lymphoma
Vinorelbine and Prednisone in Frail Elderly Patients with Intermediate-High Grade Non-Hodgkin’s Lymphoma
Abstract & Commentary
By Stuart M. Lichtman, MD, Associate Attending, Memorial Sloan-Kettering Cancer Center, Commack, New York. Dr. Lichtman reports no financial relationship to this field of study.
Advanced age is an adverse prognostic factor in aggressive non-Hodgkin’s lymphoma (NHL). The analysis of the cumulative case series of aggressive NHL carried out by The International Non-Hodgkin’s Lymphoma Prognostic Factor Project has shown that patients aged older than 60 years have a worse prognostic outcome than younger patients,1 although a direct comparison of response and survival of patients aged older than 70 years with younger patients is complicated by the fact that the randomized studies were specifically designed for patients aged < 70 years.2,3 When the same chemotherapy regimen was used for all patients regardless of age in clinical trials, patients aged older than 70 with poor performance status and the very old were probably excluded. However, even in the absence of specific data, it is generally accepted that prognosis is worse for patients aged older than 70 years than for patients aged more than 60 years.
To reduce the risk of toxicity without decreasing therapeutic activity, novel regimens have been tried in patients aged 70 years or older. Although various specifically designed regimens have not been shown to be superior to the standard CHOP regimen, the reports are important by demonstrating that a clinical trial with combination chemotherapy can be performed even in vulnerable elderly patients.4-6 There are inadequate data to make a therapeutic strategy in patients who have severe comorbidity, who are dependent, or who are well but older than 80-85 years. These patients are defined by geriatricians as frail.7 There are questions remaining whether they should be left without treatment, modified CHOP regimens are a less intense regimen. This paper is an attempt to provide an initial limited answer to these questions. The investigators carried out a prospective trial on a small population of frail patients admitted to the cooperating institutions. Since vinorelbine has been proven as an agent active in NHL and is well tolerated by elderly patients, they decided to use the combination of vinorelbine and prednisone to determine its tolerability and activity in a group of patients in which intensive chemotherapy may not be considered indicated or even feasible. Rituximab was not used in this trial as it was not available at its initiation.
Commentary
This trial had a unique eligibility. All frail patients with a newly diagnosed biopsy-proven NHL referred to the Italian participating institutions were entered in this phase II study. Patients were required to have stage II-IV or I bulky disease. To provide evidence of frailty, all patients with NHL were tested in each centre with a shortened version of the Comprehensive Geriatric Assessment (CGA) including a functional evaluation in terms of activities of daily living (ADL) and number and rate of comorbidities according to their severity assessed using the Cumulative Illness Rating Scale (CIRS). Patients were also examined with the Mini-Mental Status Examination (MMSE) to allow diagnosis and grading of dementia and the Geriatric Depression Scale (GDS) as a screening tool for depression. In addition to dementia and depression, patients were screened for other geriatric syndromes such as delirium, incontinence, osteoporosis, neglect and abuse, failure to thrive, and more than 3 falls in a month. The criteria used to define a patient as frail were age > 80 years, or age > 70 years and 3 or more comorbidities of grade 3 or at least one comorbidity of grade 4 according to the CIRS, or dependence in one or more activities of daily living (bathing, dressing, toilet use, transferring, urine and bowel continence, eating) or the presence of one or more of the geriatric syndromes. CIRS items, dementia and delirium were assessed by the hematologist or medical oncologist taking care of the patient, and ADL, MMS and GDS were assessed by the same physician or a psychologist.
The treatment consisted of vinorelbine 25 mg/m2 i.v. on days 1 and 8 and oral prednisone 30 mg total dose (2 prednisone tablets of 25 mg and 5 mg) on days 1-8, which was repeated after a 3-week interval.
Ten were male and 20 were female. The median age was 83 years (range, 70-96 years). Twenty-two patients were considered frail because they were aged > 80 years, 11 because of severe comorbidities according to the CIRS, and 13 because of their level of dependence in ADL. The median number of courses administered was 4 (range, 1-8). No dose reduction for vinorelbine was necessary. Only three patients achieved CR [10%; confidence interval (CI), 2.1%-26.5%] and 9 achieved PR (30%; CI, 14.7%-59.4%). A higher response rate was observed in stage III and IV than in stage I and II (P = 0.016). No correlation of response was found between IPI 0 and 1 compared with IPI 2 and 3 (P = 0.098). The 3 patients who achieved CR were frail because of advanced age only. Three of the 9 patients who achieved PR were judged to be frail because of age only, five because of age and other age-associated conditions, and one because of severe comorbidities only. Only one long-lasting CR (36 months) was achieved. Only 2 of the 18 patients with stable disease or progression were judged to be frail because of advanced age only. The median duration of the CRs was 29 months (range, 5-36 months) and that of the PRs was 1 month (range, 1-22 months). Stable disease occurred in eight patients. The median survival was only 10 months.
Patients aged > 80-85 years or > 70 years, but with severe comorbidity or with geriatric syndromes and advanced solid tumors, can be treated with simple palliation. However, patients with chemo-sensitive disease such as NHL could probably benefit from chemotherapy. The decision regarding therapy can be very difficult as there are limited options in frail patients. This group has rarely been studied and the benefits of chemotherapy have never been truly assessed. In the present study the accrual was lower than expected. As the authors point out, enrollment of frail patients in a clinical study is difficult. Vinorelbine and prednisone can be considered as a relatively well tolerated combination but, as anticipated, it has a low therapeutic activity. Therefore the authors do not recommend this regimen in all frail patients. However, this combination could be clinically useful for temporary palliation in a substantial number of patients for whom aggressive combination chemotherapy has been deemed appropriate. The use of rituximab can potentially improve the results.
This trial is important as it is one of the only studies in any malignancy which has used frailty as eligibility for a clinical study. This regimen should be used as a starting point for future clinical trials in this vulnerable patient population. Hopefully treatment in the future will be not be based on empiricism, but on the results of prospective studies, even if these are small and imperfect.
References
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2. Sonneveld P, et al. Comparison of doxorubicin and mitoxantrone in the treatment of elderly patients with advanced diffuse non-Hodgkin’s lymphoma using CHOP vs CNOP chemotherapy. J Clin Oncol. 1995;13:2530-2539.
3. Tirelli U, et al. CHOP is the standard regimen in patients > or = 70 years of age with intermediate-grade and high-grade non-Hodgkin’s lymphoma: results of a randomized study of the European Organization for Research and Treatment of Cancer Lymphoma Cooperative Study Group. J Clin Oncol. 1998;16:27-34.
4. Meyer RM, et al. Randomized phase II comparison of standard CHOP with weekly CHOP in elderly patients with non-Hodgkin’s lymphoma. J Clin Oncol. 1995;13:2386-2393.
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6. Lichtman SM, et al. Treatment of aggressive non-Hodgkin’s lymphoma in elderly patients with thiotepa, Novantrone (mitoxantrone), vincristine, prednisone (TNOP). Am J Clin Oncol. 2001;24: 360-362.
7. Rockwood K, et al. A brief clinical instrument to classify frailty in elderly people. Lancet. 1999;353:205-206.
8. Monfardini S, et al. Vinorelbine and prednisone in frail elderly patients with intermediate-high grade non-Hodgkin’s lymphomas. Ann Oncol. 2005;16:1352-1358.
Advanced age is an adverse prognostic factor in aggressive non-Hodgkins lymphoma (NHL). The analysis of the cumulative case series of aggressive NHL carried out by The International Non-Hodgkins Lymphoma Prognostic Factor Project has shown that patients aged older than 60 years have a worse prognostic outcome than younger patients, although a direct comparison of response and survival of patients aged older than 70 years with younger patients is complicated by the fact that the randomized studies were specifically designed for patients aged < 70 years.Subscribe Now for Access
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