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Journal of Clinical Oncology, Vol 23, No 21 (July 20), 2005: pp. 4799 © 2005 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.014464
In Reply:Erasmus MC, Department of Hematology, Groene Hilledijk, Rotterdam, the Netherlands The Dutch-Belgian Hemato-Oncology Cooperative Group (HOVON) study comparing cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) every 3 weeks versus CHOP every 3 weeks plus G-CSF was initiated in 1994 to investigate if granulocyte colony-stimulating factor (G-CSF) support in elderly patients with aggressive non-Hodgkin's lymphoma (NHL) could achieve a higher relative dose-intensity (RDI), resulting in a better outcome.1 At that time, it was well known that elderly patients had a poor outcome with CHOP compared with younger patients.2 Until then, many studies on elderly patients with aggressive NHL had focused on reducing toxicity, assuming that standard CHOP every 3 weeks was too toxic for most of the patients. Our study showed that standard CHOP every 3 weeks was tolerable for the majority of the elderly patients, using standard in- and exclusion criteria, provided that the criteria for dose reduction were strictly followed using a predefined algorithm. G-CSF could not improve the RDI by a large extent which was due to the higher RDI (> 90%) than expected in the standard treatment arm. This reflects the fact that the majority of patients, with a median age of 72 years, completed the planned schedule and chemotherapy dose without problems. The results of the study by Campbell et al were not yet published in 1994, but it showed that without a stringent algorithm on dose reduction a considerable number of their patients received less than 90% of the planned dose of chemotherapy.3 In contrast, 43% of the patients older than 80 years in our study completed six or more CHOP-cycles. Even then, higher age was an adverse prognostic factor for complete remission and overall survival. However, this was not related to increased toxicity or early death, and therefore we disagree with Dr Alliot that age older than 80 years is an absolute contraindication for full-dose CHOP. The risk of toxicity of a chemotherapy regimen in elderly patients should be weighed against the morbidity and a short survival due to the disease if not treated with curative intent. The observed treatment-related mortality of 7.5% in our patient group with a median age of 72 years is in accordance with other studies.4-6 The results of our quality of life analysis in this patient group do not suggest that the toxicity is unacceptable to these subjects.7 Oral toxicity in our study was relatively rare: only in 2% of the cycles mucositis was observed. As to the multiple age dependent factors that contribute to the increased toxicity of CHOP in elderly patients we agree with Dr Alliot that changes in pharmacokinetics might be important. Reduced elimination and/or higher concentrations of active drugs may contribute to the increased toxicity in elderly patients, however it is no explanation for the lower CR-rate and higher relapse rate that are observed in elderly patients. In the literature there is no consensus as to pharmacokinetic alterations to explain increased toxicity in elderly patients. A prospective study in breast cancer patients treated with doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2 intravenously observed no age-related differences in the clearance of these drugs, and no age-related trends in toxicity.8 Indeed, pharmacologic factors that are not related to age are more likely to influence the toxicity of chemotherapy. For example, drugs which inhibit or induce the activity of cytochrome P-450 may interfere with the cytotoxic effect of cyclophosphamide. Another factor contributing to differences in pharmacokinetics is the presence of polymorphism of several cytochrome P-450 enzymes.9,10 Taken together, age-related differences of pharmacokinetics of doxorubicin and cyclophosphamide do not seem to have a dominant effect on the outcome of therapy, while comorbidity, concomitant drug use or genetic factors seem more important. Several recent studies have shown that standard or even more intensified treatment of aggressive NHL in elderly patients is feasible and results in a better outcome than with dose-reduced chemotherapy.6,11 Authors' Disclosures of Potential Conflicts of Interest The authors indicated no potential conflicts of interest. REFERENCES
1. Doorduijn JK, van der Holt B, van Imhoff GW, et al: CHOP compared with CHOP plus granulocyte colony-stimulating factor in elderly patients with aggressive non-Hodgkin's lymphoma. J Clin Oncol 21:3041-3050, 2003
2. A predictive model for aggressive non-Hodgkin's lymphoma. The International Non-Hodgkin's Lymphoma Prognostic Factors Project. N Engl J Med 329:987-994, 1993 3. Campbell C, Sawka C, Franssen E, et al: Delivery of full dose CHOP chemotherapy to elderly patients with aggressive non-Hodgkin's lymphoma without G-CSF support. Leuk Lymphoma 35:119-127, 1999[Medline]
4. Tirelli U, Errante D, Van Glabbeke M, 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 16:27-34, 1998
5. Zinzani PL, Storti S, Zaccaria A, et al: Elderly aggressive-histology non-Hodgkin's lymphoma: First-line VNCOP-B regimen experience on 350 patients. Blood 94:33-38, 1999
6. Coiffier B, Lepage E, Briere J, et al: CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med 346:235-242, 2002 7. Doorduijn JK, Buijt I, van der Holt B, et al: Self-reported quality of life in elderly patients with aggressive non-Hodgkin's lymphoma treated with CHOP chemotherapy. Eur J Haematol (in press) 8. Dees EC, O'Reilly S, Goodman SN, et al: A prospective pharmacologic evaluation of age-related toxicity of adjuvant chemotherapy in women with breast cancer. Cancer Invest 18:521-529, 2000[Medline] 9. Chang TK, Yu L, Goldstein JA, et al: Identification of the polymorphically expressed CYP2C19 and the wild-type CYP2C9-ILE359 allele as low-Km catalysts of cyclophosphamide and ifosfamide activation. Pharmacogenetics 7:211-221, 1997[CrossRef][Medline] 10. Touw DJ: Clinical implications of genetic polymorphisms and drug interactions mediated by cytochrome P-450 enzymes. Drug Metabol Drug Interact 14:55-82, 1997[Medline]
11. Pfreundschuh M, Trumper L, Kloess M, et al: Two-weekly or 3-weekly CHOP chemotherapy with or without etoposide for the treatment of elderly patients with aggressive lymphomas: Results of the NHL-B2 trial of the DSHNHL. Blood 104:634-641, 2004
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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