This Article Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Alliot, C. Search for Related Content PubMed PubMed Citation Articles by Alliot, C. Related Articles Related Reply Social Bookmarking                            What's this?

CHOP Versus CHOP Plus Granulocyte Colony-Stimulating Factor in Elderly Patients With Aggressive Non-Hodgkin's Lymphoma

Hematology/Oncology Division, General Hospital of Annemasse, Annemasse, France

To the Editor:

I read with interest the article by Doorduijn and the Dutch-Belgian Hemato-Oncology Cooperative Group (HOVON) group in the August 15, 2003, issue.¹ In a randomized study, the authors compared the cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) regimen given every 3 weeks to the same regimen plus granulocyte colony-stimulating factor (G-CSF) in elderly patients with aggressive non-Hodgkin's lymphoma. The studied population, aged from 65 to 90 years (median, 72 years), seems older than that of previous comparable studies. The modest improvement in relative dose-intensity (RDI) in the group with G-CSF leads logically neither to a higher response rate nor to a better overall survival. Patients older than 80 years completed significantly fewer treatments with 57% receiving less than six cycles and only 14% receiving eight cycles. Treatment-related toxicity led to the death of 29 patients (7.5%), including 17 cardiac events. The first point to discuss is the ambitious goal of a 15% increase in complete response only by adding G-CSF. Because the RDI of cyclophosphamide and doxorubicin were of approximately 93% in the control arm, this strategy appears clearly insufficient in terms of efficacy. In line with this, the French multicenter trial of Coiffier et al comparing CHOP to CHOP plus rituximab showed that more than 90% of patients received more than 90% of the planned dose while 43% had received G-CSF curatively after 8 cycles.² A retrospective study of patients aged over 65 years treated with CHOP before routine use of G-CSF showed that 65% of them received more than 90% of the planned dose although 21% received less than 75%.³ Thus, a vast proportion of the younger patients do not beneficiate from G-CSF in terms of RDI. The RDI may depend not only on improvement in hematologic recovery but also on compliance favored by various recent advances such as psychological support, long-term venous access or recent molecules improving tolerance, such as setrons or modern antidepressants. The present study confirms that nonhematologic toxicities become prevalent in patients aged over 70 and clearly unacceptable over age 80. A multicenter Spanish phase II study of CHOP with GM-CSF support previously showed a treatment-related mortality of 18% in patients over age 70 v 0 in those aged 60 to 69 years.⁴ In this study, mucositis has been observed in 21% of the cycles in patients younger than 70 years versus 42% in the older. In fact, standard full-dose CHOP represents an intensified therapy in this population given the numerous pharmacokinetic changes arising during ageing. Several mechanisms result in changes in the volume of distribution (Vd) of the drugs, including a loss of total body water, an increased total body fat, a decreased albumin by approximately 20% between 25 and 75 years.⁵ Certain drugs, such as the anthracyclins, are intensively bound on the erythrocytes. Thus, the Vd may also be increased by anemia. There is a prolongation in the early distribution phase of doxorubicin in the elderly, leading to the persistence of high plasma concentrations and potentially favoring cardiotoxicity.⁶ The aging of the kidneys results in a progressive decline of the glomerular filtration rate of 1 mL/min each year after age 40.⁷ Thus, dose adaptation has been proposed for creatinine clearance lower than 60 mL/min.⁸ Certain treatments of comorbid illnesses may interfere with chemotherapy, in particular for cytochrome P-450 enzyme or conjugation reactions. These interactions may play a role in the case of cyclophosphamide which is extensively metabolized in the liver by the cytochrome P-450 isoenzymes CYP2B6, CYP3A4, and CYP2C.⁹ For example, CYP3A4 can be induced by carbamazepin or phenytoin and inhibited by macrolides, fluvoxamine, or antifungal imidazoles.¹⁰ Moreover, numerous drugs such as warfarin, phenytoin, salicylates, or tolbutamide may displace chemotherapeutic agents from albumin binding sites.¹¹ The importance of polypharmacy has been illustrated by a study at H. Lee Moffit Cancer Center revealing that 56% of the patients usually take more than four drugs.¹² On the other hand, a significant improvement in terms of survival can be obtained either by time intensification as shown by the German multicenter trial LNH-B using 2-weekly CHOP¹³ or by dose intensification in the French LNH 93-5 trial using 3-weekly ACVBP regimen (with doxorubicin, 75 mg/m², cyclophosphamide, 1200 mg/m²).¹⁴ Nevertheless, the median ages were 67 and 65 years, respectively, and these strategies seem beneficial essentially in patients younger than 66 years because of toxicity.

In conclusion, this study confirms the limits of support with G-CSF. A number of measures could decrease toxicity such as adaptation of usual treatments, dose adaptation of cyclophosphamide according to creatinine clearance, correction of anemia by transfusion or erythropoietin. Given a half-life of about 19 days, albumin might be administered simultaneously to chemotherapy. Because cardiotoxicity is largely unpredictable and doxorubicin remains the kee-drug, dexrazoxane should be administered before the cumulative dose of 300 mg/m². The only alternative to these measures would consist in exploring standard adaptations of CHOP within age brackets of less than 10 years. Obviously, standard full-dose CHOP should not be used in patients aged over 80.

Author's Disclosures of Potential Conflicts of Interest

The author indicated no potential conflicts of interest.

REFERENCES

1. Doorduijn JK, van der Holt GW, van Imhoff KG, 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[Abstract/Free Full Text]

2. Coiffier B, Lepage E, Brière 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[Abstract/Free Full Text]

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. Gómez H, Mas L, Casanova L, et al: Elderly patients with aggressive non-Hodgkin's lymphoma treated with CHOP chemotherapy plus granulocyte-macrophage colony-stimulating factor: Identification of two age subgroups with differing hematologic toxicity. J Clin Oncol 16:2352-2358, 1998[Abstract]

5. Wallace SM, Verbeck RK: Plasma protein binding of drugs in the elderly. Clin Pharmacokin 12:41-72, 1987[Medline]

6. Robert J, Hoerni B: Age dependence of the early phase pharmacokinetics of doxorubicin. Cancer Res 43:4467-4469, 1983[Abstract/Free Full Text]

7. Evers BM, Townsend CM, Thompson JC: Organ physiology of ageing. Surg Clin North Am 74:23-39, 1994[Medline]

8. Kintzel PE, Dorr RT: Anticancer drug renal toxicity and elimination: Dosing guidelines for altered renal function. Cancer Treat Rev 21:33-64, 1995[CrossRef][Medline]

9. Huang Z, Roy P, Waxman DJ: Role of human liver microsomal CYP3A4 and CYP2B6 in catalysing N-dechloroethylation of cyclophosphamide and ifosfamide. Biochem Pharmacol 59:961-972, 2000[CrossRef][Medline]

10. Balis FM: Pharmacokinetic drug interactions of commonly used anticancer drugs. Clin Pharmacokinet 11:223-235, 1986[Medline]

11. Spina E, Scordo MG: Clinically significant drug interactions with antidepressants in the elderly. Drugs Aging 19:299-320, 2002[CrossRef][Medline]

12. Extermann M, Aapro M: Assessment of the older cancer patient. Hematol Oncol Clin North Am 14:63-77, 2000[CrossRef][Medline]

13. Pfreundschuh MG, Trumper L, Kloess M, et al: 2-weekly CHOP (CHOP-14): The new standard regimen for patients with aggressive non-Hodgkin's lymphoma (NHL) >60 years of age. Blood 98: 725a, 2001

14. Tilly H, Mounier N, Coiffier B, et al: Superiority of intensive conventional chemotherapy ACVBP over CHOP in advanced aggressive non-Hodgkin's lymphoma (NHL). Results of the GELA study LNH 93-5with a median follow-up of 5 years. Hematology J 4: 264a, 2003

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

Related Reply

• In Reply:
  Jeanette K. Doorduijn and Pieter Sonneveld
  JCO 2005 23: 4799 [Full Text]

This Article Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Alliot, C. Search for Related Content PubMed PubMed Citation Articles by Alliot, C. Related Articles Related Reply Social Bookmarking                            What's this?