CHOP and Non-Hodgkin’s Lymphoma
Abstracts & Commentary
Synopsis: CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) is still considered the gold standard in first-line therapy for aggressive non-Hodgkin’s lymphoma. Despite its place in clinical practice for 3 decades, there are issues that still are being evaluated. The February 2003 issue of the Annals of Oncology reports on the issue of cardiotoxicity of CHOP, and a second article discussed the use of a modified CHOP regimen in patients older than 65.
Sources: Limat S, et al. Ann Oncol. 2003;14:277-281; Bessel EM, et al. Ann Oncol. 2003;14:258-267.
Anthracyclines are a main component for the treatment of various solid tumors and hematologic malignancies. They have a known spectrum of toxicity, particularly cardiac toxicity. Cardiotoxicity is increased in the elderly and pediatric patients.1 Cardiac function is monitored during therapy and as follow-up through the MUGA (multiple-gated acquisition) scan. Monitoring can detect changes in left ventricular function but may not decrease the incidence of cardiomyopathy due to its inability to predict toxicity. In order to minimize life-time risk of cardiotoxicity, it is recommended to limit cumulative doxorubicin doses to 550 mg/m2 and daunorubicin doses to 500 mg/m2 in adults. The cumulative incidence of congestive heart failure varies from 1.6% to 2.8%. Depending on the sensitivity of the measure, cardiac abnormalities can be seen in up to 57% of long-term survivors. Dexrazoxane (Zinecard®) is a cardioprotectant for patients receiving doxorubicin that decreases the incidence of cardiotoxicity with therapy above recommended dosage limits in breast cancer.2-4
Comment by Stuart M. Lichtman, MD, FACP
Limat and colleagues carried out a retrospective study to analyze the early doxorubicin-induced cardiotoxicity in aggressive NHL patients. The primary objective was to determine the incidence of cardiac abnormalities within 1 year of treatment with the CHOP regimen. The secondary objective was to identify risk factors. Cardiac events were defined as either a decline in resting LVEF of 15% from baseline, or a decline in LVEF of < 50%, or clinical evidence of CHF. Twenty-seven patients (20%) developed a cardiac event within 1 year of treatment. Among these, 14 patients had clinical signs of CHF. Three patients died suddenly from presumed cardiac causes. An analysis showed a cumulative dose of doxorubicin > 200 mg/m2 and age older than 50 years appeared to be significant risk factors. These were unselected patients who had previously not had chemotherapy or radiation therapy. The use of more sensitive investigators has led to a wider definition of cardiotoxicity, including subclinical cardiomyopathy. The evaluation of diastolic dysfunction and serum troponin-T levels needs to be further evaluated as diagnostic or predictive tools. Preventive strategies to decrease toxicity can include prolonged infusions, potentially less cardiotoxic drugs (ie, epirubicin, mitoxantrone), and liposomal compounds. These alterations in treatment programs including the use of dexrazoxane need to be evaluated in prospective trials.
Studies should include those patients who potentially are at increased risk such as the elderly, patients with prior heart disease, and patients with prior or concomitant chest irradiation.5,6
Bessel and colleagues conducted a study to determine whether there was a difference in toxicity between modified CHOP and MCOP chemotherapy in elderly patients (median, 74 years; range, 65-91). CHOP was modified by lowering the dose of cyclophosphamide to 600 mg/m2 and doxorubicin to 30 mg/m2. MCOP substituted mitoxantrone 10 mg/m2 for doxorubicin.
The treatment of elderly patients with lymphoma has been studied with a number of different regimens trying to improve on standard CHOP. To date, CHOP remains the standard of care. More recently, the addition of rituxamib has been shown to improve outcome.7 The complete response rate in the current study was CHOP 62% and MCOP 52% (NS; P = .26). The only significant difference in toxicity was in red cell transfusion and white cell counts. There were no sufficient data to determine whether there was any difference in cardiac toxicity. There was no significant difference in overall survival.
The International Prognostic Index indicates that age older than 60 years is an adverse prognostic factor.8 Due to poor survival and decreased tolerance to standard chemotherapy, a number of trials have tried to improve on the standard CHOP regimen for elderly patients.9 This has included weekly therapy, substitution of mitoxantrone for doxorubicin, and elimination of the anthracycline.10-12 These modifications have led to less-effective regimens. The current study and those cited do not include the supportive care measures that are now commonly employed. Newer antiemetic regimens and hematopoietic growth factors were often not included. This certainly can ameliorate some of the toxicities seen in these studies. In addition, the current study also demonstrated that in lymphoma trials in elderly patients, many deaths on study are not due to lymphoma or toxicity.13 In this trial, 26% of patients died from other causes. Therefore, cause of death, comorbidity and other functional factors need to be assessed to determined the overall efficacy of a particular regimen.
Dr. Lichtman is Associate Professor of Medicine, NYU School of Medicine, Division of Oncology; Don Monti Division of Medical Oncology, North Shore University Hospital, Manhasset, NY.
References
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3. Doroshow JH. Anthracyclines and anthracenediones. In: Chabner BA, Longo DL, eds. Cancer Chemotherapy and Biotherapy: Principles and Practice. 2nd ed. Philadelphia: Lippincott-Raven; 1996:409-434.
4. Doroshow JH. N Engl J Med. 1991;324:843-845.
5. Von Hoff DD, et al. Ann Intern Med.1979;91:710-717.
6. Ibrahim NK, et al. Ann Oncol. 2000;11:1597-1601.
7. Coiffier B, et al. N Engl J Med. 2002;346:235-242.
8. N Engl J Med. 1993;329:987-994.
9. Lichtman SM. Crit Rev Oncol Hematol. 2000;33: 119-128.
10. Meyer RM, et al. J Clin Oncol. 1995;13:2386-2393.
11. Sonneveld P, et al. J Clin Oncol. 1995;13:2530-2539.
12. Bastion Y, et al. J Clin Oncol. 1997;15:2945-2953.
13. Vose JM, et al. J Clin Oncol. 1988;6:1838-1844.
CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) is still considered the gold standard in first-line therapy for aggressive non-Hodgkins lymphoma. Despite its place in clinical practice for 3 decades, there are issues that still are being evaluated.
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