Abstracts & Commentary
Synopsis: The standard chemotherapy regimen for the treatment of aggressive non-Hodgkin’s lymphoma has been CHOP (cyclophosphamide, adriamycin, vincristine, prednisone).1 This was based on a study comparing this regimen to other more intensive second and third generation regimens. Dose intensity using a myeloablative regimen has been used with autologous stem cell salvage in the treatment of chemosensitive relapse.2 In the untreated patient the role of bone marrow transplantation or dose intensity remains unproven. Many of the high-risk patients according to the International Prognostic Index would not appropriate candidates due to age and comorbid conditions. Two articles are presented addressing alterations in the basic CHOP program. Sources: Balzarotti M, et al. Ann Oncol. 2002;13:1341-1346; Itoh K, et al. Ann Oncol. 2002;13:1347-1355; Portlock CS. Ann Oncol. 2002;13:1329-1330.
The October 2002 issue of the Annals of Oncology contains 2 articles and an editorial describing a dose-dense and dose- intense CHOP regimen in hopes to optimize outcome. In the study by Itoh and colleagues 2 regimens were used.3 They were standard-dose CHOP given every 2 weeks and a dose-escalated CHOP regimen given every 3 weeks. The doses of the latter regimen were based on a prior Japanese study. The Balzarotti study treated patients with a dose-intense regimen every 2 weeks.4
The Japanese Clinical Oncology Group (JCOG) undertook a study to assess 2 aggressive regimens which are variants of standard-dose CHOP. Their goal is to compare one of these regimens in a future randomized study against standard CHOP. The patients were randomly assigned to receive either biweekly CHOP or dose-escalated CHOP with the groups balanced by institution and IPI score.5 Biweekly CHOP consisted of 8 cycles of standard CHOP every other week (cyclophosphamide 750 mg/m2 i.v. day 1, doxorubicin 50 mg/m2 i.v. day 1, vincristine 1.4 mg/m2 (max, 2 mg) i.v. day 1 and prednisolone 100 mg p.o. for 5 days). Dose escalated CHOP consisting of cyclophosphamide 1.5 gm/m2 i.v. day 1, doxorubicin 70 mg/m2, vincristine 1.4 mg/m2 (max, 2 mg) i.v. day 1 and prednisolone 100 mg p.o. for 5 days every 3 weeks for 6 cycles. The dose escalation arm was based on a previous study.6 Both arms used G-CSF support. Seventy (63 eligible) patients were randomized to each arm with a median age of 61 years. Complete response (CR + CRu) rates and progression-free and overall survival rates were similar in both groups. Toxicity was significantly different with increased neutropenia (50% vs 86%; P < 0.0001) and thrombocytopenia (3% vs 20%; P < 0.001) in the dose-escalated group. Therefore based on similar efficacy and differing toxicity, biweekly CHOP is currently being compared to standard CHOP in the JCOG.
Balzarotti et al extended a previous study of CHOP intensification by increasing the dose intensity of their regimen by shortening the between-course intervals with the support of growth factors. They had previously published the results of a phase I-II CHOP intensification study in which the maximal tolerated doses of cyclophosphamide and doxorubicin were found to be 1750 mg/m2 and 75 mg/m2 given every 21 days. In this current paper they attempted to further increase the CHOP dose intensity by shortening the interval to 14 days. There were 67 patients (median age, 48 years) entered into the study. There was a dose finding phase in which cyclophosphamide was dose escalated. The maximum dose deliverable was 1750 mg/m2. Forty-four additional patients were then treated at that dose. In an intention-to-treat analysis, the 12-month freedom from progression (FFP) and overall survival (OS) for the entire series was 71% and 86% respectively. On the basis of IPI categories, FFP was 74% and 58% (P = 0.103) and OS was 92% and 71% (P = 0.005) for patients with 0-2 or > 3 adverse factors. In the highest dose range of cyclophosphamide 2250 mg/m2, the delivered dose was actually less than the dose of cyclophosphamide of 2000 mg/m2. Dr. Portlock comments on the differences between these trials including age, histology, IPI risk groups.7 She points out that if nonmyeloablative CHOP dose escalation has any role to play in the treatment of these diseases, the increment of increased curability is small. Other modalities need to be explored.
Comment by Stuart M. Lichtman, MD
The studies reported in this issue of the Annals of Oncology are attempts at increases in dose intensity (dose of effective drug administered per unit time) and dose density (the frequency of effective drug dose administered). Part of the background of these trials is that myeloablative dose intensity regimens have been established in the autologous stem cell salvage therapy of chemotherapy sensitive relapsed disease. In untreated patients the role of dose intensity remains questionable. It has been a difficult issue to study due to the role of CHOP as a potentially curative regimen that is tolerable, particularly with hematopoietic growth factors, and that myeloablative therapy is essentially limited to younger high-risk patients. The IPI index clearly shows that age and advanced disease leads to poor outcome. In patients with intermediate or high-risk scores, the probability of cure is still < 40-50%. Even if these dose-dense or intense regimens were to show some advantage they would not be appropriate for a large proportion of patients who are either older or have significant comorbid illness. The study by Fisher et al randomized patients to either standard CHOP or to regimens that were felt to be more intense or have additional drugs. These regimens (m-BACOD, ProMACE-CytaBOM, MACOP-B) were thought to be more effective based on smaller phase II trials.8-10 In the treatment of lymphoma in older patients, manipulation of the basic CHOP schedule has resulted in inferior outcome.11 These studies have emphasized that prospective testing of dose-dense and/or dose-intense regimens need to be studied in careful prospective manner, preferable in multiple institutions or in cooperative groups. It may be that we have reached a plateau in benefit with the basic CHOP or any other currently available chemotherapy combination in the untreated patient. The recent study showing the benefit of adding a target therapy (ie, rituximab) should give us encouragement to further explore the addition of these or similar drugs.12 The trials reported in the Annals of Oncology also emphasize the need for improved therapy for the poor-risk (high IPI score) patients. Such studies need to be different for the younger and older patients, as each group has specific needs. These 2 papers (and the accompanying editorial) demonstrate that before significant alterations in standard therapies are embraced, they need to be studied in a prospective and cautious manner and that high-dose therapy in the untreated patient remains unproven.
Dr. Lichtman is Associate Professor of Medicine NYU School of Medicine Division of Oncology Manhasset, NY.
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2. Philip T, et al. N Engl J Med. 1995;333(23):1540-1545.
3. Itoh K, et al. Ann Oncol. 2002;13(9):1347-1355.
4. Balzarotti M, et al. Ann Oncol. 2002;13(9):1341-1346.
5. Shipp MA. Blood. 1994;83:1165-1173.
6. Itoh K, et al. Ann Oncol. 2000;11(10):1241-1247.
7. Portlock CS. Ann Oncol. 2002;13(9):1329-1330.
8. Longo DL, et al. J Clin Oncol. 1991;9(1):25-38.
9. Shipp MA, et al. Ann Intern Med. 1986;104:757-765.
10. Klimo P, Connors JM. Ann Intern Med. 1985;102: 596-602.
11. Lichtman SM. Crit Rev Oncol Hematol. 2000;33(2): 119-128.
12. Coiffier B, et al. N Engl J Med. 2002;346(4):235-242.