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© 2003 American Society for Clinical Oncology
Increasing Chemotherapy Intensity in Aggressive Lymphomas: A Renewal?Hospices Civils de Lyon and Université Claude Bernard, Lyon, France THE FIRST demonstration of cure in patients with aggressive lymphoma was presented more than 25 years ago with the first report of the cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) regimen.1 This regimen became the "gold standard" and none of the so-called third generation regimens showed better results in randomized trials,2–4 because of its ease of administration and its lack of severe toxicity in most patients, and because the results were widely reproducible. In all these trials, CHOP was given for 8 cycles with standard doses of cyclophosphamide (750 mg/m2), doxorubicin (50 mg/m2), and vincristine (1.4 mg/m2 to a maximum of 2 mg), even if the dose of corticosteroids was slightly variable (from 40 mg/m2 to 100 mg), with cycles given every 3 weeks. The use of high-dose therapy with autologous stem-cell transplant has been the only major progress made since the introduction of CHOP, but its use in first-line patients remains controversial. Several studies that compared cohorts of young patients with aggressive lymphoma and adverse prognostic factors treated either with standard chemotherapy or high-dose therapy with autologous transplant (HDT) failed to demonstrate improved efficacy. 5 Early HDT did not increase the complete remission (CR) rate and failed to improve outcome, except in the sequential trial presented by Gianni.6,7 HDT in slow responders also failed to improve the outcome.8 However, in a group of patients with very poor prognosis, HDT in CR resulted in prolonged survival.9 If the use of HDT in relapsing patients is currently accepted, its use in first-line patients is still debated more than 10 years after the first trials were reported. These studies comprise a group of patients with a very poor outcome and a 5-year survival rate of less than 25%. This high-risk group corresponds to patients who have either a low CR rate, high relapse rate, or both. Tentative solutions to improve the outcome of these patients have been diverse and without positive results. If HDT in first CR may reduce the risk of relapse in a subgroup of patients, it does not increase the CR rate.5,9 Adding more drugs and, in the alternative, increasing doses to increase the CR rate have been attempted and have usually failed.4,10 Whatever the reason, whether it be failure to respond or relapse, the survival rate of these patients when treated with CHOP chemotherapy is unsatisfactory. Five- and 10-year survivals were approximately 20%, presenting an opportunity to improve on these results. Even in those patients with good prognosis, survival is around 50% to 70%, which also allows for numerous possibilities to improve outcome.
Several attempts have been made to increase the CR rate and reduce the relapse rate by adding new drugs to the CHOP regimen, such as in the methotrexate, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin (MACOP-B) regimen, the methotrexate, bleomycin, cyclophosphamide, and etoposide (M-BACOD) regimen, and the prednisone, methotrexate, doxorubicin, cyclophosphamide, etoposide–cytarabine, bleomycin, vincristine, and methotrexate (ProMACE-CytaBOM) regimen. The first phase II results of these regimens suggested benefit in comparison to historical controls, but randomized trials showed comparable results to those observed with CHOP.3,4,11,12 Only 10 randomized studies showed a statistically significant improvement for survival compared to CHOP (Table 1
If the addition of more drugs to the CHOP regimen has been frequently attempted and has failed to show any benefit, few studies have addressed the potential of increasing doses of standard drugs. A recent study by the Groupe d’Etudes des Lymphomes de l’Adulte (GELA) compared 8 cycles of CHOP to doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone (ACVB) plus sequential consolidation in 635 elderly patients (60 to 69 years old) with aggressive lymphoma and at least one adverse prognostic parameter according to the International Prognostic Index. The results showed a similar CR rate (56% v 58%) but a statistically longer event-free survival (39% in the ACVB group and 29% in the CHOP group) and longer overall survival (46% compared to 38%, respectively) at 5 years.15 These results were comparable to a previous study from the GELA, in which ACVB was compared to M-BACOD and resulted in better outcome in patients with adverse prognosis.21
In this issue of the Journal of Clinical Oncology, Blayney et al22 present a phase II study of CHOP-DI (for dose-intense), a regimen with the same drugs of CHOP, but with increased doses of doxorubicin and cyclophosphamide, and with courses repeated every 2 weeks. These modifications resulted in a dose increase of 320% for cyclophosphamide and 190% for doxorubicin (Table 2
The GELA studies used another approach, with four alterations of the CHOP regimen: a sequential consolidation after induction with the modified CHOP regimen, a shortening of the interval between courses to 2 weeks, an increase of doses, and a repeat of nonhematotoxic drugs on day 5 of each course.23 The ACVB regimen was used as standard arm in several randomized studies since 1987 and had shown its superiority over M-BACOD and CHOP for patients with poor risk lymphoma, and equivalence with HDT in patients with good risk lymphoma.15,21,24,25 The Blayney study, together with the French and German studies, suggests that the CHOP regimen may be improved by increasing doses and reducing intervals between cycles. 22 Even if these regimens are associated with a higher hematological toxicity, particularly neutropenia, the infectious risk is not significantly increased, and may be reduced by the use of granulocyte colony-stimulating factor. However, if moving from CHOP to one of these regimens as the future gold standard regimen in patients with aggressive lymphoma was feasible a few years ago, it may be less clinically relevant at present because of the breakthrough of the combination of rituximab and chemotherapy.16 R-CHOP combines CHOP every 3 weeks for 8 cycles with rituximab given on day 1 of each cycle. This regimen is associated with a dramatic increase in the survival of patients, and has been shown to decrease the refractoriness to chemotherapy associated with bcl-2 protein expression.26,27 R-CHOP has become the reference regimen for patients with diffuse large B-cell lymphoma and for other B-cell lymphoma subtypes. However, several questions remain to be answered regarding the combination of chemotherapy and monoclonal antibodies: Is the benefit identical in young patients? Is CHOP the best regimen in combination with rituximab? Do other monoclonal antibodies have the same effect as rituximab? What is the necessary number of rituximab infusions? Can we increase the benefit by using higher doses of chemotherapy? Can we increase the benefit by giving maintenance treatment? Some of these questions will be answered by current studies, but others will have to be addressed in future randomized studies. Thus, current results suggest that CHOP may soon be considered a historical standard because we have several means of improving the results by increasing doses, reducing intervals between cycles, and combining new drugs with different mechanisms of action. But the best combination is not yet known and efforts have to be made to design appropriate randomized studies that will allow us to establish the next gold standard. Entering patients into prospective trials remains the best clinical practice.
REFERENCES 1. DeVita VT, Canellos GP, Chabner B, et al: Advanced diffuse histiocytic lymphoma, a potentially curable disease. Lancet 1:248–250, 1975[CrossRef][Medline] 2. Coltman CA, Dahlberg S, Jones SE. CHOP is curative in thirty percent of patients with large cell lymphoma: a twelve-year Southwest Oncology Group follow-up. In: Skarin A, ed. Update on treatment for diffuse large cell lymphoma. New York, NY: Park Row, 1986:71–77 3. Gordon LI, Harrington D, Andersen J, et al: Comparison of a second-generation combination chemotherapeutic regimen (m-BACOD) with a standard regimen (CHOP) for advanced diffuse non-Hodgkin’s lymphoma. N Engl J Med 327:1342–1349, 1992[Abstract]
4. Fisher RI, Gaynor ER, Dahlberg S, et al: Comparison of a standard regimen (CHOP) with three intensive chemotherapy regimens for advanced non-Hodgkin’s Lymphoma. N Engl J Med 328:1002–1006, 1993
5. Shipp MA, Abeloff MD, Antman KH, et al: International consensus conference on high-dose therapy with hematopoietic stem cell transplantation in aggressive non-hodgkin’s lymphomas: Report of the jury. J Clin Oncol 17:423–429, 1999
6. Gisselbrecht C, Lepage E, Molina T, et al: Shortened first-line high-dose chemotherapy for patients with poor-prognosis aggressive lymphoma. J Clin Oncol 20:2472–2479, 2002
7. Gianni AM, Bregni M, Siena S, et al: High-dose chemotherapy and autologous bone marrow transplantation compared with MACOP-B in aggressive B-cell lymphoma. N Engl J Med 336:1290–1297, 1997
8. Verdonck LF, Vanputten W, Hagenbeek A, et al: Comparison of CHOP chemotherapy with autologous bone marrow transplantation for slowly responding patients with aggressive non-hodgkins lymphoma. N Engl J Med 332:1045–1051, 1995
9. Haioun C, Lepage E, Gisselbrecht C, et al: Survival benefit of high-dose therapy in poor-risk aggressive non-Hodgkin’s lymphoma: Final analysis of the prospective LNH87-2 protocol-A Groupe d’Etude des Lymphomes de l’Adulte Study. J Clin Oncol 18:3025–3030, 2000 10. Bosly A, Lepage E, Coiffier B, et al: Outcome is not improved by the use of alternating chemotherapy in elderly patients with aggressive lymphoma. Hematol J 2:279–285, 2001[CrossRef][Medline] 11. Cooper IA, Wolf MM, Robertson TI, et al: Randomized comparison of MACOP-B with CHOP in patients with intermediate-grade non-Hodgkin’s lymphoma. J Clin Oncol 12:769–778, 1994[Abstract] 12. Gottlieb AJ, Anderson JR, Ginsberg SJ, et al: A randomized comparison of methotrexate dose and the addition of bleomycin to CHOP therapy for diffuse large cell lymphoma and other non-Hodgkin’s lymphomas. Cancer and Leukemia Group B Study 7851. Cancer 66:1888–1896, 1990[CrossRef][Medline] 13. Pfreundschuh M, Trümper L, Kloess M, et al: 2-weekly vs. 3-weekly CHOP with and without etoposide for patients >60 years of age with aggressive non-Hodgkin’s lymphoma: Results of the completed NHL-B-2 trial of the DSHNHL. Blood 100: 774a, 2002 (suppl 1) 14. Pfreundschuh M, Trümper L, Schmits R, et al: 2-weekly vs. 3-weekly CHOP with and without etoposide in young patients with low-risk (low LDH) aggressive non-Hodgkin’s lymphoma: Results of the completed NHL-B-1 trial of the DSHNHL. Blood 100:110a, 2002 (suppl 1) 15. Tilly H, Coiffier B, Casanovas O, et al: Survival advantage of ACVBP regimen over standard CHOP in the treatment of advanced aggressive non-Hodgkin’s lymphoma. The LNH93-5 study. Ann Oncol 13:28, 2002 (Suppl 2)
16. 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 17. Carde P, Meerwaldt JH, van Glabbeke M, et al. Superiority of second over first generation chemotherapy in a randomized trial for stage III-IV intermediate and high-grade non-Hodgkin’s lymphoma (NHL): the 1980–1985 EORTC trial. The EORTC Lymphoma Group. Ann Oncol 6:431–435, 1991 18. Intragumtornchai T, Prayoonwiwat W, Numbenjapon T, et al: CHOP versus CHOP plus ESHAP and high-dose therapy with autologous peripheral blood progenitor cell transplantation for high-intermediate-risk and high-risk aggressive non-Hodgkin’s lymphoma. Clin Lymphoma 1:219–225, 2000[Medline] 19. Linch DC, Smith P, Hancock BW, et al: A randomised British National Lymphoma Investigation trial of CHOP vs. a weekly multi-agent regimen (PACEBOM) in patients with histologically aggressive non-Hodgkin’s lymphoma. Ann Oncol 11:87–90, 2000 (suppl 1)
20. Wolf M, Matthews JP, Stone J, et al: Long-term survival advantage of MACOP-B over CHOP in intermediate-grade non-Hodgkin’s lymphoma. Ann Oncol 8:71–75, 1997
21. Tilly H, Mounier N, Lederlin P, et al: Randomized comparison of ACVBP and m-BACOD in the treatment of patients with low-risk aggressive lymphoma: The LNH87-1 study. J Clin Oncol 18:1309–1315, 2000
22. Blayney DW, LeBlanc ML, Grogan T, et al: Dose intense, every two week chemotherapy (CHOP-DI) may improve survival in intermediate and high grade lymphoma. J Clin Oncol 21:2466–2473, 2003
23. Coiffier B: Fourteen years of high-dose CHOP (ACVB regimen): Preliminary conclusions about the treatment of aggressive-lymphoma patients. Ann Oncol 6:211–217, 1995 24. Coiffier B, Gisselbrecht C, Herbrecht R, et al: LNH-84: a multicenter study of intensive chemotherapy in 737 patients with aggressive malignant lymphoma. J Clin Oncol 7:1018–1026, 1989[Abstract]
25. Haioun C, Lepage E, Gisselbrecht C, et al: Benefit of autologous bone marrow transplantation over sequential chemotherapy in poor-risk aggressive non-Hodgkin’s lymphoma. Updated results of the prospective study Lnh87-2. J Clin Oncol 15:1131–1137, 1997 26. Coiffier B. Treatment of aggressive lymphomas, disseminated cases. ASCO Educational Book, Spring: 606–611, 2003 27. Mounier N, Briere J, Gisselbrecht C, et al: Rituximab plus CHOP (R-CHOP) overcomes bcl-2-associated resistance to chemotherapy in elderly patients with diffuse large B-cell lymphoma (DLBCL). Blood 2003:DOI 10.1182/blood-2002-11-3442 This article has been cited by other articles:
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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