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Journal of Clinical Oncology, Vol 26, No 12 (April 20), 2008: pp. 1913-1914 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.13.8172
What Constitutes "Improved Prognosis"?Dana-Farber Cancer Institute, Boston, MA The article, "Improved prognosis of diffuse histiocytic and undifferentiated lymphoma by use of high-dose methotrexate alternating with standard agents (M-BACOD),"1 describes one of several multidrug regimens that were conceived in the 1970s after the demonstration that combination chemotherapy was capable of curing patients with what was then called diffuse histiocytic/undifferentiated lymphoma and now is better known—after multiple classifications—as diffuse large B cell (or T cell) lymphoma. The era of this publication generally preceded immunophenotypic markers. The therapeutic era for combination chemotherapy in diffuse large cell lymphoma, in fact, was launched with the demonstration by the National Cancer Institute (NCI) Bethesda group that cyclophosphamide, vincristine, procarbazine, and prednisone (C-MOPP), a variant of the chemotherapy nitrogen mustard, vincristine, procarbazine, and prednisone (MOPP) regimen for Hodgkin's lymphoma, could induce long-term disease-free survival, which was tantamount to cure.2 In the 1970s, a number of regimens referred to in the discussion were emerging, and all were showing good results in uncontrolled phase II trials. This was the era of cyclophosphamide, vincristine, methotrexate, leucovorin, cytarabine (COMLA; Yale), bleomycin, doxorubicin, cyclophosphamide, vincristine, prednisone (BACOP; NCI), methotrexate, leucovorin, doxorubicin, cyclophosphamide, vincristine, bleomycin, prednisone (MACOP-B; Vancouver), prednisone, doxorubicin, cyclophosphamide, etoposide, cytarabine, bleomycin, vincristine, methotrexate, leucovorin (PRO-MACE-MOPP or CYTO-BOM; NCI), Lymphome non-Hodgkin-80 (Groupe d'Etude des Lymphomes de l'Adulte), and indeed cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP; Southwest Oncology Group).3-8 However, the 1970s and early 1980s were devoid of the histochemical and molecular tools available today for prognostic determinants in diffuse large cell lymphoma. The only exception was probably serum lactic dehydrogenase. The M-BACOD regimen was designed to incorporate high-dose methotrexate with folinic acid rescue during the phase (day 14) of bone marrow suppression secondary to doxorubicin, cyclophosphamide, and vincristine, which were given on day 1 every 21 days for six cycles. The therapeutic lessons of that era are still with us, except that now there is the nonmyelotoxic antiCD20 antibody, rituximab, added to CHOP (CHOP-R) that is the current standard, having been shown to be superior to CHOP alone.9-11 That era taught us, however, the value and need for prospective randomized trials as opposed to institutional phase II trials. The first lesson was to distinguish single-institution trials from cooperative group trials, where the influence of selection bias is less in the latter. Secondly, there was the need to evaluate new regimens against a standard, and in circumstances where patients are matched by stage, age, and other prognostic factors. Those early phase II trials were brought to ground in a prospective randomized trial conducted by Southwest Oncology Group that compared CHOP alone to M-BACOD, MACOP-B, and PROMACE-CYTOBOM. That trial was an important lesson in the field as there was a "standardization" of risk factors built into the randomization.12 As is now well known, that trial failed to show an advantage of the more complicated regimens over CHOP. It is noteworthy that the median age in the M-BACOD trial reported in Journal of Clinical Oncology was 48 years for a disease for which the median age is known to be in the latter part of the sixth decade. The added hope in that trial was that high-dose methotrexate might discourage CNS recurrence because methotrexate readily passes the blood-brain barrier, and given that the incidence of CNS relapse is low in general and more commonly seen with aggressive lymphomas, such as Burkitt's lymphoma and T-lymphoblastic lymphoma. No conclusion could be reached on that issue, but the regimen, M-BACOD, had a life in the later management of AIDS-related diffuse lymphoma.13 The lesson that prognostic factors are important in assessing the impact of a treatment was brought to light in the M-BACOD trial. An analysis of clinical prognostic factors from that trial defined three distinct prognostic groups.14 This observation further led to a multinational analysis of large cell lymphoma involving 2,031 patients. That study resulted in the International Prognostic Index, to which many centers and cooperative groups in North America and Europe contributed.15 This has remained a useful clinical scheme, but in the passage of time the moving edge of molecular biology has been applied to the lymphoma field, resulting in a gene-defined categorization of large B cell lymphoma.16-18 The clinical trial of M-BACOD, as published from the Dana-Farber Cancer Institute, can be said to have generated lessons for the investigators, which, in succeeding years, were instrumental in the design and evaluation of therapeutic results. These lessons include emphasis on the importance of prognostic factors and stratification in clinical trials where randomization entails comparison with standard regimens. An example of current efforts in this area include a comparative evaluation of an NCI-generated infusional chemotherapy regimen of etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin plus rituximab (EPOCH-R) versus a pulse-dose standard CHOP-R in the Cancer and Leukemia Group B.19 Some trials have been designed to study the impact of dose intensification with neutrophil growth factor support.20-22 The interval between cycles has also been abbreviated to every 14 days with the addition of etoposide.23,24 This efficacy must be balanced against the increased toxicity of higher doses and/or shorter intervals between treatments. Another positive spin-off of the high-dose methotrexate studies was the demonstration of its approach in primary CNS lymphoma and its use independent of radiation therapy.25 In conclusion, the M-BACOD trial helped stimulate an understanding of the importance of prognostic factors, highlight the need for randomized trials, and not to be neglected, offer hope for the patients in the knowledge that curative therapy has arrived and is being improved for an otherwise fatal disease. AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: None Consultant or Advisory Role: George P. Canellos, Celgene (C) Stock Ownership: None Honoraria: George P. Canellos, Celgene Research Funding: None Expert Testimony: None Other Remuneration: None REFERENCES 1. Skarin AT, Canellos GP, Rosenthal DS, et al: Improved prognosis of diffuse histiocytic and undifferentiated lymphoma by use of high dose methotrexate alternating with standard agents (M- BACOD). J Clin Oncol 1:91-98, 1983[Abstract] 2. DeVita VT, Canellos GP, Chabner BA, et al: Advanced diffuse histiocytic lymphoma: A potentially curable disease. Lancet 1:248-250, 1975[CrossRef][Medline] 3. Newcomer LN, Cadman EC, Nerenberg MI, et al: Randomized study comparing doxorubicin, cyclophosphamide, vincristine, methotrexate with leucovorin rescue, and cytarabine (ACOMLA) with cyclophosphamide, doxorubicin, vincristine, prednisone, and bleomycin (CHOP-B) in the treatment of diffuse histiocytic lymphoma. Cancer Treat Rep 66:1279-1284, 1982[Medline] 4. Schein PS, DeVita VT Jr, Hubbard S, et al: Bleomycin, adriamycin, cyclophosphamide, vincristine, and prednisone (BACOP) combination chemotherapy in the treatment of advanced diffuse histiocytic lymphoma. Ann Intern Med 85:417-422, 1976 5. Klimo P, Connors JM: MACOP-B chemotherapy for the treatment of diffuse large-cell lymphoma. Ann Intern Med 102:596-602, 1985 6. Longo DL, DeVita VT Jr, Duffey PL, et al: Superiority of ProMACE-CytaBOM over ProMACE-MOPP in the Treatment of advanced diffuse aggressive lymphoma: Results of a prospective randomized trial. J Clin Oncol 9:25-38, 1991 7. Dumontet C, Bastion Y, Felman P, et al: Long-term outcome and sequelae in aggressive lymphoma patients treated with the LNH-80 regimen. Ann Oncol 3:639-644, 1992 8. McKelvey EM, Gottlieb JA, Wilson HE, et al: Hydroxyldaunomycin (Adriamycin) combination chemotherapy in malignant lymphoma. Cancer 38:1484-1493, 1976[CrossRef][Medline] 9. 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 10. Sehn LH, Donalson J, Chhanabhai M, et al: Introduction of combined CHOP plus rituximab therapy dramatically improved outcome of diffuse large B-Cell lymphoma in British Columbia. J Clin Oncol 23:5027-5033, 2005 11. Pfreundschuh M, Trumper L, Osterborg A, et al: CHOP-like chemotherapy plus rituximab versus CHOP-like chemotherapy alone in young patients with good-prognosis diffuse large-B-cell lymphoma: A randomised controlled trial by the MabThera International Trial (MinT) Group. Lancet Oncol 7:379-391, 2006[CrossRef][Medline] 12. 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 13. Levine AM, Tulpule A, Espina B, et al: Low dose methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine, and dexamethasone with zalcitabine in patients with acquired immunodeficiency syndrome-related lymphoma: Effect on human immunodeficiency virus and serum interleukin-6 levels over time Cancer 78:517-526, 1996 14. Shipp MA, Harrington DP, Klatt MM, et al: Identification of major prognostic subgroups of patients with large-cell lymphoma treated with m-BACOD or M-BACOD. Ann Intern Med 104:757-765, 1986 15. The international non-hodgkin's lymphoma prognostic factors project. A predictive model for aggressive non-hodgkin's lymphoma. N Engl J Med 329:987-994, 1993 16. Rosenwald A, Wright G, Chan WC, et al: The use of molecular profiling to predict survival after chemotherapy for diffuse large B-cell lymphoma. N Engl J Med 346:1937-1947, 2002 17. Shipp MA, Ross KN, Tamayo P, et al: Diffuse large B-cell lymphoma outcome prediction by gene-expression profiling and supervised machine learning. Nat Med 8:68-74, 2002[CrossRef][Medline] 18. Lossos IS, Morgensztern D: Prognostic biomarkers in diffuse large B-cell lymphoma. J Clin Oncol 24:995-1007, 2006 19. Wilson WH, Grossbard ML, Pittaluga S, et al: Dose-adjusted EPOCH chemotherapy for untreated large B-cell lymphomas: A pharmacodynamic approach with high efficacy. Blood 99:2685-2693, 2002 20. Shipp MA, Neuberg D, Janicek M, et al: High-dose CHOP as initial therapy for patients with poor-prognosis aggressive non-Hodgkin's lymphoma: A dose-finding pilot study. J Clin Oncol 13:2916-2923, 1995[Abstract] 21. Tilly H, Lepage E, Coiffier B, et al: Intensive conventional chemotherapy (ACVBP regimen) compared with standard CHOP for poor-prognosis aggressive non-Hodgkin lymphoma. Blood 102:4284-4289, 2003 22. Portlock CS, Qin J, Schaindlin P, et al: The NHL-15 protocol for aggressive non-hodgkin's lymphomas: A sequential dose-dense, dose-intense regimen of doxorubicin, vincristine and high-dose cyclophosphamide Ann Oncol 15:1495-1503, 2004 23. Pfreundschuh M, Trumper L, Kloess M, et al: Two-weekly or 3-weekly CHOP chemotherapy with or without etoposide for the treatment of young patients with good-prognosis (normal LDH) aggressive lymphomas: Results of the NHL-B1 Trial of the DSHNHL. Blood 104:626-633, 2004 24. Verdonck LF, Notenboom A, de Jong DD, et al: Intensified 12-week CHOP (I-CHOP) plus G-CSF compared with standard 24-week CHOP (CHOP-21) for patients with intermediate-risk aggressive non-Hodgkin lymphoma: A phase 3 trial of the Dutch-Belgian Hemato-Oncology Cooperative Group (HOVON). Blood 109:2759-2766, 2007 25. Skarin AT, Zuckerman KS, Pitman SW, et al: High-dose methotrexate with folinic acid in the treatment of advanced non-Hodgkin lymphoma including CNS involvement. Blood 50:1039-1047, 1977
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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