What constitutes "improved prognosis"?

The article, “Improved prognosis of diffuse histiocytic and undifferentiated lymphoma by use of high-dose methotrexate alternating with standard agents (M-BACOD),” 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 diseasefree survival, which was tantamount to cure. 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). 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. 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. 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 AIDSrelated diffuse lymphoma. 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. 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. 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 genedefined categorization of large B cell lymphoma. The clinical trial of M-BACOD, as published from the DanaFarber 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. JOURNAL OF CLINICAL ONCOLOGY C E L E B R A T I N G 2 5 Y E A R S O F J C O VOLUME 26 NUMBER 12 APRIL 2