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Editorial Reviews
From The New England Journal of Medicine
Consistency is the last refuge of the unimaginative. -- Oscar Wilde Astonishing progress has been made over the past few years in our understanding of the pathogenesis and biology of non-Hodgkin's lymphomas, and many new and effective treatments for these tumors have become available -- more than for almost any other form of cancer. There are at least 30 different entities referred to as non-Hodgkin's lymphomas, and they range from the indolent to the very aggressive. Taken together, the non-Hodgkin's lymphomas are the fifth most common cancers in the United States and the fifth leading cause of death due to cancer. They are among the few cancers whose incidence is increasing in the United States, for reasons that are not well understood. It is in the context of this rapidly evolving field that a new book, Non-Hodgkin's Lymphomas, appears. Each of its editors is a world-renowned leader in the biology, classification, or treatment of lymphomas. A particular strength of the book is the many chapters written collaboratively by clinicians, pathologists, and translational researchers. For this reason alone, the book is an exceptional resource for hematologists and oncologists, radiation oncologists, trainees, and students. The extremely well written and comprehensive chapters reveal a clear view of the history and current status of non-Hodgkin's lymphomas. They cover the epidemiology, pathogenesis, and biology of these disorders, diagnosis, staging, new imaging techniques, treatment planning, approaches to treatment, and the late effects of therapy. Although there is, as yet, no known cause for most types of non-Hodgkin's lymphoma, an increasing number of infectious agents have been implicated, and in cases in which such an agent can be identified, appropriate antimicrobial therapy resolves the tumors. This observation adds weight to experiments conducted decades ago, which showed that long-term immunostimulation can result in lymphomas (M.Y.K. Armstrong, et al. "Chronic Allogeneic Disease: II." Journal of Experimental Medicine 1960;132:417-39). Physicians who treat lymphomas have been frustrated by the marked variability in responsiveness of tumors that appear quite similar under the microscope. Gene-expression profiling has now demonstrated important differences within diffuse large-B-cell non-Hodgkin's lymphomas and, more recently, follicular non-Hodgkin's lymphomas that predict outcome (see Figure) (A. Rosenwald, et al. "The Use of Molecular Profiling to Predict Survival after Chemotherapy for Large-B-Cell Lymphoma." New England Journal of Medicine 2002;346:1937-47). Indeed, the genetic signature of primary mediastinal B-cell non-Hodgkin's lymphoma is more closely related to the disease it resembles clinically, Hodgkin's lymphoma, than to other diffuse large-B-cell lymphomas. The recent improvements in treatment have been facilitated by a new, universally accepted scheme for the classification of lymphomas, the systematic assessment of clinically relevant prognostic factors, and more sensitive methods of appraising responses to treatment. The Working Formulation categorized non-Hodgkin's lymphomas into low-grade, intermediate-grade, and high-grade types; this system, however, was not clinically useful and did not include a number of subtypes that were recognized only later. In 1994, the Revised European-American Lymphoma classification, more recently modified into the classification of the World Health Organization (N.L. Harris, et al. "World Health Organization Classification of Neoplastic Diseases of the Hematopoietic and Lymphoid Tissues." Journal of Clinical Oncology 1999;17:3835-49), used morphology, immunophenotype, genetics, and clinical features to distinguish the various subtypes. The International Prognostic Index used routine clinical and laboratory features to categorize patients with diffuse large-B-cell non-Hodgkin's lymphomas into meaningful risk groups, thus permitting comparisons among clinical trials and potentially influencing management decisions. An international prognostic index for follicular lymphomas separates these lymphomas into risk groups, but both of these indexes will probably be replaced by a system based on genetic profiling and the functions of relevant genes. Positron-emission tomography has improved the sensitivity of the monitoring of disease and will be incorporated into revised criteria for evaluating responses to treatment. The discovery that small lymphocytic lymphoma-chronic lymphocytic leukemia can be divided into two entities according to the mutational status of immunoglobulin V genes was important. Recent studies have shown that the more available assay for zeta-associated protein-70 (ZAP-70) may be a more important predictor of survival and a possible surrogate for gene-mutational studies (L.Z. Rassenti, et al. "ZAP-70 Compared with Immunoglobulin Heavy-Chain Gene Mutation Status as a Predictor of Disease Progression in Chronic Lymphocytic Leukemia." New England Journal of Medicine 2004;351:893-901). How these various factors, in conjunction with the analysis of chromosomes, might predict outcome is being evaluated in prospective trials. The obvious goal is to use this information to determine when and how patients should be treated. For decades, resources for research on non-Hodgkin's lymphoma were squandered on the study of mundane, empirical combinations of nonspecific cytotoxic drugs. We are witnessing a revolution sparked by targeted therapies, notably the chimeric anti-CD20 monoclonal antibody rituximab, which is now used in virtually all patients with B-cell lymphomas. The encouraging preliminary data on treatment with the antibody alone have now been validated by randomized trials, and the addition of rituximab to chemotherapy has increased the cure rate for patients with diffuse large-B-cell lymphoma (B. Coiffier, et al. "CHOP Chemotherapy plus Rituximab Compared with CHOP Alone in Elderly Patients with Diffuse Large-B-Cell Lymphoma." New England Journal of Medicine 2002;346:235-42). Similar combinations have improved the response rate and prolonged time to progression in follicular lymphoma, although the confirmation of prolonged survival requires longer follow-up. Despite these advances, we now run the risk of relapsing into a state of ennui in regard to clinical trials by repeatedly testing one chemotherapy regimen with rituximab merely against another with the same antibody. It is time for imagination and creativity to come into play. When a patient's lymphoma fails to respond to a standard therapy, the message should be that the tumor is not what we think it is but a different disease requiring a new approach. A primary goal of lymphoma research should be to tailor the therapy to each patient with the use of microarray technology and guided by receptor polymorphisms and overexpression of various oncogenes. The future of treatment for lymphoma lies in the rational development of combinations of agents with specific targets in or on the tumor cell. Non-Hodgkin's Lymphomas should convince the reader that, not only have we the ammunition to load up our therapeutic arsenal with Paul Ehrlich's magic bullets, but we will soon hit the bull's-eye. Bruce D. Cheson, M.D.
Copyright © 2004 Massachusetts Medical Society. All rights reserved. The New England Journal of Medicine is a registered trademark of the MMS.
Review
See all Editorial Reviews
Consistency is the last refuge of the unimaginative. -- Oscar Wilde Astonishing progress has been made over the past few years in our understanding of the pathogenesis and biology of non-Hodgkin's lymphomas, and many new and effective treatments for these tumors have become available -- more than for almost any other form of cancer. There are at least 30 different entities referred to as non-Hodgkin's lymphomas, and they range from the indolent to the very aggressive. Taken together, the non-Hodgkin's lymphomas are the fifth most common cancers in the United States and the fifth leading cause of death due to cancer. They are among the few cancers whose incidence is increasing in the United States, for reasons that are not well understood. It is in the context of this rapidly evolving field that a new book, Non-Hodgkin's Lymphomas, appears. Each of its editors is a world-renowned leader in the biology, classification, or treatment of lymphomas. A particular strength of the book is the many chapters written collaboratively by clinicians, pathologists, and translational researchers. For this reason alone, the book is an exceptional resource for hematologists and oncologists, radiation oncologists, trainees, and students. The extremely well written and comprehensive chapters reveal a clear view of the history and current status of non-Hodgkin's lymphomas. They cover the epidemiology, pathogenesis, and biology of these disorders, diagnosis, staging, new imaging techniques, treatment planning, approaches to treatment, and the late effects of therapy. Although there is, as yet, no known cause for most types of non-Hodgkin's lymphoma, an increasing number of infectious agents have been implicated, and in cases in which such an agent can be identified, appropriate antimicrobial therapy resolves the tumors. This observation adds weight to experiments conducted decades ago, which showed that long-term immunostimulation can result in lymphomas (M.Y.K. Armstrong, et al. "Chronic Allogeneic Disease: II." Journal of Experimental Medicine 1960;132:417-39). Physicians who treat lymphomas have been frustrated by the marked variability in responsiveness of tumors that appear quite similar under the microscope. Gene-expression profiling has now demonstrated important differences within diffuse large-B-cell non-Hodgkin's lymphomas and, more recently, follicular non-Hodgkin's lymphomas that predict outcome (see Figure) (A. Rosenwald, et al. "The Use of Molecular Profiling to Predict Survival after Chemotherapy for Large-B-Cell Lymphoma." New England Journal of Medicine 2002;346:1937-47). Indeed, the genetic signature of primary mediastinal B-cell non-Hodgkin's lymphoma is more closely related to the disease it resembles clinically, Hodgkin's lymphoma, than to other diffuse large-B-cell lymphomas. The recent improvements in treatment have been facilitated by a new, universally accepted scheme for the classification of lymphomas, the systematic assessment of clinically relevant prognostic factors, and more sensitive methods of appraising responses to treatment. The Working Formulation categorized non-Hodgkin's lymphomas into low-grade, intermediate-grade, and high-grade types; this system, however, was not clinically useful and did not include a number of subtypes that were recognized only later. In 1994, the Revised European-American Lymphoma classification, more recently modified into the classification of the World Health Organization (N.L. Harris, et al. "World Health Organization Classification of Neoplastic Diseases of the Hematopoietic and Lymphoid Tissues." Journal of Clinical Oncology 1999;17:3835-49), used morphology, immunophenotype, genetics, and clinical features to distinguish the various subtypes. The International Prognostic Index used routine clinical and laboratory features to categorize patients with diffuse large-B-cell non-Hodgkin's lymphomas into meaningful risk groups, thus permitting comparisons among clinical trials and potentially influencing management decisions. An international prognostic index for follicular lymphomas separates these lymphomas into risk groups, but both of these indexes will probably be replaced by a system based on genetic profiling and the functions of relevant genes. Positron-emission tomography has improved the sensitivity of the monitoring of disease and will be incorporated into revised criteria for evaluating responses to treatment. The discovery that small lymphocytic lymphoma-chronic lymphocytic leukemia can be divided into two entities according to the mutational status of immunoglobulin V genes was important. Recent studies have shown that the more available assay for zeta-associated protein-70 (ZAP-70) may be a more important predictor of survival and a possible surrogate for gene-mutational studies (L.Z. Rassenti, et al. "ZAP-70 Compared with Immunoglobulin Heavy-Chain Gene Mutation Status as a Predictor of Disease Progression in Chronic Lymphocytic Leukemia." New England Journal of Medicine 2004;351:893-901). How these various factors, in conjunction with the analysis of chromosomes, might predict outcome is being evaluated in prospective trials. The obvious goal is to use this information to determine when and how patients should be treated. For decades, resources for research on non-Hodgkin's lymphoma were squandered on the study of mundane, empirical combinations of nonspecific cytotoxic drugs. We are witnessing a revolution sparked by targeted therapies, notably the chimeric anti-CD20 monoclonal antibody rituximab, which is now used in virtually all patients with B-cell lymphomas. The encouraging preliminary data on treatment with the antibody alone have now been validated by randomized trials, and the addition of rituximab to chemotherapy has increased the cure rate for patients with diffuse large-B-cell lymphoma (B. Coiffier, et al. "CHOP Chemotherapy plus Rituximab Compared with CHOP Alone in Elderly Patients with Diffuse Large-B-Cell Lymphoma." New England Journal of Medicine 2002;346:235-42). Similar combinations have improved the response rate and prolonged time to progression in follicular lymphoma, although the confirmation of prolonged survival requires longer follow-up. Despite these advances, we now run the risk of relapsing into a state of ennui in regard to clinical trials by repeatedly testing one chemotherapy regimen with rituximab merely against another with the same antibody. It is time for imagination and creativity to come into play. When a patient's lymphoma fails to respond to a standard therapy, the message should be that the tumor is not what we think it is but a different disease requiring a new approach. A primary goal of lymphoma research should be to tailor the therapy to each patient with the use of microarray technology and guided by receptor polymorphisms and overexpression of various oncogenes. The future of treatment for lymphoma lies in the rational development of combinations of agents with specific targets in or on the tumor cell. Non-Hodgkin's Lymphomas should convince the reader that, not only have we the ammunition to load up our therapeutic arsenal with Paul Ehrlich's magic bullets, but we will soon hit the bull's-eye. Bruce D. Cheson, M.D.
Copyright © 2004 Massachusetts Medical Society. All rights reserved. The New England Journal of Medicine is a registered trademark of the MMS.
Review
American Journal of Surgical Pathology, Volume 29, Issue 1 -- "With this impressive list of contributors, one is not disappointed in the quality of this comprehensive text. This textbook is an essential addition to the library of anyone who wishes to gain a clear view of non-Hodgkin lymphoma as a whole: pathology, genetics, and management principles."—American Journal of Surgical Pathology
See all Editorial Reviews
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- The Journey Through Cancer: An Oncologist's Seven-Level Program for Healing and Transforming the Whole Person by Jeremy R. Geffen in Back Matter
- Abdominal Surgery of Infancy and Childhood by Willliam L Donnellan on page 653
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