Who Should Receive Myeloablative Therapy for Lymphoma?
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《新英格兰医药杂志》
The lymphomas are a heterogeneous group of cancers of the lymphoid system that are of increasing importance to the medical community. There has been a threefold increase in the incidence of these tumors for reasons that are incompletely understood, and the effect of therapy on the natural history of lymphomas has been dramatic. Without treatment, these disorders are almost invariably fatal — survival is measured in months to years, depending on the subtype. But most patients will benefit from irradiation, chemotherapy, biologic therapy, or combinations of these approaches, even if only transiently, and a proportion of them will be cured.
Irradiation was first used to treat lymphomas at the turn of the 20th century. By the middle of the century, it was clear that this form of treatment cured some patients with localized lymphadenopathy, especially those with Hodgkin's disease. Most patients, however — particularly those with non-Hodgkin's lymphoma — present with widespread adenopathy for which irradiation may provide valuable palliation but no more. The successive demonstrations that alkylating agents such as nitrogen mustard or cyclophosphamide, then vinca (periwinkle) alkaloids, and subsequently other types of cytotoxic compounds could, when administered in low doses over the long term, increase well-being and reduce lymphadenopathy in up to 50 percent of cases across the spectrum of lymphomas led to the intensification of treatment through combination chemotherapy, which had dramatic results. Randomized clinical trials were not necessary in order to convince physicians that four antitumor drugs administered cyclically at intervals of approximately four to six weeks would lead to the complete remission of Hodgkin's disease, even in patients with advanced disease. Long follow-up has indicated that half the patients who enter a complete remission are probably cured. Similar, though not quite as impressive, results were obtained in the 1970s in two small series of patients with aggressive non-Hodgkin's lymphoma (most cases of which would probably be categorized today as diffuse large-B-cell lymphoma, according to the clarification of the World Health Organization). Not long thereafter, the value of adding an anthracycline to the regimen became evident, and the CHOP regimen (cyclophosphamide, doxorubicin, vincristine, and prednisone) became established as the treatment of choice for aggressive non-Hodgkin's lymphoma, curing perhaps a third of younger patients.
Further intensification of treatment was investigated in trials in which more drugs were added to the regimen and the schedule of treatment was modified; this approach had provocative results in single-center phase 2 trials, but they were not borne out in a large phase 3 study conducted by the Southwestern Oncology Group. By default, CHOP was considered the "best" therapy for newly diagnosed aggressive lymphoma in the 1990s. Much more intensification, with the use of autologous hematopoietic stem-cell rescue to overcome drug-induced myeloablation (the primary dose-limiting toxic effect of chemotherapy), was shown to prolong survival and even to cure a proportion of patients who had had a recurrence of aggressive, high-risk, but chemosensitive lymphoma. Confirmation of these single-center phase 2 trials came in the form of a small randomized trial, which established myeloablative chemotherapy with peripheral-blood hematopoietic stem-cell rescue as the treatment of choice for patients with high-risk, aggressive lymphoma who, after a first relapse, had had successful reinduction therapy and were thus eligible for very intensive treatment.
It is not yet clear whether this success with aggressive lymphoma in patients who have had a relapse can be extrapolated to patients who are in a first remission after CHOP therapy but who have a high risk of recurrence, according to the international prognostic index, or to patients in whom a response to initial treatment was hard to achieve. As a result, the argument in favor of early high-dose therapy for patients with high-risk, aggressive lymphoma is not overwhelming.
In this issue of the Journal, Milpied et al. (pages 1287–1295) report an advantage of early intensive myeloablative therapy over CHOP in terms of event-free survival among patients with aggressive lymphoma considered to be of low-to-intermediate risk. This result is entirely in keeping with expectations. It seems logical that the group that is most likely to benefit from an intensification of therapy would include patients who have been nearly cured with conventional-dose therapy and can be pushed toward cure by very intensive therapy. The results constitute a modest advance, and it is questionable whether they justify recommending such therapy for all patients with diffuse large-B-cell lymphoma of low-to-intermediate risk. Clearly, at least two thirds of the patients who have been cured in this way would have been cured with CHOP alone and were therefore overtreated, with an approach that must be associated with greater short-term and long-term morbidity and mortality. Such overtreatment cannot be good for the individual patient or for the health care system. Better prognostic indexes are needed — and may soon be at hand, with the aid of molecular technology.
As Milpied et al. themselves point out, in determining how to act on their results, we must remember that CHOP is no longer the gold standard for the treatment of the most common of the aggressive lymphomas, diffuse large-B-cell lymphoma. The combination of anti-CD20 (rituximab) and CHOP has been shown to be superior to CHOP alone in both older and younger patients with non-Hodgkin's lymphoma; chemoimmunotherapy is becoming the order of the day. Shortening the interval between cycles of CHOP by a week (from 21 days to 14 days) is also finding favor. What result would have been obtained had Milpied et al. compared CHOP plus rituximab administered every 14 days with myeloablative therapy? Is myeloablative therapy appropriate for the substantial proportion of patients who present in later life with coexisting conditions?
The answers to these questions notwithstanding, this critique does not devalue the relevance of the data presented by Milpied et al. These investigators have shown that considerable intensification of treatment is feasible for most patients with aggressive lymphoma of low-to-intermediate risk and that the fraction of patients who are cured may well be increased. It is incumbent on us to build on this information, in the context of the new treatments available today and our new tools for understanding the nature and prognoses of this heterogeneous group of diseases, so that we can continue to make incremental improvements in care.
Source Information
From the Department of Medical Oncology, St. Bartholomew's Hospital, London.
Related Letters:
Intensive Therapy for Aggressive Lymphoma
Aguiar Bujanda D., Bohn Sarmiento U., Aguiar Morales J., Bola?os-Meade J., Herishanu Y., Zomas A., Skandalis A., Milpied N.(T. Andrew Lister, M.D.)
Irradiation was first used to treat lymphomas at the turn of the 20th century. By the middle of the century, it was clear that this form of treatment cured some patients with localized lymphadenopathy, especially those with Hodgkin's disease. Most patients, however — particularly those with non-Hodgkin's lymphoma — present with widespread adenopathy for which irradiation may provide valuable palliation but no more. The successive demonstrations that alkylating agents such as nitrogen mustard or cyclophosphamide, then vinca (periwinkle) alkaloids, and subsequently other types of cytotoxic compounds could, when administered in low doses over the long term, increase well-being and reduce lymphadenopathy in up to 50 percent of cases across the spectrum of lymphomas led to the intensification of treatment through combination chemotherapy, which had dramatic results. Randomized clinical trials were not necessary in order to convince physicians that four antitumor drugs administered cyclically at intervals of approximately four to six weeks would lead to the complete remission of Hodgkin's disease, even in patients with advanced disease. Long follow-up has indicated that half the patients who enter a complete remission are probably cured. Similar, though not quite as impressive, results were obtained in the 1970s in two small series of patients with aggressive non-Hodgkin's lymphoma (most cases of which would probably be categorized today as diffuse large-B-cell lymphoma, according to the clarification of the World Health Organization). Not long thereafter, the value of adding an anthracycline to the regimen became evident, and the CHOP regimen (cyclophosphamide, doxorubicin, vincristine, and prednisone) became established as the treatment of choice for aggressive non-Hodgkin's lymphoma, curing perhaps a third of younger patients.
Further intensification of treatment was investigated in trials in which more drugs were added to the regimen and the schedule of treatment was modified; this approach had provocative results in single-center phase 2 trials, but they were not borne out in a large phase 3 study conducted by the Southwestern Oncology Group. By default, CHOP was considered the "best" therapy for newly diagnosed aggressive lymphoma in the 1990s. Much more intensification, with the use of autologous hematopoietic stem-cell rescue to overcome drug-induced myeloablation (the primary dose-limiting toxic effect of chemotherapy), was shown to prolong survival and even to cure a proportion of patients who had had a recurrence of aggressive, high-risk, but chemosensitive lymphoma. Confirmation of these single-center phase 2 trials came in the form of a small randomized trial, which established myeloablative chemotherapy with peripheral-blood hematopoietic stem-cell rescue as the treatment of choice for patients with high-risk, aggressive lymphoma who, after a first relapse, had had successful reinduction therapy and were thus eligible for very intensive treatment.
It is not yet clear whether this success with aggressive lymphoma in patients who have had a relapse can be extrapolated to patients who are in a first remission after CHOP therapy but who have a high risk of recurrence, according to the international prognostic index, or to patients in whom a response to initial treatment was hard to achieve. As a result, the argument in favor of early high-dose therapy for patients with high-risk, aggressive lymphoma is not overwhelming.
In this issue of the Journal, Milpied et al. (pages 1287–1295) report an advantage of early intensive myeloablative therapy over CHOP in terms of event-free survival among patients with aggressive lymphoma considered to be of low-to-intermediate risk. This result is entirely in keeping with expectations. It seems logical that the group that is most likely to benefit from an intensification of therapy would include patients who have been nearly cured with conventional-dose therapy and can be pushed toward cure by very intensive therapy. The results constitute a modest advance, and it is questionable whether they justify recommending such therapy for all patients with diffuse large-B-cell lymphoma of low-to-intermediate risk. Clearly, at least two thirds of the patients who have been cured in this way would have been cured with CHOP alone and were therefore overtreated, with an approach that must be associated with greater short-term and long-term morbidity and mortality. Such overtreatment cannot be good for the individual patient or for the health care system. Better prognostic indexes are needed — and may soon be at hand, with the aid of molecular technology.
As Milpied et al. themselves point out, in determining how to act on their results, we must remember that CHOP is no longer the gold standard for the treatment of the most common of the aggressive lymphomas, diffuse large-B-cell lymphoma. The combination of anti-CD20 (rituximab) and CHOP has been shown to be superior to CHOP alone in both older and younger patients with non-Hodgkin's lymphoma; chemoimmunotherapy is becoming the order of the day. Shortening the interval between cycles of CHOP by a week (from 21 days to 14 days) is also finding favor. What result would have been obtained had Milpied et al. compared CHOP plus rituximab administered every 14 days with myeloablative therapy? Is myeloablative therapy appropriate for the substantial proportion of patients who present in later life with coexisting conditions?
The answers to these questions notwithstanding, this critique does not devalue the relevance of the data presented by Milpied et al. These investigators have shown that considerable intensification of treatment is feasible for most patients with aggressive lymphoma of low-to-intermediate risk and that the fraction of patients who are cured may well be increased. It is incumbent on us to build on this information, in the context of the new treatments available today and our new tools for understanding the nature and prognoses of this heterogeneous group of diseases, so that we can continue to make incremental improvements in care.
Source Information
From the Department of Medical Oncology, St. Bartholomew's Hospital, London.
Related Letters:
Intensive Therapy for Aggressive Lymphoma
Aguiar Bujanda D., Bohn Sarmiento U., Aguiar Morales J., Bola?os-Meade J., Herishanu Y., Zomas A., Skandalis A., Milpied N.(T. Andrew Lister, M.D.)