Correspondence
CHOP versus Intensive Regimens in Non-Hodgkin's Lymphoma
N Engl J Med 1993; 329:580-582August 19, 1993
- Article
To the Editor:
Several pieces of data are needed to interpret the conclusion of Fisher et al. (April 8 issue)1 that CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) “remains the best available treatment for patients with advanced-stage intermediate-grade or high-grade non-Hodgkin's lymphoma.” First, how many centers contributed patients, and how many patients did the average center assign to each regimen? The study included 233 patients treated with ProMACE-CytaBOM (prednisone, doxorubicin, cyclophosphamide, and etoposide followed by cytarabine, bleomycin, vincristine, and methotrexate with leucovorin rescue), and the complete-response rate was 56 percent, a level 30 percent lower than that reported by the National Cancer Institute2. The rate of complete response with MACOP-B (methotrexate with leucovorin rescue, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin) was more than 30 percent lower than that reported by O'Reilly et al.3. If 75 to 100 centers contributed patients, then each center contributed about three patients treated with each regimen. Since accrual to the study took place over a five-year period, the average physician treating patients as part of the study may have used each regimen less than once a year.
One explanation offered by cooperative groups for their lower rates of complete response in patients with aggressive lymphoma, as compared with the rates in referral centers, is that their patients have worse prognoses. Though there are counterarguments to this point, the best way to evaluate the issue is to compare the outcome for patients with similar prognostic factors. Fisher et al., however, did not analyze the results for prognostic groups. Their results should be as good as those of the other multicenter and single-institution trials involving patients with similar prognostic factors. The results of an analysis of the Southwest Oncology Group pilot study with ProMACE-CytaBOM did not support the conclusion that the differences in the rates of complete response were due to differences in patient populations4.
Unfortunately, the results with CHOP are not better than those with C-MOPP (cyclophosphamide, vincristine, procarbazine, and prednisone), BACOP (bleomycin, doxorubicin, cyclophosphamide, and vincristine), or COMLA (cyclophosphamide, vincristine, methotrexate with leucovorin rescue, and cytarabine)5. With respect to the patients in the study by Fisher et al. who have been followed for a decade or more, the earlier published data suggest that 30 to 35 percent of those treated with CHOP will survive6. This rate is half as good as the survival rate reported by several other centers with large numbers of patients followed for 6 to 10 years or more. The real danger presented by the report of Fisher et al. is that many physicians may opt to use CHOP in the belief that long-term disease-free survival has been established to be equivalent to that for other published therapies. Indeed, since CHOP was introduced and widely adopted in the mid-1970s, there has been no apparent change in mortality from lymphoma in the United States. This “best available treatment” leaves much room for improvement. It seems unlikely that the continued widespread use of CHOP will result in any decrease in mortality from lymphoma.
6 ReferencesDan L. Longo, M.D.
National Cancer Institute, Frederick, MD 21702Vincent T. DeVita, Jr., M.D.
Memorial Sloan-Kettering Cancer Center, New York, NY 10021Robert C. Young, M.D.
Fox Chase Cancer Center, Philadelphia, PA 191111
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 1993;328:1002-1006
Full Text | Web of Science | Medline2
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 1991;9:25-38
Web of Science | Medline3
O'Reilly SE ,Hoskins P ,Klimo P ,Connors JM . MACOP-B and VACOP-B in diffuse large cell lymphomas and MOPP/ABV in Hodgkin's disease. Ann Oncol 1991;2:Suppl 1:17-23
Web of Science | Medline4
Longo DL ,Duffey PL ,DeVita VT Jr ,Wesley MN ,Hubbard SM ,Young RC . The calculation of actual or received dose intensity: a comparison of published methods. J Clin Oncol 1991;9:2042-2051
Web of Science | Medline5
Armitage JO . Treatment of non-Hodgkin's lymphoma. N Engl J Med 1993;328:1023-1030
Full Text | Web of Science | Medline6
Coltman CA Jr, Dahlberg S, Jones SE, et al. CHOP is curative in thirty percent of patients with large cell lymphoma: a twelve-year Southwest Oncology Group follow-up. In: Skarin AT, ed. Update on treatment for diffuse large cell lymphoma. New York: Park Row, 1986:71-7.
To the Editor:
Although the number of patients with small-noncleaved-cell lymphoma (group J in the working formulation classification1) included in the study by Fisher et al. was small, chemotherapy regimens without central nervous system prophylaxis might be inadequate for such patients. In addition, at least 25 percent of the patients in the study had bone marrow involvement -- a potential risk factor for relapse involving the central nervous system2,3. How many patients had recurrence of disease in the central nervous system, how many of these recurrences were in those with bone marrow involvement, and did the prophylaxis used in the MACOP-B or ProMACE-CytaBOM regimen have significant effect? Finally, do the authors have specific recommendations regarding central nervous system prophylaxis in patients with advanced intermediate-grade or high-grade non-Hodgkin's lymphoma?
3 ReferencesEmile Salloum, M.D.
Mark Levin, M.D.
Metropolitan Hospital Center, New York, NY 100291
The Non-Hodgkin's Lymphoma Pathologic Classification Project
CrossRef | Web of Science | Medline2
Herman TS ,Hammond N ,Jones SE ,Butler JJ ,Byrne GE Jr ,McKelvey EM . Involvement of the central nervous system by non-Hodgkin's lymphoma: the Southwest Oncology Group experience. Cancer 1979;43:390-397
CrossRef | Web of Science | Medline3
Young RC ,Howser DM ,Anderson T ,Fisher RI ,Jaffe E ,DeVita VT Jr . Central nervous system complications of non-Hodgkin's lymphoma: the potential role for prophylactic therapy. Am J Med 1979;66:435-443
CrossRef | Web of Science | Medline
Author/Editor Response
Dr. Fisher replies:
To the Editor: Dr. Longo and colleagues question whether differences between our study -- the National High Priority Lymphoma Study -- and single-institution pilot studies can be explained by the physicians' inexperience with third-generation regimens. This does not appear to be the case. In the randomized study, 1138 patients were treated over a five-year period. The cooperative groups had previously treated 561 additional patients in phase 2-3 trials with these same regimens1,2. Only 94 patients were treated at the National Cancer Institute with ProMACE-CytaBOM in seven years3. Nineteen institutions enrolled more than 10 patients in the randomized trial. When only these institutions were considered, there was no difference among treatment regimens in the length of time to treatment failure (P = 0.68).
A second question concerns the lower rates of complete response. The frequent detection of residual abnormalities on computed tomography or magnetic resonance imaging at restaging makes the determination of complete-response rates very difficult, but we used a very conservative estimate of these rates and selected the length of time to treatment failure as a more reliable end point. Although retrospective comparisons and analysis of subgroups can generate testable hypotheses, we believe that the best way to make definitive comparisons is to conduct randomized trials with large enough numbers of patients to detect important differences, as in this study. Large, randomized trials also tend to ensure the equal distribution of patients with both known and unknown prognostic factors. Furthermore, the patients in our study were not comparable to those in the single-institution ProMACE-CytaBOM study3. The patients in the randomized trial were older (median age, 54 vs. 47 years), did not have low-volume stage II disease, and were more likely to have bulky disease (41 percent vs. 22 percent). Analyses have been conducted for known prognostic factors; we have not identified any subgroup of patients for whom the third-generation regimens provide superior results. The conclusion that CHOP provides equivalent failure-free survival is also supported by all other randomized comparisons of CHOP with any of the third-generation regimens, as we noted. We agree that none of the currently available therapies are effective enough. We urge all investigators to encourage appropriate patients to enter clinical trials evaluating innovative treatment approaches.
We cannot make definite recommendations about central nervous system prophylaxis, as requested by Drs. Salloum and Levin. To date, there is no significant difference in the rate of relapse involving the central nervous system between patients who received such prophylaxis and those who did not. Most such relapses have been accompanied by relapses involving other parts of the body.
3 ReferencesRichard I. Fisher, M.D.
Loyola University Medical Center, Maywood, IL 605211
Fisher RI ,Miller TP ,Dana BW ,Jones SE ,Dahlberg S ,Coltman CA Jr . Southwest Oncology Group clinical trials for intermediate- and high-grade non-Hodgkin's lymphomas. Semin Hematol 1987;24:Suppl 1:21-25
Web of Science | Medline2
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 1992;327:1342-1349
Full Text | Web of Science | Medline3
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 1991;9:25-38
Web of Science | Medline
- Citing Articles (1)
Citing Articles
1
Leonidas G Koniaris, George Drugas, Philip J Katzman, Rabih Salloum. (2003) Management of gastrointestinal lymphoma. Journal of the American College of Surgeons 197:1, 127-141
CrossRef
