Correspondence
Treatment of Intermediate-Grade and High-Grade Non-Hodgkin's Lymphoma
N Engl J Med 1998; 339:1475-1477November 12, 1998
- Article
To the Editor:
Miller et al. (July 2 issue)1 are to be commended on their report of the randomized trial comparing full-dose chemotherapy with limited chemotherapy and involved-field radiation for the treatment of localized intermediate-grade and high-grade non-Hodgkin's lymphoma. Previously, the management of this condition with chemotherapy and radiotherapy has been based on retrospective reports and small phase 2 studies and has been the subject of some controversy.2
Miller et al. demonstrated that three cycles of chemotherapy followed by involved-field radiotherapy, as compared with eight cycles of chemotherapy alone, resulted in an improvement of 10 percentage points in the estimated five-year overall survival (P=0.02). Furthermore, the estimated progression-free survival at five years was 13 percentage points higher in the combined-treatment group than in the group assigned to chemotherapy alone (P= 0.03), a difference that corresponded to 20 fewer patients with progression. However, as defined in this study, the calculation of progression-free survival included deaths from all causes, and consequently, part of the observed difference in progression-free survival is due to the additional five deaths from cardiac causes in the group assigned to chemotherapy alone. It remains unclear how much of the remaining difference was accounted for by other deaths that were not due to lymphoma and whether the increase in progression-free survival remains statistically significant after the exclusion of patients who died in complete remission.
It would be helpful to have data clarifying the relative efficacy of the two treatments with respect to the prevention of disease progression. Further information on the causes of death and the types of progression and a statistical comparison of the time to disease progression would address this concern. We believe that the case for the routine use of combined treatment would be further strengthened if it could be shown that such treatment is both less toxic and more effective in preventing disease progression than chemotherapy alone.
2 ReferencesAndrew Wirth, M.B., B.S.
H. Miles Prince, M.B., B.S., M.D.
Max Wolf, M.B., B.S.
Peter MacCallum Cancer Institute, Victoria 3000, Australia1
Miller TP ,Dahlberg S ,Cassady JR , et al. Chemotherapy alone compared with chemotherapy plus radiotherapy for localized intermediate- and high-grade non-Hodgkin's lymphoma. N Engl J Med 1998;339:21-26
Full Text | Web of Science | Medline2
Cosset JM . Chemoradiotherapy for localized non-Hodgkin's lymphoma. N Engl J Med 1998;339:44-45
Full Text | Web of Science | Medline
To the Editor:
Miller et al. suggest that a regimen of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) in combination with radiotherapy was superior to CHOP alone in patients with localized intermediate-grade or high-grade non-Hodgkin's lymphoma. Their results provide valuable information on what constitutes adequate treatment for localized non-Hodgkin's lymphoma.
However, we have some issues of concern about the study. The median age of the patients was 59 years, which is old. Older patients tolerate intensive chemotherapy poorly, and it is difficult for them to complete the full course of treatment.1 Of the 201 patients who were assigned to CHOP therapy alone, 28 did not complete the treatment and dropped out of the study. In contrast, only 3 of the 200 patients who were assigned to the combination of CHOP and radiotherapy dropped out of the study. This difference is statistically significant (P<0.001) and suggests that eight cycles of CHOP therapy is inappropriate for older patients. Moreover, the large difference in dropout rates between the two groups makes it impossible to evaluate the efficacy of local radiotherapy in this trial.
1 ReferencesUtako Machida, M.D.
Masahiro Kami, M.D.
Hisamaru Hirai, M.D.
University of Tokyo, Tokyo 113, Japan1
Dixon DO ,Neilan B ,Jones SE , et al. Effect of age on therapeutic outcome in advanced diffuse histiocytic lymphoma: the Southwest Oncology Group experience. J Clin Oncol 1986;4:295-305
Web of Science | Medline
To the Editor:
The conclusions of Miller et al. that three cycles of CHOP followed by involved-field radiotherapy are superior to eight cycles of CHOP alone as treatment for localized stages of aggressive non-Hodgkin's lymphoma seem statistically misleading. As they noted, late complications may become manifest in time and relapses may also occur. In our experience as part of the French Groupe d'Etude des Lymphomes de l'Adulte, the risk of death in these patients after the 5th year is still about 3 percent a year, suggesting that follow-up will have to last more than 10 years in order to yield definitive data on survival.1,2 In the study by Miller et al., the median follow-up of 4.4 years and the convergent overall survival curves suggest that these results represent an interim analysis. If so, a P value of much less than 0.05 should be used to indicate statistical significance. In particular, if two subsequent analyses were planned, the P value would have to be set at 0.02. For this reason, the observed differences in progression-free survival (P=0.03) and overall survival (P=0.02) cannot be considered statistically significant.3
Moreover, patient characteristics such as age and tumor immunophenotype can strongly influence the outcome of both induction and salvage treatments.4 Standard univariate analysis of randomized trials is not designed to account for such confounding factors. A more informative solution would have been to include the set of covariates in a Cox regression model, investigate stability with respect to the inclusion of interactions between treatment and covariates, and thus evaluate the effect of therapy after adjustment for major adverse factors. Instead, the authors used the international prognostic index that was modified according to the stage of localized aggressive non-Hodgkin's lymphoma. This interesting approach allowed them to identify the low survival rate among higher-risk patients. However, the model should have been used only after external validation or, at least, data splitting or a bootstrap resampling procedure.5
5 ReferencesNicolas Mounier, M.D.
Centre Hospitalier Universitaire Henri Mondor, 94010 Creteil, FranceChristian Gisselbrecht, M.D.
Centre Hospitalier Universitaire Saint Louis, 75010 Paris, FranceEric Lepage, M.D., Ph.D.
Centre Hospitalier Universitaire Henri Mondor, 94010 Creteil, France1
Mounier N ,Morel P ,Haioun C , et al. A multivariate analysis of the survival of patients with aggressive lymphoma: variations in the predictive value of prognostic factors during the course of the disease. Cancer 1998;82:1952-1962
CrossRef | Web of Science | Medline2
Coiffier B . Fourteen years of high-dose CHOP (ACVB regimen): preliminary conclusions about the treatment of aggressive-lymphoma patients. Ann Oncol 1995;6:211-217
Web of Science | Medline3
Armitage P ,McPherson K ,Rowe BC . Repeated significance test on accumulative data. J R Stat Soc [A] 1969;132:235-244
CrossRef | Web of Science4
Gisselbrecht C ,Gaulard P ,Lepage E , et al. Prognostic significance of T-cell phenotype in aggressive non-Hodgkin's lymphomas. Blood 1998;92:76-82
Web of Science | Medline5
Sauerbrei W ,Schumacher M . A bootstrap resampling procedure for model building: application to the Cox regression model. Stat Med 1992;11:2093-2109
CrossRef | Web of Science | Medline
To the Editor:
Miller et al. report the results of what is to our knowledge the largest prospective, randomized study conducted so far comparing a standard regimen of CHOP (eight courses) with three courses of CHOP supplemented by radiotherapy in patients with localized (stage I to II) intermediate-grade and high-grade non-Hodgkin's lymphoma. The conclusions favor the use of radiotherapy after three courses of CHOP. However, many issues must be addressed before the results can be accepted as a standard of care.
No data are provided regarding analysis of the intensity of the dose in the treatment groups during the first three cycles of CHOP. It seems from the data on hematologic toxicity that more patients who received eight courses of CHOP had grade 4 neutropenia (71, as compared with 54 in the combined-treatment group), and given that therapy with colony-stimulating factors was not allowed, these patients must have had more frequent dose reductions than patients in the combined-treatment group.
Patients with stage I or IE bulky disease were allowed to enter the study, since it is believed that they do better when radiotherapy is incorporated into the treatment plan.1 The inclusion of these patients may have biased the results in favor of the combined-treatment group.
Another problem is that 10 percent of the patients had follicular large-cell lymphoma and 6 percent had diffuse small-noncleaved-cell lymphoma. It is currently unknown whether the addition of radiotherapy improves the outcome of patients with follicular large-cell lymphoma, and in general, patients with small-noncleaved-cell lymphoma do poorly with standard chemotherapy regimens. Small-noncleaved-cell lymphomas can be cured by brief courses of high-intensity chemotherapy together with intrathecal prophylaxis.2 Clearly, radiotherapy has no role in the treatment of patients with even localized small-noncleaved-cell lymphoma. Patients with these two subtypes should not be mixed with other patients with intermediate-grade or high-grade non-Hodgkin's lymphoma in clinical trials.
2 ReferencesChristos Kosmas, M.D.
Nikolaos A. Malamos, M.D.
Minas J. Antonopoulos, M.D.
Helena Venizelou Hospital, 115 21 Athens, Greece1
Glick JH ,Kim K ,Earle J ,O'Connell MJ . An ECOG randomized phase III trial of CHOP vs. CHOP + radiotherapy for intermediate grade early stage non-Hodgkin's lymphoma. Prog Proc Am Soc Clin Oncol 1995;14:391-391 abstract.2
Magrath I ,Adde M ,Shad A , et al. Adults and children with small-noncleaved-cell lymphoma have a similar excellent outcome when treated with the same chemotherapy regimen. J Clin Oncol 1996;14:925-934
Web of Science | Medline
To the Editor:
In the Discussion section of their article, Miller and colleagues did not address several points. Although the standard curative dose of radiotherapy for non-Hodgkin's lymphoma is approximately 4000 cGy,1 the majority of patients in the study received 4500 to 5000 cGy, which suggests that there was heterogeneity in the radiation doses. Because of the late toxic effects of radiotherapy, particularly coronary artery disease and secondary solid tumors,2,3 it is important to define the optimal doses of radiation for localized non-Hodgkin's lymphoma. Is an increase in the dose of radiotherapy by 20 to 25 percent justified in order to decrease safely the number of chemotherapy courses? Similarly, would not four or six courses of CHOP without radiotherapy be sufficient to cure patients with a small tumor mass?
3 ReferencesDidier Decaudin, M.D., Ph.D.
Institut Curie, 75248 Paris, France1
Cosset JM . Chemoradiotherapy for localized non-Hodgkin's lymphoma. N Engl J Med 1998;339:44-45
Full Text | Web of Science | Medline2
Gustavsson A ,Eskilsson J ,Landberg T , et al. Late cardiac effects after mantle radiotherapy in patients with Hodgkin's disease. Ann Oncol 1990;1:355-363
Web of Science | Medline3
Henry-Amar M . Second cancer after the treatment for Hodgkin's disease: a report from the International Database on Hodgkin's Disease. Ann Oncol 1992;3:Suppl 4:117-128
Web of Science | Medline
Author/Editor Response
The authors reply:
To the Editor: The primary objective of our study was to compare the merits of two standard treatments for localized intermediate-grade and high-grade non-Hodgkin's lymphoma. We chose progression-free survival and overall survival as primary end points to account for any important negative effects of treatment and to reduce investigator bias. We found that three cycles of CHOP followed by involved-field radiotherapy had significant benefits. The cause of death was not censored, but in fact, eight patients in each treatment group died without an apparent recurrence of lymphoma. Thus, there is no evidence that the results are solely the product of the greater toxicity of eight cycles of CHOP.
Our report was the planned final report, and the study was adjusted for stratification factors. We chose not to look at all interactions between treatments and covariates, because we believe that such an analysis is subject to false positive associations as a result of the many comparisons entailed. Our study used the previously defined international prognostic index regardless of treatment assignment, rather than data dredging, and therefore issues of overfitting are less important.
We share the letter writers' interest in subgroups of patients that may have unique outcomes. Unfortunately, comparisons between treatment groups of such subgroups leave too few patients in the analysis for the study to have sufficient power to detect significant differences and thus run the risk of yielding both false positive and false negative results. The issue of multiple unplanned subgroup analyses in clinical trials of patients with cancer has recently been addressed by Tannock.1
The points raised by Machida et al. deserve special comment. They state that we treated older patients, who tolerate therapy poorly, and that as a result, artifactually caused eight cycles of treatment with CHOP to appear inferior. We disagree, because non-Hodgkin's lymphoma is a disease of the elderly and patients older than 60 years are just as likely to complete eight cycles of CHOP as younger patients.2 The numbers of fatal toxic effects in the two age groups were the same. Others have suggested that less therapy may be better because it reduces the toxicity and thereby improves the outcome. We believe that such suggestions should be tested in pilot settings. Our purpose was to compare two well-defined and thoroughly tested treatment programs, and as a result, we have established a benchmark for future comparisons of new and previously untested treatment programs.
2 ReferencesThomas P. Miller, M.D.
Arizona Cancer Center, Tucson, AZ 85724Michael LeBlanc, Ph.D.
Southwest Oncology Group Statistical Center, Seattle, WA 98109-4417Richard I. Fisher, M.D.
Cardinal Bernardin Cancer Center, Maywood, IL 60153for the Southwest Oncology Group
1
Tannock IF . False-positive results in clinical trials: multiple significance tests and the problem of unreported comparisons. J Natl Cancer Inst 1996;88:206-207
CrossRef | Web of Science | Medline2
Gaynor ER ,Dahlberg S ,Fisher RI . Factors affecting reduced survival of the elderly with intermediate and high grade lymphoma: an analysis of SWOG-8516 (INT 0067). Prog Proc Am Soc Clin Oncol 1994;13:370-370 abstract.
