Correspondence

CHOP versus m-BACOD in Non-Hodgkin's Lymphoma

N Engl J Med 1993; 328:581February 25, 1993

Article

To the Editor:

The results of a randomized trial reported by Gordon et al. (Nov. 5 issue)1 indicate that a chemotherapeutic regimen containing cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) and one containing bleomycin, doxorubicin, cyclophosphamide, vincristine, dexamethasone, methotrexate, and leucovorin (m-BACOD) were equivalent in their activity against diffuse advanced non-Hodgkin's lymphoma but that m-BACOD was more toxic. The authors stated that “the normalized dose intensity with CHOP was higher than that with m-BACOD . . . even though the prescribed doses of both cyclophosphamide and doxorubicin were higher in the CHOP regimen.” Although the authors then state that “the actual dose intensity . . . was higher in this regimen,” they did not state just how much higher the dose intensity was.

In fact, the received dose intensity of cyclophosphamide in the CHOP group was almost 50 percent higher than in the patients receiving m-BACOD (232 vs. 156 mg per square meter of body-surface area per week), and that of doxorubicin almost 30 percent higher (14.3 vs. 11.0 mg per square meter per week). Differences of this magnitude could at least partly explain why the addition of methotrexate and bleomycin in the m-BACOD group failed to improve the therapeutic outcome.

William Hryniuk, M.D.
University of California, San Diego, Cancer Center, San Diego, CA 92103

1 References

1. 1

   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 | Medline

Author/Editor Response

The authors reply:

To the Editor: We appreciate Dr. Hryniuk's thoughtful comments. He suggests that the lower received dose intensity of cyclophosphamide and doxorubicin in the m-BACOD group as compared with the CHOP group could balance any therapeutic advantage that may have occurred with the addition of bleomycin and methotrexate. This is certainly a logical explanation of our results, but it highlights the difficulties inherent in attempting to correlate data on dose intensity with outcomes from retrospective studies that were not designed to answer the question.

These two chemotherapeutic combinations were compared not for differences in dose, but as defined regimens with dose adjustments made as outlined in the original descriptions. It is apparent that the addition of bleomycin and methotrexate resulted in greater toxicity in the m-BACOD group. This was largely responsible for the reduced normalized dose intensity and consequently the reduced received dose intensity in the m-BACOD group. The median dose of cyclophosphamide in the CHOP group was 221.6 mg per square meter per week, and that in the m-BACOD group 158.3 mg per square meter per week, and the median dose of doxorubicin in the CHOP group was 13.9 mg per square meter per week, and that in the m-BACOD group 11.1 mg per square meter per week, when the median is given according to treatment group for the calculated actual dose intensity, defined as the total dose of a drug per square meter divided by the time a patient remains in the study. It is impossible to measure the relative effect of the dose reductions of cyclophosphamide and doxorubicin against the potential benefit of the addition of two putatively active drugs (bleomycin and methotrexate). In order to answer the question of dose intensity, the trial design would have to compare CHOP with high-dose CHOP or m-BACOD with high-dose m-BACOD.

The median normalized dose intensity in our patients did not differ between those who did and those who did not respond to treatment in either regimen. It is interesting that patients who had early progression of disease or who did not have a response had the highest dose intensity. This may be because these patients had only two or three cycles and were no longer in the study when dose reductions occurred.

The retrospective interpretation of outcome based on dose intensity is no longer adequate. The best way to answer Dr. Hryniuk's important question would be to address the issue of dose intensity in cancer chemotherapy in the same way that the question of regimens is addressed: in a prospective randomized trial.

Leo I. Gordon, M.D.
Northwestern University Medical School, Chicago, IL 60611

David Harrington, Ph.D.
Janet Andersen, M.S.
Dana-Farber Cancer Institute, Boston, MA 02115

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