Letters to the Editor Djulbegovic et al.’s conclusion, therefore, that &dquo;third-genregimens (MACOP-B) offer a survival advantage over first-generation regimens (CHOP), leading to prolongation of life expectancy for about 3 4 years,&dquo; is not sustainable on the evidence they present Moreover, subsequent data from

Better Right than Quick?

eration

To the Editor:-I write to express concern about the paper by Djulbegovic et al., &dquo;Comparison of Different Treatment Strategies for Diffuse Large Cell Lymphomas. A Decision

randomized trial suggest there is little if any difference The authors’ opinions regarding randomized controlled trials are also of concern. Participation in a randomized trial can be &dquo;ethically unacceptable&dquo; only if it results in patients’ being exposed to treatments that are known to be inferior Present practice clearly reflects a state of clinical equipoise14 with regard to the treatment of diffuse large-cell lymphoma. Under these circumstances, recommending to a patient that he or she participate in a well-designed, randomized trial is perhaps the only ethical course. The four-arm, randomized trial activated by SWOG in April 1986, comparing CHOP, MACOP-B, and two other aggressive chemotherapy regimenus,&dquo; was cited indirectly by the authors. While it is recognized that randomized controlled trials are time-consuming, the data from the ANZ trial and the potential results of the SWOG study should provide authoritative guidance in the near future It seems, at least from the ANZ data, that the conclusions reached will be different from those of Djulbegovic et al. Until then, the need to make timely decisions under conditions of uncertainty should not distract from the need to use and gather highquality data. Perhaps it is more important to be right than quick.-MARTIN STOCKLER, MBBS, Department ofmedical Oncology, Royal Prince Alfred Hospital, Missenden Road, Camperdown NSW 2050, Australia a

Analysis.&dquo;’ They sought to compare two chemotherapeutic regimens for diffuse large-cell lymphoma. One, MACOP-B is a more

recent and more intensive

combination, while the

perhaps more standard therapy The Markov process provides an elegant model, but, like any model, the quality of its output is limited by the quality of its input z The fundamental assumption on which the authors’ model is based is that the data chosen for CHOP and MACOP-B are comparable. This assumption is false. The authors have selected data for MACOP-B from publications from a single institution between 1981 and 1986,4-b but have ignored other published experience with this regimen 7 Preference for the Vancouver data for MACOP-B (with a complete response rate of 84%),over the report from the Memorial Sloan-Kettering Cancer Center (complete response rate of 52%o ) on the basis of maturity of data is not tenable; minimum follow-up was longer in the latter. Another data set worthy of consideration is that from the series of consecutive phase-2 trials conducted by the Southwest Oncology Group (SWOG) between 1984 and 1986 which yielded a complete response rate of 50% in patients treated with MACOP-B.8 The data for CHOP come from several randomized, controlled trials performed between 1972 and 19839 10 The CHOP data are almost a decade older, suggesting that stage shift,ll improved supportive care, and better selection of host and disease factors&dquo; could contribute to any differences observed between the two regimens. The duration of followup similarly favors the more recent data set (MACOP-B). In addition, although the MACOP-B data have been updated twice over six years, new patients have been included at each update, diluting the effect of longer follow-up in the other, CHOP, is

an

original group. It is not possible

older and

References 1

1-8

Beck JR, Pauker SG The Markov process in medical prognosis Med Decis Making 1983,3 419-58 3 Hillner BE, Smith TJ Efficacy and cost effectiveness of adjuvant chemotherapy in women with node-negative breast cancer—a decision-analysis model N Engl J Med 1991,324160-8 4 Klimo P, Connors JM MACOP-B chemotherapy for the treatment of diffuse large-cell lymphoma Ann Intern Med 1985,102 2

importance of differences key prognostic factors (such as age, performance status) in the two groups. to assess

B, Hollenberg, J, Woodcock TM, Herzig R Comparison of different treatment strategies for diffuse large-cell lymphomas a decision analysis Med Decis Making 1991,11

Djulbegovic

the

in the distribution of

disease stage, and However, examination of the inclusion and exclusion criteria for the two protocols suggests that the patients treated with CHOP were older (no age limit) and had more advanced disease (stages III and IV, or recurrence following radiotherapy) than patients treated with MACOP-B (maximum age of 70; stages IIB, III or IV; previously untreated). In addition, patients who had symptomatic pulmonary disease were excluded from treatment with MACOP-B. In short, this Markov model is based on a selected, historically controlled comparison with all the biases inherent to this approach The methodology used to &dquo;demonstrate the validity&dquo; of the Markov model is also flawed. Testing the model against the data from which it was derived does not demonstrate the model’s ability to predict outcomes, nor does it demonstrate generalizability of the findings to other groups of patients.

596-602 5

Klimo P, Connors JM

6

B Semin Haematol 1987,24 26-34 Klimo P, Connors JM MACOP-B chemotherapy for

Updated clinical experience with MACOPmalignant update and additional 1988,25 41-6(suppl 2)

lymphomas and related conditions observations Semm Haematol 7 Schneider

1987

AM, Strauss DJ, Schluger AE, et al Treatment results with an aggressive chemotherapeutic regimen (MACOP-B) for intermediate- and some high-grade non-Hodgkin’s lymphomas J Clin Oncol 1990,8 94-102 8 Weick JK, Dahlberg S, Miller T, et al The treatment of nonHodgkms Lymphomas with m-BACOD, ProMACE-CytaBOM, and MACOP-B the Southwest Oncology Group (SWOG) experience Proc Am Soc Clin Oncol 1989,8 254 9 Jones SE, Grozea PN, Miller TP, et al Chemotherapy with cyclophosphamide, doxorubicm, vincristine and prednisone alone

76

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77

or

with levamisole or with levamisole plus BCG for malignant a Southwest Oncology Group study J Clin Oncol

lymphoma 10

11

12

13

14

15

1985,3 1318-24 Coltman CA, 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 Proc Am Soc Clin Oncol 1986,15 197 Feinstein A The Will Rogers phenomenon Stage migration and new diagnostic techniques as a source of misleading statistics in cancer N Engl J Med 1985,312 1604-8 Sacks H, Chalmers TC, Smith H Randomized versus historical controls for clinical trials Am J Med 1982,72 233-40 Cooper IA, Ding JC, Matthews JP, et al , for the Australia and New England Lymphoma Group A randomized comparison of MACOP-B and CHOP in intermediate grade non-Hodgkin’s lymphoma Proc Am Soc Clin Oncol 1991,10 942 Freedman B Equipoise and ethics of clinical research N Engl J Med 1987,317141-5 Miller TP, Dana BW, Weick JK, et al Southwest Oncology Group clinical trials for intermediate- and some high-grade non-Hodgkin’s lymphomas Semm Haematol 1988,25 17-22 (suppl 2)

Mathematical Modeling or Waiting Decades for an Empirical Answer? In reply:-Dr. Stockler expresses concern that our model showing that third-generation regimen (MACOP-B) may offer survival advantage over first-generation regimens (CHOP) is not correct because of difficulties in: 1) comparability of data

between two arms (CHOP vs MACOP-B), 2) validation of model; and 3) new data about remission rates for MACOP-B regimen. We agree that results of a mathematical model will be better if the data used in the comparison of two treatment strategies come from groups of patients with similar clinical and biological characteristics As specified in our paper, we dealt with this problem by extracting only those data that were comparable in relation to the most important prognostic factors for non-Hodgkin’s lymphoma: pathologic subtype, stage of disease, and sex and age of the patient The ages of typical patients (median ages) differ among various studies, making a direct comparison of data more difficult We chose the age of 57 years for both treatment groups because that was median age for diffuse large-cell lymphoma reported in the largest study of its clinical course so far (see Simon et al Ann Intern Med 1988;109:939). This study was based on 1,175 patients from four institutions treated between 1971 and 1975, before the introduction of either CHOP or MACOP-B. By adopting this value we ensured the same age-specific mortality in both arms of our model. In this way the difference in the results could be ascribed only to the

prognostic factors may be important, do not know how to integrate them into this model However, the same argument can be applied to clinical trials, because our knowledge of prognostic factors is changing, and what is applicable today may not be of equal importance treatment effect. Other

but

we

tomorrow

We agree there is no substitute for empirical data. Any mathematical model should be compared against available data. We compare our model not against data from which the model was derived, but against a final outcome the model was designed to predict-survival. Our model included 12 states (first remission, first relapse, etc.) and it was compared with available data about survival for chemotherapeutic regimens without knowledge whether all of the patients actually went through all the states assumed by the model Our model accurately predicted survival (life expectancy) and thus gave us reassurance that the model could be realistic We are eager to learn how it will behave compared with data that are prospectively collected. MACOP-B remission rates were adopted from a single institution’s experience because we felt that these data were more mature than data from other institutions, the majority of which had been reported only in abstract form. While it may be true that the remission rate for MACOP-B is not as high as the 84% assumed in our model, it does not invalidate the results of the model, i.e., that the first-remission rate and functional status after the first remission is achieved are the most important determinants of life expectancy Our analysis does not exclude CHOP as a better treatment, should it be shown that the remission rate with MACOP-B is less than the CHOP remission rate (fig 3. in the paper), as it seems that ANZ data suggest. Furthermore, our analysis indicates that the model is a quite robust to variation in acute toxicities and relapse rates, as well as to salvage-therapy remission rates-a rather unexpected finding. This may be of critical significance in everyday clinical practice, where the key issue so far as the efficacy of a particular treatment is concerned relates to the trade-off between the remission rate (believed to be increased by adding more aggressive drugs) and the toxicity of treatment. Clinicians are not sure whether they should start treatment with less aggressive therapy and administer salvage therapy after relapse, or begin treatment with more aggressive but more toxic treatment hoping for long-lasting remission. When no empirical data exist regarding such an issue, we believe that it is better to offer an analytic approach to the problem than to passively wait for an answer, which has been expected by the oncology community for almost two decades with regard to lymphoma treatment.- BENJAMIN DJULBEGOVIC, MD, PhD, and THOMAS M WooDCOCK, MD, Division of Medical Oncology and Hematology} Department of medicine, School of Medicine,

University of Louisville, Louismlle,

Downloaded from mdm.sagepub.com at UQ Library on March 13, 2015

KY 40292

Better right than quick?

Letters to the Editor Djulbegovic et al.’s conclusion, therefore, that &dquo;third-genregimens (MACOP-B) offer a survival advantage over first-generat...
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