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Correspondence
Treatment of Intermediate-Grade
and High-Grade Non-Hodgkin’s Lymphoma
To the Editor: Miller et al. (July 2 issue)1 are to be
com-mended on their report of the randomized trial comparing full-dose chemotherapy with limited chemotherapy and involved-field radiation for the treatment of localized in-termediate-grade and high-grade non-Hodgkin’s lympho-ma. Previously, the management of this condition with che-motherapy 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 chemo-therapy followed by involved-field radiochemo-therapy, as com-pared 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 esti-mated progression-free survival at five years was 13 per-centage 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 addi-tional five deaths from cardiac causes in the group as-signed 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
statistical-ly 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 preven-tion of disease progression. Further informapreven-tion on the causes of death and the types of progression and a statis-tical comparison of the time to disease progression would address this concern. We believe that the case for the rou-tine use of combined treatment would be further strength-ened if it could be shown that such treatment is both less toxic and more effective in preventing disease progression than chemotherapy alone.
ANDREW 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, Australia
1. Miller TP, Dahlberg S, Cassady JR , et al. Chemotherapy alone com-pared with chemotherapy plus radiotherapy for localized intermediate- and high-grade non-Hodgkin’s lymphoma. N Engl J Med 1998;339:21-6. 2.Cosset JM. Chemoradiotherapy for localized non-Hodgkin’s lympho-ma. N Engl J Med 1998;339:44-5.
To the Editor: Miller et al. suggest that a regimen of cy-clophosphamide, doxorubicin, vincristine, and prednisone (CHOP) in combination with radiotherapy was superior to CHOP alone in patients with localized intermediate-grade or high-intermediate-grade non-Hodgkin’s lymphoma. Their re-sults provide valuable information on what constitutes ad-equate 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
as-signed 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 combina-tion of CHOP and radiotherapy dropped out of the study. This difference is statistically significant (P<0.001) and
The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne
suggests that eight cycles of CHOP therapy is inappropri-ate 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.
UTAKO MACHIDA, M.D. MASAHIRO KAMI, M.D. HISAMARU HIRAI, M.D.
University of Tokyo Tokyo 113, Japan
1.Dixon DO, Neilan B, Jones SE, et al. Effect of age on therapeutic out-come in advanced diffuse histiocytic lymphoma: the Southwest Oncology Group experience. J Clin Oncol 1986;4:295-305.
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 lympho-ma seem statistically misleading. As they noted, late com-plications 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 progres-sion-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
univari-ate 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 inter-national 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 mod-el should have been used only after external validation or, at least, data splitting or a bootstrap resampling procedure.5
NICOLAS MOUNIER, M.D. Centre Hospitalier Universitaire Henri Mondor 94010 Creteil, France
CHRISTIAN GISSELBRECHT, M.D.
Centre Hospitalier Universitaire Saint Louis 75010 Paris, France
ERIC LEPAGE, M.D., PH.D. Centre Hospitalier Universitaire Henri Mondor 94010 Creteil, France
1. Mounier N, Morel P, Haioun C, et al. A multivariate analysis of the sur-vival of patients with aggressive lymphoma: variations in the predictive val-ue of prognostic factors during the course of the disease. Cancer 1998;82: 1952-62.
2.Coiffier B. Fourteen years of high-dose CHOP (ACVB regimen): pre-liminary conclusions about the treatment of aggressive-lymphoma patients. Ann Oncol 1995;6:211-7.
3.Armitage P, McPherson K, Rowe BC. Repeated significance test on accumulative data. J R Stat Soc [A] 1969;132:235-44.
4. 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. 5. Sauerbrei W, Schumacher M. A bootstrap resampling procedure for model building: application to the Cox regression model. Stat Med 1992; 11:2093-109.
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 sup-plemented 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 ra-diotherapy after three courses of CHOP. However, many issues must be addressed before the results can be accept-ed 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 pa-tients 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 out-come 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
treat-ment 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.
CHRISTOS KOSMAS, M.D. NIKOLAOS A. MALAMOS, M.D. MINAS J. ANTONOPOULOS, M.D.
Helena Venizelou Hospital 115 21 Athens, Greece
1. 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. abstract.
2.Magrath I, Adde M, Shad A, et al. Adults and children with small-non-cleaved-cell lymphoma have a similar excellent outcome when treated with the same chemotherapy regimen. J Clin Oncol 1996;14:925-34.
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To the Editor: In the Discussion section of their article, Miller and colleagues did not address several points. Al-though the standard curative dose of radiotherapy for non-Hodgkin’s lymphoma is approximately 4000 cGy,1 the
ma-jority 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 in-crease in the dose of radiotherapy by 20 to 25 percent jus-tified in order to decrease safely the number of chemo-therapy courses? Similarly, would not four or six courses of CHOP without radiotherapy be sufficient to cure pa-tients with a small tumor mass?
DIDIER DECAUDIN, M.D., PH.D. Institut Curie 75248 Paris, France
1.Cosset JM. Chemoradiotherapy for localized non-Hodgkin’s lymphoma. N Engl J Med 1998;339:44-5.
2.Gustavsson A, Eskilsson J, Landberg T, et al. Late cardiac effects after mantle radiotherapy in patients with Hodgkin’s disease. Ann Oncol 1990; 1:355-63.
3.Henry-Amar M. Second cancer after the treatment for Hodgkin’s dis-ease: a report from the International Database on Hodgkin’s Disease. Ann Oncol 1992;3:Suppl 4:117-28.
The authors reply:
To the Editor: The primary objective of our study was to compare the merits of two standard treatments for local-ized 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 impor-tant negative effects of treatment and to reduce investiga-tor 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 recur-rence of lymphoma. Thus, there is no evidence that the re-sults 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, be-cause 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 internation-al prognostic index regardless of treatment assignment, rather than data dredging, and therefore issues of overfit-ting are less important.
We share the letter writers’ interest in subgroups of pa-tients 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 com-ment. They state that we treated older patients, who tol-erate therapy poorly, and that as a result, artifactually
caused eight cycles of treatment with CHOP to appear in-ferior. 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 sug-gestions 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.
THOMAS P. MILLER, M.D. Arizona Cancer Center Tucson, AZ 85724
MICHAEL LEBLANC, PH.D. Southwest Oncology Group Statistical Center Seattle, WA 98109-4417
RICHARD I. FISHER, M.D.
Cardinal Bernardin Cancer Center Maywood, IL 60153 FORTHE 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; 88:206-7.
2.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. abstract.
Prevention of Stroke by Transfusions
in Children with Sickle Cell Anemia
To the Editor: The results of the carefully conducted study by Adams et al. (July 2 issue)1 of the value of transfusion
in preventing strokes in children with sickle cell anemia and abnormal results on transcranial Doppler studies were impressive and promise to change approaches to the man-agement of strokes in this disease. Adams et al. do not ad-dress the timing of the first transcranial Doppler study or the interval between studies. These important issues need to be addressed before a protocol based on transcranial Doppler ultrasonography can be universally applied.
A point requiring clarification is the total number of transcranial Doppler studies that the subjects underwent to determine their eligibility for the study. Only 79 chil-dren who had normal results at the first screening subse-quently had abnormal results and thus would have required a third imaging examination. From the total number of transcranial Doppler studies (3929) performed on the 1934 patients in the study, it appears that an inordinately large number of patients had a third study. The authors should describe their criteria for a third study, since there is a potential for bias in this regard.
It is hardly surprising that transfusions prevented a first episode of stroke in children with sickle cell anemia. Since the late 1970s several studies2,3 have shown that maintaining
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fusion can prevent recurrent strokes and largely eliminate the symptoms of the disease. However, the risks and diffi-culties of multiple transfusions, particularly given the need for long-term iron-chelation therapy, are formidable, as clearly stated in the accompanying editorial.4 The value of
screening with transcranial Doppler ultrasonography in predicting a stroke is suggested by the finding of Adams et al. of a stroke rate of 10 per 102 patient-years in the un-transfused group of study patients with repeatedly positive transcranial Doppler studies. This represents an increase by a factor of 10 over the results of previous studies, which showed a rate of 1.02 per 100 patient-years in a similar age group of unscreened children.5 It is disappointing that the
authors did not present any data regarding the clinical out-come of the roughly 1700 patients who were found to have normal results on transcranial Doppler ultrasonogra-phy on one or more occasions. Ascertaining the preva-lence of stroke in this cohort would have added consider-able credibility to their conclusions about the value of screening with transcranial Doppler ultrasonography as a predictor of stroke.
SHARADA A. SARNAIK, M.D.
Children’s Hospital of Michigan Detroit, MI 48201
1.Adams RJ, McKie VC, Hsu L, et al. Prevention of a first stroke by fusions in children with sickle cell anemia and abnormal results on trans-cranial Doppler ultrasonography. N Engl J Med 1998;339:5-11. 2.Pegelow CH, Adams RJ, McKie V, et al. Risk of recurrent stroke in pa-tients with sickle cell disease treated with erythrocyte transfusions. J Pediatr 1995;126:896-9.
3.Sarnaik S, Soorya D, Kim J, Ravindranath Y, Lusher J. Periodic trans-fusions for sickle cell anemia and CNS infarction. Am J Dis Child 1979; 133:1254-7.
4. Cohen AR. Sickle cell disease — new treatments, new questions. N Engl J Med 1998;339:42-4.
5. Ohene-Frempong K, Weiner SJ, Sleeper LA, et al. Cerebrovascular ac-cidents in sickle cell disease: rates and risk factors. Blood 1998;91:288-94.
The authors reply:
To the Editor: Dr. Sarnaik points out several important aspects of our study, which confirmed the ability of trans-cranial Doppler ultrasonography to identify a subgroup of children with a high risk of stroke and demonstrated that transfusion therapy significantly reduced the risk of stroke. The study was designed to investigate the efficacy of such treatment, but further research is needed to develop an optimal screening program.
The age at which the first screening study was performed in our study was two years, because stroke is not common in children younger than two years and younger patients often cannot lie quietly for the 30 to 40 minutes needed for the examination. The interval between studies and the total number of studies were determined by the screening algorithm, which based the interval between tests on the results of the first screening. It could be as short as a few weeks if the results of the first study were abnormal or as long as six to nine months if the initial results were normal, assuming the patient’s compliance with the date arranged for the next test. Finally, children who were first screened late in the trial may not have had subsequent studies.
With such a design, described in detail elsewhere,1
re-screening is biased toward patients who comply with the protocol of the study and who have more abnormal results.
However, the rate of stroke in the standard-care group was sufficient to test the study question, and any screening bias was not detrimental to the trial.
We agree that the current state of knowledge of sickle cell disease is not optimal2 and that better treatment for
complications of the disease are being sought. However, our study provides solid information on the risks and ben-efits of a treatment that can be used today.
When Dr. Adams reviewed the galley proofs of the arti-cle, he made changes in the order of authorship without the permission of the four authors involved and added a further author to the list. The correct list of authors and other authors is as follows:
Robert J. Adams, M.D., Virgil C. McKie, M.D., Lewis Hsu, M.D., Ph.D., Beatrice Files, M.D., Elliott Vichin-sky, M.D., Charles Pegelow, M.D., Miguel Abboud, M.D., Gerald Woods, M.D., Nancy Olivieri, M.D., Catherine Driscoll, M.D., Scott Miller, M.D., and Donald Brambilla, Ph.D.
Other authors were Winfred Wang, M.D., Anne Hurlet, M.D., Charles Scher, M.D., Brian Berman, M.D., Eliz-abeth Carl, B.A., Fenwick T. Nichols, M.D., E. Steve Roach, M.D., Abdullah Kutlar, M.D., Elizabeth Wright, Ph.D., Robert A. Zimmerman, M.D., Dianne Galla-gher, M.S., Myron A. Waclawiw, Ph.D., and Duane R. Bonds, M.D.
LEWIS HSU, M.D. Emory University School of Medicine Atlanta, GA 30303
BEATRICE FILES, M.D. East Carolina University School of Medicine Greenville, NC 27858
ROBERT J. ADAMS, M.D.
Medical College of Georgia Augusta, GA 30912-3200
1. Adams RJ, McKie VC, Brambilla D. et al. Stroke Prevention Trial in Sickle Cell Anemia. Controlled Clin Trials 1997;19:110-29.
2.Cohen AR. Sickle cell disease — new treatments, new questions. N Engl J Med 1998;339:42-4.
Assessing the Appropriateness of Medical Care
To the Editor: The article by Ayanian and colleagues (June 25 issue),1 reporting agreement among specialists
with respect to indications for cardiac catheterization, pro-vides reassuring data for patients seeking second opinions. These data, however, are based on expert opinions ren-dered on abstract descriptions of common clinical indica-tions, rather than on specific cases, which may have differ-ent combinations of clinical and diagnostic factors. We wish to sound a note of caution about ratings of appropri-ateness derived in this manner, since our data yielded quite different conclusions.
In the course of a study of the efficacy of cardiac nuclear scanning,2-4 we prepared abstracts of clinical and
diagnos-tic data derived from 596 patients who underwent nuclear scanning because their referring physicians thought that they might have ischemia. We assembled a panel of 22
C O R R E S P O N D E N C E
board-certified, expert cardiologists, recommended by di-rectors of cardiology at all medical schools and affiliated hospitals in the metropolitan New York area; 12 were in academic medicine, and 10 were primarily private practi-tioners. Each panelist was asked either to recommend or not to recommend coronary angiography in the case of each patient. Each case was judged by two of the expert panelists, as well by the referring physician.
Our results were as follows. Of 188 patients (total, 596) for whom the academic cardiologist recommended angi-ography, the cardiologist in private practice agreed with the decision 47 percent of the time; of 161 patients for whom the private-practice cardiologist recommended an-giography, the academic expert agreed with the decision 55 percent of the time. The rate of agreement was higher (about 78 percent) for cases in which angiography was not recommended. The kappa coefficient of overall agreement was 0.31 (with a kappa value of 1 indicating perfect agree-ment and a value of 0 indicating no agreeagree-ment that was greater than chance). The rate of agreement between the referring physician and either the academic or private-practice cardiology expert was equally low, ranging from 44 to 56 percent.
We concluded that the rate of agreement between two board-certified cardiologists on whether to recommend coronary angiography for a given patient was not much better than chance. Part of the discrepancy between our results and those of Ayanian et al. may be that things have changed since we concluded our study. But we suspect that a large part of the discrepancy is due to the difference between making judgments about theoretical clinical situ-ations and making judgments about real cases. We believe that our method provides more realistic results than those of Ayanian et al. and hope to repeat our study in view of their report.
SYLVIA WASSERTHEIL-SMOLLER, PH.D. Albert Einstein College of Medicine Bronx, NY 10461
JONATHAN TOBIN, PH.D. Clinical Directors Network New York, NY 10011
RICHARD STEINGART, M.D.
Winthrop University Hospital Mineola, NY 11501
1.Ayanian JZ, Landrum MB, Normand S-LT, Guadagnoli E, McNeil BJ. Rating the appropriateness of coronary angiography — do practicing phy-sicians agree with an expert panel and with each other? N Engl J Med 1998;338:1896-904.
2.Tobin JN, Wassertheil-Smoller S, Wexler JP, et al. Sex bias in consider-ing coronary bypass surgery. Ann Intern Med 1987;107:19-25. 3.Wassertheil-Smoller S, Steingart RM, Wexler JP, et al. Nuclear scans: a clinical decision making tool that reduces the need for cardiac catheteriza-tion. J Chronic Dis 1987;40:385-97.
4.Steingart RM, Wassertheil-Smoller S, Budner N, et al. The clinical use of nuclear exercise tests. Int J Technol Assess Health Care 1988;4:613-22.
To the Editor: Ayanian et al. present an important study demonstrating that the appropriateness ratings of practic-ing physicians and an expert panel are similar. One con-cern is the potential for response bias. Although the
au-thors note that their adjusted response rate approximates the rate of 54 percent reported by Asch et al.1 in a mail
survey of physicians, the rate in that study was largely based on the raw ratio of the number of surveys returned to the number distributed. Thus, in the study by Ayanian et al., the rate would be 24 percent (1058 surveys re-turned ÷ 4345 surveys distributed). The applicability of the authors’ methods of adjustment to a study that in-volved as many as three mailings and more than eight tele-phone reminders is also unclear. Moreover, as Asch et al. indicate, response rates are at best an indirect measure of the real issue, which is whether respondents differ mean-ingfully from nonrespondents. In a survey that appears to test respondents’ knowledge of indications for coronary angiography, respondents may be more familiar with the literature or with existing guidelines than nonrespondents. A comparison of the respondents and nonrespondents in the study could help alleviate this concern. In addition, the potential effect of any disagreement between groups of respondents is unclear without an interpretation of the differences in ratings, as is clear in the article by Shekelle et al. (June 25 issue).2 Readers are left to wonder about
the clinical significance of the reported differences in ap-propriateness ratings. Would any of the observed differ-ences result in different decisions with respect to recom-mending coronary angiography?
Furthermore, Ayanian et al. used different methods to elicit the appropriateness ratings from the expert panel and from the practicing physicians. Applying the same methods to both populations may be a more appropriate approach in attempts to determine whether the beliefs of practicing physicians are similar to those of an expert pan-el. If, however, the aim is to compare experts’ ratings with decisions that a practicing physician might make, then a few changes would be helpful. For example, Ayanian et al. suggest that many internists and family practitioners may rely heavily on the results of a cardiology consultation in deciding to proceed with coronary angiography. “Do you make the primary decision to send a patient for coronary angiography?” may be a more informative question than “What is your specialty training?” As Naylor suggests in his editorial,3 understanding the way in which the relevant
physicians weight the appropriateness of the indication for angiography in relation to other factors, such as patients’ preferences and history and the location of the infarct, is important. This evaluation may be especially dependent on the findings of clinical trials and on the diffusion of those findings. In short, the noteworthy study by Ayanian et al. raises many questions for future research.
JOHN HSU, M.D., M.B.A. University of Pennsylvania School of Medicine Philadelphia, PA 19103
1.Asch DA, Jedrziewski MK, Christakis NA. Response rates to mail sur-veys published in medical journals. J Clin Epidemiol 1997;50:1129-36. 2.Shekelle PG, Kahan JP, Bernstein SJ, Leape LL, Kamberg CJ, Park RE. The reproducibility of a method to identify the overuse and underuse of medical procedures. N Engl J Med 1998;338:1888-95.
3.Naylor CD. What is appropriate care? N Engl J Med 1998;338:1918-20.
To the Editor: The studies by Ayanian et al. and Shekelle et al. highlight the conflicting evidence regarding the
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ability of the use of consensus-development methods to establish the appropriateness of interventions. A recent systematic review of such methods revealed six studies in the health care sector that had examined the extent to which a group’s decision is affected by its individual mem-bers.1 Some of the studies showed that groups with similar
makeups made similar decisions, whereas others found that there were differences between groups. In all six stud-ies, however, the number of groups compared was small (usually two), and thus the findings are weak.
What is clear is that the particular application of the method is an important determinant of reliability between groups. For example, the reliability of algorithms for the clinical management of dyspepsia was high, whereas this was not true for algorithms for acute sinusitis.2 The fact
that this view is supported by the results of Shekelle et al. should not be seen as surprising: one does not expect the results of questionnaires as a general class to be equally re-liable. Rather, one assesses the reliability of a particular questionnaire. So, too, with consensus instruments; their reliability seems highly dependent on the particular appli-cation of the method.
NICK BLACK, M.D.
London School of Hygiene and Tropical Medicine London WC1E 7HT, United Kingdom
1.Murphy MK, Sanderson CF, Black NA, et al. Consensus development methods, and their use in clinical guideline development. Health Technol Assess 1998;2(3):1-88.
2.Pearson SD, Margolis CZ, Davis S, Schreier LK, Sokol HN, Gottlieb LK. Is consensus reproducible? A study of an algorithmic guidelines devel-opment process. Med Care 1995;33:643-60.
The authors reply:
To the Editor: Our study assessed the concordance be-tween community-based physicians and clinical experts with respect to the appropriateness of coronary angiogra-phy for common indications after acute myocardial infarc-tion. Wassertheil-Smoller and colleagues demonstrate that experienced physicians often disagree about whether to recommend coronary angiography for individual patients. Unlike our study, which focused on acute myocardial in-farction, theirs covered a wider range of clinical indica-tions. Because many of the indications they studied have not been evaluated as thoroughly as the use of coronary angiography for acute myocardial infarction, some of the disagreement they detected may have resulted from the greater frequency of indications of uncertain value.
Hsu reiterates a limitation that we noted in our dis-cussion: respondents may have been more familiar than nonrespondents with studies of the appropriate use of cor-onary angiography. As we reported, we had limited infor-mation (name, address, and self-reported specialty) about the physicians in our sample, so we were unable to com-pare the characteristics of respondents and nonrespond-ents. However, in a previous survey of physicians regarding the treatment of acute myocardial infarction, we did not find evidence of response bias when more information about nonrespondents was available.1 Furthermore, in our
recent study, we estimated that nonrespondents’ ratings of appropriateness would have had to differ from
respond-ents’ ratings by a substantial amount to alter the high level of agreement we found between community-based physi-cians and clinical experts. We share Hsu’s view that recom-mendations about major procedures are often based on the opinion of more than one physician, as shown in Table 2 of our report. Therefore, the effects of formal and infor-mal consultations on medical decision making are impor-tant topics for further research.2
We agree with Black that the reliability of appropriate-ness ratings may vary for different clinical conditions and in different settings, particularly when there is substantial uncertainty about the best course of action.3,4 Better
clin-ical studies will often be required to reduce uncertainty about the most beneficial care. By determining how and why medical care varies, research on health care services can have a vital role in showing where such studies are needed and then translating the findings into practice.
JOHN Z. AYANIAN, M.D., M.P.P. Harvard Medical School Boston, MA 02115
1.Ayanian JZ, Hauptman PJ, Guadagnoli E, Antman EM, Pashos CL, McNeil BJ. Knowledge and practices of generalist and specialist physicians regarding drug therapy for acute myocardial infarction. N Engl J Med 1994;331:1136-42.
2.Keating NL, Zaslavsky AM, Ayanian JZ. Physicians’ experiences and be-liefs regarding informal consultation. JAMA 1998;280:900-4.
3.Bickell NA, Earp J, Evans AT, Bernstein SJ. A matter of opinion about hysterectomies: experts’ and practicing community gynecologists’ ratings of appropriateness. Am J Public Health 1995;85:1125-8.
4.Shekelle PG, Kahan JP, Bernstein SJ, Leape LL, Kamberg CJ, Park RE. The reproducibility of a method to identify the overuse and underuse of medical procedures. N Engl J Med 1998;338:1888-95.
To the Editor: Dr. Black makes the point that the clinical condition being considered is an important determinant of the reliability of appropriateness ratings. We agree. In fact, we chose coronary revascularization and hysterectomy to represent both ends of the spectrum. There are many clin-ical trials of revascularization and relatively simple and wide-ly agreed on goals of treatment. There is much less infor-mation on the outcomes of hysterectomy, and the goals of treatment are much more controversial and dependent on individual preference.
We now have a careful study of the reproducibility of the panel method for two diverse conditions. To our knowledge there has been no such study, not even for a single condition, of any of the competing methods (meta-analysis, decision (meta-analysis, or informal expert-judgment methods used by many guideline developers and insurance companies to set criteria for care).
PAUL G. SHEKELLE, M.D., PH.D. R.E. PARK, PH.D.
RAND Santa Monica, CA 90407-2138
To the Editor: Dr. Hsu’s thoughtful letter indirectly un-derscores two points about the appropriateness of care. First, even if Ayanian et al. had obtained responses from a totally representative sample of U.S. physicians who
unan-C O R R E S P O N D E N unan-C E
imously agreed with the judgments of a U.S. expert panel, physicians from other nations might well disagree with some of the panel’s judgments. Appropriateness remains a complex social construct that mixes evidence, values, and inferences and is inevitably colored by context and culture. Second, shadings of appropriateness are difficult to in-terpret. One intervention may be rated slightly less appro-priate than another, but this finding is of little help to the practicing clinician, who must constantly translate uncer-tainties and probabilities into decisions and actions. On the other hand, there is a logical recourse when doubts arise about the balance of the risks and benefits of a par-ticular intervention; one should ask the patient or his or her proxy for guidance. More generally, since the ultimate purpose of defining appropriateness is to improve patient care, future research must leaven the medical profession’s judgments of appropriateness with patients’ perspectives and preferences.
C. DAVID NAYLOR, M.D., D.PHIL. University of Toronto Toronto, ON M5S 1A8, Canada
An Endoscopic View of Appendicitis
To the Editor: The diagnosis of acute appendicitis is of-ten, but not always, straightforward. Imaging studies, such as ultrasonography and computed tomography, may be helpful. When other diagnoses seem more likely, colonos-copy may be performed,1,2 although acute appendicitis may
occur as a complication of colonoscopy.3,4 I describe a
pa-tient in whom appendicitis was diagnosed by colonoscopy. A 42-year-old man was evaluated in the emergency de-partment because of the sudden onset of poorly localized, right-sided abdominal pain with nausea and vomiting. He was afebrile, and there was no change in bowel motion. He had a history of intermittent hematochezia and had been given a diagnosis of colitis. The results of the physical examination were unremarkable. The white-cell count was 17,500 per cubic millimeter, with 83 percent granulocytes. He was thought to have colitis and underwent elective co-lonoscopy 10 days later.
Colonoscopy showed periappendiceal inflammation and purulent discharge from the appendiceal orifice into the cecum (Fig. 1). Emergency surgery was performed and re-vealed a perforated retrocecal appendix and
periappen-diceal abscess. Appendectomy was performed, and the ab-scess was drained. The patient had an uneventful recovery. ANIL MINOCHA, M.D.
University of Oklahoma Oklahoma City, OK 73126
1.Said M, Ledochowski M, Dietze O, Simader H. Colonoscopic diagnosis and treatment of acute appendicitis. Eur J Gastroenterol Hepatol 1995; 7:569-71.
2.Nyam DC, Davendran K, Seow-Choen F. An endoscopic diagnosis of appendicular intussusception in chronic appendicitis. Singapore Med J 1997;38:131.
3.Vender R , Larson J, Garcia J, Topazian M, Ephraim P. Appendicitis as a complication of colonoscopy. Gastrointest Endosc 1995;41:514-6. 4.Hirata K, Noguchi J, Yoshikawa I, et al. Acute appendicitis immediately after colonoscopy. Am J Gastroenterol 1996;91:2239-40.
©1998, Massachusetts Medical Society.
Figure 1. Endoscopic View of the Cecum, Showing Periappen-diceal Inflammation and Purulent Discharge from the Appen-diceal Orifice (Arrow).
