Correspondence

Prognostic Score for Hodgkin's Disease

N Engl J Med 1999; 340:1288-1290April 22, 1999

Article

To the Editor:

The prognostic scoring system for Hodgkin's disease proposed by Hasenclever and Diehl (Nov. 19 issue)1 has addressed a difficult challenge for clinicians. We wish to raise two issues of concern regarding this article. First, there was no histologic review, and it is uncertain whether cases of the nodular lymphocyte-predominant subtype were included. This form of Hodgkin's disease is different in both presentation and prognosis from the classic form of the disease. Only 3 percent of cases had lymphocyte-predominant Hodgkin's disease; distortion of the analysis would have been slight, but it would be incorrect to apply the conclusions of the study to this small and unrepresentative subgroup.

Second, we have attempted to place the findings in a population-based setting. There are 1281 patients with classic Hodgkin's disease, all of whom were negative for the human immunodeficiency virus, whose presentation and follow-up data are registered in the Scotland and Newcastle Lymphoma Group data base. This registry represents most cases of Hodgkin's disease diagnosed in our population of 8.5 million since 1986. One hundred eighty-seven (14.6 percent) are at least 66 years old and 41 (3.2 percent) are under 15; these patients were excluded from the scoring system developed by the authors. Of the remaining 1053 patients (82.2 percent), 459 had complete data for the score. The rates of disease-specific survival for these patients are presented in Table 1Table 1Survival Characteristics of a Population-Based Cohort of Patients with Hodgkin's Disease According to the Prognostic System of Hasenclever and Diehl.. We looked at disease-specific survival rather than freedom from progression for three reasons: disease-specific survival is a definitive measure of failure; if disease-specific survival is not related to presentation features, the argument for intensifying initial treatment is diminished; and the assessment of progression is notoriously difficult in patients with Hodgkin's disease in whom residual masses after therapy are common and may be inactive.

In only 17 of 459 patients (3.7 percent) was the prognostic score >4. Fifteen of these 17 had Ann Arbor stage IV disease. We conclude that the system proposed by Hasenclever and Diehl identifies only a small proportion of patients with poor outcome, with nearly all disease-specific deaths occurring in “low-risk” categories. We have long been concerned with the identification of patients for whom conventional four-drug regimens are likely to fail and will continue to use the index of the Scotland and Newcastle Lymphoma Group2 to select candidates for our eight-drug hybrid regimen. To date, no prognostic system for Hodgkin's disease based on traditional factors has been entirely satisfactory, and we agree with Hasenclever and Diehl that efforts should be intensified in the search for new and more pathologically relevant markers of prognosis.

Fergus R. Jack, M.R.C.Path., M.R.C.P.
Brian Angus, F.R.C.Path.
Penny R.A. Taylor, M.B., B.S.
Royal Victoria Infirmary, Newcastle upon Tyne NE1 4LP, United Kingdom

2 References

1. 1

   Hasenclever D, Diehl V. A prognostic score for advanced Hodgkin's disease. N Engl J Med 1998;339:1506-1514
   Full Text | Web of Science | Medline

2. 2

   Proctor SJ, Taylor P, Mackie MJ, et al. A numerical prognostic index for clinical use in identification of poor-risk patients with Hodgkin's disease at diagnosis. Leuk Lymphoma 1992;7:Suppl:17-20
   CrossRef | Web of Science | Medline

To the Editor:

Hasenclever and Diehl describe a prognostic score for advanced Hodgkin's disease based on seven factors, among which four are laboratory measurements (i.e., serum albumin, blood hemoglobin, white-cell count, and lymphocyte count). However, they do not mention the methods used to measure these factors. It would therefore be impossible for an independent team to reproduce their results (a basic principle of good science). It is not possible to compare the prognostic value of any particular laboratory measurements if such measurements are made with different techniques. For example, electrophoretic, colorimetric, turbidimetric, and nephelometric procedures do not yield identical results for serum albumin concentrations, and an international standardization for the measurement of serum protein has been routine practice in most laboratories only since 1995.1 Such a lack of consistency among methods may exist for most of the other laboratory tests performed in their study.

Joseph Watine, M.D.
Hôpital Général, 12027 Rodez CEDEX 09, France

1 References

1. 1

   Ward AM, Committee on Plasma Protein. In: Proceedings of the 16th International Congress of Clinical Chemistry, London, July 8–12, 1996:35-6.
   

Author/Editor Response

Dr. Hasenclever replies:

To the Editor: Watine is concerned about our using laboratory tests in a prognostic score without fully specifying the methods involved. Our project combined most of the prospectively documented trial data that were collected in the 1980s by leading centers and study groups worldwide. In these data sets, individual normal ranges were not routinely documented or were only documented for laboratory measurements in which the normal range varies considerably (e.g., lactate dehydrogenase and serum alkaline phosphatase). For these tests, only values standardized in units of the upper bound of the normal range were used in the analysis. Concerning the other tests, in particular those incorporated into the score, the center-specific normal ranges and the center-specific distributions of the values appeared to overlap sufficiently to justify a joint evaluation. In addition, since we used cutoff points chosen to demarcate a clearly abnormal state qualitatively, the error due to differing methods of measurement should be negligible. Nevertheless, we agree with Watine that the quality of data in prospective clinical trials can be improved by systematically collecting information on methods of measurement and normal ranges for all laboratory tests.

Jack et al. correctly point out that the prognostic score applies to classic Hodgkin's disease. There are no specific data on the validity of the score in the recently delineated very small subgroup of patients with the nodular lymphocyte-predominant subtype. Jack et al. applied the score to the Scotland and Newcastle Lymphoma Group data base and concluded that “the system identifies only a small proportion of patients with poor outcome.” Their results are fully compatible with the data on the score applied to survival presented in Figure 1B of our paper with regard to both the five-year survival rates and the proportions of patients with a particular number of adverse factors.

Unfortunately, they did not use the main end point, freedom from progression of disease, but instead used disease-specific survival. It should be stressed that the score was constructed and optimized for freedom from progression of disease. As discussed in our article, a score optimized for disease-specific survival would have to give age a much stronger influence, because age is a major prognostic factor for survival after relapse. A validation of the score in the intended context would be preferable.

The score we reported was developed for advanced-stage Hodgkin's disease. Jack et al. appear not to have excluded patients with early stages of the disease (stages I and II, without any risk factors), who were probably treated with therapy that was not as aggressive as the treatment for advanced stages. A recent analysis of the data of the German Hodgkin's Lymphoma Study Group on patients with early stages of disease1 shows that the prognostic score also works for these patients, although the adverse factor of stage IV disease should be interpreted to encompass any extranodal involvement (E stage). This finding deserves further validation in independent data sets.

Dirk Hasenclever, Ph.D.
University of Leipzig, D-04103 Leipzig, Germany

1 References

1. 1

   Lieberz D, Paulus U, Franklin J, Tesch H, Diehl V. Applicability of the international prognostic score for advanced stage Hodgkin's disease to early and intermediate stages. Blood 1998;92:Suppl 1:86a-86a abstract.
   Web of Science