The New England Journal of Medicine
e-mail icon  FREE NEJM E-TOC    HOME   |   SUBSCRIBE   |   CURRENT ISSUE   |   PAST ISSUES   |   COLLECTIONS   |    Advanced Search
Sign in | Get NEJM's E-Mail Table of Contents — Free | Subscribe
 
Original Article
PreviousPrevious
Volume 339:1506-1514 November 19, 1998 Number 21
NextNext

A Prognostic Score for Advanced Hodgkin's Disease
Dirk Hasenclever, Ph.D., Volker Diehl, M.D., James O. Armitage, David Assouline, Magnus Björkholm, Ercole Brusamolino, George P. Canellos, Patrice Carde, Derek Crowther, David Cunningham, Houchingue Eghbali, Christophe Ferm, Richard I. Fisher, John H. Glick, Bengt Glimelius, Paolo G. Gobbi, Harald Holte, Sandra J. Horning, T. Andrew Lister, Dan L. Longo, Franco Mandelli, Aaron Polliack, Stephen J. Proctor, Lena Specht, John W. Sweetenham, Gillian Vaughan Hudson, for The International Prognostic Factors Project on Advanced Hodgkin's Disease

 

This Article
-Abstract
- PDF

Commentary
-Editorial
by Brice, P.
-Letters

Tools and Services
-Add to Personal Archive
-Add to Citation Manager
-Notify a Friend
-E-mail When Cited

More Information
-PubMed Citation
ABSTRACT

Background Two thirds of patients with advanced Hodgkin's disease are cured with current approaches to treatment. Prediction of the outcome is important to avoid overtreating some patients and to identify others in whom standard treatment is likely to fail.

Methods Data were collected from 25 centers and study groups on a total of 5141 patients treated with combination chemotherapy for advanced Hodgkin's disease, with or without radiotherapy. The data included the outcome and 19 demographic and clinical characteristics at diagnosis. The end point was freedom from progression of disease. Complete data were available for 1618 patients; the final Cox model was fitted to these data. Data from an additional 2643 patients were used for partial validation.

Results The prognostic score was defined as the number of adverse prognostic factors present at diagnosis. Seven factors had similar independent prognostic effects: a serum albumin level of less than 4 g per deciliter, a hemoglobin level of less than 10.5 g per deciliter, male sex, an age of 45 years or older, stage IV disease (according to the Ann Arbor classification), leukocytosis (a white-cell count of at least 15,000 per cubic millimeter), and lymphocytopenia (a lymphocyte count of less than 600 per cubic millimeter, a count that was less than 8 percent of the white-cell count, or both). The score predicted the rate of freedom from progression of disease as follows: 0, or no factors (7 percent of the patients), 84 percent; 1 (22 percent of the patients), 77 percent; 2 (29 percent of the patients), 67 percent; 3 (23 percent of the patients), 60 percent; 4 (12 percent of the patients), 51 percent; and 5 or higher (7 percent of the patients), 42 percent.

Conclusions The prognostic score we developed may be useful in designing clinical trials for the treatment of advanced Hodgkin's disease and in making individual therapeutic decisions, but a distinct group of patients at very high risk could not be identified on the basis of routinely documented demographic and clinical characteristics.

Since the advent of combination chemotherapy with the MOPP (mechlorethamine, vincristine, procarbazine, and prednisone)1 and ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) regimens,2 only minor progress has been made in the treatment of Hodgkin's disease,3 although ABVD or alternating cycles of MOPP and ABVD may have better results than MOPP alone.4 Current therapies fail to cure about one third of patients with advanced Hodgkin's disease, and a similar proportion of patients may be overtreated. The latter problem is apparent from long-term remissions in patients who stop treatment after two to six cycles of chemotherapy5,6 or who receive reduced treatment in an individualized approach.7

For these reasons, prediction of the outcome of treatment may allow the identification of patients who are likely to benefit from reduced treatment or who are unlikely to have a sustained response to standard treatment.8,9,10 There is an extensive literature on prognostic factors in Hodgkin's disease.11,12 Several groups have developed prognostic indexes for overall survival on the basis of data from samples of moderate size.13,14,15,16,17,18,19 Some of these indexes have been partially confirmed.20,21 The International Database on Hodgkin's Disease was used to develop a parametric model for predicting survival. This model was based on data from 5023 patients who were at various stages of the disease and who received various treatments.3,22

There is a need for a simple scoring system to predict freedom from progression of disease that is based on data from a large number of similarly treated cases of advanced Hodgkin's disease. An international collaboration was organized to develop such a scoring system for patients treated with combination chemotherapy, with or without radiotherapy.

Freedom from progression of disease was chosen as the main end point because overall survival involves three factors that should be considered separately: the ability of the initial treatment to control the disease, an appreciable second chance of a cure with salvage treatment in the case of recurrent disease,23,24,25,26 and deaths due to late toxicity or disorders unrelated to Hodgkin's disease in patients with continuous complete remissions.

Methods

Data Collection

Patients with histologic confirmation of advanced Hodgkin's disease (according to the local definition of advanced disease) were eligible if they had been treated with an established protocol still considered to be state of the art, with at least four planned cycles of combination chemotherapy (preferably containing doxorubicin), with or without radiotherapy. Treatment must have started before January 1, 1992, in order to allow a sufficient period of follow-up. Data for 5141 patients were obtained. Ninety-five percent of the patients started treatment after 1983. Patients were excluded if the outcome was unknown (248 patients), or if they had received outmoded or only palliative therapy (88). Analyses were further restricted to patients between the ages of 15 and 65 years, the age range of a typical study population. Data for the remaining 4695 patients were analyzed. The quality of the data appeared to be adequate on extensive inspection.

Participating centers were asked to specify the treatment strategies used and to provide the relevant protocols or reports.4,5,7,21,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47 More than 75 percent of the patients were treated with standard doxorubicin-containing regimens; 20 percent received MOPP or a similar regimen. Sixty percent of the patients received no radiotherapy. Thirty-three percent received full or selected involved-field irradiation; 2 percent underwent more extensive irradiation with a mantle or inverted-Y field, and 5 percent underwent subtotal or total nodal irradiation.

Demographic and Clinical Factors

The following variables documented at diagnosis were analyzed as potential prognostic factors: age; sex; histologic type; Ann Arbor stage of disease; presence or absence of systemic symptoms; mediastinal grade of involvement; presence or absence of inguinal involvement; lung, liver, and bone marrow involvement; hemoglobin level; serum albumin level; erythrocyte sedimentation rate; white-cell and platelet counts; absolute and relative lymphocyte counts; serum alkaline phosphatase level; serum lactate dehydrogenase level; and serum creatinine level.

Since the techniques of measuring mediastinal masses can vary considerably,48 the participating centers and study groups were asked to grade masses as absent, small, large, or very large, according to their own definitions. Masses graded as large typically occupied more than 33 percent of the thoracic aperture, and those graded as very large occupied more than 45 percent of the thoracic aperture. The centers and study groups were asked to provide their normal ranges for all laboratory values. There was sufficient overlap of the normal ranges to justify a joint analysis, except for the normal ranges of serum alkaline phosphatase and lactate dehydrogenase levels, which were expressed as the ratio of the measured value to the upper limit of the normal range.

End Points

Freedom from progression of disease was defined as the interval from the initiation of primary treatment to the first recurrence of disease (progression or relapse); data on deaths that occurred during remission and that were not preceded by the recurrence of disease were censored. Overall survival was defined as the interval from the initiation of primary treatment to death from any cause.

Statistical Analysis

Time-to-event distributions were estimated with the life-table method with one-month intervals. Univariate curves were compared with generalized Gehan's Wilcoxon k-sample test. Multivariate regression analysis of time to treatment failure was performed with a Cox proportional-hazards model.49

Some centers and study groups provided only partial information on mediastinal involvement. Masses were reported as present, with no information on size, in 219 patients, as large or very large in 242, and as small or large in 59. The distribution of the mediastinal mass in the overall study population was estimated on the assumption that the distribution in patients for whom only partial information was available was similar to that in patients for whom full information was available (conditional distribution). For the Cox regression analysis, incomplete data were coded according to the estimated probability that a mass was a given size.

The problem of missing data was resolved by carrying out "complete case" analyses. Since the data appeared to be randomly missing and since the data on potential predictive factors were collected before the data on the outcome of treatment, the complete case analyses should be unbiased. Follow-up times appeared to be unrelated to clinical variables.

The construction of the prognostic model started with a univariate assessment of the prognostic effect of each factor and an analysis of the correlations between the factors in order to identify groups of statistically as well as biologically related items. Laboratory variables were initially coded as continuous variables.

In constructing the model, we had to take into account the degree of completeness of the covariates analyzed. A step-down procedure was used to analyze all variables for which we had nearly complete data (i.e., data from more than 4000 patients). Improvement of the resulting model was investigated by adding variables for which data were missing one by one in a step-up fashion, always with the use of the respective complete data set.

To develop a practical scoring system, all laboratory variables were dichotomized. Cutoff points were chosen to make optimal use of the information, with the conditions that the smaller group contain at least 20 percent of all patients, that the cutoff value demarcate a clearly abnormal state and if possible agree with cutoff values used in the literature, and that the effects of the dichotomized variables be of the same order of magnitude. No dichotomized covariates were entered into the model unless the continuous analogue had a significant independent prognostic effect. This strategy was used to ensure that the selection of prognostic factors for the model would be independent of the choice of the various cutoff points.

All the prognostic effects were small to moderate. Restricting the analysis to the patients for whom complete data were available reduced the sample to 1618 patients. To retain sufficient statistical power, we fitted the model to the set of complete data without setting aside a validation sample. The resulting model was validated with the data from the 2643 patients for whom we had complete information except for albumin values, lymphocyte counts, or both. Missing serum albumin levels were roughly estimated by linear regression from hemoglobin levels and other nearly complete covariates (correlation coefficient, 0.51). Missing lymphocyte counts could not reasonably be estimated from other variables. Since scores with different numbers of factors are difficult to compare, inguinal involvement (the last factor dropped from the model) was used as a surrogate for lymphocytopenia. The estimation of serum albumin levels and the substitution of a variable with a presumably smaller prognostic effect for lymphocytopenia would be expected to reduce the predictive power of the score, and this validation approach should therefore not be biased in favor of the predictive effect of the variables.

Results

Univariate Analyses

At five years, the rate of freedom from progression of disease was 66 percent and the rate of overall survival was 78 percent. The median period of follow-up for the analysis of freedom from progression of disease was 68 months. Table 1 summarizes the results of the univariate analyses. Since the sample was large, most of the factors were significant in the univariate analyses.

View this table:
[in this window]
[in a new window]
  		Table 1. Results of the Univariate Analysis of Freedom from Progression of Disease and Overall Survival at Five Years.

 
The univariate effect of age on freedom from progression of disease was moderate. The effect of age was much greater on overall survival, mainly because of the poor results of salvage chemotherapy among older patients with relapses. Survival rates at five years among patients with a progression or relapse of disease decreased in an orderly fashion with age, from 42 percent in patients who were up to 34 years old at diagnosis to 5 percent in patients who were 55 to 65 years old at diagnosis. Age was the only factor that was predictive of death during continuous complete remission. With cases of disease progression censored at the time of progression, the survival rate among patients with complete continuous remission at seven years was 97 percent for those up to 44 years old, 91 percent for those 45 to 54 years, and 84 percent for those 55 to 65 years.

Histologic type was significantly associated with overall survival but not with freedom from progression of disease. As reported elsewhere,3,50 patients with the histologic subtype characterized by lymphocyte depletion had a worse prognosis than those with other subtypes, but this subgroup is very small, and the number of such diagnoses has decreased in recent years.

Seventy-five percent of the study population had classic advanced disease (Ann Arbor stage IIIB, 33 percent; stage IVA, 13 percent; and stage IVB, 29 percent), and 12 percent had stage IIIA disease. Thirteen percent of the patients presented with stage I or II disease (stage I, 1 percent; stage IIA, 4 percent; and stage IIB, 8 percent). These patients were treated for advanced disease because they had additional risk factors indicating an advanced stage: systemic symptoms (fever, sweats, and weight loss) were present in 69 percent, and 43 percent had large mediastinal masses. The presence of these risk factors in patients with stage I or II disease explains the relatively small prognostic difference we saw between stage I or II and stage III.

In the group of patients with stage IV disease, organ involvement was analyzed to determine whether the combination of stage IV disease and particular sites of involvement had additional prognostic importance.51 There were only small differences in freedom from progression of disease according to the site of involvement. Liver involvement was associated with poor overall survival because the survival rate among patients with such involvement is low after a relapse regardless of their age. The presence of a mediastinal mass52 did not appear to have a strong prognostic effect, except in the small subgroup of patients (5 percent) with very large masses (i.e., those occupying more than 45 percent of the thoracic aperture). Serum lactate dehydrogenase also did not appear to be a major prognostic factor in advanced Hodgkin's disease, but this finding must be interpreted cautiously, because missing data considerably reduced the sample size.

Systemic symptoms occurred in 71 percent of the patients. Systemic symptoms together with the erythrocyte sedimentation rate, the hemoglobin level, the serum albumin level, and to a lesser degree, the serum alkaline phosphatase level formed a cluster of moderately correlated clinical factors (correlation coefficient, approximately 0.37 for all pairs of variables), all of which had a prognostic effect in the univariate analyses. In contrast to the erythrocyte sedimentation rate, which undergoes short-term changes, hemoglobin and serum albumin values change over a period of weeks and are thus biometrically more reliable. Both variables were consistently correlated with prognosis over the whole range of values.

Leukocytosis (a white-cell count of at least 15,000 per cubic millimeter) was present in one fifth of the study population.49 Although 74 percent of the patients presented with normal absolute lymphocyte counts (more than 1000 per cubic millimeter), more than 80 percent had subnormal relative counts (less than 25 percent of the white-cell count). The joint distribution of white-cell and absolute lymphocyte counts reveals a clear shift of the bivariate distribution away from normal values toward leukocytosis and at least relative, if not absolute, lymphocytopenia. This bivariate shift was clearly prognostic. To derive a practical representation, a cutoff point of 15,000 per cubic millimeter was used for the white-cell count, and one unifying item was used for lymphocytopenia (a lymphocyte count of less than 600 per cubic millimeter, a count that was less than 8 percent of the white-cell count, or both). The overlap of the two partial criteria for lymphocytopenia is about 60 percent. On the basis of these criteria, lymphocytopenia was present in 21 percent of the patients.

Multivariate Analyses

The final model (Table 2) incorporates seven prognostic factors: a serum albumin level of less than 4 g per deciliter, a hemoglobin level of less than 10.5 g per deciliter, male sex, an age of 45 years or older, stage IV disease, leukocytosis (a white-cell count of at least 15,000 per cubic millimeter), and lymphocytopenia (a lymphocyte count of less than 600 per cubic millimeter, a count that was less than 8 percent of the white-cell count, or both). All seven factors had a relatively small effect of the same order of magnitude. They can thus be combined into a simple prognostic score without loss of relevant information.

View this table:
[in this window]
[in a new window]
  		Table 2. The Final Cox Regression Model.

 
Figure 1A shows that the proposed prognostic score predicts rates of freedom from progression of disease at five years ranging from 42 percent (for a score of 0) to 84 percent (for a score of 5 or higher). The curves for the scores are equally spaced, with each additional factor reducing the plateau by about 8 percent. Table 3 shows the distribution of scores together with rates of freedom from progression of disease and overall survival at five years. Figure 1B shows that the prognostic score is also predictive of overall survival.



View larger version (10K):
[in this window]
[in a new window]
  		Figure 1. Use of the Prognostic Score to Predict Rates of Freedom from Progression of Disease (Panel A) and Overall Survival (Panel B) in 1618 Patients with Advanced Hodgkin's Disease.

The number and percentage of patients with each score were as follows: a score of 0, 115 patients (7 percent); 1, 360 (22 percent); 2, 464 (29 percent); 3, 378 (23 percent); 4, 190 (12 percent); and 5 or higher, 111 (7 percent).

 
View this table:
[in this window]
[in a new window]
  		Table 3. Rates of Freedom from Progression of Disease and Overall Survival at Five Years According to Individual and Grouped Prognostic Scores.

 
The model was validated with the data from 2643 patients for whom albumin or lymphocyte counts were missing, with less-predictive information substituted. As explained in the Methods section, the predictive power of the score should therefore be reduced in this validation sample. Nevertheless, as Figure 2 shows, the separation of the curves was quite good.


View larger version (5K):
[in this window]
[in a new window]
  		Figure 2. Validation of the Prognostic Score in a Group of 2643 Patients with Incomplete Data on Albumin or Lymphocyte Values.

Surrogate information was substituted for the missing data, as described in the Methods section. The number and percentage of patients with each score were as follows: a score of 0, 196 patients (7 percent); 1, 671 (25 percent); 2, 809 (31 percent); 3, 578 (22 percent); 4, 292 (11 percent); and 5, 97 (4 percent).

 
To determine the potential effect of differences in treatment, an indicator variable for patients treated with a non–doxorubicin-containing or slightly inferior regimen was added to the final model. This variable provided independent prognostic information — that is, improved the fit of the model to the data — but did not interact with the factors forming the prognostic score. The same applies to indicator variables for center or study-group heterogeneity.

Discussion

We developed a seven-factor prognostic scoring system that predicts five-year rates of freedom from progression of disease in the range of 45 to 80 percent. Each additional factor reduced the predicted rate by about 8 percent. The prognostic score is also predictive of overall survival, and the predictive effects were reproducible in a large (partial) validation sample.

The factors incorporated into the prognostic score are well known and make biologic sense. Age and sex frequently influence the outcome of Hodgkin's lymphoma, and the disseminating potential of the disease is noted by stage IV. Inflammatory processes and effects driven by cytokine release are reflected by serum albumin17,18,53,54 and hemoglobin14,16,17,18,20,55,56 levels, as well as by abnormalities of white-cell counts (leukocytosis49 and lymphocytopenia14,40,50,57,58).

The score was derived from a large, broadly representative, and fairly homogeneous set of data provided by 25 study groups and institutions. Most of the patients were treated in the 1980s with ABVD, MOPP and ABVD, a hybrid regimen of MOPP with alternating cycles of doxorubicin, bleomycin, and vinblastine, or a similar regimen. Moderate variations in treatment and moderate center effects appeared to be independent of the prognostic factors and therefore probably did not affect the validity of the prognostic score.

Table 3 shows the prognosis for each subgroup of patients with a given score, as well as for low- and high-risk groups defined on the basis of grouped scores (0 or 1 vs. 2 or higher, 0 to 2 vs. 3 or higher, and 0 to 3 vs. 4 or higher). For each pair of low- and high-risk groups, the difference in freedom from progression of disease at five years was more than 19 percent. This difference should be consistently reproducible in data sets of moderate size.

A score of 3 or more (accounting for 42 percent of the study population) represented a moderately high risk, with an expected 55 percent rate of freedom from progression of disease (Figure 3) and a 70 percent rate of overall survival at five years. Only 19 percent of the patients had a score of 4 or higher, which was associated with a 47 percent rate of freedom from progression of disease and a 59 percent rate of overall survival at five years. Thus, there was no distinct group of patients with advanced Hodgkin's disease that could be identified as being at very high risk on the basis of routinely documented clinical features.


View larger version (4K):
[in this window]
[in a new window]
  		Figure 3. Freedom from Progression of Disease in 1618 Patients According to Whether the Prognostic Score Was 0 to 2 or 3 or Higher.

 
This finding is relevant to the question of whether early high-dose chemotherapy with autologous stem-cell support should be used as consolidation therapy in patients with responses to induction therapy8,9,10,20,59,60 who are nevertheless considered to remain at high risk for a relapse. There may be few such patients.61,62 Rates of freedom from progression of disease at five years for the patients in our study who had complete remissions were considerably higher than the rates for the entire sample: 73 percent, 70 percent, and 65 percent for patients with scores of at least 2, at least 3, and at least 4, respectively. Thus, toxic effects should be considered carefully in comparing early high-dose chemotherapy and late high-dose chemotherapy (in cases of relapse only).

Finally, the clinical features and laboratory variables incorporated in the prognostic score are biologically rather nonspecific. It is important to obtain sufficient data on more specific features, including serum CD3063,64 and cytokine65,66 levels. Meanwhile, the proposed prognostic score can be used to establish enrollment criteria and to describe study populations as well as to support decisions about treatment in individual patients.

We are indebted to Oana Brosteanu and Markus Loeffler for their support, encouragement, and critical review of the manuscript.

* The participants in the International Prognostic Factors Project on Advanced Hodgkin's Disease are listed in the Appendix.


Source Information

From the Institute of Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig (D.H.); and Clinic I for Internal Medicine, University of Cologne, Cologne (V.D.) — both in Germany. Other authors were James O. Armitage, David Assouline, Magnus Björkholm, Ercole Brusamolino, George P. Canellos, Patrice Carde, Derek Crowther, David Cunningham, Houchingue Eghbali, Christophe Fermé, Richard I. Fisher, John H. Glick, Bengt Glimelius, Paolo G. Gobbi, Harald Holte, Sandra J. Horning, T. Andrew Lister, Dan L. Longo, Franco Mandelli, Aaron Polliack, Stephen J. Proctor, Lena Specht, John W. Sweetenham, and Gillian Vaughan Hudson.

Address reprint requests to Dr. Hasenclever at IMISE, University of Leipzig, Liebigstr. 27, D-04103 Leipzig, Germany.

References

  1. Longo DL, Young RC, Wesley M, et al. Twenty years of MOPP therapy for Hodgkin's disease. J Clin Oncol 1986;4:1295-1306. [Free Full Text]
  2. Bonadonna G, Santoro A, Gianni AM, et al. Primary and salvage chemotherapy in advanced Hodgkin's disease: the Milan Cancer Institute experience. Ann Oncol 1991;2:Suppl 1:9-16. [Free Full Text]
  3. Henry-Amar M, Aeppli DM, Anderson J, et al. Workshop statistical report. In: Somers R, Henry-Amar M, Meerwaldt JH, Carde P, eds. Colloque INSERM. Vol. 196. London: John Libbey Eurotext, 1990:169-418.
  4. Canellos GP, Anderson JR, Propert KJ, et al. Chemotherapy of advanced Hodgkin's disease with MOPP, ABVD, or MOPP alternating with ABVD. N Engl J Med 1992;327:1478-1484. [Abstract]
  5. Hasenclever D, Loeffler M, Diehl V. Rationale for dose escalation of first line conventional chemotherapy in advanced Hodgkin's disease: German Hodgkin's Lymphoma Study Group. Ann Oncol 1996;7:Suppl 4:95-98. [Free Full Text]
  6. Diehl V, Loeffler M, Pfreundschuh M, et al. Further chemotherapy versus low-dose involved-field radiotherapy as consolidation of complete remission after six cycles of alternating chemotherapy in patients with advance Hodgkin's disease. Ann Oncol 1995;6:901-910. [Free Full Text]
  7. Bjorkholm M, Axdorph U, Grimfors G, et al. Fixed versus response-adapted MOPP/ABVD chemotherapy in Hodgkin's disease: a prospective randomized trial. Ann Oncol 1995;6:895-899. [Free Full Text]
  8. Gisselbrecht C, Fermé C. Prognostic factors in advanced Hodgkin's disease: problems and pitfalls: towards an international prognostic index. Leuk Lymphoma 1995;15:Suppl 1:23-24.
  9. Straus DJ. High-risk Hodgkin's disease prognostic factors. Leuk Lymphoma 1995;15:Suppl 1:41-42.
  10. Carde P. Should poor risk patients with Hodgkin's disease be sorted out for intensive treatments? Leuk Lymphoma 1995;15:Suppl 1:31-40.
  11. Specht L. Prognostic factors in Hodgkin's disease. Cancer Treat Rev 1991;18:21-53. [CrossRef][Medline]
  12. Specht L. Prognostic factors in Hodgkin's disease. Semin Radiat Oncol 1996;6:146-161. [CrossRef][Medline]
  13. Proctor SJ, Taylor P, Donnan P, Boys R, Lennard A, Prescott RJ. A numerical prognostic index for clinical use in identification of poor-risk patients with Hodgkin's disease at diagnosis. Eur J Cancer 1991;27:624-629.
  14. 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 7:17-20.
  15. Proctor SJ, Taylor PR. Classical staging of Hodgkin's disease is inappropriate for selecting patients for clinical trials of intensive therapy: the case for the objective use of prognostic factor information in addition to classical staging. Leukemia 1993;7:1911-1914. [Medline]
  16. Straus DJ, Gaynor JJ, Myers J, et al. Prognostic factors among 185 adults with newly diagnosed advanced Hodgkin's disease treated with alternating potentially noncross-resistant chemotherapy and intermediate-dose radiation therapy. J Clin Oncol 1990;8:1173-1186. [Abstract]
  17. Gobbi PG, Gobbi PG, Mazza P, Zinzani PL. Multivariate analysis of Hodgkin's disease prognosis: fitness and use of a directly predictive equation. Haematologica 1989;74:29-38. [Medline]
  18. Gobbi PG, Cavalli C, Federico M, et al. Hodgkin's disease prognosis: a directly predictive equation. Lancet 1988;1:675-679. [CrossRef][Medline]
  19. Wagstaff J, Steward W, Jones M, et al. Factors affecting remission and survival in patients with advanced Hodgkin's disease treated with MVPP. Hematol Oncol 1986;4:135-147. [Medline]
  20. Hasenclever D, Schmitz N, Diehl V. Is there a rationale for high-dose chemotherapy as first line treatment of advanced Hodgkin's disease? Leuk Lymphoma 1995;15:Suppl 1:47-49.
  21. Fermé C, Bastion Y, Brice P, et al. Prognosis of patients with advanced Hodgkin's disease: evaluation of four prognostic models using 344 patients included in the Group d'Etudes des Lymphomes de l'Adulte Study. Cancer 1997;80:1124-1133. [CrossRef][Medline]
  22. Gobbi PG, Comelli M, Grignani GE, Pieresca C, Bertoloni D, Ascari E. Estimate of expected survival at diagnosis in Hodgkin's disease: a means of weighting prognostic factors and a tool for treatment choice and clinical research: a report from the International Database on Hodgkin's Disease (IDHD). Haematologica 1994;79:241-255. [Free Full Text]
  23. Reece DE, Connors JM, Spinelli JJ, et al. Intensive therapy with cyclophosphamide, carmustine, etoposide +/- cisplatin, and autologous bone marrow transplantation for Hodgkin's disease in first relapse after combination chemotherapy. Blood 1994;83:1193-1199. [Free Full Text]
  24. Longo DL, Duffey PL, Young RC, et al. Conventional-dose salvage combination chemotherapy in patients relapsing with Hodgkin's disease after combination chemotherapy: the low probability for cure. J Clin Oncol 1992;10:210-218. [Abstract]
  25. Fermé C, Bastion Y, Lepage E, et al. The MINE regimen as intensive salvage chemotherapy for relapsed and refractory Hodgkin's disease. Ann Oncol 1995;6:543-549. [Free Full Text]
  26. Pfreundschuh MG, Rueffer U, Lathan B, et al. Dexa-BEAM in patients with Hodgkin's disease refractory to multidrug chemotherapy regimens: a trial of the German Hodgkin's Disease Study Group. J Clin Oncol 1994;12:580-586. [Abstract]
  27. Assouline D, Adeleine P, Jaubert J, et al. Advanced stages of Hodgkin's disease (HD): long term results of the LMS 80 protocol. Proc Am Soc Clin Oncol 1993;12:381. abstract.
  28. Somers R, Carde P, Henry-Amar M, et al. A randomized study in stage IIIB and IV Hodgkin's disease comparing eight courses of MOPP versus an alteration of MOPP with ABVD: a European Organization for Research and Treatment of Cancer Lymphoma Cooperative Group and Groupe Pierre-et-Marie-Curie controlled clinical trial. J Clin Oncol 1994;12:279-287. [Abstract]
  29. Radford JA, Crowther D, Rohatiner AZ, et al. Results of a randomized trial comparing MVPP chemotherapy with a hybrid regimen, ChlVPP/EVA, in the initial treatment of Hodgkin's disease. J Clin Oncol 1995;13:2379-2385. [Free Full Text]
  30. Brusamolino E, Lazzarino M, Morra E, et al. Combination chemotherapy with alternating MOPP-ABVD in advanced Hodgkin's disease. Haematologica 1989;74:173-179. [Medline]
  31. Brusamolino E, Orlandi E, Morra E, et al. Analysis of long-term results and prognostic factors among 138 patients with advanced Hodgkin's disease treated with the alternating MOPP/ABVD chemotherapy. Ann Oncol 1994;5:Suppl 2:53-57.
  32. Fermé C, Lepage E, Brice P, et al. Combined chemotherapy-radiotherapy in advanced Hodgkin's disease: results of a prospective clinical trial with 70 stage IIIB-IV patients. Int J Radiat Oncol Biol Phys 1993;26:397-405. [Medline]
  33. Fermé C, Brice P, Bourstyn E, et al. Surgical restaging of advanced Hodgkin's disease after first line chemotherapy. Eur J Haematol 1991;46:306-311. [Medline]
  34. Hill M, Milan S, Cunningham D, et al. Evaluation of the efficacy of the VEEP regimen in adult Hodgkin's disease with assessment of gonadal and cardiac toxicity. J Clin Oncol 1995;13:387-395. [Free Full Text]
  35. Gobbi PG, Pieresca C, Federico M, et al. MOPP/EBV/CAD hybrid chemotherapy with or without limited radiotherapy in advanced or unfavorably presenting Hodgkin's disease: a report from the Italian Lymphoma Study Group. J Clin Oncol 1993;11:712-719. [Abstract]
  36. Glick JH, Young ML, Harrington D, et al. MOPP/ABV hybrid chemotherapy for advanced Hodgkin's disease significantly improves failure-free and overall survival: the 8-year results of the intergroup trial. J Clin Oncol 1998;16:19-26. [Free Full Text]
  37. Horning SJ, Ang PT, Hoppe RT, Rosenberg SA. The Stanford experience with combined procarbazine, Alkeran and vinblastine (PAVe) and radiotherapy for locally extensive and advanced stage Hodgkin's disease. Ann Oncol 1992;3:747-754. [Free Full Text]
  38. Horning SJ, Rosenberg SA, Hoppe RT. Brief chemotherapy (Stanford V) and adjuvant radiotherapy for bulky or advanced Hodgkin's disease: an update. Ann Oncol 1996;7:Suppl 4:105-108. [Free Full Text]
  39. Specht L, Nissen NI. Prognostic factors in Hodgkin's disease stage III with special reference to tumour burden. Eur J Haematol 1988;41:80-87. [Medline]
  40. Specht L, Nissen NI. Prognostic factors in Hodgkin's disease stage IV. Eur J Haematol 1988;41:359-367. [Medline]
  41. Hancock BW, Vaughan Hudson G, Vaughan Hudson B, et al. LOPP alternating with EVAP is superior to LOPP alone in the initial treatment of advanced Hodgkin's disease: results of a British National Lymphoma Investigation trial. J Clin Oncol 1992;10:1252-1258. [Free Full Text]
  42. Hancock BW, Vaughan Hudson G, Vaughan Hudson B, Linch DC, Anderson L, MacLennan KA. Hybrid LOPP/EVA is not better than LOPP alternating with EVAP: a prematurely terminated British National Lymphoma Investigation randomized trial. Ann Oncol 1994;5:Suppl 2:117-120.
  43. Holte H, Mella O, Wist E, Telhaug R, Hannisdal E, Abrahamsen AF. ChlVPP is as effective as alternating ChlVPP/ABOD in advanced stage Hodgkin's disease. Acta Oncol 1996;35:Suppl 8:73-80. 
  44. Glimelius B, Enblad G, Kalkner M, et al. Treatment of Hodgkin's disease: the Swedish National Care Programme experience. Leuk Lymphoma 1996;21:71-78. [Medline]
  45. Simmonds PD, Mead GM, Sweetenham JW, et al. PACE BOM chemotherapy: a 12-week regimen for advanced Hodgkin's disease. Ann Oncol 1997;8:259-266. [Free Full Text]
  46. Uziely B, Isacson R, Weshler Z, Lugassy G, Libson E, Polliak A. Hodgkin's lymphoma: results of ABVD chemotherapy in 40 patients with advanced or bulky disease. Leuk Lymphoma 1990;1:123-127.
  47. Lotan C, Paltiel O, Dann E, Gordon L, Uziely B, Polliak A. MOPP-ABV for advanced Hodgkin's disease: results from Hadassah University Hospital 1990-1993. Ann Oncol 1996;7:Suppl 3:114-114.abstract [Free Full Text]
  48. Hopper KD, Diehl LF, Lynch JC, McCauslin MA. Mediastinal bulk in Hodgkin disease: method of measurement versus prognosis. Invest Radiol 1991;26:1101-1110. [Medline]
  49. Kaplan HS. Hodgkin's disease. 2nd ed. Cambridge, Mass.: Harvard University Press, 1980.
  50. Ranson MR, Radford JA, Swindell R, et al. An analysis of prognostic factors in stage III and IV Hodgkin's disease treated at a single centre with MVPP. Ann Oncol 1991;2:423-429. [Free Full Text]
  51. Munker R, Hasenclever D, Brosteanu O, Hiller E, Diehl V. Bone marrow involvement in Hodgkin's disease: an analysis of 135 consecutive cases: German Hodgkin's Lymphoma Study Group. J Clin Oncol 1995;13:403-409. [Free Full Text]
  52. Anderson H, Jenkins JP, Brigg DJ, et al. The prognostic significance of mediastinal bulk in patients with stage IA-IVB Hodgkin's disease: a report from the Manchester Lymphoma Group. Clin Radiol 1985;36:449-454. [CrossRef][Medline]
  53. Gobbi PG, Gendarini A, Crema A, et al. Serum albumin in Hodgkin's disease. Cancer 1985;55:389-393. [CrossRef][Medline]
  54. Gobbi PG, Cavalli C, Gendarini A, et al. Prognostic significance of serum albumin in Hodgkin's disease. Haematologica 1986;71:95-102. [Medline]
  55. MacLennan KA, Vaughan Hudson B, Easterling MJ, Jelliffe AM, Vaughan Hudson G, Haybittle JL. The presentation haemoglobin level in 1103 patients with Hodgkin's disease (BNLI report no. 21). Clin Radiol 1983;34:491-495. [Medline]
  56. Vaughan Hudson B, MacLennan KA, Bennett MH, Easterling MJ, Vaughan Hudson G, Jelliffe AM. Systemic disturbance in Hodgkin's disease and its relation to histopathology and prognosis (BNLI report no. 30). Clin Radiol 1987;38:257-261. [CrossRef][Medline]
  57. Tubiana M, Attie E, Flamant R, Gerard-Marchant R, Hayat M. Prognostic factors in 454 cases of Hodgkin's disease. Cancer Res 1971;31:1801-1810. [Free Full Text]
  58. Anderson H, Crowther D, Deakin DP, Ryder WD, Radford JA. A randomised study of adjuvant MVPP chemotherapy after mantle radiotherapy in pathologically staged IA-IIB Hodgkin's disease: 10-year follow-up. Ann Oncol 1991;2:Suppl 2:49-54.
  59. Carella AM, Prencipe E, Pungolino E, et al. Twelve years experience with high-dose therapy and autologous stem cell transplantation for high-risk Hodgkin's disease patients in first remission after MOPP/ABVD chemotherapy. Leuk Lymphoma 1996;21:63-70. [Medline]
  60. Federico M, Clo V, Carella AM. High-dose therapy autologous stem cell transplantation vs conventional therapy for patients with advanced Hodgkin's disease responding to first-line therapy: analysis of clinical characteristics of 51 patients enrolled in the HD01 protocol: EBMT/ANZLG/Intergroup HD01 Trial. Leukemia 1996;10:Suppl 2:69-71. 
  61. Schmitz N, Hasenclever D, Brosteanu O, et al. Early high-dose therapy to consolidate patients with high-risk Hodgkin's disease in first remission? Results of an EBMT/GHSG matched-pair analysis. Blood 1995;86:Suppl 1:439a-439a.abstract 
  62. Lee SM, Radford JA, Ryder WD, Collins CD, Deakin DP, Crowther D. Prognostic factors for disease progression in advanced Hodgkin's disease: an analysis of patients aged under 60 years showing no progression in the first 6 months after starting primary chemotherapy. Br J Cancer 1997;75:110-115. [Medline]
  63. Pizzolo G, Vinante F, Chilosi M, et al. Serum levels of soluble CD30 molecule (Ki-1 antigen) in Hodgkin's disease: relationship with disease activity and clinical stage. Br J Haematol 1990;75:282-284. [Medline]
  64. Gause A, Jung W, Schmits R, et al. Soluble CD8, CD25 and CD30 antigens as prognostic markers in patients with untreated Hodgkin's lymphoma. Ann Oncol 1992;3:Suppl 4:49-52.
  65. Trumper L, Jung W, Dahl G, Diehl V, Gause A, Pfreundschuh M. Interleukin-7, interleukin-8, soluble TNF receptor, and p53 protein levels are elevated in the serum of patients with Hodgkin's disease. Ann Oncol 1994;5:Suppl 1:93-96. [Free Full Text]
  66. Gorschülter M, Bohlen H, Hasenclever D, Diehl V, Tesch H. Serum cytokine levels correlate with clinical parameters in Hodgkin's disease. Ann Oncol 1995;6:477-482. [Free Full Text]
Appendix

The following persons and institutions or study groups participated in the International Prognostic Factors Project for Advanced Hodgkin's Disease: J. Armitage and M. Bast, Nebraska Lymphoma Study Group, Omaha; D. Assouline and B. Coiffier, Groupe Lyon, Marseille et St. Etienne, Lyons, France; M. Björkholm, U. Axdorph, and G. Grimfors, Karolinska Hospital, Stockholm, Sweden; E. Brusamolino, Istituto di Ematologia, Università di Pavia, Pavia, Italy; G. Canellos, B. Peterson, G. Petroni, and J. Johnson, Cancer and Leukemia Group B, United States; P. Carde, M. Henry-Amar, E. Noordijk, R. Somers, and J. Raemaekers, European Organization for Research and Treatment of Cancer–Lymphoma Cooperative Group, Europe; D. Crowther and D. Ryder, Manchester Lymphoma Group, United Kingdom; D. Cunningham and S. Milan, Royal Marsden Hospital, Sutton, United Kingdom; V. Diehl and D. Hasenclever, German Hodgkin's Lymphoma Study Group, Germany; H. Eghbali and V. Picot, Institut Bergonié, Bordeaux, France; C. Fermé and C. Gisselbrecht, Groupe d'Etude des Lymphomes de l'Adulte, Paris; R. Fisher, Southwest Oncology Group, United States; J. Glick and D. Harrington, Eastern Cooperative Oncology Group, United States; B. Glimelius, G. Enblad, and A. Gustavsson, Swedish Lymphoma Study Group, Sweden; P. Gobbi, V. Silingardi, and M. Federico, Gruppo Italiano per lo Studio dei Linfomi, Italy; H. Holte, Norwegian Radium Hospital, Oslo; S. Horning and J. Allen, Stanford University, Stanford, Calif.; T.A. Lister, St. Bartholomew's Hospital, London; D. Longo and P. Duffey, National Cancer Institute, Frederick, Md.; F. Mandelli, A. Anselmo, and C. Cartoni, Università La Sapienza, Rome; A. Polliack, O. Paltiel, C. Lotan, and B. Uziely, Hadassah University Hospital, Jerusalem, Israel; S. Proctor, P. Taylor, and J. White, Scotland and Newcastle Lymphoma Group, United Kingdom; L. Specht, University of Copenhagen, Copenhagen, Denmark; J. Sweetenham and P. Smartt, University of Southampton, Southampton, United Kingdom; G. Hudson, British National Lymphoma Investigation, United Kingdom.


 

This Article
-Abstract
- PDF

Commentary
-Editorial
by Brice, P.
-Letters

Tools and Services
-Add to Personal Archive
-Add to Citation Manager
-Notify a Friend
-E-mail When Cited

More Information
-PubMed Citation

Related Letters:

Prognostic Score for Hodgkin's Disease
Jack F. R., Angus B., Taylor P. R.A., Watine J., Hasenclever D.
Extract | Full Text  
N Engl J Med 1999; 340:1288-1290, Apr 22, 1999. Correspondence

This article has been cited by other articles:


HOME  |  SUBSCRIBE  |  SEARCH  |  CURRENT ISSUE  |  PAST ISSUES  |  COLLECTIONS  |  PRIVACY  |  TERMS OF USE  |  HELP  |  beta.nejm.org

Comments and questions? Please contact us.

The New England Journal of Medicine is owned, published, and copyrighted © 2009 Massachusetts Medical Society. All rights reserved.