Is the international prognostic score for advanced stage Hodgkin’s disease applicable to early stage patients?

Annals of Oncology 11: 617-623. 2000. © 2000 Kluwer Academic Publishers. Primed in the Netherlands

Original article Is the international prognostic score for advanced stage Hodgkin's disease applicable to early stage patients? J. Franklin, U. Paulus, D. Lieberz, K. Breuer, H. Tesch & V. Diehl for the German Hodgkin Lymphoma Study Group

Results: The IPS identified 40% of the unfavourable early stage patients with an 8% lower disease-free survival at six Background: The seven-factor International Prognostic Score years (hazard ratio 1.66, P - 0.0018). The factor 'low albumin' (IPS) has been developed and verified for patients with ad- was the only score component giving a significant individual vanced stage Hodgkin's disease (HD). This report aims to assess contribution. Allowing for the IPS, extranodal involvement, particularly in stages IIB-IIIA, was associated with worse the predictive power of the IPS for early stage HD patients. Patients and methods: Data on patient characteristics, ther- prognosis, but no further significantly prognostic factors were apy and follow-up were available for 1424 adult patients in revealed. The IPS identified a similar hazard ratio in HD4, clinical stages I-IIIA treated for primary HD in two German although here the effect was not significant. Hodgkin's Lymphoma Study Group (GHSG) trials (1988Conclusions: The IPS for advanced HD has modest predic1994). Patients with risk factors or in stage IIIA received tive ability in unfavourable early stage patients. Modification chemo-radiotherapy (CMT; trial HD5); others received of the IPS for use with early stages may improve its prognostic extended field radiotherapy (RT) alone (HD4). The IPS could power. be calculated for 712 HD5 and 249 HD4 patients (70%). The prognostic value of the IPS and its component factors was assessed using Cox proportional hazards regression. A search was made for additional factors which could add predictive Key words: disease free survival, early stage Hodgkin's disease, power to the IPS. prognostic factor, prognostic index Summary

Background

Hodgkin's disease patients receive a treatment according to the stage of disease and to the presence or absence of various prognostic factors [1]. The criteria for allocation of patients to treatment groups and the corresponding treatment schemes are not entirely uniform over all practitioners and study groups. Generally, a division into early and advanced stage disease is recognised, chiefly according to the Ann Arbor clinical stage (typically CSI-II vs. CSIII-IV). Most advanced stage patients receive extensive chemotherapy (CT) with or without adjuvant irradiation. Early stage patients may be given either radiotherapy (RT) alone or combined chemo-radiotherapy (CMT), or more rarely CT alone; the CT is less extensive than that for the advanced stages. Many study groups subdivide the early stages into favourable and unfavourable patients. This division was originally motivated by inadequacy of the then current treatment with RT alone for a considerable subgroup of these patients [2]. Today, unfavourable (or 'intermediate stage') cases invariably receive CMT, while favourable cases may receive RT alone. The factors employed for this subdivision are only partly consistent between study

groups, and there is no universally recognised method [3]. This may be partly due to the high cure rates (around 80% at five years) in early stage patients and the consequent low event rate for a statistical analysis. Further, treatment modality is heterogeneous, hindering combined data analysis and perhaps leading to different prognostic factors according to the modality used. Moreover, certain factors (e.g., mixed cellularity subtype) are associated with occult abdominal disease [4], and are therefore prognostic in clinically staged cohorts but not in patients staged by laparotomy. Prognostic factors in HD have been reviewed by Specht [3] and by Specht and Hasenclever [4]. Several independent adverse prognostic factors for early stage disease have been described, including tumour burden, age, gender, B symptoms, bulky disease, anaemia, erythrocyte sedimentation rate, serum albumin, and possibly histological subtype. The European Organisation for Research and Treatment of Cancer (EORTC) Lymphoma Group has used the factors large mediastinal mass, elevated erythrocyte sedimentation rate (ESR), involvement of 4 or more lymph node areas and age above 50 years to define unfavourable disease [5]. In the trial H5 (1977-1982) favourable patients received RT alone and unfavourable

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Department of Internal Medicine, University of Cologne, Cologne, Germany

618

DFS (years)

Figure 1. HD6 (advanced stages: CS IIB and IIIA with one or more GHSG risk factor; CS IIIB and IV): disease-free survival according to IPS 0-1 (n = 90), 2-3 (« = 252), 4-5 (n = 101) and 6-7 (n = 8).

patients CMT [6]. In H7 (1988-1993) favourable patients were randomised to extensive RT or to combined modality with EBVP and IF.RT, while unfavourable patients received EBVP or MOPP-ABV combined with IF.RT [7]. In the GHSG, five adverse factors large mediastinal mass, extranodal disease, massive splenic involvement, elevated ESR and involvement of three or more lymph node areas were recognised for the division of stage I—II patients into'early'and 'intermediate' stages [8, 9]. From 1988 to 1994, favourable patients received radiotherapy alone and from 1994 to 1998 they were randomised between RT alone and RT preceded by two ABVD cycles. Unfavourable GHSG patients were given combined modality treatment with four chemotherapy cycles and extended or involved field irradiation. The National Cancer Institute of Canada's (NCIC) current trial H-6 defines favourable ES patients as those aged under 40 years with lymphocyte predominant or nodular sclerosing histology, without elevated ESR and with less than four disease sites. Favourable patients are randomised between RT alone and CT alone (four ABVD cycles), while unfavourable cases are randomised between CMT and CT alone, with two and four ABVD cycles respectively. For the advanced stages, the recent International Prognostic Factor Project, involving an analysis of more than 5000 cases from 23 different centres, yielded a prognostic score (IPS) which has been widely recognised [10]. The IPS includes 7 adverse factors: age 45 years and above, male sex, anaemia (< 10.5 g/dl haemoglobin), serum albumin < 4 g/dl, stage IV, white cell count > 15,000/mm3 and lymphocyte count (< 600/mm3 or < 8% of white cell count). The first four factors have also been identified in early stages, while stage IV is irrelevant and the remaining two factors have not been recognised as prognostic for the early stages. The IPS showed impressive discriminatory power in advanced

Patients and methods Between 1988 and 1994, 2022 adults (aged 15 to 75 years) with untreated HD were recruited into the second generation trials of the GHSG and treated in 139 hospitals and practices, mainly in Germany. The diagnosis was reviewed retrospectively by a central pathology panel: 68% of cases have been reviewed. All patients were clinically staged according to Ann Arbor [12] criteria. Treatment was administered according to stage and 5 risk factors, i.e., large mediastinal mass (more than one-third of maximum thorax diameter), extranodal disease, massive splenic involvement, ESR above 50 (with B-symptoms: 30) and involvement of 3 or more lymph node areas, as follows. HD4 trial. Patients in pathological stage I or II (obligatory laparotomy with splenectomy) without any risk factors. Treatment with extended field (EF) RT, 30 or 40 Gy. Recruitment of 399 patients. HD5 trial. Patients in clinical (or, if performed, pathological) stage I or II with at least one risk factor, and all stage IIIA patients. Treatment with two composite cycles of CT, either COPP + ABVD or COPP + ABV + IMEP, followed by EF.RT (30-40 Gy). Recruitment of 1025 patients. HD6 trial Patients in clinical (or, if performed, pathological) stage 1MB or IV. Treatment with four composite cycles of COPP + ABVD or COPP + ABV + IMEP followed by local irradiation of any initially bulky or slow responding disease. Recruitment of 598 patients. In the present report, the above-mentioned five risk factors and stage (including B symptoms), which all influence choice of GHSG treatment protocol, will be referred to as the 'GHSG prognostic factors'. Each trial involved randomisation to two arms, but the within-trial difference in treatment between the two arms was only slight. In HD4 patients were randomised to receive a dose of 30 Gy or 40 Gy to areas outside the involved field (IF always received 40 Gy). In both HD5 and HD6, patients were randomised to COPP + ABVD or COPP + ABV + IMEP. No trial demonstrated any difference in effectiveness between the two treatment arms; therefore, treatment arm was neglected in the present analysis. The median follow-up period was approximately six years in each trial. The present analysis aimed to test whether the IPS shows useful predictive ability in early stage HD. The primary analysis was restricted to the HD5 cohort for the following reasons. Firstly, this cohort includes patients both with and without each of the GHSG prognostic factors, and thus has a more representative distribution of

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s a.

stages, demonstrated for instance by application to the patients in the trial HD6 (1998-1993) of the GHSG (Figure 1). The IPS has already been used to select advanced stage patients for a particular treatment scheme [11]. In view of the lack of generally accepted prognostic factors for the early stages and of the difficulties (mentioned above) of elucidating such factors by an exploratory analysis of early stage data, the adoption or adaptation of the IPS from advanced to early stages is an attractive option. Further, the use of an as far as possible uniform prognostic score for all stages of HD would have the advantage of conceptual and practical simplicity. Therefore, the present report aims to test the prognostic and discriminatory power of the IPS in the early stages using data from the GHSG trials HD4 and HD5, to compare the importance of the various factors within the IPS and to assess whether further factors might improve its prognostic value.

619 Table 1. Frequencies of IPS factors in each GHSG trial. HD4(%) Factor Age > 45 years Male sex Stage IV Albumin <4.0g/dl Haemoglobin WBC Lymphocytes Number of factors 0 1 2 3 4 5 6 7

HD5 (%)

HD6 (%)

21 62 16 < l 2 2

20 53 33 6 13 12

28 58 50 61 21 22 25

24 52 20 4 <1 -

19 41 27 11 2
4 16 30 26 16 7 2 <>

albumin is the only other frequent factor (17%), the others each occurring in 2% of patients or less, whereas in HD5 each factor (other than age and sex) occurs in between 33% (albumin) and 6% of patients. These other four factors all have prevalences which increase markedly with increasing disease burden. Correspondingly, the distribution of IPS scores shifts towards larger values from HD4 to HD5 to HD6. The results in the HD5 cohort (cases with GHSG prognostic factors) were as follows. HD5 enrolled 1025 qualified patients. Some patients had missing data for one or more of the IPS factors: these were excluded from the present analysis, leaving 712 patients (70%) with all factors known ('evaluable') and 127 events. Comparison of the DFS between evaluable and non-evaluable patients showed no evidence of any difference in prognosis (P = 0.24). Prognostic power of the IPS (HD5)

DFS for the four groups IPS = 0,1, 2 and ^ 3 are shown in Figure 2 (univariate Kaplan-Meier analysis). The groups differ significantly (P - 0.018), although the ordering of the curves does not reflect the ordering of the categories. The most balanced dichotomy possible was 60% of patients with IPS 0-1 versus 40% with IPS 2-6. Figure 3 compares the DFS in these two groups, which have significantly different DFS of 85% and 78% atfiveyears (P - 0.0029). With the requirement that each group contain at least 20% of patients, no other dichotomy was Results possible. Cox regression analysis considering dichotoTable 1 shows the prevalences of the IPS factors and the mous IPS alone gave an estimated hazard ratio of 1.66 distribution of the IPS for evaluable patients in each (95% confidence interval (95% CI): 1.2-2.4). Overall survival (OS) differed highly significantly trial (for comparison, the trial HD6 for advanced stages has also been included). The factor male sex applies to according to IPS (P = 0.0001). Estimated five-year OS about 60% of patients and older age to about 20% - rates were: 94% with no factors, 92% with one factor, these two factors have similar prevalences in favourable, 89% with two factors and 82% with three or more unfavourable and advanced stage patients. In HD4, factors.

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patient characteristics than HD4. which only contains patients lacking all risk factors. Secondly, the combined modality therapy employed in HD5 is more relevant to modern strategies for early stage HD than the pure radiotherapy of HD4. Thirdly, the HD5 cohort is much larger, giving more statistical power. With 126 events for disease-free survival, if one-third of patients were to show a worse prognosis with a relative risk of failure of 1.7 then the power to detect an effect at the 5% level of significance would be 80% (calculated by the method of Schoenfeld [13]). In addition to the six IPS items (excluding stage IV) the following factors were considered in the analysis: reviewed histological subtype (LP and NS grade 1 versus NS grade 2, MC and LD), Karnofsky performance index (10 versus $ 9 ) and the six GHSG prognostic factors (see above). For the present analysis the treatment outcome of main interest was disease free survival (DFS), defined as the time between randomisation and progression, failure to achieve CR at completion of treatment, relapse or date of last information. Only Hodgkin-specific events were counted and not death due to treatment or other causes. Overall survival (OS), counting only death - from any cause - as an event, was analysed as a secondary endpoint. Univariate analysis was performed by the Kaplan-Meier method and the significance of the prognostic factor was assessed by the logrank statistic. Multivariate analysis was done by Cox's proportional hazards regression, using the likelihood ratio statistic to test for significance of factors. Cox regression yields the quantity 'hazard ratio' as a measure of the relative risk of failure in two groups of cases. This quantity is defined as the ratio of the probabilities of failure in the two groups during any (small) time interval. The relative risk (risk ratio) of failure between the two groups after a given elapsed time (e.g., five years) is approximately equal to the hazard ratio if the risks are small, as they are for early stage HD. Therefore, in the present paper, hazard ratios will be reported where appropriate, and these can be interpreted as approximate relative risks of failure. Firstly, a univariate analysis of the IPS was made to assess its prognostic significance and discrimination. Patients were initially divided into several groups according to their score between 0 and 6, amalgamating neighbouring scores to avoid group frequencies less than 10%. Then two dichotomous groupings were made: firstly such that approximately equal numbers of cases fell into each group, and secondly such that the largest possible prognostic discrimination (hazard ratio) was achieved (conditional on each group being at least 20% of the whole). Secondly, the six IPS factors were assessed and their prognostic power compared in a multivariate analysis. The Wald statistic for significance of removing each factor from the full model incorporating all factors was calculated, and the hazard ratios estimated for each factor were compared. To assess directly the value of including each factor in the index, a Cox model incorporating that factor and the IPS omitting that factor was fitted, and the P-value and hazard ratio for that factor recorded. Thirdly, the ability of the GHSG prognostic factors (see above), Karnofsky performance score and histological subtype to improve on the IPS was tested in a multivariate analysis. The significance and estimated hazard ratio of these additional factors was evaluated. The conclusions from the analysis of HD5 patients were then tested in the HD4 cohort, in order to assess their relevance for early stage patients without GHSG risk factors.

620 Table 2 Cox regression with each IPS factor X and the index omitting factor X(HD5).

100

80

60-

40-

20-

Factor X

Percentage F-value of patients forX

Age 45 Male sex LowHB Low albumin Leukocytosis Lymphopenia

20 53 6 33 13 12

0.23 0.24 0.28 0.016 0.54 0.75

P-value for indexa without X

Hazard ratio forX

95% CI forHR

0.027 0.013 0.046 0.70 0.0038 0.0075

1.28 0.81 1.41 1.55 1.16 1.09

0.86-1.92 0.57-1.15 0.75-2.63 1.09-2.20 0.72-1.88 0.64-1.84

p=0.0018

1 2

3

4

5

10

6

11

12

DFS (years)

Figure 2. HD5 (unfavourable early stages: CS I—II with one or more GHSG risk factor, and CS IIIA without any risk factors): disease-free survival according to IPS 0 (n = 132), 1 (n = 294), 2 (n = 191) and > 3 (« = 95).

Table 3. Cox regression with IPS and additional factors X (one at a time)(HD5). Factor X

Percentage l v a l u e of patients forX

NS2, MC or LD histology Karnofsky < 9 stage IIB-IIIA Extranodal disease Extranodal & stage IIB-IIIA Large mediast. mass Massive splenic inv. Erythrocyte sedim. rate 3+ nodal areas involved

35 37 55 12 5 25 7 49 63

Hazard ratio forX

95% CI forHR

0 74 0.75 0.26 0.086

0.92 1.06 1.23 1.54

0.57-1.49 0.74-1.52 0.86-1.77 0.94-2.50

0.0017 0.22 0.22 0.79 0.79

2.62 1.27 0.57 0.95 1.05

1.44-4.77 0.87-1.88 0.23-1.39 0.67-1.36 0.73-1.53

0-1 802-5

i II i o •

60-

40-

20-

p=0.0029

0 9

10

11

12

Columns 2-5 describe (respectively) the number of patients with the adverse factor, the multivariate significance of the factor, the estimated hazard ratio (relative risk of failure) for the factor and the 95% confidence interval for the true value of this hazard ratio.

DFS (years)

Figure 3. HD5 (unfavourable early stages: CS I—II with one or more GHSG risk factor, and CS IIIA without any risk factors): disease-free survival according to IPS 0-1 (n = 426) and > 2 (n = 286).

Karnofsky index (10 versus =%9, P = 0.031) and extranodal disease (p=0.043). The factors histology, large mediastinal mass, massive splenic involvement, elevated ESR and >2 involved nodal areas were not significant Prognostic power of the component IPSfactors (P > 0.05). In a multivariate analysis of each of these factors together with IPS, none of these factors were Multivariate analysis of the HD5 data indicated that the significant (P > 0.05) - see Table 3. Only extranodal factor 'low albumin level' was the only significant com- disease showed signs of prognostic value (P = 0.086) ponent (P - 0.016) of the IPS, taking account of the additional to the IPS. The small group of patients (5%) other factors. Moreover, the factor albumin was the only in stages IIB-IIIA with extranodal disease had a particone which significantly contributed to the fit when incor- ularly poor prognosis, significant in addition to the IPS porated in the multivariate model alongside the index (P = 0.0017). This latter result is exploratory, since the omitting albumin (Table 2). The IPS omitting albumin comparison was not originally planned. did not contribute significantly, when the contribution Figure 4 shows the discriminatory power of the IPS. of the factor albumin was accounted for. Each point represents a dichotomy based upon the number of IPS factors. The usefulness of the discrimPrognostic power of additionalfactors ination depends upon the percentage of patients in the poor prognosis group (horizontal axis) and the hazard Additional factors with univariate prognostic significance ratio (relative risk of failure - see 'Patients and methods') in HD5 were stage (I-IIA versus IIB-IIIA, P = 0.0023), between the two groups (vertical axis). The IPS identifies

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0

Columns 2-6 describe (respectively) the proportion of patients with the adverse factor, the multivariate significance of the factor, the multivariate significance of the remaining index, the estimated hazard ratio (relative risk of failure) for the factor and the 95% confidence interval for the true value of this hazard ratio. ° Dichotomised.

621 40% of patients with an approximately 1.7 times higher risk of progression/relapse. Confirmation in HD4

a. "5

10

20

30

40

50

60

70

80

90

100

Percentage of pts. with poorer prognosis

Figure 4. Prognostic strength of the IPS in HD5. The index was dichotomised at each possible value (0-4 vs. 5; 0-3 vs. 4-5; 0-2 vs. 3-5; 0-1 vs. 2-5 and 0 vs 1-5) For each dichotomy, the percentage of patients in the unfavourable group and the hazard ratio (relative risk of disease-related failure in unfavourable group compared with favourable group) were calculated and plotted on the horizontal and vertical axes, respectively.

100

Discussion

The results of the present analysis suggest that the international prognostic score for advanced stage HD is also relevant to the disease-specific prognosis of patients in unfavourable early stages. The prognostic relevance has been demonstrated in the trial HD5 for unfavourable early stage HD treated with combined modality therapy. The effect size (IPS 0-1 vs. IPS 2-5) was of approximately 8% difference in long-term disease free survival or a hazard ratio of about 1.7. Only the factor 'low albumin' had significant individual prognostic value. Allowing for the influence of the IPS, extranodal disease in stages IIB or IIIA appeared to be associated with adverse prognosis. In the smaller HD4 cohort of favourable early stages the IPS was of only borderline significance, although the estimated hazard ratio agreed with that seen in HD5. The small size of the difference in prognosis identified by the IPS is partly due to the overall good prognosis of early stage patients. Hasenclever and Diehl [10] obtained five-year progression-free rates of 74% and 55% for patients with 0-2 and 3+ factors respectively, a difference of 19% and a relative risk of 1.7. Thus although the absolute differences are larger in the advanced stages than in HD5 (8%), the relative risk is comparable to the hazard ratio (1.7) observed in HD5 and in HD4. Since albumin was the only significant component of

8

9

10

11

12

DFS (years)

Figure 5. HD4 (favourable early stages: CS I—II without any GHSG risk factors): disease-free survival according to IPS 0 (n = 59), I (n= I3l)and > 2 ( n = 60).

the IPS, it could be argued that we do not need the remaining factors for the early stages. This is true for many practical purposes. However, our aim was to assess the suitability of the IPS as a uniform index applicable to all stages. An increased risk was estimated in association with each factor except male sex, thus suggesting (without reaching statistical significance) consistency with the advanced stages. Several of the IPS factors (anaemia, albumin, leukocytosis, lymphopenia) involve the choice of a threshold value or 'cut-point' on a continuous scale. It is possible that a different choice of cut-point could improve the prognostic value of the factors in the early stages, espe-

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Analogous results in the HD4 cohort (without GHSG risk factors) were as follows. Three hundred ninety-nine patients were enrolled and two hundred forty-nine of these were evaluable, withfifty-threeevents. DFS for three groups IPS = 0, 1, ^ 2 are shown in Figure 5 (univariate Kaplan-Meier analysis). As for HD5, the most balanced dichotomy possible was 76% of patients with IPS 0-1 versus 24% with IPS 2-6. The DFS in these two groups were 85% and 72% at five years (P = 0.094). It is clear from Figure 5 that the other possible division, 0 versus 1-4 factors, would discriminate poorly. Cox regression analysis considering dichotomous IPS alone gave an estimated hazard ratio of 1.63 (95% CI: 0.94-2.9). Only age, sex and albumin are candidates for verifiable and useful discrimination in HD4, since the remaining factors apply to at most 2% of patients (Table 1). No factor was significant on its own (P > 0.05). Additionally to the IPS, histology (MC and NS2 versus LP and NS1) showed borderline prognostic significance in HD4 (P - 0.056). The factors stage, B-symptoms and Karnofsky index were not significant (P > 0.10). In a multivariate analysis of each of these factors together with IPS, no factor was significant (P > 0.10).

622 100 ^

1

^ "'•»"••"

80-

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60-

S

80

40-

20.

s

0 10

11

12

DFS (years)

Q.

8

9

10

11

12

Years

Figure 6. HD5 (unfavourable early stages): disease-free survival ac- Figure 7 HD5 (unfavourable early stages)- failure not directly related cording to modified IPS (with extranodal IIB-II1A) 0 (n = 130), 1 to Hodgkin's disease according to IPS. Most of these events were (n = 282), 2 (n = 189) and > 3 (n = 105). deaths in continuing complete remission due to cardio-respiratory disease, second malignancies or unknown causes. (Numbers of patients as in Figure 2.)

cially those which apply, with present cut-points, to very few patients. Informally, this possibility was tested in an exploratory manner. A raising of the cut-point for haemoglobin was found to lead to a significant but small (circa 5%) DFS difference in univariate analysis, although the prognostic discrimination of the accordingly modified IPS was not increased. Modifications of the cut-points for leukocytosis and lymphcytopenia, respectively, did not show any prognostic value. There is thus no evidence from our data that changes of cut-point could improve the IPS in early stages. The HD5 cohort with 712 evaluable cases and 127 events is large enough for a reliable analysis including a limited number of factors, although statistical power is much lower than in the large, internationally pooled analysis of Hasenclever and Diehl. By contrast, the HD4 data contain rather few events (53) for a reliable analysis. It is therefore not surprising that no significant IPS effect could be detected in HD4 despite similar estimates of hazard ratio. The hypothesis that the IPS applies, to the first order of magnitude, equally to early favourable, early unfavourable and advanced HD, is to some extent supported by our data. Further conclusions will be guided mainly by our results in HD5, rather than HD4, for the reasons given in 'Patients and methods'. In the analysis of the HD5 cohort it was noted that the presence of extranodal disease in stage IIB-IIIA is significant for prognosis, allowing for the effect of the IPS. The addition of such a factor to the IPS is a natural modification for early stages, as a substitute for the factor 'stage IV employed in the IPS for advanced stages. Firstly, both factors represent the fact that higher stage tends to be associated with worse prognosis. Secondly, the distinction between extranodal stage II or III disease (a localised extranodal extension anatomically linked to nodal disease) and stage IV disease (disseminated or lymph-node-independent extranodal involvement) is not always reliably made [14]. Thus, the diag-

nosis of extranodal disease may be an adverse factor in stage IIB and IIIA in this setting due to the unintentional inclusion of some stage IV cases. Figure 6 shows that the addition of the factor 'extranodal stage IIBIIIA' to the IPS increases the correlation between IPS and prognosis in HD5. This proposed modification of the IPS is, however, exploratory, and its usefulness - or otherwise - needs to be confirmed. The main endpoint chosen for this analysis was the disease-specific measure DFS, in which deaths from other causes are not counted as events. By contrast, an analysis of overall survival (OS) showed much larger prognostic differences according to the IPS. These differences, however, are mainly due to later deaths from cardio-respiratory diseases, second malignancies or miscellaneous or unknown causes. Deaths in each of these categories were more frequent in older patients, while cardio-respiratory deaths were more frequent in males: this immediately explains the 'prognostic' power of the IPS for OS. This effect is made clear in Figure 7, a Kaplan-Meier plot where only deaths not directly related to HD were counted as events. The main purpose of a prognostic index is to identify patients who are likely to benefit from a more intensive therapy, or conversely those who would be adequately treated with less therapy. It is assumed that patients with more virulent or more treatment-resistant disease need more intensive therapy, and vice versa. The virulence or treatmentresistance of the disease is indicated only by diseasespecific events, not by treatment-related or unrelated deaths. It is therefore essential to use a disease-specific endpoint in a prognostic factor study, especially in diseases, such as early-stage HD, where the majority of deaths are not disease-related. The relatively modest prognostic differences detected by use of the IPS in early stages are unlikely to justify

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p=0.0091

623

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Received 3 November 1999; accepted 30 March 2000.

Correspondence to: J. Franklin, MD Klinik I fur Innere Medizin Universitat Koln Herderstr. 52-54 D-50931 Koln Germany E-mail: Jeremy/ranklingbiometrie.uni-koeln.de

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radically different treatment strategies. However, in recent years there has been a trend towards the use of combined modality treatment for all Hodgkin's disease patients, even the favourable early stages, and the use of lower dose involved field irradiation. This trend follows recognition of the increased rates of solid tumours one to two decades after irradiation [15], and of the excellent treatment results in paediatric trials using chemotherapy alone or combined with mild irradiation [16]. The role of a prognostic index in early stage HD is therefore now less concerned with treatment modality than with quantity and intensity of treatment, for instance type of chemotherapy, number of cycles, extent and dosage of radiotherapy. The current GHSG trials (HD10, HD11) investigate the number of chemotherapy cycles and the radiotherapy dose required in favourable and unfavourable early stages (excluding all stage III). Even small prognostic differences could justify the use of different values of these parameters. At present, divergent criteria are used by different study groups to separate favourable from unfavourable disease. The widespread adoption of combined modality strategies both facilitates and demands the development of a widely recognised and optimal prognostic score for this purpose. An internationally pooled analysis, similar to that of Hasenclever and Diehl for the advanced stages, is needed. Alternatively, by combining certain arms of the current GHSG trials HD10 and HD11, a cohort of both 'favourable' and 'unfavourable' patients uniformly treated with four cycles of ABVD plus involved field radiation, approximately 750 cases in total, will be available. This cohort will provide an opportunity to evaluate prognostic factors in uniformly treated early stage HD.

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