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Prognostic Factors for Children With Hodgkin’s Disease Treated With Combined-Modality Therapy

From the Departments of Radiation Oncology and Pediatrics, Stanford University School of Medicine, Stanford, CA; Departments of Hematology-Oncology and Radiation Oncology, St Jude Children’s Research Hospital, Memphis, TN; Department of Pediatric Oncology and Division of Radiation Oncology, Children’s Hospital, Dana-Farber Cancer Institute, Harvard Medical School; and Division of Pediatric Hematology-Oncology and Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA.

Address reprint requests to Ron S. Smith, MD, Department of Radiation Oncology, Mayo Clinic, Immanuel-St Joseph’s Hospital, 1025 Marsh St, PO Box 8673, Mankato, MN 56002; email: smith.ron{at}mayo.edu.

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Purpose: Evaluation of pretreatment factors to identify children at high risk for relapse after combined-modality therapy for Hodgkin’s disease.

Patients and Methods: From 1990 to 2000, 328 pediatric patients with clinical stage I to IV Hodgkin’s disease were treated with chemotherapy and low-dose involved-field radiotherapy on prospective, collaborative, risk-adapted protocols at three institutions. Pretreatment factors were analyzed by univariate and multivariate analysis for prognostic significance for 5-year disease-free survival (DFS) and overall survival (OS).

Results: With a median follow-up of 59 months (range, 8 to 125 months), the 5-year DFS and OS for all patients were 83% and 93%, respectively. Several factors were associated with inferior DFS and OS by univariate analysis. By multivariate analysis, male sex; stage IIB, IIIB, or IV disease; bulky mediastinal disease; WBC more than 13.5 x 10³/mm³; and hemoglobin less than 11.0 g/dL were significant for inferior DFS. A prognostic index was developed incorporating the five significant factors from the multivariate analysis, assigning each a score of 1. The 5-year DFS and OS for children with a prognostic score of 0 to 1 were 94% and 99%; score 2, 85% and 96%; score 3, 71% and 92%; and score 4 or 5, 49% and 72%, respectively. There was a significant difference in DFS among each of these groups, with significantly worse OS in those with a score of 4 to 5.

Conclusion: A prognostic index that was based on five pretreatment factors correlated with inferior DFS by multivariate analysis stratified patients by outcome; this may be useful in assigning children with Hodgkin’s disease to risk-adapted therapy.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
CONTEMPORARY TREATMENT for children and adolescents with Hodgkin’s disease often uses a combined-modality approach with multiagent chemotherapy and involved-field radiotherapy. This approach has yielded excellent results, with long-term disease-free survival (DFS) of 85% to 100% in patients with early-stage disease and of more than 60% in those with more advanced disease.^1–20 Consequently, the focus of current treatment protocols has been to reduce treatment-related sequelae while maintaining excellent survival rates in those with early-stage disease and to improve survival in patients with advanced-stage disease. To achieve these goals, the intensity and duration of treatment would ideally be tailored according to pretreatment factors that are prognostic for outcome.

Prognostic factors have been identified in adult patients with Hodgkin’s disease, and several prognostic indices have been developed to guide therapy decisions.^21–28 However, these indices may not be relevant for children with Hodgkin’s disease. Few studies have analyzed prognostic factors for pediatric Hodgkin’s patients^{10,16,17,19,20} and one study proposed a prognostic index for children with early-stage disease²⁰; however, a prognostic index encompassing all stages of pediatric Hodgkin’s disease has not been developed.

The objective of this study was to determine the prognostic significance of several clinical factors present at diagnosis among children with stage I to IV Hodgkin’s disease who received combined-modality therapy and to develop a prognostic index that could stratify patients for risk-adapted treatment.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Study Population
Between August 1990 and February 2000, 334 pediatric patients with histologically proven Hodgkin’s disease were enrolled onto collaborative protocols using combined-modality therapy at Stanford University Medical Center (Stanford, CA), St Jude Children’s Research Hospital (Memphis, TN), and Dana-Farber Cancer Institute (Boston, MA). All patients were staged according the Ann Arbor staging classification,²⁹ and two patients underwent staging laparotomy. Six patients did not undergo radiotherapy by patient or family choice, against medical advice (none had progressive disease [PD] after chemotherapy), and were excluded from our analysis of prognostic factors after combined-modality therapy. Therefore, 328 pediatric patients were included in this study. One hundred ten patients with stage I to II nonbulky disease received four cycles of vinblastine, doxorubicin, methotrexate, and prednisone (VAMP), whereas 61 patients with bulky disease (mediastinal mass ratio more than one third the intrathoracic diameter or peripheral nodal disease measuring 6 cm in the greatest dimension) or stage III to IV disease received six cycles of vinblastine, etoposide, prednisone, and doxorubicin (VEPA). Accrual to the VEPA regimen was closed in 1993 because of inferior event-free survival.³⁰ Since then, patients with bulky or advanced disease were treated with six cycles (153 patients) or four cycles (one patient) of alternating VAMP and cyclophosphamide, vincristine, and procarbazine (COP). Three patients who received four cycles of VEPA at the time of closure of this arm were subsequently given four cycles of COP. Chemotherapy was alternated with involved-field radiotherapy given to all sites of initial disease, excluding the bone marrow; the prescribed radiation dose was based on disease response after two cycles of chemotherapy. Those achieving a complete response (CR) to the initial two cycles of chemotherapy received 15 Gy, whereas those with a partial response or those with bulky disease at presentation were prescribed 25.5 Gy.

Prognostic Factor Analysis
A spectrum of pretreatment factors were evaluated for prognostic significance: age (stratified at the median), sex, stage, histology, presence of systemic B symptoms, presence of extranodal disease, presence and location of bulky disease, number of Ann Arbor nodal sites involved (< three v three), WBC count ( 13.5 v > 13.5 x 10³/mm³), hemoglobin (< 11.0 v 11.0 g/dL), erythrocyte sedimentation rate (ESR; < 50 v 50 mm/h), site of involvement (supraclavicular, axillary, hilar, para-aortic, porta hepatis, celiac, iliac, and inguinal nodes, as well as chest wall, pericardium, spleen, bone, bone marrow, and lung), and type of chemotherapy used. Although albumin level was routinely collected at diagnosis with other clinical data, this information was unavailable for more than 10% of the patients. In addition, the distribution of these missing data was disproportionate among patients who had disease recurrence (30%). Therefore, it was not analyzed as a prognostic factor. Parameters for leukocytosis and anemia were based on published laboratory standards for children.³¹

Statistical Analysis
DFS was calculated from the initiation of treatment to relapse, PD, or the most recent follow-up examination. Overall survival (OS) was determined as the time from initiation of therapy to death or the last follow-up examination. Patients who died as a result of causes other than Hodgkin’s disease without evidence of recurrence at the time of death were censored. Pretreatment factors were evaluated with univariate analysis using the Kaplan-Meier product-limit method³² to calculate survival probabilities for both DFS and OS at 5 years. Survival differences were compared by using the log-rank test³³ and survival curves were generated with the Kaplan-Meier method. Associations between variables were assessed with Pearson’s correlation. To determine the independent prognostic significance of pretreatment factors on DFS, multivariate analysis was conducted using the Cox proportional hazard regression method.³⁴ DFS was chosen as the end point in the multivariate analysis because of the combination of a small percentage of deaths in the study group and the fact that 14% of the deaths occurred in patients without evidence of active Hodgkin’s disease. In the multivariate analysis, stage and presence of B symptoms were combined into one variable, and histology was analyzed as a dichotomous variable (nodular sclerosis [NS] histology v all other histologies), as described in Results. Type of chemotherapy was included in the multivariate analysis to control for treatment variations. However, the proportion of patients with specific sites of involvement was insufficient to provide a stable model in the multivariate analysis; thus, this parameter was not included. Therefore, the variables analyzed by multivariate analysis were age, sex, stage and B symptoms, histology, presence of extranodal disease, status of bulky disease, number of Ann Arbor sites involved, WBC, hemoglobin, ESR, and type of chemotherapy. A prognostic index was devised that was based on the pretreatment factors identified as significant for DFS by multivariate analysis. All calculations were performed with SPSS version 9.0 statistical software (SPSS Inc, Chicago, IL).

	RESULTS

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The median age of the 328 patients in this study group was 14 years (range, 2 to 20 years) and most (60%) were male. Fifty-three patients had stage I disease, 160 patients had stage II disease, and 51 and 64 patients had stage III and IV disease, respectively. Forty-eight patients (15%) received a radiotherapy dose of 15 Gy, 274 patients (84%) received 25.5 Gy, and six patients (1%) received more than 25.5 Gy. The median length of follow-up for the entire group was 59 months (range, 8 to 125 months). Forty-eight patients (15%) relapsed, and 21 patients (6%) died: 18 patients from Hodgkin’s disease, two patients from motor vehicle accidents, and one patient from congestive heart failure. After two cycles of chemotherapy, 63 patients (19.2%) had a CR, 263 patients (80.2%) had a partial response, and two patients (0.6%) had PD. None of the patients with a CR after two cycles of chemotherapy has relapsed. Thirty-one (65%) of the 48 relapsing patients experienced treatment failure in the site of initial disease involvement, and all had received 25.5 Gy. The 5-year DFS and OS rates for the entire group were 83% and 93%, respectively.

Univariate analysis, summarized in Table 1, revealed the following pretreatment factors to be prognostic for both inferior 5-year DFS and OS: stage IV disease; NS histology; B symptoms; extranodal disease; bulky mediastinal disease; combination of bulky mediastinal and bulky peripheral disease; involvement of three or more nodal sites; hemoglobin less than 11.0 g/dL; ESR 50 mm/h; involvement of axilla, chest wall, or pericardium; and VEPA chemotherapy. In addition, stages IIB and IIIB, bulky peripheral disease, WBC more than 13.5 x 10³/mm³, involvement of hilar or porta hepatis nodes, and VAMP–COP chemotherapy were associated with significantly worse DFS but not OS.

Patients with NS histology had significantly worse DFS and OS versus those patients with other histologies (Table 1), whereas DFS and OS were not significantly different among non-NS histologic subtypes; therefore, histology was analyzed as NS versus non-NS histologies combined in the multivariate analysis. By univariate analysis, patients with bulky mediastinal disease (n = 74) or the combination of bulky mediastinal and bulky peripheral disease (n = 31) had significantly worse DFS and OS than those who had no bulky disease or had only bulky peripheral disease (P < .05). However, there was no significant difference in DFS or OS between the former two subgroups (P = .16). Thus, because of the relatively small number of patients with both bulky mediastinal and bulky peripheral disease, this group was combined in the multivariate analysis with patients who had bulky mediastinal disease.

Although male sex was not associated with significantly inferior DFS by univariate analysis, analysis of the relationships between pretreatment variables by Pearson’s correlation showed that male sex had a significant advantage compared with female sex in several of the prognostic categories (less likely to have NS histology, extranodal disease, bulky mediastinal disease, involvement of three or more nodal sites, hemoglobin < 11.0 g/dL, ESR 50 mm/h, and WBC > 13.5 x 10³/mm³; all P values < 0.01). In addition, males had a higher CR rate to initial chemotherapy than did females (24% v 12%, respectively; P = .01). However, these advantages for males did not translate into better outcome compared with outcome in females. Additional univariate analysis with stratified data revealed that among patients with bulky mediastinal disease, males (n = 52) had a significantly worse 5-year DFS than females (n = 53; 62% v 84%, respectively; P = .02). In addition, for those with extranodal disease, the 5-year DFS was significantly less for males (n = 37) than females (n = 42; 58% v 77%, respectively; P = .03). These data indicate that sex was not a significant prognostic factor in univariate analysis because of confounding by other variables; therefore, sex was entered into the multivariate analysis.

Multivariate analysis revealed five factors that were independently predictive of significantly inferior DFS: male sex; stage IIB, IIIB, and IV disease; bulky mediastinal disease; WBC more than 13.5 x 10³/mm³; and hemoglobin less than 11.0 g/dL, as shown in Table 2.

View larger version (13K): [in this window] [in a new window]   Fig 1. Projected 5-year disease-free (A) and overall (B) survival by prognostic score in 328 children with stage I to IV Hodgkin’s disease.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

Our study identified five pretreatment factors prognostic for outcome by multivariate analysis: male sex; stage IIB, IIIB, or IV disease; bulky mediastinal disease; leukocytosis (WBC > 13.5 x 10³/mm³); and anemia (hemoglobin level < 11.0 g/dL). Incorporating these five factors into a prognostic index stratified patients to four groups with significantly different 5-year DFS. In addition, the treatment factor of response to initial chemotherapy was a strong predictor of outcome, with no relapses in patients who achieved a CR. Our prognostic index was predictive of the response to initial chemotherapy; 99% of complete responders had a prognostic score of 0, 1, or 2.

The fact that VEPA and VAMP–COP were prognostic for inferior outcome by univariate analysis reflected the use of these two regimens in patients with advanced disease who were expected to have a worse prognosis, compared with patients with more favorable prognoses who received VAMP. When pretreatment factors were analyzed simultaneously by multivariate analysis, type of chemotherapy was no longer significantly associated with outcome.

In a large study of adults with advanced Hodgkin’s disease treated with combination chemotherapy with or without radiotherapy, the International Prognostic Factors Project²¹ identified seven factors prognostic for freedom from progression: male sex; age 45 years; stage IV disease; hemoglobin less than 10.5 g/dL; white blood count 15,000/mm³; lymphocyte count less than 600/mm³, less than 8% of total WBC, or both; and serum albumin less than 4 g/dL. From these factors, a prognostic score was developed to predict outcome on the basis of the number of factors present at diagnosis.

Two previous studies analyzed prognostic factors, excluding laboratory characteristics, in children with stage I to IV Hodgkin’s disease treated with combined-modality therapy. Schellong et al¹⁹ analyzed pretreatment risk factors among patients with stage I to IV disease enrolled onto the DAL-HD-90 trial and treated with chemotherapy and low-dose involved-field radiotherapy. They found that NS histology and B symptoms were associated with worse outcome by multivariate analysis. In another study, Vecchi et al¹⁶ reported NS histology, B symptoms, and large mediastinal mass to be prognostic for inferior outcome by multivariate analysis.

Prognostic factor analysis has been reported in two studies of children with advanced Hodgkin’s disease. The Pediatric Oncology Group (POG) found stage IV and male sex as prognostic for inferior event-free survival,¹⁷ whereas the Children’s Cancer Group found stage, ESR, liver size, and mediastinal bulk among stage III patients as prognostic for inferior event-free survival.¹⁰

In our study, advanced stage, bulky mediastinal disease, NS histology, and B symptoms were also prognostic for both inferior DFS and OS by univariate analysis. Bulky mediastinal disease, stage, and B symptoms maintained prognostic significance in the multivariate analysis (the last two as part of the grouping of patients with stage IIB, IIIB, and IV disease); however, histology did not maintain prognostic significance. Male sex was prognostic for outcome in multivariate analysis, but not in univariate analysis. The apparent contradiction in our results between the univariate and multivariate analyses for sex and histology can be explained mathematically. The crude assessment of an association between two variables obtained from univariate analysis can often be biased because of interrelationships among other extraneous or confounding factors. Pearson’s correlation revealed significant association between sex and several other pretreatment characteristics, as well as between NS histology and two other prognostic factors (bulky mediastinal disease [P < .001] and stage [P < .001]). Confounding may cause bias in two directions: positive bias (significant in univariate analysis but not in multivariate analysis) or negative bias (not significant in univariate analysis but significant in multivariate analysis). Adjustment for confounding variables can be performed in two ways: data can be stratified in univariate analysis or multivariate analysis can be performed. When the simultaneous relationships among pretreatment factors were controlled for by multivariate analysis, male sex was prognostic for inferior outcome (negative bias), and histologic type was not prognostic for inferior outcome (positive bias).

In addition to our study, male sex has been identified as a poor prognostic factor in children with Hodgkin’s disease in the POG study¹⁷ and also in adults.^21,24,28 In the POG study, males had a lower CR rate to chemotherapy, with a trend toward statistical significance; however, in our study, male patients had a higher CR rate to initial chemotherapy. It is interesting to note that, on additional analysis, male sex had a significant correlation with several favorable clinical factors (lower stage, non-NS histology and less likely to have extranodal disease, bulky mediastinal disease, three nodal sites, hemoglobin < 11.0 g/dL, ESR 50 mm/h, and WBC > 13.5 x 10³/mm³), yet their outcome was not significantly different from that of females. By stratified univariate analysis, two subgroups of males were found to have significantly worse DFS than females: those with bulky mediastinal disease and those with extranodal disease. Therefore, males did not have the survival advantage that may have been expected because of the inferior outcome in these subgroups and, possibly, other physiologic factors, yielding male sex as a poor prognostic factor by multivariate analysis; this is consistent with the aforementioned studies.

A prognostic index for children with stage I or II Hodgkin’s disease treated with response-adapted combined-modality therapy was proposed in a study by the French Society of Pediatric Oncology.²⁰ They reported hemoglobin less than 10.5 g/dL, biologic class b (two or more of the following: ESR 40 mm/h; leukocytes > 12 x 10⁹/L, polymorphonuclear neutrophils > 70%, or both; fibrinogen > 5 g/L; alpha₂-globulin > 10 g/L; and albumin < 35 g/L), and NS histology as predictors of inferior event-free survival by multivariate analysis. They devised a prognostic index based on these three factors and assigned a score of 1 for anemia or biologic class b and 2 for NS histology. Patients with a score of 2 had an event-free survival of 98% v 64% in those with a score of 3.

Our study also showed that laboratory characteristics of anemia and leukocytosis are prognostic for inferior outcome. Abnormalities in WBC and hemoglobin levels are thought to reflect cytokine activation, which may have a wide range of effects, from gene expression and influence on apoptotic potential to expression of adhesion molecules, which may influence metastatic capability.^35,36 Investigations into the molecular processes involved in the etiology and progression of Hodgkin’s disease are yielding specific molecular features that are prognostic for outcome, including soluble CD30,³⁷ increased serum interleukin-2 receptor levels³⁸ and interleukin-10 levels,^39,40 and overexpression of proliferating cell nuclear antigen, p53, and bcl-2,²⁷ which may serve as potential targets for future therapy.

The prognostic index developed in this study for all stages of pediatric Hodgkin’s disease identified patients at high risk of relapse after contemporary combined-modality therapy. The projected relapse rate at 5 years was 29% for those with a prognostic score of 3 and 51% for those with a score of 4 or 5, with an OS rate of only 72% at 5 years in the latter group. Response to initial chemotherapy correlated with outcome and this index identified patients who were unlikely to attain a CR (1% of patients with a score of 3 and 0% of patients with a score of 4 or 5). Therefore, one strategy to improve outcome for patients predicted to have a high risk of relapse after combined-modality therapy (prognostic score 3, 4, or 5) would be to increase the CR rate to initial chemotherapy, perhaps with more intensive regimens.

This prognostic index may be specific to the treatments used in this study and should be validated in other studies. However, we believe that this index will be useful in risk-adapted therapy protocols to assign patients to the appropriate intensity and duration of treatment on the basis of individual relapse risk, with the goal of reducing treatment-related sequelae for those predicted to do well and improving survival for those identified as requiring more aggressive therapy.

	ACKNOWLEDGMENTS

 
We thank Claire Colon for her assistance.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
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Submitted July 22, 2002; accepted February 20, 2003.

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