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Journal of Clinical Oncology, Vol 18, Issue 7 (April), 2000: 1500-1507
© 2000 American Society for Clinical Oncology

Localized Childhood Hodgkin’s Disease: Response-Adapted Chemotherapy With Etoposide, Bleomycin, Vinblastine, and Prednisone Before Low-Dose Radiation Therapy—Results of the French Society of Pediatric Oncology Study MDH90

By J. Landman-Parker, H. Pacquement, T. Leblanc, J. L. Habrand, M. J. Terrier-Lacombe, Y. Bertrand, Y. Perel, A. Robert, C. Coze, I. Thuret, J. Donadieu, G. Schaison, G. Leverger, J. Lemerle, O. Oberlin

From the Departments of Pediatric Hematology and Oncology, Hopital d’Enfants Armand Trousseau, Institut Curie, Hopital Saint Louis, Paris; Institut Gustave Roussy, Villejuif; Hopital Debrousse, Lyon; Hopital Pellegrin, Bordeaux; Hopital Purpan, Toulouse; and Hopital La Timone, Marseille, France.

Address reprint requests to Judith Landman-Parker, MD, Service d’Hématologie et d’Oncologie Pédiatrique, Hôpital d’Enfants Armand Trousseau, 26 avenue Arnold Netter, 75012 Paris, France; email judith.landman-parker{at}trs.ap-hop-paris.fr


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 APPENDIX
 REFERENCES
 
PURPOSE: The French Society of Pediatric Oncology MDH82 study demonstrated the effectiveness of 20 Gy irradiation of involved fields after doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) or mechlorethamine, vincristine, procarbazine, and prednisone/ABVD chemotherapy in children with localized Hodgkin’s disease (HD). The response to primary chemotherapy was the only predictor of survival. To reduce long-term treatment complications without compromising efficacy, the MDH90 study was based on a new chemotherapy regimen devoid of both alkylating agents and anthracycline, followed by 20 Gy of radiotherapy (RT) for good responders.

PATIENTS AND METHODS: From January 1990 to July 1996, 202 children were enrolled from 30 institutions. Good responders to four cycles of vinblastine, bleomycin, etoposide (VP16), and prednisone (VBVP) were given 20 Gy of RT and no further therapy. Poor responders were given vincristine, procarbazine, prednisone, and doxorubicin. After a second evaluation, good responders were given 20 Gy of RT, and poor responders were given 40 Gy of RT.

RESULTS: One hundred seventy-one patients (85%) were good responders to VBVP, 27 (15%) were poor responders, and four did not respond. With a median follow-up of 74 months (range, 25 to 117 months), the 5-year overall survival rate (mean ± SD) is 97.5% ± 2.1%, and the event-free survival rate (mean ± SD) is 91.1% ± 1.8%. Significant predictors of worse event-free survival in multivariate analysis were hemoglobin < 10.5 g/L, "b" biologic class, and nodular sclerosis.

CONCLUSION: These results suggest that most children with clinical stage I and II HD can be treated with chemotherapy devoid of alkylating agents and anthracycline, followed by low-dose RT.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 APPENDIX
 REFERENCES
 
ONE OF THE MAIN therapeutic aims in childhood Hodgkin’s disease (HD) is to minimize late toxicity without compromising the cure rate. The current 5-year disease-free survival (DFS) rate ranges from 88% to 100% for patients with localized disease.1-3 Most treatment programs for childhood HD consist of combined-modality therapy, with a focus on reducing the dose and field of radiation therapy (RT) and the cumulative doses of cytotoxic agents.4-9 Optimal treatment for early stages is highly controversial now that we have better knowledge of late toxicity. The French Society of Pediatric Oncology conducted its first national study (MHD82) between 1982 and 1988, enrolling 238 patients.7 The results confirmed that: (1) doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) alone is equivalent to alternating mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) and ABVD in stages IA and IIA, with 4-year DFS rates of 93% and 90%, respectively; (2) that chemotherapy followed by RT (20 Gy) is a valid therapeutic approach to most cases of HD (DFS = 86% and overall survival [OS] = 92% at 6 years); and (3) that the response to primary chemotherapy is the only factor predictive of OS and DFS (18% DFS among poor responders and 89% DFS among good responders).

Treatment-related toxicity and serious late sequelae in patients with HD include second malignancies, male infertility, and late pulmonary and cardiac damage.10-13 Therefore, we investigated a new chemotherapy regimen with less potential toxicity than contemporary combinations containing alkylating agents such as nitrogen mustard, procarbazine, and anthracycline. We adopted a treatment strategy based on the initial sensitivity and response to chemotherapy, thereby reducing the cumulative dose administrated to the majority of patients. In 1990, we used a combination of vinblastine, bleomycin, etoposide (VP16), and prednisone (VBVP) for localized HD in a large nationwide study called MDH90. Based on clinical and radiologic responses after four cycles of VBVP, only poor responders received vincristine, procarbazine, doxorubicin, and prednisone (OPPA). RT was also tailored to the response to chemotherapy, with 20 Gy of RT to involved fields for good responders and 40 Gy of RT for poor responders. The objectives were to reduce long-term toxicity and to obtain results comparable with those previously reported.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 APPENDIX
 REFERENCES
 
Study Design
From January 1990 to July 1996, 202 patients under 18 years of age were enrolled in 30 French institutions (see Appendix) and gave their informed consent to the study. Patients with human immunodeficiency virus infection (n = 1), congenital immunodeficiencies (n = 2), secondary HD (n = 4), or lymphocyte-predominant nodular HD (n = 14), and patients lost to follow-up (n = 3) were excluded. All patients had biopsy-proven HD and were classified according to the Rye pathologic classification.14 All the patients were staged clinically and biologically according to the Ann Arbor Conference classification.15,16 Surgical staging was not routinely performed. Localized disease was defined as stages IA, IB, IIA, and IIB. Biologic class "b" was defined by two or more of the following findings: erythrocyte sedimentation rate (ESR) >= 40 mm/h, fibrinogen > 5 g/L, leukocytosis > 12 x 109/L and/or polymorphonuclear neutrophil > 70%, {alpha}2-globulin > 10 g/L, and albumin < 35 g/L. Patients underwent a thorough physical examination, including the nasopharynx. Laboratory studies (full blood cell count, hemoglobin, platelets, ESR, and liver function tests), chest roentography, thoracic and abdominal pelvic computed tomography (CT), and lymphography were performed routinely, together with abdominal ultrasonography, to detect subdiaphragmatic involvement. Bilateral iliac marrow biopsies and 99Tc-bone scintigraphy were performed when "B" symptoms were present.

Treatment Strategy
The treatment strategy is summarized in Fig 1. Patients received four courses of VBVP, ie, vinblastine 6 mg/m2 intravenous (IV) on days 1 and 8, bleomycin 10 mg/m2 IV on day 1, etoposide 100 mg/m2 IV on days 1 to 5, and prednisone 40 mg/m2 orally (PO) on days 1 to 8. Cycles were repeated every 3 weeks. After completion of the fourth cycle, the treatment response was assessed clinically on all sites, and volumetrically by CT of clinically inaccessible sites. A good response was defined as either complete remission or more than a 70% reduction in tumor size. Good responders received 20 Gy of RT to initially involved fields.



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  		Fig 1. MDH90 study design. VBVP1: courses given every 3 weeks; vinblastine 6 mg/m2 on days 1 and 8, bleomycin 10 mg/m2 on day 1, etoposide 100 mg/m2 on days 1 to 5, and prednisone 40 mg/m2 on days 1 to 8; OPPA2: courses given every 4 weeks; vincristine 1.5 mg/m2 on days 1, 8, and 15, procarbazine 100 mg/m2 on days 1 to 15, prednisone 60 mg/m2 on days 1 to 15, and doxorubicin 40 mg/m2 on days 1 and 15; R: response.

 
The remaining patients (poor responders) were given one or two cycles of OPPA, ie, vincristine 1.5 mg/m2 IV on days 1, 8, and 15, procarbazine 100 mg/m2 PO on days 1 to 15, prednisone 60 mg/m2 PO on days 1 to 15, and doxorubicin 40 mg/m2 IV on days 1 and 15. Poor responders were evaluated after each cycle of OPPA, with a view to minimizing the total dose of chemotherapy. If no response was obtained after one cycle of OPPA, RT was administered at 40 Gy. If the response after the first or the second cycle exceeded 70%, the patient received 20 Gy to involved fields. A second cycle of OPPA was delivered in the other cases, and RT was adjusted to the final response. Treatment failure was defined as refractory or progressive disease before RT. Irrespective of their response status, patients with stage IB or IIB disease or ESR > 70 mm/h received a further 20 Gy of RT to an aortosplenic field.

RT
RT modalities are defined in the MDH82 protocol.7 Good responders to either VBVP or OPPA received 20 Gy, starting 1 month after the completion of chemotherapy, in daily fractions of 1.8 to 2.0 Gy over a 2-week period, with high-energy photon or electron radiation. Poor responders to OPPA received 40 Gy over a 4-week period. RT fields were limited to involved sites, as identified by the initial physical examination and imaging. Adjacent areas were not irradiated. All the patients were treated with personalized blocks. In patients with mediastinal involvement at diagnosis, RT was delivered to the mediastinal area but adapted to the volumetric reduction after chemotherapy. In patients with a large residual mediastinal mass after chemotherapy (mediastinal/thoracic ratio [M/T] 1/3), the protocol authorized a local boost up to 40 Gy, even for good responders. Irrespective of the response status, patients with B symptoms or ESR > 70 mm/h received prophylactic paraaortic and splenic irradiation (20 Gy) after a 2-week rest period.

Statistical Analysis
Event-free survival (EFS) was measured from enrollment to relapse, disease progression, death, second malignancy, or last follow-up. OS was measured from enrollment to the last visit or death. The probability estimates of EFS and OS were calculated by the Kaplan-Meier life tables probability method.

Candidate prognostic factors were age, sex, stage, symptom class ("A" v B), biologic class ("a" v b), hemoglobin (< 10.5 g/dL v >= 10.5 g/dL), number of involved areas, histology, nodular sclerosis versus others, mediastinal involvement, and M/T ratio (> 1/3 v <= 1/3). The treatment response (good or poor) was assessed after four cycles of VBVP and after OPPA. The impact of the above variables on EFS and OS was assessed by using the log-rank test. Factors that were significant in univariate analysis were entered as candidate variables in the multivariate analysis (Cox model and stepwise analysis).17


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 APPENDIX
 REFERENCES
 
Characteristics of the Patients
Patient characteristics are listed in Table 1. The median age of the 202 patients at diagnosis was 12 years (range, 3 to 18 years). There were 125 males (62%). The sex distribution varied with age; 44 (86%) of the 51 children under 9 years old were males compared with only 81 (53%) of the 151 children older than 9 years (P < .001). The stage distribution was as follows: 68 patients were stage IA, four were IB, 88 were IIA, and 42 were IIB. Lymphography was performed routinely but was unsuccessful, for technical reasons, in 27 (13%) of the 202 patients. Eight patients had only subdiaphragmatic disease. Lymphography was abnormal in seven of these eight patients (one technical failure), showing lateroaortic and iliac involvement. In one case, subdiaphragmatic involvement was demonstrated by CT and ultrasound examination. Mediastinal disease was detected in 109 patients (54%). The M/T ratio was measured on the initial chest roentogram, and exceeded 1/3 in 50 of 109 patients. Seventy-two patients had one site of lymph node involvement, whereas 86, 36, and eight patients had two, three, and four or more sites of node involvement, respectively. Histology was nodular sclerosis in 121 patients (60%), mixed cellularity in 48 patients (24%), lymphocyte predominant in 23 patients (11.5%), and lymphoid depletion in one patient. Nine patients (4.5%) were considered unclassifiable.


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  		Table 1. Clinical Characteristics of the 202 Patients
 
The ESR was known in 196 of the 202 patients. It was less than 40 mm/h and more than 70 mm/h in 117 (59%) and 39 patients (19%), respectively. B symptoms correlated strongly with higher ESR values; 37 of the 46 patients with B symptoms had ESR >= 40 mm/h compared with only 42 of the 156 patients without B symptoms (P < .001).

The initial hemoglobin level was known in 194 cases. Anemia, with hemoglobin < 10.5 g/dL, was diagnosed in 18 patients (9.2%). This variable also correlated strongly with B symptoms; 12 of 46 patients with B symptoms had anemia compared with only six of 156 patients without B symptoms (P < .001).

Response to Treatment and Outcome
After four VBVP cycles, 83 (41%) of 202 patients entered complete remission, and 88 (44%) had a good response (> 70% reduction in tumor size). Twenty-seven patients (13%) had a poor response, and four (2%) failed to respond to the response-adapted strategy. Of these four patients, one had refractory disease (IB with nephrotic syndrome), and three progressed after an initial response to VBVP (one case each of IIBE pulmonary, IIA, and IIB) before starting RT (Fig 1 and Table 2). Responses to chemotherapy assessed before RT and outcome are described below.


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  		Table 2. Treatment Outcome According to the Response to Chemotherapy
 
Good responders. The 171 good responders (85% of eligible patients) received 20 Gy to involved fields. Of these, 33 patients with B symptoms or ESR > 70 mm/h received 20-Gy aortosplenic RT. Three patients received a boost up to 40 Gy for large residual mediastinal disease, and one patient received 40 Gy to all involved areas (protocol violation). All the patients with initially only subdiaphragmatic involvement were good responders and are in first complete remission. Thirteen (7.6%) of these 171 good responders relapsed after a median of 14.5 months (range, 5 to 56 months), eight within the irradiated field, four in extranodal (lung) and initial disease sites, and only one in a new node site. Seven of 13 good responders had aortosplenic radiation during initial therapy because of B symptoms, and none of them relapsed subdiaphragmatically. One of these 13 patients died of disease progression after 14 months, whereas other patients are alive, with a median follow-up of 48 months after the relapse (range, 20 to 101 months).

Poor responders. Of the 27 poor responders to VBVP chemotherapy, 18 received one cycle of OPPA, and nine received two cycles. Thirteen patients had a good response to OPPA (10 after one cycle and three after two cycles), with one patient entering complete remission. All 13 patients received 20 Gy to involved fields, and two received a boost up to 40 Gy for residual mediastinal disease (M/T > 1/3); none relapsed. The other 14 poor responders to VBVP had radiologically stable disease after one cycle of OPPA (n = 8) or a tumor reduction of < 70% after two OPPA cycles (n = 6) and, subsequently, received 40 Gy to involved fields (10 patients) or 20 Gy with local boosting up to 40 Gy (four patients), considering the mediastinum as the sole site of poor response. Three of these poor responders to OPPA relapsed after 9, 13, and 23 months. Relapse occurred in a previously irradiated field in one patient and in the lungs and a previously irradiated field in two patients. One of these three patients died of refractory disease, whereas the other two are alive after autologous stem-cell transplantation 26 and 64 months after the relapse.

Refractory patients and patients with early progression. One patient had refractory disease and a nephrotic syndrome. He died of uncontrolled disease 9 months after diagnosis. Three patients had early progression after the fourth VBVP cycle and received second-line chemotherapy (OPPA x 2; OPPA + mesna uroprotection, ifosfamide, mitoxantrone, and etoposide; and MOPP + doxorubicin, bleomycin, vinblastine, and prednisone [ABVP]). One died of uncontrolled disease at 14 months, whereas the other two are alive and in complete remission 59 and 97 months after autologous stem-cell grafting without RT.

Toxicity and Related Morbidity
Treatment was generally well-tolerated. The proportion of cycles postponed for more than 7 days (median, 7 days) was 4.7%. Hematologic toxicity necessitated blood transfusions in 3% of the cycles (3.7% of VBVP cycles and 3% of OPPA cycles). Varicella or zoster infection occurred in two children. Febrile neutropenia or documented infections occurred in 11% of the cycles (10.8% and 0.5% in VBVP and OPPA, respectively; not significant). One patient developed therapy-related acute bronchiolitis obliterans organizing pneumonia after the second cycle of VBVP but fully responded to corticosteroid treatment. No other patients developed clinical manifestations of pulmonary fibrosis. Two children had acute anaphylactic reactions to etoposide and, subsequently, received ABVP. There were no toxic deaths.

Two patients developed second malignancies. One female with IIA nodular sclerosis HD was initially treated with four cycles of VBVP and 20 Gy of RT. She developed acute monoblastic leukemia (French-American-British subtype M5) within 17 months of completing therapy. Southern blotting and cytogenetic analysis failed to reveal MLL gene or 11q23 chromosome rearrangements. She died in relapse, despite allogenic bone marrow transplantation, 9 months after the diagnosis of acute monoblastic leukemia. The second case occurred in a female initially treated for stage IA nodular sclerosis HD with four cycles of VBVP and one cycle of OPPA. She then received 20 Gy to a mediastinal site and a boost to 40 Gy on the residual mass. She developed acute myeloblastic leukemia 65 months after diagnosis (French-American-British subtype M2). No clonal bone marrow cytogenetic abnormalities were found, and she is alive in remission 51 months after the diagnosis of acute myeloblastic leukemia after undergoing allogenic bone marrow transplantation.

Statistical Analysis
OS and DFS are depicted in Fig 2. As of September 1999, the median follow-up was 74 months (range, 25 to 117 months). The projected 5-year OS rate (mean ± SD) is 97.5% ± 2.1%, and the EFS (mean ± SD) is 91.1% ± 1.08%. Overall, there were 20 treatment failures (four failures to achieve remission and 16 relapses) and two second malignancies. There were five deaths from progressive disease (n = 4) or secondary leukemia (n = 1). The 3-year survival rate (mean ± SD) among patients who relapsed is 86% ± 12%.



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  		Fig 2. OS and EFS rates for the 202 patients.

 
In univariate analysis (Table 3), B symptoms adversely influenced EFS (EFS of patients with A v B symptoms: 94.2% v 76%, respectively; P = .004). Other factors that influenced EFS are as follows: biologic staging (a v b: 94.3% v 77.2%; P < .0001), hemoglobin (>= 10.5 g/dL v 10.5 g/dL: 92% v 72.8%; P = .02), mediastinal involvement (involvement v no involvement: 83.8% v 95.8%; P = .003), sex (females v males: 82% v 94%; P = .002), and histology (scleronodular v others: 83% v 100%; P = .0001). The M/T ratio (>1/3 or <= 1/3) did not influence EFS (79.7% v 88.5%, respectively; P = .33) or the response to VBVP (P = .71). When the outcome of good responders and poor responders was compared, EFS was influenced by the response to four cycles of VBVP (90.9% v 78.1%, respectively; P = .017) but not by the response to OPPA (81% v 73.3%, respectively; P = .65). The number of involved sites did not influence outcome (one or two v >= three: 91.1% v 88.9%, P = .72). Age and sex were not independent predictors of EFS, which was 96% among patients under 9 years of age at diagnosis compared with 87% in older children (P = .08).


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  		Table 3. Univariate and Multivariate Analysis of Prognostic Factors
 
In multivariate analysis (Table 3), b biologic symptoms, anemia (hemoglobin < 10.5 g/dL), and nodular sclerosis independently had a negative impact on EFS because most of the studied variables in the univariate analysis are strongly associated. The response to VBVP did not significantly influence outcome, suggesting that OPPA is an effective treatment for poor responders to VBVP.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
APPENDIX
 REFERENCES
 
The first study by the French Society of Pediatric Oncology (MDH82) assessed the efficacy of four cycles of ABVD versus two alternating MOPP/ABVD cycles for stage IA and IIA disease and three cycles of MOPP plus three cycles of ABVP for stage IB and IIB disease, combined with low-dose RT of involved fields.7 In this first study the DFS rate was 89% among patients with stage I and II disease, after a median follow-up of 6 years (176 patients), and the OS rate was 92% at 6 years. The results of the MDH90 protocol are comparable with an EFS of 91% and an OS of 97.5% at 5 years. Thus, a response-adapted strategy with VBVP and 20 Gy of RT for good responders had efficacy similar to a classical regimen for localized HD. The treatment failure rate was 2%, and the mortality rate was 2.5%; these values are comparable with those of other contemporary regimens reported by cooperative pediatric groups.3-10,18 Finally, 79% of the patients in our study did not receive mechlorethamine, anthracycline, or procarbazine. Univariate analysis of known prognostic variables showed that B symptoms, anemia, biologic class b, mediastinal involvement, nodular sclerosis, the response to VBVP, and sex were significantly related to EFS. However, only anemia, biologic class b, and nodular sclerosis were independent predictors of EFS in multivariate analysis because most of the above factors are clearly interdependent.

Combined-modality treatment of pediatric HD allows the dose and fields of RT to be reduced, along with late toxicity. Our nationwide study confirmed the results of the Stanford group, who used 15 to 25 Gy.18 The German-Austrian group carried out three studies with RT doses (depending on the duration of chemotherapy) of 25, 25, and 20 Gy in stages I-IIA, IIB-IIIA, and IIIB-IV, respectively, in the HD90 study; EFS among patients with localized disease was 92% to 96%.19 In this study, we used a clinical staging method based on clinical and radiologic findings without laparotomy. Previous studies have shown a positive correlation between B symptoms or an ESR > 70 mm/h and an increased frequency of abdominal or spleen involvement.20-22 Moreover, in clinical stage IB and IIB patients, restaging laparotomy after MOPP showed residual disease in subdiaphragmatic sites in 10% of cases.23 Therefore, we added aortosplenic irradiation of 20 Gy for these patients to eradicate occult disease from these sites.

The use of etoposide in HD has been reported since the early 1980s, with a 26% response rate in single-agent trials.24 In 1990, the German group included etoposide in a combined-modality treatment, with vincristine, etoposide, prednisone, and doxorubicin, for males; the 5-year EFS was 88% for all stages in the HD90 trial.19 The Pediatric Oncology Group investigated vinblastine, etoposide, prednisone, and doxorubicin and doxorubicin, etoposide, vincristine, and bleomycin.25,26 We used a maximum cumulative dose of 2 g/m2 of etoposide to decrease the use of anthracycline and procarbazine. Overall, the cumulative incidence of secondary leukemia in the 202 patients is 0.9% (95% confidence interval, 0% to 0.23%) at 5 years. Over the past two decades, many groups have reported the incidence and risk factors of second hematologic neoplasms after childhood malignancies, particularly HD.13,27-32 The incidence of secondary leukemia in this study is comparable with that observed elsewhere, even without alkylating agents. Because the median follow-up in our study is now 74 months, we assume that the rate of second hematologic malignancies will remain low.

Anemia, biologic class b, and nodular sclerosis were associated with an increased risk of events. In the Italian study AIEOP MH’89, B symptoms were the only independent risk factor in a multivariate analysis of 273 patients.33 Other cooperative groups have correlated a response to chemotherapy with better survival in both adult and childhood HD.7,34 In the MDH90 study, multiple-site relapses were frequent (six of 16 patients), and most involved the initially involved node site (n = 8) and/or extra nodal sites (n = 5). This pattern of relapse indicates that these patients might have benefited from more intensive systemic treatment. Nevertheless, the survival of the patients who relapsed is good (82% at 3 years) and is comparable with that reported by Donaldson and Link18 after initial standard treatment with MOPP. Hasenclever and Dielh35 recently published a prognostic score for advanced HD based on age, hemoglobin level, sex, stage IV, WBC count, and lymphocyte count. Localized stages represented 13% of the population and were included because of an imprecise definition of advanced stages. The rate of progression-free survival (mean ± SD) was 74% ± 2%, and the OS rate (mean ± SD) was 84% ± 2%. However, this prognostic index is not applicable to children, mainly because of obvious differences in age and stage IV disease. We propose a scoring system for localized childhood HD based on the independent variables identified in our outcome analysis (nodular sclerosis, anemia, and b biologic class); each variable is weighted according to its Cox model coefficient (2.8, 1.4, and 0.8, respectively), with a default value of 0. Anemia and b biologic class were attributed a score of 1 and nodular sclerosis a score of 2. For each patient, the score was the arithmetic sum of the scores for the three variables. This prognostic index splits the patient population into two groups. Patients with a standard prognosis are defined by a score below 3 and represented 80% of the patients in this study, with an EFS (mean ± SD) of 98% ± 1.8%. The poor-risk group is defined by a score of 3 or more and represented 20% of patients, with an EFS of 64% ± 12%. This scoring system is simple to use and offers a way of stratifying therapy for childhood localized HD. However, the prognostic index may be strongly dependent on the therapeutic approach used here and must, therefore, be validated by other cooperative groups to assess its reproducibility. Our next study will attempt to further de-escalate therapy for good-risk patients on the basis of this scoring system.


   APPENDIX
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 APPENDIX
REFERENCES
 
Additional participating members and institutions include the following: A. Babin-Boilletot (Hôpital Hautepierre, Strasbourg); C. Beard (Hôpital Americain, Reims); C. Bergeron (Centre Leon Berard, Lyon); Y. Bertrand (Hôpital Debrousse, Lyon); P. Boutard (Caen), C. Coze, I. Huret (Hôpital La Timone, Marseille); C. De Lumley (Hôpital Dupuytren, Limoges); M.C. Demaille (Centre Oscar Lambret, Lille); F. Demeocq (Hôpital Hotel-Dieu, Clermont-Ferrand); C. Devalck (Hôpital Reine Fabiola, Bruxelles); A. Deville (Hôpital Lenval, Nice); F. Dusol (Hôpital Saint Antoine, Lille); J.P. Lamagnere (Hôpital Clocheville, Tours); J. Landman-Parker (Hôpital d’Enfants Armand Trousseau, Paris); T. Leblanc (Hôpital Saint Louis, Paris); F. Mechinaud-Lacroix (Centre Hospitalier Universitaire, Nantes); F. Millot (Hôpital Jean Bernard, Poitiers); B. Nelken (Hôpital Huriez, Lille); O. Oberlin (Institut Gustave Roussy, Villejuif); H. Pacquement (Institut Curie, Paris); B. Pautard (Centre Hospitalier Universitaire, Amiens); Y. Perel (Hôpital Pellerin, Bordeaux); D. Plantaz (Hôpital Michalon, Grenoble); E. Plouvier (Hôpital Saint Jacques, Besançon); A. Robert (Hôpital Purpan, Toulouse); C. Schmitt (Hôpital d’Enfants, Vandoeuvre les Nancy); J.L. Stephan (Centre Hospitalier Universitaire Nord, Saint Etienne); J.P. Vannier (Hôpital Charles Nicolle, Rouen, France).


   ACKNOWLEDGMENTS
 
Supported in part by clinical research contract no. 6943 from the Association for the Research Against Cancer.

We thank Dr H. Mahmoud for comments and helpful review and David Young for editing the manuscript.


   NOTES
 
Preliminary results of this study were presented at the Annual Meeting of American Society of Hematology (ASH), 1996.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 APPENDIX
 REFERENCES
 
1. Hudson MM, Donaldson SS: Hodgkin’s disease. Pediatr Clin North Am 44:891-906, 1997[Medline]

2. Oberlin O: Present and future strategies of treatment in childhood Hodgkin’s lymphomas. Ann Oncol 7:73-78, 1996 (suppl 4)

3. Beverly Raney R: Hodgkin’s disease in childhood: A review. J Pediatr Hematol Oncol 20:362-363, 1998[Medline]

4. Schellong G: The balance between cure and late effects in childhood Hodgkin’s lymphoma: The experience of the German-Austrian study group since 1978—An overview. Ann Oncol 7:67-72, 1996 (suppl 4)

5. Fryer CJ, Hutchinson RJ, Krailo M, et al: Efficacy and toxicity of 12 courses of ABVD chemotherapy followed by low-dose regional radiation in advanced Hodgkin’s disease in children: A report from the Cancer Children’s Study Group. Clin Oncol 8:1971-1980, 1990

6. Hunger SP, Link MP, Donaldson SS: ABVD/MOPP and low-dose involved-field radiation therapy in pediatric Hodgkin’s disease: The Stanford experience. J Clin Oncol 12:2160-2166, 1994[Abstract/Free Full Text]

7. Oberlin O, Leverger G, Pacquement H, et al: Low-dose radiation therapy and reduced chemotherapy in childhood Hodgkin’s disease: The experience of the French Society of Pediatric Oncology. J Clin Oncol 10:1602-1608, 1992[Abstract/Free Full Text]

8. Hudson MM, Greenwald C, Thompson E, et al: Efficacy and toxicity of multiagent chemotherapy and low-dose involved-field radiation therapy in children and adolescents with Hodgkin’s disease. Clin Oncol 11:100-108, 1993

9. Vecchi V, Pileri S, Burnelli R, et al: Treatment of pediatric Hodgkin disease tailored to stage, mediastinal mass, and age: An Italian (AIEOP) multicenter study on 215 patients. Cancer 72:2049-2057, 1993[Medline]

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Submitted April 19, 1999; accepted November 17, 1999.




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