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© 2002 American Society for Clinical Oncology Randomized Comparison of Low-Dose Involved-Field Radiotherapy and No Radiotherapy for Children With Hodgkin’s Disease Who Achieve a Complete Response to ChemotherapyByFrom the Section of Pediatric Hematology-Oncology, University of Chicago, Chicago, IL; Department of Preventive Medicine, Keck School of Medicine, University of Southern California, and Department of Pathology/Research, Children’s Hospital Los Angeles, Los Angeles, CA; Group Health Cooperative of Puget Sound, Department of Pediatric Hematology-Oncology, Redmond, WA; Mayo Clinic and Foundation, Rochester, MN; Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, NY; Departments of Radiotherapy and Pediatric Medical Imaging, Primary Children’s Medical Center, Salt Lake City, UT; Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA; Department of Hematology-Oncology, Children’s Healthcare of Atlanta at Scottish Rite Hospital, Atlanta, GA; and Division of Pediatric Hematology-Oncology, C.S. Mott Children’s Hospital, Ann Arbor, MI. Address reprint requests to James B. Nachman, MD, Children’s Oncology Group, PO Box 60012, Arcadia, CA 91066-6012; email: jnachman{at}peds.bsd.uchicago.edu
PURPOSE: Current standard therapy for children and adolescents with Hodgkin’s disease includes combination chemotherapy and low-dose involved-field radiation (LD-IFRT). Because radiation may be associated with adverse late effects, the Children’s Cancer Group (CCG) investigated whether radiation could be omitted in patients achieving a complete response to initial chemotherapy without jeopardizing the excellent outcome obtained with combined-modality therapy. PATIENTS AND METHODS: Between January 1995 and December 1998, 829 eligible patients were enrolled onto CCG 5942. A total of 501 patients who achieved an initial complete response after risk-adapted combination chemotherapy were randomized to receive LD-IFRT or no further treatment. Event-free survival (EFS) and overall survival were assessed from the date of study entry or the date of randomization, as appropriate. RESULTS: The projected 3-year EFS from study entry for the entire cohort was 87% ± 1.2%. Among patients who achieved a complete response to initial chemotherapy, 92% ± 1.9% of those randomized to receive LD-IFRT were alive and disease free 3 years after randomization, versus 87% ± 2.2% for patients randomized to receive no further therapy (stratified log-rank test; P = .057). With an "as-treated" analysis, 3-year EFS after randomization for the radiation cohort was 93% ± 1.7% versus 85% ± 2.3% for patients receiving no further therapy (stratified log-rank test; P = .0024). Three-year survival estimates for patients treated with and without LD-IFRT were 98% ± 1.1% for patients who received radiation and 99% ± 0.5% for patients who did not receive radiation. CONCLUSION: LD-IFRT after an initial complete response to risk-adapted chemotherapy improved EFS. At this time, there is no survival advantage for LD-IFRT, but follow-up remains short.
CURRENT STANDARD treatment for children with Hodgkin’s disease consists of combined-modality treatment with cyclophosphamide, vincristine, procarbazine, and prednisone (COPP); doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD); or variants of these regimens and radiation (25 Gy) to the involved regions of disease.1-8 Approximately 95% of children with early-stage and 85% of children with advanced-stage Hodgkin’s disease survive long-term after these regimens. Therefore, the current focus in treating children with Hodgkin’s disease is to reduce late effects from both chemotherapy and radiation while maintaining efficacy. A major late effect among survivors of pediatric Hodgkin’s disease is an increased risk for second malignant tumors, particularly breast cancer or other solid tumors, which commonly occur in previously irradiated fields.9-12 The risk of secondary breast cancer was greatest for females who received standard-dose radiotherapy (36 to 40 Gy) to fields including breast tissue.11 The risk for secondary breast cancer associated with lower-dose radiotherapy is not known. Standard-dose radiotherapy has also been implicated in the development of late thyroid, cardiac, and pulmonary toxicity.13-15 Therapeutic trials in adults with Hodgkin’s disease have compared outcome between patients treated with chemotherapy alone and those treated with combined-modality therapy. In some studies, patients treated with combined-modality therapy have an event-free survival (EFS) benefit but no survival benefit. In other studies, EFS and survival are similar.16 One pediatric trial that compared chemotherapy with or without radiation for patients with advanced-stage Hodgkin’s disease indicated no benefit to the addition of radiation.17 In 1995, the Children’s Cancer Group (CCG) initiated a comprehensive risk-adjusted chemotherapy protocol for newly diagnosed patients with Hodgkin’s disease to compare, in a randomized fashion, the effects on outcome of low-dose involved-field radiation (LD-IFRT) in patients who achieved a complete response to initial chemotherapy. The study goal was to test the hypothesis that the excellent EFS and survival produced with combined-modality therapy could be preserved with chemotherapy alone in patients achieving an initial complete response to chemotherapy.
Patients Children and adolescents younger than 21 years with newly diagnosed Hodgkin’s disease were enrolled onto CCG 5942 between January 1995 and December 1998. Staging was based on clinical evaluation, regardless of the results of staging laparotomy in the few patients who had the procedure performed. Stages were as defined by the Ann Arbor staging system.18 Patients also were classified with respect to the absence or presence of one or more of the following systemic symptoms: unexplained loss of more than 10% of body weight, unexplained recurrent fever greater than 38°C, and drenching night sweats. In addition, patients were classified according to the presence or absence of the following adverse disease features: hilar adenopathy, involvement of more than four nodal regions, presence of a mediastinal tumor with a diameter one third of the intrathoracic diameter, and presence of an extra thoracic nodal mass with a maximum diameter of 10 cm. Pathologic material was reviewed centrally and classified based on the system of Lukes and Butler.19 The clinical staging and presenting features described previously were used to assign patients to one of three treatment groups. Clinical group 1 comprised all stage I and IIA patients who lacked adverse disease features. Clinical group 3 comprised all stage IV patients. Clinical group 2 comprised patients who did not meet the criteria for the other two groups (Table 1).
Treatment Protocol Details of the treatment regimens are listed in Table 2. Group 1 and 2 patients received four and six courses, respectively, of the COPP/ABV hybrid chemotherapy protocol at 28-day intervals. Group 3 patients received two courses of intensive multidrug chemotherapy with granulocyte colony-stimulating factor support repeated at 63-day intervals. All patients who achieved a complete response to chemotherapy were eligible for randomization to receive either LD-IFRT or no additional therapy (Fig 1). Radiotherapy was scheduled to begin 3 weeks after completion of chemotherapy. A total dose of 21 Gy was given in 12 fractions of 1.75 Gy to all involved fields. Stage IV patients with pulmonary involvement received 10.5 Gy to the lungs, given in 12 fractions. The protocol was approved by the National Cancer Institute and the institutional review boards of the participating institutions. Written informed consent was obtained from patients, parents, and/or guardians as required by United States federal regulations.
Response Criteria Complete response to chemotherapy was defined on the basis of resolution of clinical, radiologic, and radioisotopic evidence of disease at completion of chemotherapy. If there was an incomplete radiologic response in the mediastinum or abdomen, response could still be classified as complete, provided that the initial tumor volume was reduced by more than 70% and any postchemotherapy residual mass that was initially gallium positive had converted to gallium negative. Patients who had 50% to 70% reduction in tumor volume were considered partial responders. Early response assessment was not undertaken on this study. Progressive disease was defined as clinical or radiographic evidence of increased tumor volume in a previously involved site or as involvement of a new site while the patient received initial chemotherapy; nonresponse was defined as a less than 50% tumor reduction after initial chemotherapy. Relapse was defined as the recurrence of Hodgkin’s disease, pathologically confirmed, after complete or partial response to initial chemotherapy.
Study Design and Statistical Analysis
Patients A total of 834 patients were enrolled between January 1995 and December 1998. Five patients were declared ineligible after review of pathologic material revealed non-Hodgkin’s lymphoma. Demographic and disease characteristics of the entire cohort (n = 829), as well as for the two randomized treatment groups, are listed in Table 3. Most patients were white, were 10 to 19 years old, had stage II disease, and had nodular sclerosing histology. Twenty-six percent of patients had "B" symptoms at presentation; these symptoms were more common among stage III and IV patients than other patients (  2; P = .001; data not shown). A total of 501 patients were randomized, 251 to receive radiation therapy and 250 to receive no radiation therapy.
Outcome for the Entire Study Cohort Complete response was achieved in 83% of assessable patients. In the overall cohort, there were 111 first events, of which 106 were relapses or progressions of Hodgkin’s disease, three were second malignant neoplasms (two acute myelogenous leukemias and one non-Hodgkin’s lymphoma), and two were deaths not related to disease progression (systemic fungal infection during the first 2 weeks of therapy; pulmonary embolism and stroke at 32 months). For the 829 eligible patients, the 3-year EFS and survival estimates from study entry were 87% ± 1.2% and 95% ± 0.78%, respectively (Fig 2). To date, a total of 41 deaths (37 disease related, two toxicity related, and two secondary acute myelogenous leukemia) have been reported. For patients assigned to clinical groups 1, 2, and 3, the 3-year EFS estimates from study entry were 95% ± 1.3%, 82% ± 2.0%, and 83% ± 3.4%, respectively (P < .001), and the 3-year survival estimates from study entry were 100%, 93% ± 1.4%, and 93% ± 2.3%, respectively (P < .001). Twenty-nine patients were not assessable for response to chemotherapy (22, early protocol breaks; seven, no response data). Fifteen patients had progressive disease during initial chemotherapy. Among 785 patients who completed chemotherapy and had responses assessed, 650 achieved complete responses and were eligible for randomization. Sixty-seven percent of patients or parents who refused randomization chose no further therapy.
Outcome for Randomized Patients A total of 51 first events were reported among the randomized cohort, 19 in patients randomized to receive radiotherapy and 32 in patients randomized to no further treatment. By an intent-to-treat analysis, 3-year EFS estimates from randomization were 92% ± 1.9% for patients randomized to radiotherapy and 87% ± 2.2% for patients randomized not to receive radiotherapy (stratified log-rank test; P = .057; Fig 3). The estimated relative failure rate from the stratified analysis was 1.7 (95% confidence interval, 0.98 to 3.05).
Thirty randomized patients switched to the alternate treatment after randomization (23 declined radiotherapy; seven received radiotherapy). Five patients who refused radiation experienced relapses. With an as-treated analysis, 3-year EFS estimates after randomization were 93% ± 1.7% for patients who received radiotherapy and 85% ± 2.3% for patients who received no further treatment (stratified log-rank test, P = .0024; Fig 3). The estimated relative failure rate was 2.5 (95% confidence interval, 1.4 to 4.7). EFS and survival estimates for as-randomized and as-treated patients in groups 1, 2, and 3 are listed in Table 4.
For the 37 patients who relapsed after chemotherapy alone, the median time to relapse was 6 months (range, 1 to 36 months). Only 10 relapses occurred more than 12 months from the discontinuation of chemotherapy. For the 34 cases in which sites of relapse were documented, 29 relapses occurred in areas of previously known disease alone, three relapses occurred in both previously involved and new areas, and two occurred only in new areas. For the 14 patients who relapsed after chemotherapy and LD-IFRT, the median time to relapse was 14 months (range, 1 to 33 months). For the 12 cases in which sites of relapse were documented, seven occurred solely within the radiation field, three occurred both in and out of the field, and two occurred in previously uninvolved areas alone. Three-year survival estimates from randomization for patients treated with and without radiation were 98% ± 1.1% and 99% ± 0.5%, respectively (P = .90) and were not different from the as-randomized analysis. Only eight deaths have been reported among randomized patients: four in each randomized treatment group. A few patients received standard-dose radiation alone after relapse, and all other patients received chemotherapy, radiation, autologous stem-cell transplantation, or a combination of these. Postrelapse survival was better for randomized patients who relapsed after chemotherapy alone compared with those who relapsed after chemotherapy and radiation (94% ± 4.0% v 84% ± 10% at 1 year; P = .020). Of the 37 patients who experienced a relapse after chemotherapy alone, three had less than 2 months of follow-up information, six experienced a second relapse (two have died), and one died in second remission after an autologous stem-cell transplantation. Six of the seven second events occurred within 7 months of the initial relapse. For the 33 patients who were alive at last contact and had follow-up of longer than 2 months, the median follow-up was 24 months (range, 1 to 50 months). There have been no second events among 13 relapsed patients who were asymptomatic and had no bulk disease at diagnosis. Of the 14 patients who experienced a relapse after chemotherapy and radiation, one had less than 2 months of follow-up information, three had a second relapse (two have died), and one died as a result of treatment complications while in second remission. For the 11 patients who were alive at last contact, the median follow-up was 13 months (range, 6 to 24 months).
Acute Toxicity of Treatment
In this study, patients with Hodgkin’s disease were enrolled onto a single protocol that allocated more intensive chemotherapy treatment to patients deemed at higher risk for treatment failure, on the basis of disease stage and other important clinical and tumor characteristics at diagnosis. Patients in any risk group who achieved a complete response to initial chemotherapy were eligible for postchemotherapy randomization to receive LD-IFRT or no further therapy. The data from this study indicate that, among patients achieving an initial complete response, those treated with radiotherapy had improved EFS compared with those who did not receive radiotherapy, both by an intent-to-treat analysis and by an as-treated analysis. At this time, there is no difference in overall survival between the radiotherapy and no-further-therapy arms. Although the follow-up for our study is not yet long enough to conclude that survival will be equivalent in patients receiving or not receiving radiotherapy, other studies that have longer postrelapse follow-up have indicated no survival benefit for postchemotherapy radiation therapy.16 Loeffler et al16 conducted a meta-analysis that included eight trials for patients with Hodgkin’s disease in which the randomized study question was chemotherapy with or without additional radiation therapy. Overall, patients who received radiation had an 11% higher rate of continuous complete remission at 10 years (15% higher for patients with stage I to III disease). The advantage was less pronounced for patients with mixed-cellularity Hodgkin’s disease. However, overall survival was better in the chemotherapy-alone arm because of an increased rate of death after relapse and from non–relapse-related causes in patients who received radiation before relapse. In the only other randomized study of radiotherapy versus no further treatment in children with Hodgkin’s disease achieving a complete response to initial chemotherapy, Weiner et al17 treated patients with advanced-stage disease who achieved complete responses to eight cycles of MOPP/ABVD with total nodal radiation or no further therapy. There was no difference in EFS or overall survival at 5 years for patients in the two randomized treatment groups. The lack of difference in EFS in the study by Weiner et al, which contrasts with our results, may be attributable to the use of eight cycles of hybrid chemotherapy in all patients or to the lack of a published as-treated analysis. Many of the patients randomized to radiotherapy did not receive it and experienced relapses, as observed in this study. Although survival is an excellent measure of outcome, EFS is an equally important end point when treating patients with Hodgkin’s disease. Although many patients who relapse can be cured, salvage therapy is more toxic and is associated with a high rate of late effects. In a study of survivors of pediatric Hodgkin’s disease from Stanford,22 relapse was the most significant risk factor for the development of a second malignancy. Late effects associated with chemotherapy used in treating Hodgkin’s disease include pulmonary, cardiac, and gonadal toxicity and an increased risk of secondary leukemia. The use of hybrid chemotherapy programs that decrease total exposure to alkylating agents, anthracyclines, and bleomycin has decreased, but not eliminated, the incidence of chemotherapy-associated late effects. Likewise, the exclusive use of LD-IFRT for treatment of children and young adults with Hodgkin’s disease should reduce the incidence of growth retardation, breast cancer, and thyroid dysfunction seen previously with standard-dose radiotherapy. In many cases, radiation treatment to sensitive tissues such as the breast, heart, and lungs can be minimized or avoided. Given that radiation is effective in eradicating some or all microscopic residual disease in patients with complete response after chemotherapy, a secondary question remains whether there are identifiable subsets of patients for whom the risks of receiving IFRT outweigh the potential benefit. Preliminary analyses of our data suggest that there may be groups of patients in whom the likelihood of residual microscopic disease is small. New-generation protocols will test these questions. Given our results, combined-modality therapy remains the standard of care for children and adolescents with Hodgkin’s disease. However, there may be a significant fraction of children and adolescents with Hodgkin’s disease who can be cured with chemotherapy alone. On the other hand, using LD-IFRT in conjunction with decreased-intensity chemotherapy may produce the best results for certain patients. Consideration of EFS, survival, and late effects of treatment are crucial in determining the optimal treatment for children and adolescents with Hodgkin’s disease. Future studies should focus on further reducing the toxicities of chemotherapy and radiation therapy while maintaining excellent EFS. Improved treatment allocation models, perhaps integrating sedimentation rate, histology, bulk disease, and early response to chemotherapy, may be able to define a group of patients who may not benefit from radiotherapy.
The appendix listing members of the Children's Cancer Group is available online at www.jco.org.
Supported by the Division of Cancer Treatment, National Cancer Institute; National Institutes of Health, and Department of Health and Human Services. Contributing Children’s Oncology Group investigators, institutions, and grant numbers are given in the Appendix, available online at www.jco.org.
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4. Oberlin O, Leverger G, Pacquement H, et al: Low-dose radiotherapy 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 5. Hutchinson RJ, Fryer CJ, Davis PC, et al: MOPP or radiation in addition to ABVD in the treatment of pathologically staged advanced Hodgkin’s disease in children: Results of the Children’s Cancer Group phase III trial. J Clin Oncol 16: 897-906, 1998[Abstract] 6. Armata J, Balwierz W, Moryl-Bujakowska A, et al: Childhood stage IV Hodgkin’s disease: Therapeutic results of the Polish Pediatric Leukemia/Lymphoma Study Group. Med Pediatr Oncol 33: 382-387, 1999[CrossRef][Medline] 7. Hudson MM, Greenwald C, Thompson E, et al: Efficacy and toxicity of multiagent chemotherapy and low-dose involved-field radiotherapy in children and adolescents with Hodgkin’s disease. J Clin Oncol 11: 100-108, 1993[Abstract] 8. Schellong G, Hornig-Franz I, Rath B, et al: Reducing radiotherapy dosage to 20-30 Gy in combined chemo-/radiotherapy of Hodgkin’s disease in childhood: A report of the cooperative DAL-HD-87 therapy study. Klin Padiatr 206: 253-262, 1994[Medline]
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
t2, were planned for 2.5, 3.5, and 4.5 years. Randomization was stopped on the recommendation of the CCG Data Monitoring Committee because of a significantly higher number of relapses on the no-radiotherapy arm. 
