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© 2002 American Society for Clinical Oncology VAMP and Low-Dose, Involved-Field Radiation for Children and Adolescents With Favorable, Early-Stage Hodgkin’s Disease: Results of a Prospective Clinical TrialByFrom Stanford University Medical Center, Stanford, and University of California, San Francisco Medical Center, San Francisco, CA; St Jude Children’s Research Hospital, Memphis, TN; Dana-Farber Cancer Institute and Massachusetts General Hospital, Boston, MA; and Barbara Bush Children’s Hospital at Maine Medical Center, Portland, ME. Address reprint requests to Sarah S. Donaldson, MD, Department of Radiation Oncology, M/C 5302, Stanford University School of Medicine, Stanford, CA 94305; email: sarah{at}reyes.stanford.edu
PURPOSE: To evaluate outcome and assess toxicity of children and adolescents with early-stage, favorable Hodgkin’s disease treated with vinblastine, doxorubicin, methotrexate, and prednisone (VAMP) and low-dose, involved-field radiation. PATIENTS AND METHODS: One hundred ten patients with clinical stages I and II, favorable (nonbulky) Hodgkin’s disease were treated with four cycles of VAMP chemotherapy and 15 Gy involved-field radiation for those who achieved a complete response, or 25.5 Gy for those who achieved a partial response to two cycles of VAMP. RESULTS: With a median follow-up of 5.6 years (range, 1.1 to 10.4 years), the 5-year survival and event-free survival were 99% (lower confidence limit [CL], 97.4%) and 93% (lower CL, 88.6%), respectively. Factors associated with event-free survival of 100% were complete response to two cycles of VAMP and histology other than nodular sclerosing Hodgkin’s disease (NSHD). No serious early or late toxicity has been observed. Patients presenting with clinical stages I and IIA, nonbulky disease involving fewer than three nodal sites have a projected survival and event-free survival of 100% and 97% (lower CL, 93%), respectively, at 5 years. CONCLUSION: Risk-adapted, combined-modality therapy using only four cycles of VAMP chemotherapy with 15 to 25.5 Gy of involved-field radiation for patients with early-stage/favorable Hodgkin’s disease is highly effective and without demonstrable late effects. These results indicate that pediatric patients with stages I and II favorable Hodgkin’s disease can be cured with limited therapy that does not include an alkylating agent, bleomycin, etoposide, or high-dose, extended-field radiation therapy.
LOW-DOSE RADIATION plus multiagent chemotherapy for pediatric Hodgkin’s disease was adopted after the pioneering studies reported using 15 to 25 Gy and six cycles of mechlorethamine, vincristine, procarbazine, and prednisone chemotherapy for children.1-4 This approach, initially using surgical staging, evolved to clinical staging,5 with a goal of reducing musculoskeletal sequelae from high-dose irradiation.6 However, when leukemia and male sterility were recognized,7 new drug combinations were designed to reduce chemotherapy toxicity as well. Risk-adapted therapy followed to further decrease toxicity for patients with the most favorable disease settings. We report here the end results of our risk-adapted therapy for children with favorable, early-stage Hodgkin’s disease using a novel chemotherapy combination and low-dose, involved-field radiation therapy.
Study Population and Eligibility Criteria This study was designed with collaborators from Stanford University, Dana-Farber, and St Jude Children’s Research Hospital. Colleagues from the Maine Children’s Cancer Program participated as a satellite partner of the Dana-Farber Cancer Institute. The study opened for patient accrual on September 30, 1990. The primary goal was to retain the survival rate of  90%, which had been achieved with invasive staging and aggressive therapy over the prior decade(s). The secondary objectives were to decrease surgery-, radiation-, and chemotherapy-related toxicity by using clinical staging, less toxic drugs for a shorter duration, and low-dose, involved-field radiation. Eligibility included age less than 21 years, Ann Arbor stage I or II Hodgkin’s disease,8 mediastinal mass ratio of less than one third the intrathoracic ratio measured on an upright posteroanterior chest radiograph, and peripheral lymph node disease less than 6 cm, which defined favorable, early-stage disease. In July 1998, the protocol was modified to exclude patients with systemic B symptoms. The study was closed to patient entry in February 2000. Pathologic specimens were classified according to the Rye modification of Lukes et al.9 Protocol approval was obtained from the institutional review board at each participating institution before patient entry. Informed consent was obtained from the parents or legal guardian.
Staging and Treatment Treatment included four cycles of chemotherapy and radiotherapy. Vinblastine, doxorubicin, methotrexate, and prednisone (VAMP) chemotherapy was administered as follows: vinblastine 6 mg/m2 intravenously (IV) on days 1 and 15; doxorubicin 25 mg/m2 IV on days 1 and 15; methotrexate 20 mg/m2 IV on days 1 and 15; and prednisone 40 mg/m2 orally on days 1 through 14. Prednisone was omitted from the cycles that followed mediastinal radiation.10 Chemotherapy cycles were repeated every 4 weeks as permitted by count recovery. The treatment philosophy was to give full doses of chemotherapy when the WBC count was more than 2 x 109/L, the absolute neutrophil count was more than 0.5 x 109/L, and the platelet count was more than 120 x 109/L. Within 2 weeks of the completion of cycle 2 of VAMP, radiation therapy was given to initially involved sites, most commonly supradiaphragmatic sites. Involved fields did not necessarily include symmetric irradiation. A modified mantle field excluded areas without clinically positive nodal disease, with the axilla(e) blocked to spare excess treatment to the developing breast. When treating mediastinal disease, the bilateral hila were included in a shaped field. A minimantle was used when the mediastinum was uninvolved; a hemiminimantle field was used for unilateral neck disease. A modified Waldeyer’s ring field was used in cases with preauricular, Waldeyer’s ring, or high cervical nodal disease. Radiation dose was determined by the response to two cycles of chemotherapy, with 15 Gy given for those achieving a complete response (CR), and 25.5 Gy for those achieving a partial response (PR). Radiation was given in 1.5 Gy fractions, five times per week, using a linear accelerator. After the radiation, the last two cycles of chemotherapy were given.
Assessment of Outcome
CR was defined as disappearance of all measurable or assessable disease. PR was defined as a reduction of After completion of therapy, patients were reevaluated every 3, 4, and 6 months for 4 years and annually thereafter. Follow-up examinations included physical examination, chest x-ray, abdominal x-ray (if lymphangiogram dye remained), and routine laboratory studies. Follow-up CT and gallium scans were obtained to assess response, and at completion of therapy. Patients were questioned concerning pulmonary, cardiac, or endocrine symptoms; menstrual function; and sexual activity at follow-up visits. Assessment of organ function and measurements of growth were performed every 1 to 2 years. Girls were taught breast self-examination, and screening mammograms were recommended beginning 8 years after therapy if treatment involved radiotherapy to the thorax or axilla(e). Patients with findings suspicious for relapse underwent restaging examinations; biopsy confirmation of progression or relapse was required. Relapsing patients were followed for survival and given retrieval therapy by preference of the institutional investigator. Recognizing that there would be limited power to prove a decrement in EFS among these patients, we performed an interim EFS analysis at each event, and considered closure to new patient entry should we observe a drop in estimated 5-year actuarial EFS to less than 88% at any point in the study. The study was not stopped early. With all patients having been followed at least 1 year, we report the results on the basis of data available as of July 2001. The primary purpose of this study was to compare the estimated 5-year EFS and OS with historical data to determine whether the success seen with earlier, more toxic regimens was maintained. For this purpose, the primary measures were the 5-year estimates from the Kaplan-Meier curves. To indicate the precision of these estimates, an approximate 95% one-tailed lower confidence limit (CL) was provided. In addition, we looked for variables to predict who, among this favorable group of patients, might be most likely to fail. These analyses were performed using the generalized Wilcoxon test of Gehan.12 Because these were exploratory analyses, the nominal P value is reported with no adjustment made for multiple comparisons, and the results are considered to be statistically significant if P < .05.
One hundred ten children were enrolled onto this trial, 24 from Stanford, 23 from Dana-Farber, and 63 from St Jude Children’s Research Hospital. During this enrollment period, there were also 213 consecutive patients with unfavorable, advanced-stage Hodgkin’s disease. Thus, these 110 children represent 34% of our total pediatric Hodgkin’s disease population. The demographic and clinical characteristics of the study population are listed in Table 1. The male-female ratio was 2.1:1. The median age was 13 years (range, 3 to 20 years); only six patients were younger than 6, whereas 11 were older than 16 years. Only one patient underwent staging laparotomy; the stage was not changed by the surgery. The final stages were stage I in 36 and stage II in 74 cases. Five of the 74 stage II patients had systemic B symptoms. None had extranodal extension (E lesion). In 105 cases, the disease was supradiaphragmatic, whereas in five it was infradiaphragmatic in origin.
Response to Treatment and Outcome All patients responded to treatment. After the initial two cycles of chemotherapy, 49 patients (45%) had achieved a CR, whereas 61 (55%) had achieved a PR. However, one of the 110 patients developed progressive cervical nodal disease after cycle 2 of VAMP while at a radiation dose of 7.5 Gy. Biopsy confirmed Hodgkin’s disease and he was taken off study to receive retrieval therapy. The remaining 109 patients completed the planned therapy, and all were scored as achieving a CR by the end of treatment. These 109 patients received full doses of chemotherapy and radiation to 226 Ann Arbor sites of disease. Radiation doses to these involved sites were as follows: 89 sites, 15 Gy; two sites, 18 Gy; four sites, 24 Gy; and 131 sites, 25.5 Gy. No patients have been lost to follow-up. Seven patients have relapsed, six after the planned therapy and one after developing progressive disease on treatment. The latest relapse occurred 52 months from diagnosis. Three of the relapsing patients died, each with progressive disease. The median follow-up duration was 5.6 years (range, 1.1 to 10.4 years). The projected actuarial OS and EFS at 5 years are 99% (lower CL, 97.4%) and 93% (lower CL, 88.6%), respectively (Fig 1). Little difference was seen in outcome on the basis of stage, sex, or age, and none of the comparisons were statistically significant. The projected 5-year OS for the stage I patients is 100%, whereas for the stage II patients it is 98.5% (lower CL, 96.1%). The projected 5-year EFS for the stage I patients is 96% (lower CL, 89.6%), whereas for the stage II patients it is 91% (lower CL, 85.1%). The projected 5-year OS for the boys is 99% (lower CL, 87.6%), whereas for the girls it is 100%. The projected 5-year EFS is 93% (lower CL, 87.6%) for the boys and 91% (lower CL, 83%) for the girls. We compared those younger than 13 years with those aged 13 to 20. The younger cohort has a projected 5-year OS of 98% (lower CL, 94.6%), compared with the 13- to 20-year group OS at 5 years of 100%. The projected 5-year EFS for the younger children is 93% (lower CL, 86.4%), whereas for those older it is 92% (lower CL, 85.7%). Also, there was no difference in either OS or EFS among any of the three participating institutions.
Because treatment was dictated by response to the initial chemotherapy, we were interested to learn whether response to two cycles of VAMP was a predictor of ultimate outcome. There were 15 patients who presented with only one site of disease, whose diagnostic excisional biopsy removed all assessable disease and who were thus converted to CR status by the diagnostic surgical procedure. As they had no abnormalities from which to evaluate response, we removed these 15 patients from the comparison group and calculated the EFS and OS of the remaining patients scored as having achieved a CR after two cycles of chemotherapy (n = 34) versus those with a PR (n = 61). The projected 5-year EFS for the CR patients with assessable disease is 100%, whereas for the PR patients it is 87% (lower CL, 79.4%; P = .04) (Fig 2). These differences do not translate into a significant difference in OS. The projected 5-year OS for these CR patients is 100%, whereas at 5 years it is 98% (lower CL, 92.6%), for patients achieving a PR (P = .2).
Because of the gratifying outcome using this protocol, we wanted to refine the risk groups more strictly to identify an even more favorable group for a next generation protocol. Although the number of events was too few to perform a formal multivariate analysis, we identified 76 of these patients who had less than three Ann Arbor sites of disease and were without B symptoms. Their projected actuarial OS and EFS at 5 years is 100% and 97% (lower CL, 93%), respectively (Fig 3).
Patterns of Failure Analysis A pattern-of-failure analysis is summarized in Table 2. One patient (patient no. 1) had growth of cervical nodal disease after two cycles of chemotherapy while beginning radiotherapy, and underwent biopsy, showing Hodgkin’s disease. He was considered to have disease resistant to VAMP, and was given retrieval therapy. Three other patients (patients no. 2, 3, and 4) relapsed 1 year from the diagnosis with aggressive disease present in multiple sites. In two patients, the disease appeared in unirradiated areas. The final two patients (patients no. 6 and 7) relapsed with much more indolent-appearing disease, failing more than 4 years from diagnosis, in one disease nodal site. All seven patients achieved only a PR to the initial two cycles of chemotherapy. The number of initially involved sites among these seven relapsing patients was as follows: one, two, two, three, three, four, and four. Their initial ESR was  20 in five and more than 20 in two patients. Thus, these features did not distinguish the relapsing patients from those who did not relapse. However, as all seven relapsing patients had the nodular sclerosing Hodgkin’s disease (NSHD) subtype, we analyzed the 58 patients (53%) who had NSHD histology versus the 52 patients with histologic subtype other than NSHD (Fig 4). The 5-year EFS of those with NSHD was 86% (lower CL, 78.1%; P = .013), whereas there were no failures in those with other histologies. These differences did not result in a significant survival difference (P = .14).
Toxicity Treatment was well tolerated and without significant early or late toxicity. All chemotherapy was given as outpatient therapy. There were mild side effects associated with chemotherapy, including temporary, partial alopecia, usually in the occipital area after high-neck radiotherapy; occasional muscle pain related to vinblastine; occasional oral mucositis managed with supportive care; mild nausea; and transient weight gain related to prednisone. Neutropenia was manageable, occasionally requiring antibiotic coverage when accompanied by fever. One child sustained a superficial burn secondary to vinblastine extravasation, which healed spontaneously. Similarly, the problems associated with radiotherapy were mild, including occasional anorexia and nausea, depending on field size and location. Skin reactions were rare. Infectious complications were also uncommon. Two children sustained bacterial infections at a site of venous access: one was superficial at a peripherally inserted central catheter line site, and one resulted in a Staphylococcus bacteremia. Viral infectious episodes were mild and similar to those of a normal pediatric population. There were five episodes of herpes zoster, four localized and one disseminated, each appearing during cycle 4 of chemotherapy. Of the 109 children completing the planned chemotherapy, 97 (89%) received therapy on schedule and 12 (11%) had delays in therapy ranging between 3 and 14 days. In five children, the delay was due to infection: herpes zoster (two patients), bacteremia (one patient), and presumed viral illness (two patients). In five children, therapy was delayed due to absolute neutropenia delaying cycles IIA (two episodes), IIIB (one episode), IVA (three episodes), and IVB (three episodes). Two children had delays in therapy because of scheduling or personal issues. Sequelae of a more chronic nature have also been mild. They included 28 children with compensated hypothyroidism detected 1 to 7 years after diagnosis, six after 15 Gy to the thyroid/neck region and the others after 25.5 Gy. Each was rendered euthyroid on replacement therapy. One patient, diagnosed with a multinodular goiter 7 years after treatment, developed a follicular adenoma. Fifteen asymptomatic patients had mild abnormalities on routine pulmonary function tests, seven with mild restrictive or obstructive changes, five with mild diffusion changes, and three with both. Five of the children received no thoracic radiation, thus raising the question of the cause of the findings. None required medical management. Seven children had cardiac abnormalities 18 months to 7.5 years after diagnosis. Three had asymptomatic right ventricular dilatation with normal systolic function of unclear clinical significance. One had mitral valve prolapse 6 years after diagnosis, one had trace tricuspid regurgitation, and another had a 2/6 systolic flow murmur. One had abnormal left ventricular fractional shortening after 25.5 Gy mediastinal radiation and four cycles of VAMP. She is asymptomatic and remains stable. Musculoskeletal assessment was made by physical examination. Two boys have mild soft tissue atrophy, one observed 6 years after 25.5 Gy radiation and one observed 5 years after a neck dissection performed as diagnostic surgery. All pubertal girls had normal menarche, five of whom had normal pregnancies and deliveries of six full-term babies. One underwent an elective termination of pregnancy. Two males fathered normal children 4 and 6 years after therapy. There have been no secondary malignancies.
Implicit in the success of risk-adapted therapy is the refinement and reproducibility of risk groups. Traditionally, risk groups have been derived from large retrospective reviews in which various prognostic variables are compared. However, factors of good outcome change with successful therapy. When comparing adult and pediatric populations, age itself is a powerful prognostic variable, with children and adolescents faring better than adults.13,14 Although the general concept of risk-adapted therapy is broadly accepted, differing staging and treatment protocols have made comparisons across pediatric studies difficult. Most groups have defined low risk as stages I and IIA, although some have included patients with systemic symptoms. The French Society of Pediatric Oncology has included all stage I and stage II patients, irrespective of systemic symptoms, tumor size, or bulk,15 whereas others have considered a large mediastinal mass ratio and systemic symptoms to be unfavorable factors and excluded such patients from low-risk protocols. Some groups have also excluded large peripheral nodal disease from the low-risk category. We chose to define low risk as Ann Arbor stages I and IIA and IIB, excluding patients with bulky mediastinal and peripheral nodal disease, on the basis of the experience that such patients require more therapy than those with small bulk disease.16,17 We modified our protocol to exclude those with B symptoms when two of our five patients with B symptoms failed. Our goal was to define short and nontoxic therapy administered in an outpatient setting. Four cycles of VAMP was selected, as it is unlikely to cause leukemia, sterility, or cardiac or pulmonary dysfunction. Vinblastine and doxorubicin are two of the most effective agents against Hodgkin’s disease. Vinblastine is well tolerated at the dose used. Similarly, doxorubicin, at a total dose of 200 mg/m2, confers a low risk of clinically apparent cardiac dysfunction. Methotrexate has modest activity against Hodgkin’s disease and was added with prednisone, as four-drug therapy is superior to two-drug therapy. We omitted bleomycin because of its recognized pulmonary dysfunction in children. Etoposide is used by some; however, it carries a leukemia risk.15 In addition, we have found the allergic reactions to be dose limiting18 and its effectiveness disappointing in children with advanced-stage Hodgkin’s disease.19 Furthermore, the VAMP combination avoids agents such as procarbazine and mechlorethamine, which are associated with male infertility. Four cycles of VAMP and low-dose, involved-field radiation provides less total therapy than chemotherapy-only regimens which, to date, have relied on alkylating agents, bleomycin, and/or etoposide. The VAMP/radiotherapy protocol was response driven with respect to radiation dose, but not volume. This provided the ability to refine and reduce both the number of chemotherapy cycles and the dose of radiotherapy to achieve our objective of maximizing the therapeutic index and minimizing early and late toxicity. The therapy has proven to be both effective and nontoxic for these low-risk, favorable patients, who represent approximately one third of all pediatric Hodgkin’s disease. With such a successful protocol, it is difficult to determine factors that predict for relapse. Response to initial chemotherapy has been shown to predict for improved EFS (Kung et al, manuscript in preparation),15,20 and we too confirmed that a CR after two cycles of chemotherapy is associated with an improved outcome. Furthermore, we have shown that two cycles of VAMP achieved a CR in 34 (36%), and this early response continues to be an important predictor of outcome. Analysis of histology as a prognostic predictor has shown the lymphocyte-predominant Hodgkin’s disease subtype is associated with excellent outcome.21 We confirmed its good prognosis; also, those with mixed-cellularity Hodgkin’s disease fared well, whereas seven of the 58 patients with NSHD suffered a failure. Historically, NSHD failures have been explained by the common occurrence of bulky disease, often in the mediastinum in adolescent girls. In this series of nonbulky disease, we found NSHD to be the only subtype where relapse has occurred. However, when examining a large cohort of children with Hodgkin’s disease by multivariate analyses, the NSHD histologic subtype is not an independent factor predictive of relapse.22 Our results are comparable to or exceed those of other groups of low-risk patients, but with less duration and intensity of treatment and, accordingly, less toxicity. Our actuarial 5-year OS of 99% and EFS of 93% are better than reported from the French MHD90 study of 97% OS and 91% EFS using vinblastine, bleomycin, etoposide, and prednisone, in which two children developed leukemia, likely related to the etoposide. Our approach is more similar to the German/Austrian HD-90 study of two cycles (vincristine, etoposide, prednisone, and doxorubicin for boys and vincristine, procarbazine, prednisone, and doxorubicin for girls) and 25-Gy radiation for patients stages I and IIA. They reported 5-year EFS of 92% for boys and 96% for girls.23 Our data are also similar to those of the Children’s Cancer Group 5942 low-risk group, which showed an EFS at 3 years of 97% after four cycles of cyclophosphamide, vincristine, procarbazine, and prednisone/doxorubicin, bleomycin, and vinblastine (COPP/ABV) and 21 Gy radiation and 91% after chemotherapy alone (Nachman et al, manuscript in press). Four cycles of the COPP/ABV program is, however, associated with more toxicity than has been observed or is expected from the VAMP program. With median follow-up in excess of 5 years and maximal follow-up in excess of 10 years, we have not observed untoward serious toxicity from the VAMP program. This is particularly gratifying, as the follow-up of these patients involves an in-depth assessment in which we are screening for potential late effects. Lifelong surveillance and follow-up is important to continue to search for late effects. We advocate risk-based therapy and currently assess all pediatric patients to identify prognostic factors similar to those found in the adult series, to refine our therapy even further.22 Thus, using more refined risk groups in our newest protocols, we now divide patients into favorable, intermediate, and unfavorable risk groups, in which the favorable group is defined as stages I and IIA, nonbulky, and less than three Ann Arbor sites of disease. Applying this new strict definition to the current population yields a 5-year OS and EFS of 100% and 97%, respectively. This confirms that risk-adapted therapy is successful in achieving a high cure rate and reducing toxicity among the most favorable patients. Furthermore, it supports the approach of reserving more aggressive therapy and toxicity for those with the most advanced unfavorable disease. Our experience with VAMP and low-dose involved-field radiation indicates that these favorable patients can be cured with treatment that avoids an alkylating agent, bleomycin, etoposide, and high-dose, extended-field radiation therapy.
1. Donaldson SS: Pediatric Hodgkin’s disease: Focus on the future, in Van Eys J, Sulllivan MP (eds): Status of the Curability of Childhood Cancers. New York, NY, Raven Press, 1980, pp 235-249 2. Donaldson SS, Kaplan HS: A survey of pediatric Hodgkin’s disease at Stanford University: Results of therapy and quality of survival, in Rosenberg SA, Kaplan HS (eds): Malignant Lymphomas: Etiology, Immunology, Pathology, Treatment. New York, NY, Academic Press, 1982, pp 571-590 3. Donaldson SS: Hodgkin’s disease: Treatment with low dose radiation and chemotherapy, in Vaeth J (ed): Frontiers of Radiation Therapy and Oncology. Basel, Switzerland, Karger, 1982, pp 122-133
4. Donaldson SS, Link MP: Combined modality treatment with low-dose radiation and MOPP chemotherapy for children with Hodgkin’s disease. J Clin Oncol 5: 742-749, 1987 5. Jenkin D, Freedman M, McClure P, et al: Hodgkin’s disease in children: Treatment with low dose radiation and MOPP without staging laparotomy—A preliminary report. Cancer 44: 80-86, 1979[CrossRef][Medline] 6. Probert JC, Parker BR, Kaplan HS: Growth retardation in children after megavoltage irradiation of the spine. Cancer 32: 634-639, 1973[CrossRef][Medline] 7. Sherins RJ, Olweny CL, Ziegler JL: Gynecomastia and gonadal dysfunction in adolescent boys treated with combination chemotherapy for Hodgkin’s disease. N Engl J Med 299: 12-16, 1978[Abstract]
8. Carbone PP, Kaplan HS, Musshoff K, et al: Report of the Committee on Hodgkin’s Disease Staging Classification. Cancer Res 31: 1860-1861, 1971
9. Lukes RJ, Craver LF, Hall TC, et al: Report of the Nomenclature Committee. Cancer Res 26: 1311, 1966
10. Castellino RA, Glatstein E, Turbow MM, et al: Latent radiation injury of lungs or heart activated by steroid withdrawal. Ann Intern Med 80: 593-599, 1974 11. Kaplan EL, Meier P: Non-parametric estimation from incomplete observations. J Am Stat Assoc 53: 457-481, 1958[CrossRef]
12. Gehan EA: A generalized Wilcoxon test for comparing arbitrarily singly-censored samples. Biometrika 52: 650-653, 1965 13. Cleary SF, Link MP, Donaldson SS: Hodgkin’s disease in the very young. Int J Radiat Oncol Biol Phys 28: 77-83, 1994[Medline]
14. Hasenclever D, Diehl V: A prognostic score for advanced Hodgkin’s disease: International Prognostic Factors Project on Advanced Hodgkin’s Disease. N Engl J Med 339: 1506-1514, 1998
15. Landman-Parker J, Pacquement H, Leblanc T, et al: 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. J Clin Oncol 18: 1500-1507, 2000 16. Mauch P, Goodman R, Hellman S: The significance of mediastinal involvement in early stage Hodgkin’s disease. Cancer 42: 1039-1045, 1978[CrossRef][Medline]
17. Hoppe RT, Coleman CN, Cox RS, et al: The management of stage I–II Hodgkin’s disease with irradiation alone or combined modality therapy: The Stanford experience. Blood 59: 455-465, 1982
18. Hudson MM, Weinstein HJ, Donaldson SS, et al: Acute hypersensitivity reactions to etoposide in a VEPA regimen for Hodgkin’s disease. J Clin Oncol 11: 1080-1084, 1993 19. Link MP, Hudson MM, Donaldson SS: Treatment of children with unfavorable and advanced stage Hodgkin’s disease with vinblastine, etoposide, prednisone, and Adriamycin (VEPA) and low-dose, involved field irradiation. Proc Am Soc Clin Oncol 13: 392, 1994 (abstr 1334) 20. Weiner MA, Leventhal B, Brecher ML, et al: Randomized study of intensive MOPP-ABVD with or without low-dose total-nodal radiation therapy in the treatment of stages IIB, IIIA2, IIIB, and IV Hodgkin’s disease in pediatric patients: A Pediatric Oncology Group study. J Clin Oncol 15: 2769-2779, 1997[Abstract] 21. Russell KJ, Hoppe RT, Colby TV, et al: Lymphocyte predominant Hodgkin’s disease: Clinical presentation and results of treatment. Radiother Oncol 1: 197-205, 1984[Medline] 22. Smith RS, Chen Q, Hudson M, et al: Prognostic factors in pediatric Hodgkin’s disease. Int J Radiat Oncol Biol Phys 19: 119, 2001 (abstr) 23. Schellong G: Pediatric Hodgkin’s disease: Treatment in the late 1990s. Ann Oncol 9: S115-S119, 1998 (suppl) Submitted December 20, 2001; accepted March 26, 2002.
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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
