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Journal of Clinical Oncology, Vol 22, No 22 (November 15), 2004: pp. 4541-4550 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.02.139 Risk-Adapted, Combined-Modality Therapy With VAMP/COP and Response-Based, Involved-Field Radiation for Unfavorable Pediatric Hodgkin's DiseaseFrom the Department of Hematology Oncology, Radiological Sciences, and Biostatistics, St Jude Children's Research Hospital and the University of Tennessee College of Medicine, Memphis, TN; Stanford University Medical Center, Stanford, CA; Massachusetts General Hospital and Dana-Farber Cancer Institute, Boston, MA; and Barbara Bush Children's Hospital at Maine Medical Center, Portland, ME Address reprint requests to Melissa M. Hudson, MD, St Jude Children's Research Hospital, 332 N Lauderdale, Memphis, TN 38105; e-mail: melissa.hudson{at}stjude.org
PURPOSE: To evaluate the efficacy of vinblastine, doxorubicin, methotrexate, and prednisone (VAMP) and cyclophosphamide, vincristine, and procarbazine (COP) chemotherapy and response-based, involved-field radiation, a combined-modality regimen that limits doses of alkylating agents, anthracyclines, and radiation, in children with advanced and unfavorable Hodgkin's disease. PATIENTS AND METHODS: From 1993 to 2000, 159 children and adolescents with unfavorable Hodgkin's disease received three alternating cycles (total of six cycles) of VAMP/COP chemotherapy followed by response-based, involved-field radiation therapy: 15 Gy was administered to patients achieving a complete response, and 25.5 Gy was administered to those achieving a partial response after the first two cycles of chemotherapy and to all sites of bulky lymphadenopathy. Unfavorable disease was defined as clinical stage I and II with bulky peripheral nodal disease greater than 6 cm, initial bulky mediastinal mass 33% or more of the intrathoracic diameter, and/or "B" symptoms and all stage III and IV. RESULTS: Study enrollment was closed after an interim analysis estimated a 5-year event-free survival (EFS) rate below a predefined level. Disease presentation was localized (stage I/II) in 77 patients (48.4%) and advanced (stage III/IV) in 82 patients (51.6%). At a median follow-up of 5.8 years (range, 1.3 to 10.0 years), 38 patients had events, including relapse/progression (n = 35), second malignancy (n = 2), and accidental death (n = 1); nine relapses (25.7%) occurred greater than 4 years from diagnosis. Five-year survival and EFS estimates are 92.7% ± 2.5% and 75.6% ± 4.1%, respectively. CONCLUSION: Risk-adapted combined-modality therapy with VAMP/COP and response-based, involved-field radiation therapy results in an unsatisfactory outcome for pediatric patients with unfavorable presentations of Hodgkin's disease.
Because cure is likely for the majority of children and adolescents presenting with Hodgkin's disease, attention to long-term treatment complications has become increasingly important. The desire to reduce treatment-related sequelae has been the most influential factor motivating changes in pediatric treatment regimens over the last 30 years. The concept of modifying therapy to reduce adverse treatment effects was pioneered by pediatric investigators in the 1970s and 1980s in an effort to prevent impairment of skeletal and soft tissue growth in young patients after high-dose, extended-field radiation.1-3 Subsequently, appreciation of other late treatment toxicities, coupled with advances in diagnostic imaging and radiation oncology, prompted further changes. The correlation of secondary acute myeloid leukemia and infertility with higher cumulative doses of alkylating agents motivated the development of chemotherapy combinations that restricted their use.4-7 Studies demonstrating coronary artery disease in individuals treated with thoracic radiation and cardiomyopathy in younger patients after even relatively low cumulative doses of anthracycline led to reduction in dose for both of these modalities.8-10 Recognition of pulmonary fibrosis in long-term survivors treated with thoracic irradiation and bleomycin accelerated the development of newer chemotherapy combinations that reduced bleomycin exposure and refinements in radiation treatment fields that better shielded normal tissues.11,12 Appreciation of the long-term, potentially life-threatening consequences of splenectomy and the development of diagnostic imaging modalities to assess abdominopelvic disease resulted in the abandonment of surgical staging.13 Finally, reports of secondary solid tumor malignancy, particularly breast cancer, in aging survivors of pediatric Hodgkin's disease, has led to clinical trials evaluating the efficacy of chemotherapy alone.4,14-16 Risk-adapted treatment protocols, which assign intensity of therapy according to risk features at diagnosis or response to initial therapy, have become a standard treatment approach for pediatric malignancies that are highly curable with contemporary therapy.17-20 The parameters most frequently used to assign risk (and subsequent treatment intensity) in pediatric Hodgkin's disease include the presence of "B" symptoms, mediastinal and peripheral lymph node bulk, extranodal extension of disease to contiguous structures, number of involved nodal regions, and Ann Arbor stage. Although risk classifications vary across individual studies, favorable or low risk is usually defined as localized (stage I/II) nodal involvement in the absence of B symptoms and nodal bulk. Unfavorable or high-risk presentations typically include the presence of B symptoms, bulky lymphadenopathy, hilar lymphadenopathy, involvement of three to four or more nodal regions, extranodal extension to contiguous structures, or advanced stage (IIIB/IV). Inconsistency in risk designations in pediatric Hodgkin's trials are problematic and often prevent direct comparison of treatment outcomes across investigations. Risk-adapted regimens seek to maintain disease control while reducing therapy-related complications. Therefore, this approach may reduce therapy for patients with favorable diagnostic features or intensify therapy for patients with unfavorable disease presentations. Numerous investigations have established that children and adolescents with favorable presentations of Hodgkin's disease are excellent candidates for reduced therapy.17,18,20,21 Outcomes for unfavorable patients treated with contemporary combined-modality or chemotherapy-alone regimens demonstrate 5-year disease control in the range of 70% to 90%.1,3,18,20-28 Progression-free survival rates of more than 80% in subgroups of high-risk patients with advanced Hodgkin's disease have motivated investigators to attempt to limit treatment intensity as much as possible in newly diagnosed high-risk patients to reduce potential treatment-related morbidity. Unfortunately, the optimal strategy for identifying the high-risk patient who will not respond to or maintain remission after frontline therapy has not been established. This deficiency underscores the need to pursue risk-adapted initiatives with caution, because compromising primary disease control may ultimately increase the risk of progressive disease and treatment sequelae in survivors who require intensive retrieval therapy. Herein, we report outcomes after a risk-adapted, combined-modality treatment approach for children and adolescents with unfavorable Hodgkin's disease. The goal of the study was to evaluate the efficacy of vinblastine, doxorubicin, methotrexate, and prednisone (VAMP) and cyclophosphamide, vincristine, and procarbazine (COP) chemotherapy and response-based, involved-field radiation, a combined-modality regimen that limits doses of alkylating agents, anthracyclines, and radiation, in children with advanced and unfavorable Hodgkin's disease.
Study Design Between October 1993 and February 2000, 160 patients younger than 21 years of age were enrolled at four institutions (St Jude Children's Research Hospital in Memphis, TN; Stanford University Medical Center in Stanford, CA; Dana-Farber Cancer Institute in Boston, MA; and Maine Children's Cancer Program in Portland, ME). All patients meeting the study eligibility criteria were invited to participate, but the referral patterns during the study period promoted the management of most patients older than 18 years by medical oncologists, thereby resulting in very few referrals in this age group for protocol participation. In contrast, patients younger than 18 years were uniformly treated on protocol at one of the collaborating centers. One patient was enrolled and subsequently determined to be ineligible after histologic review indicated the diagnosis of large-cell non-Hodgkin's lymphoma. The remaining 159 patients are assessable for study outcomes (Table 1). Informed consent was obtained for all patients, and the protocol was approved by institutional review boards at the collaborating centers. Eligible patients had histologically confirmed Hodgkin's disease, were previously untreated, and clinically staged. Prior treatment with glucocorticoids for less than 1 week or emergent radiation was permitted if clinically warranted. Patients with unfavorable disease included all those with Ann Arbor stage III and IV disease, as well as patients with stage I and II disease who had bulky lymphadenopathy (defined as the mediastinal mass to intrathoracic cavity ratio of one third or greater on upright chest radiograph or a peripheral lymph node mass greater than 6 cm in longest diameter) or B symptoms. The required clinical staging evaluation included: history and physical examination; CBC count with differential, erythrocyte sedimentation rate, and routine renal and hepatic chemistries; chest radiograph, cervical and thoracic computed tomography (CT) scan with contrast, and CT or magnetic resonance imaging scan of abdomen and pelvis; and bone marrow biopsy. In addition, lymphography was used by two centers for staging of abdominal pelvic lymph nodes. Gallium and later positron emission tomography (PET) and bone scans were also used to monitor response.
Treatment Strategy Treatment included a total of six cycles of chemotherapy and involved-field radiotherapy with the prescribed dose based on tumor response. Three cycles of VAMP chemotherapy were alternated with three cycles of COP chemotherapy. 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/d orally on days 1 through 14 (omitted after mediastinal radiation therapy). COP chemotherapy was administered as follows: cyclophosphamide 600 mg/m2 IV on days 1 and 8; vincristine 1.4 mg/m2 on days 1 and 8 (maximum of 2 mg); procarbazine 100 mg/m2/d on days 1 through 14. Cycles were repeated every 4 weeks as permitted by blood count recovery. After completion of the second cycle, all patients were evaluated for chemotherapy response by clinical examination and CT scan. Complete response was defined as resolution of all tumor-related constitutional symptoms and disappearance of all measurable or assessable disease. Minimal residual gallium or PET-negative diagnostic imaging abnormalities representing a reduction of  75% in the original tumor volume were considered scar tissue without active tumor. Partial response was defined as at least 50% reduction in the sum of the products of two perpendicular diameters of all measurable lesions and disappearance of constitutional symptoms if initially present. After completion of therapy, patients were designated to be in complete remission as long as off-therapy evaluations did not reveal new abnormalities suggestive of disease progression. Individuals with residual abnormalities in areas previously documented as sites of disease were considered to be in complete remission as long as residual abnormalities were stable or improved when compared with previous evaluations. Biopsy confirmation of progression or relapse was required. For patients with unfavorable stage I/II and stage IIIA disease, chemotherapy was scheduled to alternate with involved-field radiotherapy in the following fashion: two cycles of chemotherapy, supradiaphragmatic radiation, two cycles of chemotherapy, infradiaphragmatic radiation (if indicated), final two cycles of chemotherapy, pelvic radiation (if indicated). Patients with stage IIIB and IV disease received consolidative radiotherapy after completion of all six cycles of chemotherapy. Radiation therapy was directed to standardized treatment volumes, including mantle, modified mantle-like volumes depending on the number of nodal sites involved supradiaphragmatically (minimantle, hemiminimantle), and mediastinum. When there was evidence of infradiaphragmatic disease, treatment volume included the spleen and para-aortic lymph nodes (to L3 or L4) at a minimum; iliac-inguinal-femoral nodal volumes were treated when involved. All sites of initial disease were irradiated. The radiation therapy dose was 25.5 Gy in 1.5 Gy fractions for all sites of bulk disease at presentation; other lymph node sites received 25.5 Gy or 15 Gy, the lower dose delivered to initial sites of nonbulky involvement that had shown complete response after the second chemotherapy cycle. Visceral sites of involvement and bone lesions were treated with lower-dose (8 to 15 Gy) radiation therapy.
After-Therapy Monitoring Risk-based yearly assessment for treatment-related organ toxicity was recommended after completion of therapy. The specific evaluations undertaken included the following: physical examination of bones and soft tissues, measurement of thyroxine and thyroid-stimulating hormone for patients treated with cervical and upper mediastinal irradiation, pulmonary function studies (spirometry and diffusion capacity) for patients treated with chest radiation, echocardiogram and ECG for all patients, menstrual cycle history in women, referral for semen analysis in men, clinical history of pregnancy attempts and outcomes, and histologic review of second tumors.
Statistical Methods EFS was defined as the interval from protocol enrollment to the date of first event (relapse or progression, second malignancy, or death from any cause) or to the date of last follow-up. Survival was defined as the interval from enrollment to the date of death from any cause or to last follow-up. EFS and survival distributions were estimated using the method of Kaplan and Meier.29 The log-rank test30 was used to examine differences in EFS. Freedom from progression was defined as the interval from enrollment date to date of relapse or progressive disease or to last follow-up for patients without recurrent disease; second malignancy and death before recurrence were considered competing events. Freedom from progression was estimated using methods of Kalbfleisch and Prentice.30 Cutoff values used to categorize WBC count, hemoglobin, and erythrocyte sedimentation rate (Table 2) were based on values found to be significantly predictive of outcome in previously published literature.31
Patient Characteristics Demographic characteristics of the patient cohort are shown in Table 1. The median age at the time of study enrollment was 15.3 years (range, 2.8 to 19.0 years). The majority of patients were white (n = 126; 79.2%); 56% were male (n = 89). Stage distribution was I in 15 patients (9.4%; B = 2, bulky = 15), II in 62 patients (39.0%; B = 25, bulky = 58), III in 38 patients (23.9%), and IV in 44 patients (27.7%). B symptoms were present in 68 patients (42.8%) and included sweats (n = 41), fever (n = 38), and weight loss (n = 34). Approximately three quarters of patients had bulky disease (n = 121; 76.1%); sites of bulk included the mediastinum in 47 patients (29.6%), peripheral lymph nodes in 53 patients (33.3%), and both in 21 patients (13.2%). Fifty-five patients (34.6%) had extranodal involvement, including 44 stage IV patients and 11 other patients with extranodal involvement from extension of contiguous lymphatic disease. The most common histology was nodular sclerosing in more than 75% of patients (n = 121), followed by mixed cellularity (n = 23; 14.5%). The median follow-up for survivors (n = 145) from the date on study was 5.8 years and ranged from 1.3 to 10.0 years. Almost 80% of survivors had been followed within the past 1.5 years (n = 112), and more than 90% of survivors had been contacted within the previous 2.5 years (n = 132).
Response to Treatment and Outcome Five-year estimates of survival and EFS (median ± SE) are 92.7% ± 2.5% and 75.6% ± 4.1%, respectively (Fig 1). EFS was notably higher, but not statistically different for the 77 patients with stage I/II unfavorable disease compared with those patients with advanced disease (5-year estimates, 82.5% ± 5.0% with stage I/II v 68.4% ± 6.5% with stage III/IV; P = .093). EFS did not differ for patients with (75.3% + 6.2%) or without (75.8% + 5.5%) B symptoms (P = .45) and for patients with (70.2% + 11.6%) and without (76.1% + 8.3%) bulky lymphadenopathy (P = .42). Five-year estimates of EFS by stage were 100% for stage I, 78.4% ± 6.1% for stage II, 68.9% ± 9.1% for stage III, and 68.5% ± 9.1% for stage IV (P = .088; Fig 2). The cumulative incidence of progression or relapse at 5 years for the VAMP/COP patients was 22.4% ± 3.5%. Twelve relapses (34.3%) occurred more than 3 years from diagnosis, and nine relapses (25.7%) occurred more than 4 years from diagnosis.
Factors potentially predictive of EFS are listed in Table 2. Demographic characteristics (ie, age, race, sex) were not prognostic of EFS. Stage (I v II v III v IV) was marginally associated with EFS (P = .088; Fig 2). Patients without evidence of extranodal disease had a 5-year EFS of 79.0% ± 4.7%, compared with 69.4% ± 8.2% for patients with extranodal disease; the difference was not significant (P = .182). Higher WBC count and lower hemoglobin at diagnosis were both associated with worse outcome (P = .046 and P = .003, respectively). Erythrocyte sedimentation rate was also not a significant predictor of EFS (P = .32).
Patterns of Failure Analysis
Acute Toxicity and Late Effects Therapy was well tolerated; hospitalization for neutropenic fever or infectious complications was uncommon (3.5% of cycles). Comprehensive information about late treatment toxicity is available for 78 long-term survivors. The most common late toxicity was hypothyroidism, which developed in 48 patients (61.5%). Five patients developed cardiac abnormalities after therapy: two patients had left ventricular hypertrophy associated with normal left ventricular systolic function, one had left ventricular dysfunction associated with a prolonged Q-T interval, and one had mild mitral valve prolapse syndrome. In the last patient, mitral and tricuspid valve insufficiency was detected during labor and delivery and subsequently resolved postpartum. Pulmonary toxicity comprised asymptomatic deficits of restriction and diffusion in 24 patients (30.8%). Gonadal toxicity for the 47 male patients is unknown in 33 patients (70.2%); hypogonadism was evident in six patients by subnormal testosterone and clinical infertility ( 2 years of inability to conceive after unprotected intercourse). Only four men underwent semen analysis; three men were azoospermic. The partners of four men conceived seven pregnancies from which four infants were born; two pregnancies ended in spontaneous abortion, and one pregnancy was electively terminated. Of the 31 long-term female survivors, 21 patients (67.7%) continue to have regular menses; ovarian function cannot be evaluated in another four patients who are receiving contraceptive hormonal therapy. Only one woman treated with pelvic radiation therapy has developed premature ovarian failure. There have been 24 pregnancies in 16 women in the cohort which produced 12 healthy infants; six pregnancies terminated in spontaneous abortions, and one patient with a tubal pregnancy had an elective abortion. Five women are currently pregnant. Two patients developed avascular necrosis of the femoral heads likely related to corticosteroid therapy; the femoral heads were not included in the radiation field of either of these patients. Second malignant neoplasms included one case each of parotid mucoepidermoid carcinoma (in radiation treatment field) and acute myeloid leukemia; the former patient is in remission after wide surgical excision and radiation therapy; the latter patient succumbed to secondary leukemia.
In an effort to maintain high cure rates and reduce treatment-related morbidity and mortality in children and adolescents with Hodgkin's disease, we implemented a trial of risk-adapted therapy using alternating cycles of VAMP/COP combination chemotherapy and involved-field radiation. Using this approach, our trial demonstrates disease control that is inferior to results published with other risk-adapted regimens in advanced and unfavorable pediatric Hodgkin's disease.18,21 The limited cumulative doses of alkylating agent and anthracycline chemotherapy in combination with low-dose, involved-field radiation seem to compromise disease control in this high-risk group. We also observed a high frequency of late recurrence, with approximately one third of cases presenting more than 3 years after diagnosis. Previous studies of combined-modality therapy trials with a median follow-up of 5 or more years indicate that the majority of patients experience relapse within the first 3 years from diagnosis.1,25,26,32 Relapse after 3 years is uncommonly reported and best documented in cases with lymphocyte-predominant Hodgkin's disease.33 Investigations describing long-term outcomes after contemporary risk-adapted regimens are not yet available. Our findings suggest that suboptimal risk-adapted therapy may be associated with delayed recurrence and underscores the need for prolonged monitoring and long follow-up to accurately define treatment outcomes. The patterns of treatment failure with this approach were within the radiation therapy treatment fields in 82% of the patients who experienced treatment failure. This high incidence of infield failure has been reported previously in a recent Children's Cancer Group study where 10 of 12 known sites of failure were within low-dose (21 Gy) treatment fields.18 Over the years, pediatric investigators have modified previously established effective treatment approaches because of concerns about potential sequelae that impact the quality of life and can result in early mortality among long-term survivors. Compared with previous pediatric trials using regimens of mechlorethamine, vincristine, procarbazine, and prednisone (MOPP, doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD), or alternating MOPP/ABVD chemotherapy alone or in combination with radiation, acute toxicity related to myelosuppression was minimal with the VAMP/COP plus radiation regimen.3,23,24,27,28 Late adverse effects, including cardiopulmonary and gonadal toxicity, are also substantially lower. However, long-term results with this risk-adapted regimen illustrate that compromising disease control can offset the potential benefits of reducing late effects. Similar results have been observed by German and Austrian investigators who pioneered risk-adapted therapy trials over the last 30 years using combination chemotherapy with vincristine, procarbazine, prednisone, and doxorubicin (OPPA) and cyclophosphamide, vincristine, procarbazine, and prednisone (COPP).21,32 Substitution of methotrexate for procarbazine in the COPP regimen was less effective for patients with intermediate- and high-risk features in the HD-85 trial.32 However, in HD-90, substitution of etoposide for procarbazine in the OPPA combination produced comparable disease control to those achieved with OPPA/COPP, with less gonadal toxicity.21 Our disappointing experience with vinblastine, etoposide, prednisone, and doxorubicin (VEPA) chemotherapy and low-dose, involved-field radiation indicate the apparent necessity of alkylating agent chemotherapy for patients with unfavorable Hodgkin's disease.34 By contrast, patients with favorable disease presentations are highly curable with modified chemotherapy regimens that omit alkylating agent chemotherapy, in conjunction with low-dose, involved-field irradiation.17,19,35
The overall 5-year survival of our cohort (92.7% ± 2.5%) suggests that the retrieval rate after recurrence is reasonably high, providing some support for use of a less toxic frontline treatment in newly diagnosed patients. The approach offers the advantage of therapy reduction for the majority of patients and reserves more intensive therapy for high-risk patients with unresponsive or recurrent disease. However, these early results do not reflect the ultimate outcome of the patients who are currently under treatment for refractory disease or those who may have a delayed recurrence after more intensive salvage therapy, including hematopoietic stem-cell transplantation.36 Numerous studies indicate that the cumulative toxicity of retrieval therapy contributes significantly to the subsequent risk of developing vital organ dysfunction and a second malignancy.4,9,37 Moreover, investigations of cause-specific mortality in long-term ( In contrast to many other pediatric malignancies, reliable biologic prognostic factors have not been identified to guide therapeutic intensity for pediatric Hodgkin's disease. Treatment outcomes have been correlated with many clinical factors, including male sex, nodular sclerosing histology and grade, advanced stage, and the presence of B symptoms, anemia, leukocytosis, and bulky mediastinal disease.20,28,31,35,39,40 Some groups have proposed prognostic indices based on combinations of these and other laboratory parameters.31,35 Distinctly missing are biologic and molecular characteristics of Hodgkin's disease that are highly correlated with treatment response and long-term outcome. Until such factors are identified, attempts at therapy reduction are likely to be associated with imperfect results in patients with moderately advanced to advanced disease. In summary, risk-adapted, combined-modality therapy with the VAMP/COP regimen, which limits alkylating agent and anthracycline chemotherapy, combined with response-based, involved-field radiation therapy that limits radiotherapy dose and volume, produces unsatisfactory results in pediatric patients with advanced and unfavorable presentations of Hodgkin's disease. Future attempts at therapy reduction for this group in an effort to reduce late treatment sequelae should be pursued carefully, as long-term disease control may be compromised. Treatment approaches using more dose-intensive chemotherapy and higher focal radiation in nodal areas with suboptimal response to chemotherapy may be required to optimize disease-free survival.21,35
The authors indicated no potential conflicts of interest.
We thank Barbara Cruchon for her assistance with manuscript preparation and Claire Colon for data management.
Supported by Cancer Center Support (CORE) grant No. CA 21765 from the National Cancer Institute and by the American Lebanese Syrian Associated Charities. Authors' disclosures of potential conflicts of interest are found at the end of this article.
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5. Schellong G, Riepenhausen M, Creutzig U, et al: Low risk of secondary leukemias after chemotherapy without mechlorethamine in childhood Hodgkin's disease: German-Austrian Pediatric Hodgkin's Disease Group. J Clin Oncol 15:2247–2253, 1997 6. Meadows AT, Obringer AC, Marrero O, et al: Second malignant neoplasms following childhood Hodgkin's disease: Treatment and splenectomy as risk factors. Med Pediatr Oncol 17:477–484, 1989[Medline] 7. Bramswig JH, Heimes U, Heiermann E, et al: The effects of different cumulative doses of chemotherapy on testicular function: Results in 75 patients treated for Hodgkin's disease during childhood or adolescence. Cancer 65:1298–1302, 1990[CrossRef][Medline]
8. Hancock SL, Donaldson SS, Hoppe RT: Cardiac disease following treatment of Hodgkin's disease in children and adolescents. J Clin Oncol 11:1208–1215, 1993 9. Green DM, Gingell RL: Regarding cardiac function and morbidity in long-term survivors of Hodgkin's disease. Int J Radiat Oncol Biol Phys 41:971, 1998 10. Lipshultz SE, Colan SD, Gelber RD, et al: Late cardiac effects of doxorubicin therapy for acute lymphoblastic leukemia in childhood. N Engl J Med 324:808–815, 1991[Abstract] 11. Bossi G, Cerveri I, Volpini E, et al: Long-term pulmonary sequelae after treatment of childhood Hodgkin's disease. Ann Oncol 8:19–24, 1997 (suppl 1) 12. Polliack A: Late therapy-induced cardiac and pulmonary complications in cured patients with Hodgkin's disease treated with conventional combination chemo-radiotherapy. Leuk Lymphoma 15:7–10, 1995 (suppl 1) 13. Hays DM, Ternberg JL, Chen TT, et al: Postsplenectomy sepsis and other complications following staging laparotomy for Hodgkin's disease in childhood. J Pediatr Surg 21:628–632, 1986[Medline]
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25. Hunger SP, Link MP, Donaldson SS: ABVD/MOPP and low-dose involved-field radiotherapy in pediatric Hodgkin's disease: The Stanford experience. J Clin Oncol 12:2160–2166, 1994 26. 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] 27. 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 Children's Cancer Study Group. J Clin Oncol 8:1971–1980, 1990[Abstract] 28. 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] 29. Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457–481, 1958[CrossRef] 30. Kalbfleisch JD, Prentice RL. The Statistical Analysis of Failure Time Data. New York, NY, Wiley, 1980, p 169
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35. 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
36. Baker KS, Gordon BG, Gross TG, et al: Autologous hematopoietic stem-cell transplantation for relapsed or refractory Hodgkin's disease in children and adolescents. J Clin Oncol 17:825–831, 1999
37. Bhatia S, Robison LL, Oberlin O, et al: Breast cancer and other second neoplasms after childhood Hodgkin's disease. N Engl J Med 334:745–751, 1996 38. Hudson MM, Poquette CA, Lee J, et al: Increased mortality after successful treatment for Hodgkin's disease. J Clin Oncol 16:3592–3600, 1998[Abstract] 39. 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[CrossRef][Medline] 40. Weiner MA, Leventhal BG, Marcus R, et al: Intensive chemotherapy and low-dose radiotherapy for the treatment of advanced-stage Hodgkin's disease in pediatric patients: A Pediatric Oncology Group study. J Clin Oncol 9:1591–1598, 1991[Abstract] Submitted February 20, 2004; accepted September 1, 2004.
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
), censoring.
