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Journal of Clinical Oncology, Vol 24, No 36 (December 20), 2006: pp. 5735-5741 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.05.6879 Survival and Late Effects in Children With Hodgkin's Lymphoma Treated With MOPP/ABV and Low-Dose, Extended-Field Irradiation
From the Division of Haematology & Oncology, Department of Paediatrics; Department of Diagnostic Imaging; Division of Radiation Oncology, Toronto Sunnybrook Regional Cancer Centre, The Hospital for Sick Children; and the Department of Radiation Oncology, Princess Margaret Hospital, The University of Toronto, Toronto, Ontario, Canada Address reprint requests to Mark L. Greenberg, MBChB, Division of Haematology & Oncology, Department of Paediatrics, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, Canada M5G 1X8; e-mail: mark.greenberg{at}sickkids.ca
PURPOSE: Reduced-intensity protocols for pediatric Hodgkin's lymphoma are aimed at preserving excellent relapse-free survival while decreasing the incidence of late effects. PATIENTS AND METHODS: We retrospectively reviewed the outcome of 123 children treated consecutively for Hodgkin's lymphoma at a single institution. Patients with stages I-IIIB disease received three cycles of mechlorethamine, vincristine, procarbazine, and prednisone (MOPP)/ doxorubicin, bleomycin, and vinblastine (ABV) followed by 15 Gy of extended-field irradiation, while those with stage IV disease were treated with six to eight cycles of MOPP/ABV chemotherapy with or without radiotherapy.
RESULTS: At a median follow-up of 8.5 years (range, 1.4 to 15.5 years), the estimated 10-year overall survival and event-free survival are 94% (SE, 2.2%) and 88% (SE, 3.1%) respectively. There have been 12 treatment failures and six disease-related deaths. A very large mediastinal mass ( CONCLUSION: MOPP/ABV and low-dose, extended-field radiotherapy is an effective treatment for pediatric Hodgkin's lymphoma. With median follow-up of 8.5 years, late cardiopulmonary effects and secondary malignancies from this treatment regimen are infrequent. Continued longitudinal observations, particularly for breast cancer in female patients and gonadotoxicity, will determine whether the goal of decreasing treatment-related complications while maintaining excellent survival has been achieved.
Contemporary combined-modality therapy for pediatric Hodgkin's lymphoma results in greater than 85% long-term survival.1 Survival is higher still when patients with disease limited to the peripheral lymphoid organs (clinical stages I-III) are considered separately. Numerous investigators have reported the use of multiagent chemotherapy with or without low-dose (ie, less than 35 Gy) extended- or involved-field irradiation.2 A common goal is to combine effective agents with nonoverlapping toxicities to optimize survival while minimizing therapy-related sequelae. Although most studies have achieved desired survival outcomes, data on late effects of therapy await long-term follow-up studies. We have reported previously our experience with the combination of MOPP chemotherapy (mechlorethamine, vincristine, procarbazine, and prednisone) and low-dose, extended-field radiotherapy (EFRT).3,4 Subsequently, data from studies in adults demonstrated that combinations of seven or eight drugs would likely result in improved outcomes with less toxicity.5 Therefore, in 1987, we adopted a new approach for Hodgkin's lymphoma, which consisted of MOPP plus ABV (doxorubicin, bleomycin, and vinblastine) hybrid6,7 combined with low-dose EFRT, substantially reducing exposure to chemotherapy and radiation. Herein, we present the long-term survival outcomes and report on the notable long-term complications of this approach.
Patients Patients were included in this retrospective analysis if they were younger than 19 years old at diagnosis with Hodgkin's lymphoma and treated in this uniform manner. Diagnostic investigations included biopsy of a clinically involved lymph node, chest x-ray (CXR), computed tomography (CT) scan from the base of the skull to the inguinal region, gallium scan, bilateral bone marrow aspirates and biopsies, and baseline studies of pulmonary function (spirometry, diffusion capacity for carbon monoxide [DLCO]) and cardiac function (two-dimensional and M-mode echocardiography). No patients underwent staging laparotomy. To standardize the interpretation of CXR results, available pretherapy radiographs were reevaluated by two observers (A.B. and D.M.), and the ratio of maximal mediastinal mass to maximal thoracic diameter at full inspiration calculated. After completing therapy, most patients were followed at the Hospital for Sick Children Aftercare Clinic (Toronto, Ontario, Canada) until 18 years of age. Subsequent annual follow-up occurred at one of two survivor clinics in adult cancer centers and consisted of screening for thyroid (annual thyroid-specific hormone [TSH], T4 measurement), cardiac (echocardiogram every 2 to 3 years) and pulmonary dysfunction (pulmonary function tests every 3 years), and monitoring of pubertal development. Patients were monitored for secondary malignancies; in particular, annual mammographic screening for breast cancer commenced 8 years after therapy. Many patients residing outside the metropolitan Toronto area opted for local follow-up by their primary care physician. Specific evaluations carried out and their schedule varied depending on location. Updated data were obtained from these locations and, in some cases, by contacting patients directly via mailed questionnaire. This treatment approach was adopted as the institutional guideline for Hodgkin's lymphoma. Research ethics board (REB) approval was not required at that time according to hospital policy. However all patients and/or guardians signed a consent to treatment. REB approval was obtained for this chart review and questionnaire.
Treatment Protocol
For stage IV patients, MOPP/ABV was administered until a complete response was obtained, followed by two additional cycles for a minimum of six and a maximum of eight cycles. Radiotherapy was delivered as herein only if all disease sites could be encompassed in the volume irradiated. Pulmonary or hepatic extranodal disease, if present, was included in the treatment volume.
Statistical Analysis
Patient Population From May 1987 to December 1997, 135 consecutive patients younger than 19 years old presented to the Hospital for Sick Children with newly diagnosed Hodgkin's lymphoma. Of these, 124 were treated with MOPP/ABV plus EFRT (Fig 1). Of the remaining 11 patients, five presented with favorable stage IA disease and were treated with IFRT alone, three were unable to tolerate oral chemotherapy, a 3-year old was electively not irradiated, one patient was initially misdiagnosed and treated for Burkitt's lymphoma, while another presented with a solitary scalp lesion and underwent excisional biopsy alone. Furthermore, one patient was incorrectly staged and therefore undertreated. Data from the remaining 123 patients are presented (Fig 1).
Table 2 presents patient demographic and disease characteristics. Pretreatment CXR's were available for re-evaluation in 70 patients (57% of the cohort); in the remainder, films from referring institutions were unavailable. There were no significant differences in demographic or disease characteristics in patients for whom a CXR was or was not available (data not shown).
Treatment Tolerance and Adherence One hundred twenty-three individuals commenced MOPP/ABV therapy. In these patients, the median number of cycles received for stages I-IIIB was three (range, 0.5 to 8 cycles), whereas the median for stage IV was six cycles (range, 2.5 to 8 cycles; Table 3). Six patients required major deviations from planned therapy because of treatment intolerance (Fig 1). Two patients experienced seizures during the first cycle (Table 3), presumed related to procarbazine, and chemotherapy was modified to eliminate this agent. Chemotherapy was suspended after two cycles in one stage IIA patient because of venous thrombosis. This patient received EFRT with a boosted dose. Bleomycin-related acute pulmonary toxicity affected two stage IVB patients after two and three courses of ABV, respectively. Finally, one stage IVB patient suffered avascular necrosis of the hip after three cycles. The latter three patients subsequently received alternate chemotherapy. All patients are included in survival analyses (Fig 1).
There were 97 stage I-IIIB patients; 94 did not require major modifications to treatment. Eighty-one (86%) of these patients received the minimum three cycles of MOPP/ABV (Table 3) corresponding to cumulative doses of 18 mg/m2 mechlorethamine, 2,100 mg/m2 procarbazine, 105 mg/m2 doxorubicin, and 30 U/m2 bleomycin (Table 1). Patients treated during the first half of the study (1987 to 1991) were more likely to receive more than minimal chemotherapy compared with patients enrolled later (1992 to 1997; P < .001). The intended radiation dose of 15 Gy was delivered to 94% of patients. Those treated in the earlier era were also more likely to receive a higher dose to the entire treatment field (four of 31 patients compared with one of 63 in latter half; P = .006). A radiation boost dose was administered to 14 patients (15%); there was no significant difference in boosts given between different study periods, suggesting that the fraction of patients with residual bulk was not reduced by increased chemotherapy or radiation within the study limits. The extended field was the only volume of treatment in 88% of patients. Taken together, 67 (71%) of 94 stages I-IIIB patients received the minimum three cycles of MOPP/ABV and 15 Gy EFRT (Fig 1). The prescribed chemotherapy was tolerated by 23 of 26 stage IV patients (Fig 1). Twelve patients received six cycles of MOPP/ABV, whereas nine received additional cycles (Table 3). One patient with progressive disease underwent salvage chemotherapy after four cycles; a second patient received five cycles of MOPP/ABV followed by EFRT with no reason recorded for omitting the sixth. Seventeen of 19 patients who received radiotherapy received 15 Gy; 10 patients had treatment confined to the extended field. Altogether, 10 (43%) of 23 stage IV patients received six cycles of MOPP/ABV with or without 15 Gy radiotherapy (Fig 1).
Treatment Outcome
There have been 12 cases of disease progression or relapse; six patients are alive after salvage therapy (four disease free) with a median follow-up after progression or relapse of 8.5 years (range, 3.0 to 14.4 years). All were treated with intensive chemotherapy using mini-BEAM (carmustine, etoposide, cytarabine, melphalan), APE (cytarabine, cisplatinum, etoposide), or DHAP (dexamethasone, high-dose cytarabine, cisplatinum), followed by autologous bone marrow transplantation (ABMT). Of the six disease-related deaths, all received similar intensive chemotherapy and three underwent ABMT. Median time to death after relapse was 18.6 months (range, 7.5 to 46.4 months). A seventh patient died in a motor vehicle accident in sustained remission of 37 months.
Late Effects of Therapy Cardiac late effects. All survivors received anthracyclines and all but three mediastinal irradiation. Of the survivors, 43 (41%) of 105 had echocardiography performed at least 3 years after therapy (median, 4.7 years). There were no differences between patients who did and did not have an echocardiogram except that patients tested were more likely to have been treated during the more recent study period (median follow-up, 4.1 years). Only one patient (2.3%) in first remission had an abnormal echocardiogram. This patient was treated with three cycles of MOPP/ABV and 15 Gy of EFRT and developed an asymptomatic increase in left-ventricular end-diastolic volume. Pulmonary late effects. All survivors received bleomycin with or without chest irradiation. Fifty-one patients (49%) had a pulmonary function test performed at least 2 years after therapy (median, 3.9 years). There was no difference between patients who did and did not have testing performed. Four (7.8%) of the 51 patients had an abnormal result. Two patients had a restrictive pattern, including one with a concomitant scoliosis. One patient demonstrated a decreased DLCO, whereas the fourth patient received 25 Gy of radiotherapy to the mantle and whole abdomen and showed an obstructive pattern. Thyroid dysfunction. Data on thyroid hormone–replacement were available for 97 (92%) of 105 survivors. Fourteen patients (14%) required thyroid hormone replacement, of whom six received increased doses of radiotherapy (higher initial dose, boost to bulk disease or pulmonary irradiation). This represents a higher rate of thyroid dysfunction in the group of 22 such patients than for the remainder who received 15 Gy to nodal fields only (P = .05; odds ratio = 3.14).
Second Malignancies
In this cohort with a long median follow-up, the combination of MOPP/ABV chemotherapy and low-dose EFRT has achieved excellent results with modest intensity of therapy when compared with most reported studies. Physicians gained confidence in the effectiveness of this approach, as demonstrated by improved adherence to the intended number of MOPP/ABV cycles and radiation dose as the study matured. The majority of patients (68%) received three cycles of chemotherapy, reflecting substantial reductions in cumulative drug exposure compared with published MOPP or ABVD protocols, whereas 70% were irradiated with 15 Gy without any boosts. We are aware of one small pediatric study of Hodgkin's lymphoma utilizing a similar regimen with short follow-up.11 Many investigators consider bulky localized and stage III diseases as unfavorable prognostic indices and treat such patients with six to eight cycles of chemotherapy followed by radiotherapy.12-16 Our results are equivalent or superior in this group of patients using significantly reduced therapy. Perhaps, as has been suggested,7 the rapid introduction of seven effective agents improves efficacy by limiting the capacity for cellular somatic mutation. Hamilton et al13 employed hybrid chemotherapy, substituting cyclophosphamide for the mechlorethamine in MOPP/ABV. This change, and the smaller study size, may explain the inferior EFS when compared with the present study. Stage IV disease is a consistent predictor of adverse outcome in pediatric studies. The approach used here resulted in a similar OS in stage IV patients compared with lower-stage patients, although the difference in EFS approached statistical significance in favor of lower-stage disease (Fig 3B). The superior survival of our stage IV patients when compared with other combined-modality regimens was achieved with less chemotherapy and irradiation.12,14,15,17 Although a history of B symptoms and the presence of bulky disease at diagnosis are prognostic indicators in adult patients,5 they have not consistently predicted outcome in children. In our study, the presence of B symptoms or mediastinal mass greater than one third of the thoracic diameter did not predict a poorer outcome. However, patients whose mediastinal mass occupied greater than one half of maximal thoracic diameter had significantly worse survival (Table 4). The utility of this criterion for mediastinal bulk requires prospective validation. Long-term survivors of Hodgkin's lymphoma carry an increased risk of second malignancies, particularly leukemias and breast, lung, and thyroid tumors.18 In an effort to reduce their occurrence, investigators have modified chemotherapy combinations and duration in attempts to eliminate radiotherapy. Such studies have relied on six to eight cycles of chemotherapy for all patients, usually alternating cycles of MOPP and ABVD.19-21 A recent large randomized study of adult advanced-stage Hodgkin's patients treated with MOPP/ABV demonstrated that radiotherapy could be omitted in patients achieving complete remission with chemotherapy alone.22 However, other reports contradict these conclusions.17,23,24 Our study does not address the question of eliminating radiotherapy. However we suggest that 15 Gy EFRT, the lowest published level of radiotherapy, after chemotherapy is adequate for disease control in most pediatric cases. Additional investigations will determine whether involved-field irradiation or further dose reduction is possible in the face of adequate chemotherapy. Response-based therapy has been addressed in pediatric patients with localized Hodgkin's lymphoma.25 In that study, 85% of patients were deemed good responders and avoided exposure to alkylating agents and anthracyclines, with excellent survival. However, therapy included etoposide, and two patients developed secondary leukemia. Additional investigations of response-based treatment in children are warranted to minimize exposure to mutagenic agents. Although we did not obtain toxicity data for all patients, our analysis of late effects has been encouraging. There have been five patients with documented abnormal cardiopulmonary testing, and none require ongoing medical management. Nevertheless, continued cardiovascular monitoring is indicated in anthracycline-treated patients because cardiomyopathy may occur 10 years post-therapy in patients receiving as little as 45 mg/m2 of doxorubicin.26 Furthermore, our follow-up does not capture quality-of-life indicators or assess exercise tolerance, which are more relevant measures of functional cardiopulmonary status. Hypothyroidism was detected in 14% of survivors, within the 16% to 62% incidence reported in other studies.12,14,15,27 This variability may result from differences in radiation dose and/or volume of treatment as well as the duration of follow-up.28 Gonadotoxicity is an important late effect in the management of Hodgkin's lymphoma. With a median age at last follow-up for all survivors of 22.8 years (Table 2), this cohort is still too young to accurately assess fertility. We do not anticipate gonadal function to be substantially influenced; however, a formal prospective evaluation is required and will be undertaken. The major reason for avoiding mechlorethamine is the reported risk of up to 6% for secondary leukemia.29 This risk peaks at 5 years and plateaus by 15 years after treatment.18,29 We have yet to encounter a case of secondary leukemia, and 95% of survivors have been followed for at least 5 years, suggesting that their risk for leukemia is diminishing. Perhaps the low cumulative dose that our patients were exposed to has decreased this risk. We observed four cases of secondary solid malignancies, three clearly in the original radiation field. Although radiation exposure is the major contributor to secondary solid cancers, treatment with alkylators and anthracyclines have been implicated.18,30 We have no cases of breast cancer; however, the risk for this malignancy increases steadily with extended follow-up.18,31 Continuing surveillance of our patients for secondary malignancies will determine whether reduced-intensity treatment has effectively decreased their incidence. Our results should be viewed in the context of response-adapted therapy, the foundation for current Hodgkin's lymphoma trials. This hybrid approach could effectively serve as initial treatment for high-risk patients (stage III-IV disease) coupled with evaluation for early response after two cycles. However, avoidance of alkylators and anthracyclines in the majority of low-risk patients appears feasible.25 In such patients, slow responders to initial low-intensity therapy may be candidates for intensification with MOPP/ABV. Our findings suggest that such patients might achieve excellent survival with minimal late toxicity.
The authors indicated no potential conflicts of interest.
Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Hudson MM: Pediatric Hodgkin's therapy: Time for a paradigm shift. J Clin Oncol 20:3755-3757, 2002 2. Schwartz CL: The management of Hodgkin disease in the young child. Curr Opin Pediatr 15:10-16, 2003[CrossRef][Medline] 3. Jenkin D, Chan H, Freedman M, et al: Hodgkin's disease in children: Treatment results with MOPP and low-dose, extended-field irradiation. Cancer Treat Rep 66:949-959, 1982[Medline] 4. Jenkin D, Doyle J, Berry M, et al: Hodgkin's disease in children: Treatment with MOPP and low-dose, extended field irradiation without laparotomy—Late results and toxicity. Med Pediatr Oncol 18:265-272, 1990[Medline] 5. Ferme C, Cosset JM, Fervers B, et al: Hodgkins disease. Br J Cancer 84:55-60, 2001 (suppl 2)[Medline] 6. Connors JM, Klimo P: MOPP/ABV hybrid chemotherapy for advanced Hodgkin's disease. Semin Hematol 24:35-40, 1987[Medline] 7. Klimo P, Connors JM: MOPP/ABV hybrid program: Combination chemotherapy based on early introduction of seven effective drugs for advanced Hodgkin's disease. J Clin Oncol 3:1174-1182, 1985 8. Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457-481, 1958[CrossRef] 9. Mantel N: Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother Rep 50:163-170, 1966[Medline] 10. Cox DR: Regression models and life tables. J R Stat Soc 34:187-220, 1972 11. Khan SP, Gilchrist GS, Arndt CA, et al: Vancouver hybrid: Preliminary experience in the treatment of Hodgkin's disease in childhood and adolescence. Mayo Clin Proc 69:949-954, 1994[Medline] 12. Friedmann AM, Hudson MM, Weinstein HJ, et al: Treatment of unfavorable childhood Hodgkin's disease with VEPA and low-dose, involved-field radiation. J Clin Oncol 20:3088-3094, 2002 13. Hamilton VM, Norris C, Bunin N, et al: Cyclophosphamide-based, seven-drug hybrid and low-dose involved field radiation for the treatment of childhood and adolescent Hodgkin disease. J Pediatr Hematol Oncol 23:84-88, 2001[CrossRef][Medline] 14. Hudson MM, Krasin M, Link MP, et al: Risk-adapted, combined-modality therapy with VAMP/COP and response-based, involved-field radiation for unfavorable pediatric Hodgkin's disease. J Clin Oncol 22:4541-4550, 2004 15. 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 16. Kelly KM, Hutchinson RJ, Sposto R, et al: Feasibility of upfront dose-intensive chemotherapy in children with advanced-stage Hodgkin's lymphoma: Preliminary results from the Children's Cancer Group Study CCG-59704. Ann Oncol 13:107-111, 2002 (suppl 1)[Abstract] 17. 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] 18. Lin HM, Teitell MA: Second malignancy after treatment of pediatric Hodgkin disease. J Pediatr Hematol Oncol 27:28-36, 2005[CrossRef][Medline] 19. Hakvoort-Cammel FG, Buitendijk S, van den Heuvel-Eibrink M, et al: Treatment of pediatric Hodgkin disease avoiding radiotherapy: Excellent outcome with the Rotterdam-HD-84-protocol. Pediatr Blood Cancer 43:8-16, 2004[CrossRef][Medline] 20. van den Berg H, Stuve W, Behrendt H: Treatment of Hodgkin's disease in children with alternating mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) and adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD) courses without radiotherapy. Med Pediatr Oncol 29:23-27, 1997[CrossRef][Medline] 21. 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] 22. Aleman BM, Raemaekers JM, Tirelli U, et al: Involved-field radiotherapy for advanced Hodgkin's lymphoma. N Engl J Med 348:2396-2406, 2003 23. Nachman JB, Sposto R, Herzog P, et al: Randomized comparison of low-dose involved-field radiotherapy and no radiotherapy for children with Hodgkin's disease who achieve a complete response to chemotherapy. J Clin Oncol 20:3765-3771, 2002 24. Ruhl U, Albrecht M, Dieckmann K, et al: Response-adapted radiotherapy in the treatment of pediatric Hodgkin's disease: An interim report at 5 years of the German GPOH-HD 95 trial. Int J Radiat Oncol Biol Phys 51:1209-1218, 2001[CrossRef][Medline] 25. 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 26. Lipshultz SE, Lipsitz SR, Sallan SE, et al: Chronic progressive cardiac dysfunction years after doxorubicin therapy for childhood acute lymphoblastic leukemia. J Clin Oncol 23:2629-2636, 2005 27. Donaldson SS, Hudson MM, Lamborn KR, et al: VAMP and low-dose, involved-field radiation for children and adolescents with favorable, early-stage Hodgkin's disease: Results of a prospective clinical trial. J Clin Oncol 20:3081-3087, 2002 28. Sklar C, Whitton J, Mertens A, et al: Abnormalities of the thyroid in survivors of Hodgkin's disease: Data from the Childhood Cancer Survivor Study. J Clin Endocrinol Metab 85:3227-3232, 2000 29. Thomson AB, Wallace WH: Treatment of paediatric Hodgkin's disease: A balance of risks. Eur J Cancer 38:468-477, 2002[CrossRef][Medline] 30. Moppett J, Oakhill A, Duncan AW: Second malignancies in children: The usual suspects? Eur J Radiol 38:235-248, 2001[CrossRef][Medline] 31. Bhatia S, Yasui Y, Robison LL, et al: High risk of subsequent neoplasms continues with extended follow-up of childhood Hodgkin's disease: Report from the Late Effects Study Group. J Clin Oncol 21:4386-4394, 2003 Submitted February 13, 2006; accepted October 5, 2006.
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
50% of the maximal thoracic diameter) was associated with a 10-year event-free survival of 50% (SE, 14%) compared with 91% (SE, 4.0%) for smaller masses (P < .001). Late cardiopulmonary toxicity is largely absent, and the incidence of hypothyroidism is 14%. There have been no cases of secondary leukemia and four secondary solid malignancies observed to date. 
2 test for categoric variables. Overall survival (OS) and event-free survival (EFS; event defined as relapse, second malignancy, or death) were calculated using the Kaplan-Meier method.
