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© 2002 American Society for Clinical Oncology
Pediatric Hodgkin’s Therapy: Time for a Paradigm ShiftSt Jude Children’s Research Hospital, Memphis, TN CONSIDERING THAT curative therapy has been available for Hodgkin’s disease for more than 30 years, oncologists treating children and adolescents with the disease have an expectation of long-term survival for these patients. For many physicians, patients with Hodgkin’s disease have been the "bright spot" in their practice because they are a group who uniformly respond well to therapy and overcome their disease. Unfortunately, long after their exit from pediatric practices, the true cost of curative therapy becomes readily apparent as aging survivors develop a variety of medical complications unquestionably predisposed by their antineoplastic therapy. The desire to prevent or reduce treatment sequelae, especially second malignancies and cardiopulmonary dysfunction, has continued to motivate therapeutic modifications over the last several decades. While these complications adversely affect quality of life and increase the risk of early mortality, Hodgkin’s disease remains the leading cause of death observed in several cohort studies of long-term pediatric survivors, underscoring the need to proceed cautiously with therapy refinements that do not compromise disease control.1,2 The current issue of the Journal of Clinical Oncology features an article that summarizes early results of a Children’s Cancer Group (CCG) trial designed to evaluate whether outcome of children with Hodgkin’s disease treated with dose-intensive, multiagent chemotherapy is compromised by the omission of radiation.3 This study is representative of many current risk-adapted pediatric Hodgkin’s trials with the dual objectives of maintaining treatment efficacy while reducing late treatment complications. Long-term follow-up of childhood cancer survivors has permitted identification of specific clinical and treatment factors predisposing to the common sequelae of Hodgkin’s disease. For example, breast cancer is almost exclusively observed in young women treated with thoracic radiation; treatment during puberty and higher cumulative radiation doses seem to enhance this risk.4-6 With the expectation of long-term survival in 85% or more of children and adolescents who present with Hodgkin’s disease, it is essential to consider clinical risk factors predisposing to late complications during treatment planning for newly diagnosed patients. It is instructive to review the evolution of pediatric Hodgkin’s therapy to appreciate the current treatment biases of many pediatric oncologists. In early treatment regimens, the patient’s age or physical maturity was not considered during treatment planning. Standard-dose (35 to 44 Gy) radiation therapy to extended treatment volumes was the norm, for both children and adults, producing respectable disease-free survival rates for children with localized disease. However, long-term follow-up revealed treatment toxicity unique to children in the form of musculoskeletal growth inhibition.7 A desire to avoid these deformities led to the development of treatment protocols specifically designed for children, which used low-dose, involved-field radiation and fewer cycles of non–cross-resistant combination chemotherapy.8 Standard-dose radiation therapy was subsequently reserved for older, skeletally mature patients with localized disease until concerns about radiation-induced cardiovascular disease and second malignancies eventually led to the abandonment of radiation as a primary treatment modality by most pediatric oncologists.4-6,9 Despite results from numerous pediatric trials supporting the efficacy of a combined-modality treatment approach, the desire to avoid radiation-related toxicity, particularly second malignancies, has motivated continued investigation of chemotherapy-alone treatment regimens.10 Chemotherapy alone has long been established as an effective alternative to combined-modality therapy, but it confers risks associated with higher cumulative doses of anthracyclines, alkylating agents, and bleomycin.11 This is particularly significant as early trials prescribed considerably more months (usually in the range of 8 to 12 months) of chemotherapy than is typically used today. Early chemotherapy trials used nitrogen mustard, vincristine, procarbazine, and prednisone (MOPP) or similar regimens derived from MOPP. Chemotherapy-related acute toxicity was acceptable, but limited data on long-term treatment effects support the expected high incidence of gonadal toxicity.12 Contemporary chemotherapy-only trials have used non–cross-resistant chemotherapy typically derived from MOPP and doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD). Early outcomes seem comparable with those achieved with combined-modality therapy, but long-term effects on cardiac, pulmonary, and gonadal function have not been reported.12 Interpretation of these treatment results is further complicated by the fact that most of the studies comprised small numbers of clinically staged patients, assigned to treatments in a nonrandom fashion. In fact, some protocols specifically excluded patients with unfavorable features such as bulky or extensive lymphadenopathy, clinical features reported to benefit from a combined-modality treatment approach. The Nachman et al3 study joins the ranks of the relatively few prospective randomized trials evaluating treatment outcomes for pediatric Hodgkin’s disease using chemotherapy alone compared with combined-modality therapy. Two previous trials for advanced-stage pediatric Hodgkin’s disease organized by North American cooperative groups failed to show a statistically significant advantage in event-free survival or overall survival with the addition of radiation therapy to non–cross-resistant chemotherapy.13,14 The CCG compared 12 cycles of alternating MOPP/ABVD to six cycles of ABVD plus low-dose (21 Gy) radiation, and the Pediatric Oncology Group evaluated the benefit of adding low-dose radiation to eight cycles of alternating MOPP/ABVD.13 The trend in event-free and overall survival, although not statistically significant, suggested an advantage for the combined-modality approach over chemotherapy alone for the CCG trial. For the Pediatric Oncology Group trial, the intent-to-treat analysis did not indicate an event-free or overall survival advantage for the group randomized to receive radiation after completion of eight cycles of alternating MOPP/ABVD, but the as-treated analysis showed superior outcomes for patients treated with combined-modality therapy.14 The findings of both of these studies suffer from the fact that contemporary investigators have little desire to treat pediatric patients with 8 or 12 cycles of alternating MOPP/ABVD, with or without radiation therapy.
In the recent CCG trial reported by Nachman et al,3 a contemporary chemotherapy regimen is prescribed, cyclophosphamide, vincristine, procarbazine, and prednisone/doxorubicin, bleomycin, and vinblastine (COPP/ABV), which substitutes cyclophosphamide for the more leukemogenic nitrogen mustard and compacts the traditional alternating non–cross-resistant chemotherapy combinations into a dose-intensive hybrid. This treatment approach offers the advantage of a reduced duration of therapy and lower cumulative doses of individual agents. For stages I through III, a risk-adapted treatment assignment was based on the presence of adverse clinical features such as hilar adenopathy, involvement of more than four nodal regions, bulky mediastinal ( Reaching consensus about the characteristics of the pediatric patient with Hodgkin’s disease for whom therapy intensification is appropriate because of a high risk of treatment failure, or for whom outcome will not be compromised by further therapy reductions, has often been difficult to accomplish. For many trials, adverse prognostic features have included advanced (stage IIIB or IV) or unfavorable (bulky, symptomatic) disease presentations. To date, prognostic factor analyses in pediatric trials have revealed various findings related to laboratory parameters and tumor histology that have not yet been used to direct therapy. Likewise, only a few studies have correlated treatment outcome with biologic tumor activity, eg, interleukin-2 receptor elevation, but these features have not been studied prospectively to delineate their relationship with disease response and long-term outcome.15 More recent trials have demonstrated the prognostic significance of rapid early response, a paradigm that will be tested by upcoming Children’s Oncology Group Hodgkin’s trials.16 Clearly, future progress in therapy for pediatric Hodgkin’s disease will require an improved understanding of the clinical and biologic features that contribute to pathogenesis and treatment response. Until this information is available, pediatric investigators will persist with their careful manipulations of therapy in an effort to improve disease control and reduce long-term complications for children and adolescents with Hodgkin’s disease. REFERENCES 1. Hudson MM, Poquette CA, Lee JL, et al: Increased mortality after successful treatment for Hodgkin’s disease. J Clin Oncol 16: 3592-3600, 1998[Abstract] 2. Wolden SL, Lamborn KR, Cleary SF, et al: Second cancers following pediatric Hodgkin’s disease. J Clin Oncol 16: 536-544, 1998[Abstract]
3. 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 4. 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]
5. Bhatia S, Robison L, Oberlin O, et al: Breast cancer and other second neoplasms after childhood Hodgkin’s disease. N Engl J Med 334: 745-751, 1996
6. Donaldson SS, Hancock SL: Second cancers after Hodgkin’s disease in childhood. N Engl J Med 334: 792-794, 1996 7. Donaldson SS, Kaplan HS: Complications of treatment of Hodgkin’s disease in children. Cancer Treat Rep 66: 977-989, 1982[Medline]
8. 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
9. 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 10. Hudson MM, Donaldson SS: Treatment of pediatric Hodgkin’s disease. Semin Hematol 36: 313-323, 1999[Medline]
11. Hudson MM: Treatment of childhood Hodgkin’s disease with chemotherapy alone. Ann Oncol 8: 215-216, 1997 12. Ekert H, Waters KD: Results of treatment of 18 children with Hodgkin’s disease with MOPP chemotherapy as the only treatment modality. Med Pediatr Oncol 11: 322-326, 1983[Medline] 13. Hutchinson RJ, Fryer CJH, 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] 14. 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] 15. Pui C-H, Hudson M, Luo X, et al: Serum interleukin-2 receptor levels in Hodgkin’s disease and other solid tumors of childhood. Leukemia 7: 1242-1244, 1993[Medline] 16. Schwartz CL, Constine LS, London W, et al: POG 9425: Response-based, intensively timed therapy for intermediate/high stage pediatric Hodgkin’s disease. Proc Am Soc Clin Oncol 21: 389a, 2002 (abstr 1555)
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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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33% of chest diameter) or peripheral (more than 10 cm) lymphadenopathy, and "B" symptoms. Patients with favorable disease presentations received four COPP/ABV cycles, whereas patients with adverse disease features received six COPP/ABV cycles. Stage IV patients with extranodal disease received a more intensive therapy including sequential cycles of high-dose cytarabine and etoposide, COPP/ABV, and cyclophosphamide, vincristine, doxorubicin, and methylprednisolone. Treatment was also response-based, as patients who achieved a complete response to initial chemotherapy were eligible either for randomization to receive low-dose involved-field radiation or no further treatment. The randomization was stopped earlier than anticipated because of results indicating a significantly higher number of relapses on the no-radiotherapy arm. The 3-year event-free survival estimates by both an intent-to-treat and as-treated analysis were significantly lower for patients treated with chemotherapy alone, with differences being most marked in stage IV patients. Because of successful salvage therapy for relapsed patients, estimates for overall survival are not different between the randomized groups in early follow-up. However, studies of long-term survivors from other series clearly indicate that treatment for relapse increases the risk of second malignancies and early mortality.
