Balancing Efficacy and Safety in the Treatment of Adolescents With Hodgkin's Lymphoma

Abstract

Most children with Hodgkin’s lymphoma can expect to be cured with contemporary therapy. However, the improved survival in childhood cancer over the past decades has not been uniformly translated across older age groups, so that adolescents and young adults have not enjoyed the same progress in survival. Although variations in tumor biology may be responsible for some of these differences, access to care may play a more important and modifiable role. The success in pediatric oncology in Europe and the United States has largely been attributed to the almost uniform participation of children in clinical trials and the delivery of pediatric cancer care in specialized centers. In contrast, only 10% of adolescents and 1% to 2% of young adults are enrolled onto clinical trials. Historically, treatment approaches for Hodgkin’s lymphoma did not differ between children and adults, using similar extended radiation fields and doses (35 to 44 Gy) and chemotherapy regimens. However, severe musculoskeletal and soft tissue growth impairment in children and late-occurring second malignancies and cardiovascular complications motivated the development of treatment protocols prescribing lower doses of radiation (15 to 25 Gy) in combination with non–cross-resistant chemotherapy. To avoid radiation complications altogether, some pediatric investigators administered chemotherapy-alone regimens consisting of nitrogen mustard, vincristine, procarbazine, and prednisone (MOPP) or derivatives of the combination for up to 12 months. This approach proved to be quite effective in producing long-term disease-free survival in children with Hodgkin’s lymphoma and offered advantages for children treated at centers where radiation and precise clinical staging were difficult to perform. However, chemotherapy-alone protocols typically prescribe higher cumulative doses of alkylating agents compared with those used in combined-modality therapy regimens. Increased morbidity from myelosuppression, gonadal toxicity, and secondary leukemia eventually led to efforts to limit the use of MOPP. In pediatric protocols, cyclophosphamide, vincristine, procarbazine, and prednisone (COPP; the MOPP derivative that substitutes cyclophosphamide for nitrogen mustard) proved to have less leukemogenic potential and is still favored by many investigators today. The next generation of protocols was based on the doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) regimen, which did not by itself carry a significant risk of sterility or secondary malignancy. However, the ABVD combination is associated with anthracyclineinduced cardiotoxicity and bleomycin-induced pulmonary toxicity. ABVD, in combination with MOPP or COPP or as a hybrid, followed by low-dose involved-field radiotherapy achieved excellent results in pediatric trials. The hypothetical advantage of these hybrid and alternating regimens is lower cumulative doses of each agent and, possibly, enhanced antitumor effect; however, long-term effects of these regimens have not yet been systematically evaluated. The desire to further limit therapy-related long-term complications led to the development of ABVD derivatives like vinblastine, doxorubicin, methotrexate, and prednisone (VAMP); doxorubicin, bleomycin, vincristine, and etoposide (DBVE); and vincristine, procarbazine, prednisone, and doxorubicin (OPPA) or vincristine, etoposide, prednisone, and doxorubicin (OEPA; in which the procarbazine is substituted by etoposide in boys to reduce the dose of alkylators and the risk of infertility). Contemporary pediatric therapy largely using derivatives of the original MOPP and ABVD regimens in combination with or without low-dose (15 to 25 Gy), involved-field radiotherapy has led to event-free survival rates that exceed 80% for intermediateand high-risk patients and 90% for favorable-risk patients. Improvements in diagnostic imaging modalities have led to better characterization of the extent of disease involvement and have refined the concept of risk-adapted therapy. The routine use of functional imaging, initially performed with gallium scintigraphy and now largely replaced by [F]fluorodeoxyglucose positron emission tomography, has further enhanced the ability to differentiate active disease from sterile residual nodal masses. This modality continues to play an important role in modern response-based protocols in which especially low-risk patients achieving a complete response early on can be spared further radiotherapy. In the treatment of adults with Hodgkin’s lymphoma, medical oncologists have used a different paradigm than pediatric oncologists. The search for a regimen that would achieve higher cure rates has primarily been the driving force, and refinement of prognostic factors has helped characterize patients who would benefit from intensification of therapy, rather than reduction. More than 95% of patients with early-stage disease and 85% of patients with advanced-stage disease have been reported to achieve long-term survival on adult trials. For early-stage/favorable Hodgkin’s lymphoma presenting in adults, treatment with two to four cycles of ABVD followed by 30 Gy of involved-field radiotherapy is considered the standard of care. For patients with advanced-stage or unfavorable presentations of disease, JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 27 NUMBER 36 DECEMBER 2