General Treatment Consideration

Hodgkin lymphoma is highly curable in the adolescent and young adult patient population. The challenge faced by oncologists today is to find the balance between maximizing cure and minimizing the late effects in this population. Adolescents with Hodgkin lymphoma are not treated as a distinct patient population and are routinely placed on either pediatric or adult treatment regimens, without a strong foundation for the decision. Several studies, however, have reported a poorer outcome in adolescent patients treated on adult clinical trials.

Salient differences exist currently between adult and pediatric treatment strategies for Hodgkin lymphoma. The adult treatment approach stratifies stage into early (stages I and II) and advanced (stages III and IV) disease. Adolescents treated on adult regimens for advanced-stage Hodgkin lymphoma will most commonly receive six cycles of doxorubicin + bleomycin + vinblastine + dacarbazine (ABVD) chemotherapy alone rather than the combined-modality therapy used in the pediatric approach, which alternates an alkylating agent regimen with ABVD in order to decrease the ABVD-related risk of cardiopulmonary toxicity. Until recently, treatment for favorable disease presentation (stages I and II and the absence of B symptoms and nodal bulk) in both children and adults has relied on radiation alone, a practice that originated in the 1950s. The most common method was to employ mantle field irradiation (including the neck, chest, and axilla nodes) with doses of 40-44 Gy followed by inverted Y irradiation to the spleen, para-aortic and pelvic nodes. The use of radiation therapy as a single-therapeutic modality has gradually declined given that the initial effectiveness of extended-field, high-dose radiotherapy is counterbalanced by unsatisfactory risk of relapse, late side effects, and poor quality of life, especially in children and adolescents. The introduction of combined-modality therapy allows for dose and volume reduction of the radiation field and is now the preferred treatment for favorable Hodgkin lymphoms in both adults and children.

Chemotherapy alone for localized disease has been used in developing countries with some success [22].

Figure 8.7

National mortality for Hodgkin lymphoma; United States SEER, 1975-2000

Risk-adapted therapeutic strategies have been used in the pediatric trials that employ variations of combined-modality therapy dependent upon stage, symptoms, and gender. Prognostic factors specifically for children and young adults treated with combined-modality therapy have been developed [23]. A series of 328 patients, aged 2-20 years, were analyzed and five pretreatment factors were found to correlate by multi-variate analysis with inferior disease-free survival; male sex, stage IIB, IIIB, or IV disease, bulk mediastinal disease, hemoglobin <11 g/dl, and white blood cell count of >13,500/ul. Response to therapy was also shown to be a predictor of outcome. Age was not a significant factor in the comparison of patients greater or less than 14 years of age. In other studies, nodular sclerosis histology and the presence of B symptoms correlated with an inferior outcome [24]. Based upon these findings, tailored risk-adapted strategies have been explored. These strategies have incorporated stratification by stage into three risk groups: (1) early/ favorable, including localized disease involving less than three or four nodal regions in the absence of B symptoms, bulky disease, or extranodal extension, (2) intermediate/localized unfavorable, defined as localized disease involving less than or equal to three or four nodal regions in the presence of bulky lymphade-nopathy, and (3) advanced/unfavorable, which includes

Figure 8.8

Ratio of national mortality to SEER incidence for Hodgkin lymphoma, by gender; United States SEER, 1975-2000

Figure 8.9

National mortality for Hodgkin lymphoma by race/ ethnicity; United States SEER, 1975-2000

patients with stage II disease who experience constitutional symptoms of fever or weight loss, and patients with stage III or IV disease. It is believed that each pediatric patient presents with a unique combination of factors that should be evaluated in determining optimal treatment. Issues such as gender- and age-related susceptibilities to treatment toxicities have also been considered in the development of therapeutic strategies to minimize late effects.

Accumulating experience with risk-adapted approaches suggest that survival is excellent for all risk groups, and that low-risk patients may not require adjuvant radiation therapy [25]. This finding is suggested by a large recent adult study that indicates that consolidation radiation therapy increased the overall survival, especially in the subgroup of patients with B symptoms, stage III-IV disease, and patients younger than 15 years [26]. The trials that show no benefit of a consolidation radiation therapy for advanced disease were those using eight cycles of chemotherapy [alternating mechloretha-mine + vincristine + procarbazine + prednisolone (MOPP), and ABVD or "hybrid" MOPP/doxorubicin + bleomycin + vinblastine (ABV) or bleomycin + etopo-side + doxorubicin + cyclophosphamide + vincristine + procarbazine + prednisolone (BEACOPP), or doxorubicin + bleomycin + vinblastine + procarbazine + prednisolone (ABVPP). It is likely that the patients in com plete remission after 3-6 cycles of chemotherapy received some sort of consolidation therapy in the form of additional chemotherapy, obviating the benefit of radiation. However, such strategies lead to high cumulative doses of chemotherapy and the risk of male infertility due to the use of alkylating agents, cardiomyopathy from anthracyclines, pulmonary fibrosis from bleomy-cin, and of secondary leukemia and lung cancer after alkylating agents and etoposide.

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