History of Treatment for Hodgkin Lymphoma

Radiation therapy as a single modality.

Radiation therapy as a single modality.

Recognition of the excess adverse effects of high-dose radiation therapy on musculoskeletal development in children motivated investigations of multiagent chemotherapy alone or with lower radiation doses (15–25.5 Gy) and reduced treatment volumes (involved sites). It also led clinicians to abandon the use of radiation as a single modality except in select situations.[1-3]

Radiation therapy as a single modality.

Radiation therapy alone may rarely be considered for adolescents and young adults with NLPHL.[4]

Radiation therapy as a single modality.

Recognition of the excess risk of cardiovascular disease and subsequent neoplasms in adult survivors who were treated for Hodgkin lymphoma during childhood led to the restriction of radiation therapy in contemporary trials and the reduction in volume and dose when used.[5,6]

Multiagent chemotherapy.

Multiagent chemotherapy.

The establishment of the non–cross-resistant combinations of mechlorethamine, vincristine (Oncovin), procarbazine, and prednisone (MOPP) developed in the 1960s and doxorubicin (Adriamycin), bleomycin, vinblastine, and dacarbazine (ABVD) developed in the 1970s made long-term survival possible for patients with advanced and unfavorable (e.g., bulky, symptomatic) Hodgkin lymphoma.[7,8] MOPP-related sequelae include a dose-related risk of infertility and subsequent myelodysplasia and leukemia.[2,9] The use of MOPP-derivative regimens substituting less leukemogenic and gonadotoxic alkylating agents (e.g., cyclophosphamide) for mechlorethamine or restricting cumulative alkylating agent dose exposure reduces this risk.[10] However, COPP-based regimens (substituting cyclophosphamide for mechlorethamine) are not commonly used in contemporary treatment protocols because of the restricted availability of procarbazine in many parts of the world. ABVD-related sequelae include a dose-related risk of cardiopulmonary toxicity related to doxorubicin and bleomycin.[11-13] The cumulative dose of these agents has been proactively restricted in pediatric patients to reduce this risk.In an effort to reduce chemotherapy-related toxicity, hybrid regimens alternating MOPP and ABVD or derivative therapy were developed. They use lower total cumulative doses of alkylators, doxorubicin, and bleomycin.[14,15]With the use of a cardioprotectant and replacing bleomycin with other agents, ABVD-based regimens are being used more in pediatric patients.[16]

Multiagent chemotherapy.

Etoposide has been incorporated into treatment regimens as an effective alternative to alkylating agents in an effort to reduce gonadal toxicity and enhance antineoplastic activity.[17] Etoposide-related sequelae include an increased risk of subsequent myelodysplasia and leukemia that appears to be rare when etoposide is used in restricted doses in pediatric Hodgkin lymphoma regimens.[18,19]

Multiagent chemotherapy.

Pediatric trials have used procarbazine-free standard backbone regimens, such as doxorubicin, bleomycin, vincristine, etoposide, prednisone, and cyclophosphamide (ABVE-PC) in North America [20,21] and vincristine, etoposide, prednisone, doxorubicin; cyclophosphamide, vincristine, prednisone, dacarbazine (OEPA-COPDAC) in Europe.[22] Both of these regimens represent dose-dense therapies that use six drugs to maximize intensity without exceeding thresholds of toxicity.

Multiagent chemotherapy alone versus combined-modality therapy.

Multiagent chemotherapy alone versus combined-modality therapy.

Treatment with non–cross-resistant chemotherapy alone offers advantages in low-income countries lacking radiation facilities and trained personnel, as well as diagnostic imaging modalities needed for clinical staging. This treatment option also avoids the potential long-term growth inhibition, organ dysfunction, and solid tumor induction associated with radiation.

Multiagent chemotherapy alone versus combined-modality therapy.

Chemotherapy-alone treatment protocols usually prescribe higher cumulative doses of alkylating agent and anthracycline chemotherapy, which may produce acute- and late-treatment morbidity from myelosuppression, cardiac toxic effects, gonadal injury, and subsequent leukemia. However, more recent trials are designed to significantly reduce these risks, especially in those with chemotherapy-responsive disease.[20]

Multiagent chemotherapy alone versus combined-modality therapy.

In general, the use of combined chemotherapy and low-dose involved-site radiation therapy (LD-ISRT) broadens the spectrum of potential toxicities, while reducing the severity of individual drug-related or radiation-related toxicities. The results of prospective and controlled randomized trials indicate that combined-modality therapy, compared with chemotherapy alone, produces a superior event-free survival (EFS). However, because of effective second-line therapy, overall survival (OS) has not differed among the groups studied.[23,24]