Combined-Modality Therapy for Early-Stage Hodgkin Lymphoma: Maintaining High Cure Rates While Minimizing Risks

Multiple randomized studies have demonstrated that chemotherapy, most commonly ABVD (doxorubicin [Adriamycin], bleomycin, vinblastine, dacarbazine), followed by consolidation radiation therapy is the most effective treatment program for early-stage Hodgkin lymphoma. With a combined-modality approach, the great majority of patients are cured of their disease. It is also apparent that both chemotherapy and radiation therapy can increase the risk of complications in the decades following treatment, with second cancers and cardiac disease being the most common. Most studies evaluating such risks primarily include patients treated in decades past with what are now considered outdated approaches, including high-dose, wide-field radiation therapy. The treatment of Hodgkin lymphoma has evolved significantly, particularly in regard to radiation therapy. In combination with chemotherapy, much lower doses and smaller fields are employed, with success equivalent to that achieved using older methods. Many studies have shown a significant decline in both the rates of second cancers and the risk of cardiac disease with low-dose radiation confined to the original extent of disease. In favorable patients, as few as 2 cycles of ABVD have been shown to be effective. The current combined-modality approach seeks to maintain high cure rates but minimize risks by optimizing both chemotherapy and radiation therapy.

Introduction

The great majority of patients with Hodgkin lymphoma are currently cured of their disease using modern treatment regimens. It is extraordinary to recollect that until the mid-20th century this disease was inevitably fatal. In 1950, Vera Peters, MD, from Toronto, published a landmark study demonstrating long-term survival of patients with early-stage disease using radiation therapy alone.[1] After this sentinel observation by Dr. Peters, two concepts emerged from work at Stanford University. The first concept was that a dose-response relationship is seen when radiation is used as the sole modality.[2] The second concept was that the nature of Hodgkin lymphoma is to spread to contiguous lymph nodes.[3] The dose, field size, and treatment techniques were optimized over the ensuing decades using these two concepts. Long-term disease control in the prechemotherapy era was ultimately achieved in 75% to 80% of patients with stage I to II Hodgkin lymphoma using doses of 35 to 44 Gy and large fields (treatment of involved and high-risk adjacent nodal sites). With the development of effective combination chemotherapy in the 1960s, many patients who relapsed after initial radiation therapy were salvaged with chemotherapy; the overall cure rate of early-stage Hodgkin lymphoma with this approach was ~90%.[4]

This was heralded as a notable success, and indeed it was. However, with long follow-up, the risks of this treatment strategy were found to be considerable. In particular, a significant percentage of patients, successfully cured of their Hodgkin lymphoma, subsequently developed a secondary cancer or cardiovascular disease 10 to 25 years after treatment.[5] In the setting of such favorable cure rates, minimizing long-term risks of treatment, both from chemotherapy and radiation therapy, has become a dominant focus in the current design of clinical trials and the management of individual patients.

The goal of any oncologic treatment program is to maximize cure while minimizing risk (eg, acute side effects and late risks). In Hodgkin lymphoma, as with many other malignancies, a combined-modality approach has proven successful. This tactic capitalizes on the relative advantages of both modalities, yet minimizes risk by avoiding intense exposure to either. This article will summarize the data supporting this approach in early-stage Hodgkin lymphoma.

Combined-Modality Therapy: Randomized Trials

TABLE

Randomized Trials Comparing Chemotherapy vs Combined-Modality Therapy

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