ABSTRACT: Multiple randomized studies have demonstrated that chemotherapy, most commonly ABVD (doxorubicin [Adriamycin], bleomycin(Drug information on bleomycin), vinblastine(Drug information on vinblastine), dacarbazine(Drug information on 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 Most studies evaluating such risks primarily include patients treated in decades past with what are now considered outdated approaches, including high-dose, wide-field radiation therapy.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
Randomized Trials Comparing Chemotherapy vs Combined-Modality Therapy
Combination chemotherapy regimens were originally developed primarily for patients with advanced disease. Because of their success in patients with advanced disease, they were later studied for those with localized disease. The initial approach was to investigate the upfront use of chemotherapy and radiation therapy (combined-modality therapy). With high response rates to chemotherapy, however, many queried whether radiation therapy was a necessary component. Several randomized trials were conducted using a variety of chemotherapy regimens and radiation schemes (see Table).[6-14] Despite the heterogeneity, the studies consistently demonstrated a lower risk of relapse with radiation therapy added (Figure 1). Though the individual trials have not shown a consistent effect on survival (and few were powered to detect a survival benefit), a Cochrane systematic review did demonstrate improved overall survival in early-stage disease treated with a combined-modality approach compared with chemotherapy alone.[15]
Randomized Trials Comparing Chemotherapy (CT) Plus Radiation Therapy (RT) vs Chemotherapy Alone in Hodgkin Lymphoma
A few of the individual trials are briefly reviewed below to highlight important points.
Picardi et al
This study from University Medical School in Naples, Italy enrolled 160 patients with Hodgkin lymphoma (all with disease ≥ 5 cm).[12] Patients received 6 cycles of VEBEP (vinblastine, etoposide, bleomycin, epirubicin(Drug information on epirubicin), predisone). Those with a good (≥ 75% reduction in tumor size) but incomplete response by computed tomography (CT) but who were negative by positron emission tomography (PET) were randomized to consolidation radiation therapy (32 Gy) or observation. Eleven patients relapsed in the chemotherapy arm compared with two in the combined modality arm (P = .01). Event-free survival at 5 years was 96% vs 86% (P = .03).
Numerous ongoing studies are evaluating whether PET can distinguish the subgroup of patients who harbor residual disease after chemotherapy and who would therefore gain the most benefit from consolidation radiation therapy. This study is notable because all patients achieved at least a 75% reduction in the areas of bulk disease and a complete response to chemotherapy by PET imaging, but radiation therapy still decreased the risk of relapse. A limitation of this study is the choice of chemotherapy regimen (VEBEP), which may not be optimal based on studies demonstrating that non-doxorubicin (Adriamycin) anthracycline regimens are not as effective as doxorubicin(Drug information on doxorubicin)-based regimens.[16]
Patients whose PET and CT scans were both negative (n = 70) in the study by Picardi et al were not randomized and only received chemotherapy. Unfortunately, 10 patients were lost to follow-up. Among the remaining 60, there were still 7 who had relapses. Thus, a negative post-treatment PET scan, even with a negative CT scan, may lack sufficient sensitivity to indicate a true disease-free state. Interim PET, done after 2 to 3 cycles, is also being examined, but interim analyses from a joint study by the European Organisation for Research and Treatment of Cancer (EORTC) and the Groupe d’Etude des Lymphomes de l’Adulte (GELA) study (H10) have not been encouraging.[17]
Wolden et al
This Children’s Cancer Group study (CCG 5942) enrolled 498 children and adolescents who achieved a complete response by CT scan to 6 cycles of chemotherapy (mostly COPP-ABV: cyclophosphamide(Drug information on cyclophosphamide), vincristine [Oncovin], procarbazine(Drug information on procarbazine), prednisone(Drug information on prednisone), doxorubicin, bleomycin, vinblastine) or the same chemotherapy with radiation therapy (21 Gy).[14] By intent-to-treat analysis, 10-year event-free survival (EFS) was 90% vs 84% (P = .05) in the two groups, respectively. However, 23 patients randomized to radiation therapy did not receive it, and 5 of these patients relapsed. The as-treated EFS values were 91% and 83% for patients randomized to post-chemotherapy radiation vs no further therapy, respectively (P = .004). Among patients relapsing after chemotherapy alone, 85% of relapses were confined to original sites of disease.
The study by Wolden et al highlights several important points. First, quality assurance information is rarely reported in randomized lymphoma trials, making it difficult to ascertain the actual benefit of radiation therapy. Second, congruent with many other studies, patterns of failure confirmed that most recurrences after chemotherapy alone are confined to originally involved areas, supporting the current approach of targeting radiation fields to the original extent of disease. Finally, and perhaps of greatest importance, low doses of radiation therapy are effective after combination chemotherapy, 21 Gy in this study.
Meyer et al
This National Cancer Institute of Canada study (HD6) randomized patients with early-stage, unfavorable Hodgkin lymphoma to 4 to 6 cycles of ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) or 2 cycles of ABVD plus radiation therapy.[8] The latter consisted of subtotal nodal irradiation to a dose of 35 Gy. Patients with large mediastinal adenopathy, bulky disease (> 10 cm), or intra-abdominal disease were considered high-risk and not eligible for randomization. This study suffers from having two different chemotherapy regimens in the two treatment arms (4 to 6 cycles of ABVD vs 2 cycles), and from what we now know to be a radiation therapy dose and field size with unacceptable risks of complications.
Although freedom from disease progression was improved with combined-modality therapy (94% vs 86%, P = .006), survival was better with ABVD alone. However, imbalances in the number of deaths due to infections (3 vs 0) and miscellaneous causes (5 vs 0), which included Alzheimer’s disease, drowning, suicide, respiratory failure, and unknown cause, are difficult to explain. Further, the number of second cancers outside of a subtotal nodal radiation field (bladder, cervix, prostate, rectal) were higher in the combined-modality arm (n = 6) compared with the chemotherapy alone arm (n = 1).
This study is widely quoted in support of using chemotherapy alone for early-stage Hodgkin lymphoma but is primarily of historical significance, inasmuch as outdated radiation approaches were utilized. In fact, HD6 was closed early after publication of the EORTC H8F trial, which showed that involved-field radiation therapy could replace more extensive radiation fields when chemotherapy was part of the treatment program.[18] Patients in the combined-modality therapy arm were thus exposed to the risks of both chemotherapy and full-dose, wide-field radiation therapy, which may have contributed to the observed late toxicity. It is notable that patients in the combined-modality arm had fewer relapses than patients managed with chemotherapy alone (P = .006).
