Controversies in Early-Stage Hodgkin’s Disease

Early-stage Hodgkin’s disease accounts for approximately 60% of all Hodgkin’s disease cases and is associated with a high cure rate, ranging from 80% to 90%. Numerous advances made over the past 30 years have contributed to the significant improvement in treatment outcome for Hodgkin’s disease. These include the increasing sophistication of radiographic imaging used for diagnostic and staging purposes, refinement of radiation techniques that allow more homogeneous dose distribution, more accurate radiation beam targeting while limiting dose to normal organs, and development of more effective, less toxic combination chemotherapy. More recently, cooperative groups have identified sets of prognostic factors that separate patients with early-stage Hodgkin’s disease into favorable and unfavorable groups, allowing the study of treatments tailored to individual prognosis.[1-4]

In recent years, tailored therapy and treatment reduction have become a central theme in the clinical research of early-stage Hodgkin’s disease. The shift from finding ways to improve disease control to exploring measures to curtail treatment was prompted by increasing recognition of the late consequences of Hodgkin’s disease therapy, some of which can have a significant impact on the life expectancy of survivors. Late complications are especially relevant in patients with early-stage disease, because the high cure rate allows many to survive to experience the delayed effects of the disease and its treatment.

Currently, there is no consensus as to the optimal staging method and treatment strategy for early-stage Hodgkin’s disease. Studies have demonstrated differences in relapse rates between therapeutic options, but it is difficult to demonstrate survival differences because treatments associated with higher disease control rates are frequently offset by reduced salvage potential and higher rates of treatment-related complications. In this review, we will summarize data that support various management strategies in early-stage Hodgkin’s disease and ongoing studies that may help address unresolved clinical issues surrounding the disease.

Staging Work-Up

Clinical Staging

Clinical stage in Hodgkin’s disease is determined by physical examination and radiographic imaging. It is generally accepted that the basic clinical staging work-up in Hodgkin’s disease includes a history and physical examination, chest x-ray, and computed tomography (CT) scan of the chest, abdomen, and pelvis. Gallium-67 scintigraphy is considered optional but is commonly included as part of the staging work-up and is associated with a greater than 90% sensitivity for Hodgkin’s disease. In performing a gallium scan, it is important to include single photon-emission computed tomography (SPECT), which further increases the sensitivity and specificity of the test.[5] In addition, an adequate dose of gallium-67 (10 mCi) must be used to reduce the false-negative rate and allow appropriate counting statistics for SPECT imaging.

Obtaining a gallium scan prior to therapy aids in planning radiation treatment by providing additional information on active tumor sites. Furthermore, documentation of the extent of baseline disease and tumor avidity for gallium allows assessment of response to therapy and detection of recurrent disease.[6-9]

Bipedal lymphangiography is another optional radiographic test, although it is used less commonly now and has largely been replaced by CT of the abdomen and pelvis. It may have a role in staging patients who present with infradiaphragmatic Hodgkin’s disease, and can complement CT scan results by providing architectural detail of normal-sized pelvic and abdominal lymph nodes. However, only a few radiologists remain who are trained to perform the procedure and interpret the results.

The main limitation of currently available radiographic imaging methods is the ability to detect occult abdominal disease, especially occult splenic involvement, with a negative predictive value of only 65% to 75%. Whole-body positron-emission tomography using 18F-fluorodeoxyglucose may offer higher overall diagnostic accuracy. Its role in staging Hodgkin’s disease is currently under investigation, and early results appear promising.[10,11]

Pathologic Staging

Staging laparotomy, a procedure introduced in the 1960s, was developed to detect occult disease below the diaphragm, so that appropriate candidates with pathologically staged early-stage disease could be selected for radiation therapy alone. However, its use has been diminishing with improved radiographic staging, the identification of factors that predict for risk of infradiaphragmatic involvement, and the increasing use of combined-modality therapy in early-stage disease. Furthermore, in the European Organization for Research and Treatment of Cancer (EORTC) H6 trial, which randomized patients with early-stage Hodgkin’s disease and a favorable prognosis to laparotomy and tailored therapy vs no laparotomy (with all patients receiving extended-field radiation therapy), no survival differences were detected between arms.[12]

Although staging laparotomy has been abandoned in most parts of the world, it may still have a role in patients who wish to avoid chemotherapy or large-field irradiation. The results of a laparotomy may help guide the selection of patients for treatment with limited-field radiation therapy alone.

Bone marrow biopsy is another invasive procedure performed as part of pathologic staging. However, it is of limited value in most patients with early-stage disease because of its low yield of less than 1%.[13] It is therefore not indicated in early-stage Hodgkin’s disease, unless constitutional symptoms are present at initial diagnosis.

Prognostic Factors

Considerable heterogeneity exists among patients who present with Hodgkin’s disease, even when limited to those with early-stage disease. Identification of prognostic factors is important in these patients, because it not only helps predict individual patient outcome, but also allows the delivery of treatment tailored to the presence or absence of risk factors. Several prognostic indicators have been identified for early-stage Hodgkin’s disease through retrospective studies, which were based largely on patients treated with radiation therapy alone.[14-18] These factors, including the presence of large mediastinal adenopathy and B symptoms, number of involved sites, disease burden, gender, erythrocyte sedimentation rate, and histology, were mostly predictive of freedom from recurrence, but seldom of overall survival. The only factor that has been consistently shown to have a negative prognostic impact on survival is older age at diagnosis.[18-20]

Until recently, the general strategy for the management of early-stage Hodgkin’s disease had been to treat patients with a favorable prognosis with radiation therapy alone, and to add chemotherapy in the presence of unfavorable factors. However, combined-modality therapy is being used increasingly in all early-stage patients because of the safer chemotherapy agents available and concern regarding the toxicity associated with large-field radiation therapy.

Many previously identified prognostic factors are no longer significant in the context of combined-modality therapy. However, separating patients into prognostic groups continues to play an important role, especially in the design of clinical trials. Cooperative groups have used various combinations of prognostic factors to stratify patients into favorable and unfavorable prognostic groups to establish eligibility criteria for clinical trials exploring treatment reduction and modification. Some cooperative groups have also separated out a small group of patients with a very favorable prognosis, in whom minimal treatment has been studied.[2,21] Table 1 shows the prognostic classification schemes of two large European cooperative groups, EORTC and the German Hodgkin’s Lymphoma Study Group (GHSG), in their Hodgkin’s disease trials.[4,14]

Summarized below are trials evaluating various treatment options for early-stage Hodgkin’s disease. The more recently completed trials of radiation therapy alone were limited largely to patients with a favorable prognosis, whereas trials of combined-modality therapy generally stratify patients into favorable and unfavorable prognostic groups.