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Controversies in Early-Stage Hodgkin’s Disease

Controversies in Early-Stage Hodgkin’s Disease

ABSTRACT: Early-stage Hodgkin’s disease accounts for approximately 60% of all cases of the illness. Because of its excellent cure rate (80% to 90%) and high salvage rate, it is difficult to demonstrate survival advantages for different management options. Currently, there is no consensus as to the optimal staging and treatment strategy for early-stage Hodgkin’s disease. With the increasing recognition of the late consequences of Hodgkin’s disease therapy, the focus of recent clinical trials has been on exploring treatment modifications to reduce these late effects. Areas of controversy that are being explored include extent of staging work-up, radiation field size and dose (and as part of combined-modality therapy), optimal chemotherapy regimen, number of cycles of chemotherapy, and limited- vs extended-field radiation therapy and dose. In addition, several studies are investigating the feasibility of chemotherapy alone in early-stage patients. Along with the evaluation of modified treatments, long-term follow-up efforts should continue in patients who are cured in order to confirm the long-term safety of such therapies. [ONCOLOGY 16:588-618, 2002]

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.

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