In most patients with newly diagnosed Hodgkin's disease, initial therapy is curative. However, a small portion of patients treated with radiotherapy alone for limited favorable disease, and a larger percentage of patients treated with combination chemotherapy, with or without radiotherapy, for advanced-stage or unfavorable disease relapse after initial remission. Patients relapsing after radiotherapy alone should do as well with salvage combination chemotherapy as patients with advanced disease who have never received radiation. In patients who relapse after combination chemotherapy, retreatment with the same regimen or employment of a non-cross-resistant regimen offers high response rates among those with favorable characteristics. However, long-term disease-free survival is achieved in a minority of these patients, and in even fewer of those with early relapse or other unfavorable characteristics. High-dose therapy with autografting shows the greatest promise in the treatment of patients at relapse. [ONCOLOGY 10(2):233-250, 1996]
The vast majority of patients diagnosed with Hodgkin's disease are cured with initial treatment. However, a small number of patients treated with radiotherapy alone for limited disease, and a larger percentage of patients treated with combination chemotherapy, with or without radiotherapy, for advanced-stage or unfavorable disease relapse after attaining an initial remission. This review will focus on the management of patients at first relapse from an initial complete remission. Patients in whom induction therapy fails will not be discussed per se, although some data pertaining to this group will be presented because of the heterogeneity of patient populations in studies of second-line treatments.
The review is divided according to the general situations that arise in the treatment of patients at first relapse. These include relapse after initial radiotherapy alone and relapse after combination chemotherapy alone or combined with radiotherapy. The latter discussion is further divided according to the following treatment modalities: conventional chemotherapy, radiotherapy, and high-dose therapy with autografting.
Primary radiotherapy is an effective treatment for selected patients with favorable early-stage Hodgkin's disease, staged either clinically or surgically. Treatment with extended-field radiation offers high response rates and long remissions in most patients. Nonetheless, 20% to 30% of patients relapse within 5 years after initial radiotherapy [1,2].
A considerable body of evidence shows that patients who relapse after primary radiotherapy can be treated effectively with combination chemotherapy. Table 1 summarizes results from several large series in which MOPP (mechlorethamine, Oncovin, prednisone, and procarbazine) or a MOPP-based regimen was employed [3-10]. Complete response rates ranged from 72% to 95%, and most patients (50% to 80%) were alive and free of disease at 5 years following chemotherapy.
Predictors of improved outcome were similar to those for patients treated de novo; these included small tumor burden and younger age at relapse [3-6,11]. In addition, Cadman et al found that a long duration of remission (> 12 months) was predictive of improved survival after relapse , although this observation was not confirmed by others [3,7].
Impact of Chemotherapy Regimen--The importance of the particular chemotherapy regimen employed at relapse following primary radiotherapy has been addressed in a number of trials. The Cancer and Leukemia Group B (CALGB) found higher complete response rates and longer durations of remission among patients who received a lomustine (CCNU [CeeNU])-containing regimen (CVPP [CCNU, vinblastine, procarbazine, and prednisone] or COPP [CCNU, Oncovin, procarbazine, and prednisone]) than in those given regimens that contained mechlorethamine (MOPP or MVPP [mechlorethamine, vinblastine, procarbazine, and prednisone) .
Santoro et al  reported a clear benefit on complete response rate, failure-free survival, and overall survival with the use of a doxorubicin-containing regimen, compared to MOPP chemotherapy. However, the advantage of doxorubicin was not confirmed in a CALGB study that compared CVPP to ABOS (Adriamycin, bleomycin, Oncovin, streptozotocin) to alternating CVPP/ABOS . Although these studies showed the superiority of one regimen or agent over another, it is not clear whether the prior history of radiotherapy would necessarily influence the choice of chemotherapy at relapse.
Primary Radiotherapy vs Initial Chemotherapy--A number of authors have tried to determine whether patients who receive primary radiotherapy have a different prognosis at relapse than do patients presenting with advanced-stage Hodgkin's disease who have never received radiation. Several authors have reported higher complete response rates [5,9,10] and longer disease-free and overall survival  among patients who failed initial radiotherapy, compared to concurrent patients with advanced Hodgkin's disease treated with chemotherapy de novo. The better results could be explained by the more favorable characteristics of the group that received prior radiotherapy (fewer stage IV patients) [6,10].
One author  found that a history of prior radiotherapy was independently predictive of response and duration of response in multivariate analysis. However, the independent prognostic significance of this variable was not confirmed by others . It appears that patients who relapse after primary radiotherapy have at least as favorable prognosis as patients with advanced-stage disease who did not receive radiotherapy.
In summary, the outcome of patients who relapse following initial treatment with radiotherapy alone is as favorable as, and possibly better than, patients requiring initial chemotherapy. The treatment program at relapse should be based on the efficacy and toxicity profile of a particular regimen, with consideration for the cumulative effects of prior radiation.
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