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Hodgkin's Disease: Management of First Relapse

Hodgkin's Disease: Management of First Relapse

ABSTRACT: 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]

Introduction

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.

Relapse After Primary Radiotherapy

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].

Combination Chemotherapy

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 [6], 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)
[5].

Santoro et al [8] 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 [4]. 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 [5] 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 [5] 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 [9].
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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