Trial Information

Phase III Study Comparing Rituximab-supplemented ABVD (R-ABVD) With ABVD Followed by Involved-field Radiotherapy (ABVD-RT) in Limited Stage (Stage I-IIA With no Areas of Bulk) Hodgkin's Lymphoma

Limited-stage Hodgkin lymphoma is a highly curable disease, with expected long-term
disease-free and overall survival rates close to 90% and 95%, respectively. This success has
come at a cost of long-term treatment-related toxicity, such that the patients who live
beyond 10 to 15 years are more likely to die from late complications of treatment than from
the disease itself. In the last decades efforts to improve long-term results have been made
by developing curative strategies aimed to reduce toxicity while maintaining high cure
rates. Based on the observation that systemic chemotherapy can control occult sites of the
disease, thereby eliminating the requirement for staging laparotomy, in the last years the
use of combined modalities that allowed a reduction of number of cycles of chemotherapy and
of radiation field size and doses, thus reducing late toxicity was investigated in various
clinical trials. Combined modality therapy has then emerged as the standard of care for
limited-stage Hodgkin's lymphoma and doxorubicin, bleomycin, vinblastine, and dacarbazine
(ABVD) chemotherapy that is devoid of alkylating agents and associated with a low potential
for gonadal toxicity and leukemogenesis, is currently considered the gold standard.
Nevertheless, optimal treatment is still a question of debate and current investigations are
now taking into consideration to further reduce long-term toxicity. Actually two main
options are available. The first option combines radiotherapy to ABVD chemotherapy, with the
aim to maximize disease control. Using 4 cycles of ABVD followed by involved field
radiotherapy at 36 Gy, Bonadonna and coworkers first documented a 94%
freedom-from-progression and a 94% overall survival rate, respectively. The disadvantage
with this approach is represented by late cardiovascular events (myocardial dysfunction and
coronary or valvular disease), especially when the heart is within the radiation field;
bleomycin pulmonary toxicity also is increased in conjunction with RT and secondary tumors,
in particular in the RT fields. Whether these risks will be lower with fewer chemotherapy
cycles, lower RT doses, or both has been studied in many clinical trials that have
demonstrated that smaller radiation fields and lower doses are important, but a key
unanswered question is whether RT can be eliminated completely in limited-stage patients.
The second option therefore consists of chemotherapy with ABVD alone, with the aim to
eliminate the late effects of radiotherapy. This approach have resulted in an absolute
increase of the failure rate in the order of 8% (from approximately 4% up to 12%). However,
the majority of relapsing patients achieves a durable disease control with a second-line
radiation-containing combined approach, and shows an overall survival rate superimposable to
that of patients receiving upfront combined strategy with chemo-radiotherapy. We thus
designed a study aimed at treating patients with limited disease with multiagent
chemotherapy alone, without irradiation, and using radiotherapy only for relapses. In fact,
it has recently been reported that the addition of Rituximab (a monoclonal antibody directed
against the CD20 B-cell antigens) to ABVD significantly increases the antilymphoma activity
of ABVD alone in advanced-stage Hodgkin's lymphoma and in absence of added toxicity. In
conclusion, rituximab-supplemented ABVD (R-ABVD) given to early-stage Hodgkin's lymphoma
might represent a radiation-free regimen capable of increasing long-term disease control of
ABVD alone, while avoiding the late effects of radiotherapy.

The primary objective of this study is to evaluate whether the R-ABVD therapy (ARM A) is not
worse than the standard therapy of ABVD-RT (ARM B) in patients with limited Hodgkin's
lymphoma. In this trial a maximum inferiority of 8% of the 3-year Failure Free Survival rate
(FFS) in ARM A with respect to ARM B is considered acceptable to assess that ARM A is not
worse than ARM B.