Extensive radiation therapy was the first therapeutic advance
in the treatment of early-stage Hodgkin's lymphoma.
More recently, less extensive radiation therapy in combination
with chemotherapy has resulted in the lowest reported rates of
early relapse. The HD10 trial (ClinicalTrials.gov number,
NCT00265018) of the German Hodgkin Study Group showed that among
patients with very favorable stage I or II Hodgkin's lymphoma,
the outcome in those who received only two cycles of
chemotherapy with doxorubicin, bleomycin, vinblastine, and
dacarbazine (ABVD) plus involved-field radiation therapy in
reduced doses was similar to the outcome in those who received
four cycles of chemotherapy and involved-field radiation therapy
at standard doses. The
5-year relapse rate was less than 10%, which established
a new benchmark for treatment measured by this particular end
point. However, with the availability of effective salvage
treatment for relapses on the one hand and the accumulation of
late fatal treatment-related deaths on the other, long-term
outcomes are probably more important than is the low early
relapse rate.Meyer and colleagues
now report the results of the Hodgkin's Disease.6 trial (HD.6,
NCT00002561), in which 12-year overall survival was the primary
end point. In this trial, patients with nonbulky stage IA or IIA
Hodgkin's lymphoma were randomly assigned to four to six cycles
of ABVD therapy alone or to subtotal nodal radiation therapy
alone (in the case of patients with a favorable risk profile) or
in combination with two cycles of ABVD (in the case of patients
with an unfavorable risk profile). The authors were patient
during the 17 years it took to reach the designated time for the
assessment of the primary end point; the results have been well
worth the wait.
Meyer and colleagues found that at a
median follow-up time of 11.3 years, the
rate of overall survival was lower with subtotal nodal radiation
therapy, with or without two cycles of ABVD, than with ABVD
alone (hazard ratio for death with ABVD alone, 0.50;
P=0.04). This difference was due to the number of deaths from
causes other than Hodgkin's lymphoma, including second cancers.
The total numbers of second cancers and of cardiovascular events
were higher in the radiation-therapy group than in the ABVD-alone
group. As the authors state, it might be anticipated that the
rate of survival in the radiation-therapy group may decrease
further in the future, since deaths due to these causes increase
dramatically after 10 years and actually exceed those due to
Hodgkin's lymphoma at approximately 20 years.
Most randomized clinical trials for
Hodgkin's lymphoma measure short-term outcomes such as 5-year
progression-free survival or freedom from disease progression as
primary end points. It has been difficult to design trials to
look at more clinically important long-term results because of
effective secondary therapies and long survivals. Although
secondary analyses of older trials have shown outcomes similar
to those in the HD.6 trial, this is the first trial that used
late survival as the primary end point. These results support
the view that the relapse rate is not a reliable surrogate for
long-term survival, which is the most important treatment
outcome.
The authors discuss
a criticism that might
be made of this trial, namely that subtotal nodal radiation
therapy with or without chemotherapy has been superseded by
chemotherapy combined with involved-field radiation therapy, or
even the more restricted involved-node radiation therapy, as a
standard of care. The rate of late complications after subtotal
nodal radiation therapy may be higher than those that will be
seen with current treatment regimens of chemotherapy with more
limited radiation therapy. However, it is noteworthy that
even in the HD10 trial, the rate of second cancers is greater
than 4%, and at a median follow-up time of 7.5 years, the number
of deaths due to second cancers and to cardiovascular events
already exceeds the number of deaths due to Hodgkin's lymphoma.
It is possible that
these complications may still increase long-term mortality
despite reductions in the doses and fields of radiation therapy.
Moreover, it has been estimated that volumes of radiation
therapy may actually be increased by 10 to 15% when
positron-emission tomographic (PET) imaging, as compared with
computed tomography, is used to plan for involved-node radiation
therapy.
Although radiation therapy remains a
useful tool for the treatment of some patients with Hodgkin's
lymphoma, the challenge is to define the subgroup of patients
for whom the benefits outweigh the increased risk of late
complications. Several recent clinical trials are attempting to
address this issue by using PET imaging during ABVD chemotherapy
to tailor treatment (NCT00943423, NCT00433433, NCT01132807,
NCT01118026, and NCT00736320). Limiting the use of radiation
therapy to the fraction of patients who require it should make
an important contribution to the ultimate goal of maximizing the
long-term cure rate while minimizing late morbidity and
mortality.