د. حسين محمد جمعه
اختصاصي الامراض الباطنةالبورد العربي
كلية طب الموصل
2011
Chemotherapy Alone for Early-Stage Hodgkin’s Lymphoma
NEJM December 11, 2011.Extensive radiation therapy was the first therapeutic
advance in the treatment of early-stageHodgkin’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.govnumber,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.2 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 nodalradiation 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 overallsurvival 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 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 radiationtherapy 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.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 amedian 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.
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.
