Letter to the Editor: response to letter from Dr. Eroglu and Dr. Unal

Dear Sir,I appreciate the report of the study by Dr Eroglu and Dr Unal and their comments on my review [1]. However, I do not think that one can conclude that radiation therapy (RT) in addition to chemotherapy is necessary in most patients with early-stage Hodgkin lymphoma (HL). Dr Eroglu and Dr Unal report on the use of involved-field RT (IF RT) with or without chemotherapy in patients with relapsed or refractory HL after autologous stem cell transplantation (autoSCT). It is not clear whether this was as a part of the autoSCT programme or a treatment for patients relapsing after or refractory to autoSCT. It is also unclear as to whether they are reporting on a prospective clinical trial and, if so, whether or not it was randomized, or a retrospective treatment experience. The number of patients with limited disease (‘early stage’) was small, and it is not clear how comparable the patients were in the irradiated and nonirradiated groups. This makes conclusions about differences in survival between these two groups difficult. In any case, this is a different patient group from newly diagnosed patients with early-stage HL receiving their first treatment. The meta-analysis of randomized trials comparing chemotherapy alone with chemotherapy plus RT as first treatment in newly diagnosed early-stage HL had serious limitations [2]. It contained only five heterogeneous trials, three of which were over 20 years old. The populations of patients were different in the trials. For example, one trial treated entirely patients with initial bulky disease and another predominantly patients with large mediastinal disease. Another trial had very short follow-up. The chemotherapy was suboptimal in two trials. For these reasons, the trials do not seem to be comparable, and it is difficult to draw meaningful conclusions from pooling their data in the meta-analysis. Subsequent to the appearance of the our review, the final outcome of the randomized trial of the National Cancer Institute of Canada Clinical Trials Group and the Eastern Cooperative Oncology Group of ABVD only versus extended-field RT with or without ABVD, according to risk stratification, as first treatment for stage IA and IIA HL was published. Meyer et al. [3] demonstrated that their hypothesis was correct that survival would be superior for ABVD chemotherapy only to that for EF RT with or without chemotherapy at 12 years owing to deaths to causes other than HL, including second cancers. This was despite a small but statistically significant higher relapse rate for ABVD alone, suggesting that survival, not initial relapse, may be the most important outcome because of effective salvage treatment. The authors speculated that the survival in the RT group may decrease further with longer follow-up, as deaths owing to second cancers and cardiovascular events dramatically increase after 10 years and actually exceed those owing to HL at approximately 20 years [4, 5]. This result further established chemotherapy alone as a treatment option for early-stage HL. A criticism of this trial has been that EF RT with or without chemotherapy has been superseded by chemotherapy combined with IF or even more restricted involved-nodal (IN) RT as standards of care. The late complications of STN RT may be higher than those that will be seen with current treatment regimens employing chemotherapy with more limited RT. Recently, less extensive RT in combination with chemotherapy has provided the lowest reported rates of early relapse. The HD10 trial of the German Hodgkin Study Group found equivalent results in very favourable stages I and II HL with only two cycles of chemotherapy with doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD) plus reduced-dose IF RT and with four cycles and IF RT at standard doses. The 5-year relapse rate was <10%, which established a new benchmark for treatment measured by this particular endpoint [6]. However, it is noteworthy that even in the HD10 trial, the second malignancy rate is >4% and deaths owing to second malignancies and cardiovascular events already exceed those owing to HL at a median follow-up time of 7.5 years [6]. It is possible that these complications may still increase long-term mortality despite reductions in RT doses and fields. Moreover, it has been estimated that volumes of RT actually may be increased by 10–15% using positron emission tomography (PET) imaging to plan for IN RT as compared with computerized tomography [7]. Several recent clinical trials are attempting to determine in which subgroups of patients with early-stage HL the benefits of limited RT in combination with chemotherapy may outweigh the risks using PET during ABVD chemotherapy to tailor treatment (NCT00943423, NCT00433433, NCT01132807, NCT01118026 and NCT00736320). Limiting the use of RT to the fraction of patients who require it should make an important contribution to the ultimate goal of maximizing the highest long-term cure rate whilst minimizing late morbidity and mortality. No conflict of interest to declare.

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