Hodgkin disease: the sword of Damocles resheathed

Comment on Straus et al, page 3483

ABVD chemotherapy alone is as effective as ABVD plus radiation therapy in early-stage Hodgkin disease; thus, the majority of patients are curable without being exposed to the life-long, life-threatening risks of therapeutic radiation.

Damocles, a courtier to Dionysius, the tyrant king of Syracuse in the fourth century BC, persistently praised the king for his power, wealth, and the many amenities that added pleasure to the king's life. Dionysius sensed envy in the young Damocles. “How would you like to live my life?” asked the king. “I could not imagine any greater happiness,” responded Damocles. So the king prepared an elaborate banquet for Damocles with servants attending every need. He was enjoying himself immensely until he noticed a sword hovering over his head suspended precariously from the ceiling by a single horse hair. Noting the anxiety this sword induced in Damocles, Dionysius reminded the young man that the king has many enemies and his life is in constant peril. Thus, Damocles was cured of his envy and this suspended sword came to symbolize an ever-present threat.FIG1 

Patients with Hodgkin disease treated with radiation therapy live with the lesson of Damocles's sword. Large cohorts of patients treated with radiation therapy have now been followed for many years and groups have reported that deaths related to the radiation therapy treatment outnumber deaths related to Hodgkin disease. Mediastinal radiation therapy is associated with a 3-fold increased risk of fatal myocardial infarction from accelerated coronary atherosclerosis. Furthermore, patients treated with radiation therapy have a risk of developing a second malignancy of about 25% at 25 years with no evidence that the risk is decreasing with time.

Abundant data have been generated that fail to show any improvement in survival of patients treated with the addition of radiation therapy to MOPP (mustine, vincristine, procarbazine, prednisone)–like chemotherapy. In addition, somewhat less data have suggested that MOPP-like chemotherapy alone is as effective as radiation therapy alone in the treatment of early stage Hodgkin disease. However, until now, there has been a paucity of data using ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) alone as the treatment for early stage Hodgkin disease. In this issue of Blood, Straus and colleagues report results of a randomized comparison of ABVD to ABVD plus radiation therapy in patients with stages I, II, and III Hodgkin disease, and the results provide the final piece of the lever that should produce a shift in medical practice.

In a study involving 152 patients, addition of radiation therapy to ABVD chemotherapy did not improve upon results obtained with ABVD alone (see figure). The data suggest that it is possible to cure a very large fraction of patients with Hodgkin disease with ABVD chemotherapy while holding radiation therapy in reserve for the fraction of patients who require it to control their disease. Instead of exposing 100% of patients to the apparently lifelong risks associated with radiation therapy (no safe dose of radiation therapy has ever been defined), it is possible to use it in a subset of patients: the 5% to 6% who do not respond completely to ABVD and the group with very large mediastinal masses.

In the absence of persuasive data supporting the superiority of combined modality therapy and the defined long-term risks of radiation therapy, it is time to adopt a new approach to Hodgkin disease treatment: clinical staging followed by ABVD chemotherapy in all stages of disease. No life is without risk but such an approach removes the imminent threat posed by radiation exposure for the majority of patients.