Hodgkin’s Disease: the Management of “Favorable” Early Stage Disease with Radiation Therapy Alone

Radiation therapy has a long history in the curative management of Hodgkin's disease. In Toronto, Dr. Vera Peters utilized programs of high dose extended field irradiation and, as long ago as 1950, was able to conclude: "Intensive irradiation of involved lymph nodes combined with precautionary treatment to the proximal nodes seems to have improved the survival rates." At Stanford, Dr. Henry Kaplan exploited these concepts further. Kaplan had access to the first medical linear accelerator in the Western hemisphere. He reported in 1962 that patients with early stage disease who were treated radically, to extended fields and high doses (40-44 Gy), achieved significantly higher freedom from recurrence rates than patients treated palliatively (lower doses or involved fields only). He reported a freedom from recurrence rate of 75% at six years for a small group of patients treated in this fashion.

In subsequent years, the results of radiation management for early stage Hodgkin's disease continued to improve. Improved staging became possible with the introduction of lymphography, staging laparotomy, and computed tomographic scanning. Sophisticated techniques of radiation, with individually shaped blocks, conforming to an individual patient's anatomy and tumor configuration, were developed. Concepts of dose-response were developed and fractionation schemes fine-tuned, and these advanced techniques were introduced successfully, even in community clinical practices. In the late 1980s in the United States, the standard approach to the management of early stage Hodgkin's disease was to perform a staging laparotomy and if negative proceed with radiation treatment to an extended field, encompassing lymph node regions both above and below the diaphragm. The expected outcome for this management approach was a 10-year relapse-free rate of 75% to 80% and 10-year survival of 90%.

Challenges to this approach came largely from randomized clinical trials of the European Organization for the Research and Treatment of Cancer (EORTC).⁵ In the H5 study, patients with favorable early stage disease (favorable histology, age less than 40, ESR less than 70, and maximum two sites of disease) with a negative staging laparotomy were randomized to receive mantle irradiation alone or mantle plus paraortic treatment. In the most recent update, at 15 years, there is no difference in either survival or freedom from treatment failure for the two different treatment arms.⁶ In the subsequent H6 trial, the EORTC studied the value of laparotomy. Patients with favorable early clinical stage Hodgkin's disease (one or two sites of disease, erythrocyte sedimentation rate (ESR) less than 50, no large mediastinal mass) were randomized to no laparotomy followed by mantle and paraortic/spleen irradiation, or laparotomy followed by treatment adapted according to pathological stage (radiation alone or combined modality therapy). In the most recent update, at 15 years, there is no difference in freedom from treatment failure for the two different management arms; however, there is a statistically significant difference for survival in favor of no laparotomy.

Based upon these clinical trials and large single institution studies, one could conclude that the appropriate radiation treatment of favorable early stage Hodgkin's disease is with a mantle alone after a negative laparotomy, or mantle and paraortic/spleen irradiation if a laparotomy was not performed. One final issue is whether one may dispense with both laparotomy and subdiaphragmatic treatment in the very most favorable disease presentations. This was the subject of the EORTC H7VF trial. Patients who were female, younger than 40, with one site of disease, ESR less than 50, and favorable histology (lymphocyte predominance or nodular sclerosing) were treated with mantle irradiation alone, without laparotomy. In the most recent report of the results of this study, the six-year event-free survival was only 66%, which led to the conclusion that this management approach was inadequate, even for patients with the most favorable manifestations of early stage Hodgkin's disease, and the trial was abandoned.

The optimal dose to employ when using radiation therapy alone for management has been a controversial issue. Early data suggested a dose of 40-44 Gy was necessary to achieve a high likelihood of permanent disease control. Later studies suggested that lower doses were adequate. Current recommendations include a dose of 36-44 Gy to sites of involvement and 30-36 Gy to prophylactic sites. In addition, low dose irradiation (15-16.5 Gy) may be utilized to extranodal sites such as the lungs and pericardium when they are at high risk for harboring microscopic disease.

Short and intermediate term complications related to radiation management are generally mild to modest and may include minimal nausea, fatigue, mild skin reaction, sore throat, dry cough, and occipital hair loss. Effect on fertility may be an issue if pelvic irradiation is required, but preservation of fertility is usually successful if special gonadal shielding is employed in men and oophoropexy is accomplished in women. Hypothyroidism will develop in the majority of patients who receive irradiation to the cervical lymph nodes, but is easily correctable with exogenous thyroid hormone supplement. The major concern is for late complications, especially cardiovascular risks and secondary cancers. Since mediastinal irradiation is often a component of radiation management, the proximal portion of the coronary arteries and a good portion of the heart may be included in the radiation fields. The relative risk of death from cardiac disease is 3.1 in one large series of patients with long term follow up.Secondary solid tumors are the most common cancers following radiation treatment for Hodgkin's disease. The relative risk is 4.4, primarily due to an increased incidence in lung cancers (among smokers), breast cancer (usually in women who were 16 to 26 years old when irradiated), and smaller increases in melanoma, sarcomas, and gastrointestinal cancers.

Published May 2000