Treatment of Stage IIIa Hodgkin's Disease: Long Follow-Up Perspective

Abstract

Meticulous attention to detail, clinical research, and a degree of therapeutic empiricism set the stage for the spectacular improvements generated in the long-term outcome of Hodgkin’s disease in the 1960s and 1970s. The results below are a reflection of this, documenting the commitment of the generation of academic physicians pioneering hematologic oncology 40 years ago. At the time, management was based on the Ann Arbor Staging Classification based on the presumed anatomic spread of the disease, the outcome potential of megavoltage irradiation, and the assumption that systemic chemotherapy was substantially more toxic—and as yet—unproven in efficacy, hence reserved for advanced disease. It was generally accepted that disease localized to one side of the diaphragm should be treated with irradiation, at least to a mantle or inverted Y field, that advanced and symptomatic disease be treated with cyclical combination chemotherapy, and that asymptomatic nodal disease on both sides of the diaphragm (stage IIIA) receive either total nodal irradiation, chemotherapy, or both. Over time, it became clear that bulky disease and multiple nodal sites were poor prognostic factors, and combined chemoradiotherapy became the treatment of choice for those in whom they were identified. By 1974, at least at St. Bartholomew’s Hospital, 40% of patients with stage II disease were being treated this way. The article above reported interim data on a subset of patients, all identified as having pathologic stage IIIA disease on the basis of Ann Arbor Classification, including staging laparotomy, representing approximately 20% of the patients seen during the period in question. In 2008, more than a quarter of a century after the first patient was treated, none have been lost to follow-up. Forty percent are alive in first remission, presumed cured, with an additional 13% currently disease-free in a second remission for more than 3 years. The outcome was the same for both substages (IIIA1, IIIA2) and both combination chemotherapy and total nodal irradiation. This extraordinary improvement over the natural history of the disease, achieved over a short time, is only marred by a less-than-satisfactory overall survival pattern due, at least in part, to late toxicity. These data mirror the overall outcome of therapy seen in the newly diagnosed population of patients treated at St. Bartholomew’s Hospital from 1968 to 1985, only 12 having been lost to follow-up. Based on the Ann Arbor Stage, 526 adults were treated with mantle or inverted Y irradiation, combination chemotherapy with mustine, vinblastine, prednisolone, and procarbazine, or combined modality treatment with 55% undergoing laparotomy. The management at recurrence depended on the circumstances, but only included myeloablative chemotherapy in 9 patients. With only 12 lost to followup, 49% are alive, 39% in first remission for a minimum of 23 years, and an additional 10% have been in second or subsequent remission for at least 5 years. Twenty percent have died of Hodgkin’s disease and 31% have died resulting from other causes (including second malignancy 9%, cardiac event 9%; Table 1; Fig 1). Age and stage were highly statistically significant prognostic factors (P .001 and P .001, respectively; Fig 2, Fig 3). Within stage III, both the absence of B symptoms (P .01) and laparotomy staging (P .01).were favorable factors. In 2008, both investigation of the patient with Hodgkin’s disease and the treatment are substantially different, and better. Lymphography has been replaced by computed axial tomography, to the enormous benefit of the patient in terms of comfort. Laparotomy has become redundant both through the identification of surrogate markers of extensive disease obviating the need for diagnostic splenectomy and lymph node mapping, and the increasing use of combined modality therapy, which obviates the necessity for demonstrating limited anatomic spread. The most recent addition to the imaging