The history of Hodgkin's disease is one of the most exciting stories in medicine. The disorder accounts for about 1% of all cancers and is curable in 85 to 95% of cases, depending on its stage — whether it is localized or disseminated. Indeed, the article by Fermé in this issue of the Journal reports on 10-year survival estimates of 97% for patients with early-stage disease.

In 1832, in an article entitled "On Some Morbid Appearances of the Absorbent Glands and Spleen," Thomas Hodgkin discussed six patients with symptoms that differed from those associated with inflammation, tuberculosis, and syphilis. Wilksnamed this disorder Hodgkin's disease in 1865. For the next century, the fate of patients with this disease was dismal; treatment consisted mainly of surgery, herbs, and arsenic acid.

During the past 50 years, parallel developments in the United States and Europe in the study of Hodgkin's disease have led to four unprecedented successes in oncology. First, we have arrived at a new understanding of the Reed–Sternberg cell, the hallmark of Hodgkin's disease, and of the underlying mechanisms that give rise to the disease. Second, new and better staging methods have been developed, and prognostic factors have been identified that can help to tailor risk-adapted treatment. Third, radiation techniques have improved, and there has been a momentous shift from monotherapy to combination chemotherapy. Fourth, cooperative clinical trials have been organized, and international meetings have fostered the rapid exchange of ideas.

In 1994, using a single-cell microdissection technique, Küppers  showed that Reed–Sternberg cells arise from monoclonal B lymphocytes in the germinal centers of lymphoid tissue and that they carry clone-specific rearrangements of IgG genes. Apoptosis of these cells was found to be inhibited by the constitutively expressed transcription factors nuclear factor B, Stat3, Notch1, and others. hese results ended the long controversy about the nature of Hodgkin's disease: Is it an inflammatory or infectious disease or a true malignant process? It is a neoplastic disease.

There have been major advances in the staging of Hodgkin's disease. Staging by means of exploratory laparotomy and splenectomy, with or without lymphangiography, is obsolete as a result of advances in chemoradiotherapy. Recent advances in staging include the use of a sensitive metabolic imaging technique — positron-emission tomography (PET) with ¹⁸F-fluorodeoxyglucose (FDG) as a tracer. Hodgkin's disease is an FDG-avid tumor, making it possible to assess responses early in the course of treatment and thereby avoid unnecessary toxic effects while maintaining efficacy.

The third advance, the development of highly effective treatment, has been made possible by cooperative efforts by radiation oncologists and chemotherapists. Both groups of specialists had to consider how to reach high cure rates while reducing such long-term sequelae of treatment as other neoplasms and cardiopulmonary toxic effects. Radiotherapy arrived at a crossroads in the mid-20th century when it turned from conventional radiation to megavoltage therapy. This method resulted in high cure rates in patients with localized disease; patients with advanced Hodgkin's disease had prolongation of disease-free survival but not of overall survival.

Chemotherapy for Hodgkin's disease began in 1943, when Goodman reported on the treatment of six patients with "Hodgkin's disease and lymphosarcoma" with nitrogen mustard. The tumors regressed only briefly, but this trial was one of the first phase I or phase II oncology trials ever recorded. It had its origin in an explosion in the harbor of Bari, Italy, in which sailors who had been exposed to mustard gas that was released during the accident were found to have severe lymphopenia and myeloid aplasia.

Until the 1960s, among patients with an advanced stage of Hodgkin's disease who received single-agent chemotherapy, the median survival was 2 years, and only 5% of patients lived beyond 4 years. Breakthroughs came with the advent of combination chemotherapy in 1964, when Devita described the regimen of mechlorethamine, vincristine, procarbazine, and prednisone (MOPP), and in 1975, when Bonadonna  reported on a regimen of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD), which is now the standard of chemotherapy for Hodgkin's disease.

The decision as to how to treat a patient with Hodgkin's disease depends on the anatomical stage of the disease at the time of diagnosis (early or localized stages and advanced or disseminated stages). Fermé et al. subdivided the early stages of Hodgkin's disease into a favorable group (without risk factors) and an unfavorable group (with risk factors), but cooperative groups in North America recognize only early and advanced stages.

The study by Fermé et al., which recruited 1538 patients from 1993 to 1999, is like the god Janus. One of its faces shows a well-designed protocol, multinational recruitment of a large number of patients in a short time, and quality-assured data showing an excellent outcome for the patients. The other face is irony: it shows the drawback of a study by a cooperative group with a record of high cure rates. Such success necessitates two observation periods: an initial phase to collect 5-year data concerning progression-free survival and acute toxic effects, followed by a longer phase to collect data on overall survival and long-term toxic effects (even 10 years of follow-up might not be adequate). As a result of the long second phase — up to 10 years in some instances — it is possible that results reported by Fermé et al. are already outdated.

Fermé et al. conclude that for patients with favorable early-stage Hodgkin's disease, combination chemotherapy with MOPP plus doxorubicin, bleomycin, and vinblastine (ABV) is superior to subtotal nodal irradiation, whereas for unfavorable early-stage disease, four courses of chemotherapy plus involved-field radiation should be the standard treatment. These conclusions are based on a study that was designed more than 14 years ago and in which the recruitment of patients ended 8 years ago. Since then, MOPP-ABV for early-stage Hodgkin's disease has been abandoned in favor of ABVD, because patients treated with MOPP have a long-term risk of leukemia and other cancers. (In the study by Fermé et al., acute leukemia or myelodysplasia developed in 12 patients.)

In studies by the German Hodgkin's Study Group, more than 1300 patients with favorable early-stage Hodgkin's disease and 1500 patients with unfavorable disease were treated with ABVD alone. With two and four courses of ABVD, respectively, plus 30 Gy of involved-field radiotherapy, the 5-year progression-free survival rate was 92% for the favorable group and 87% for the unfavorable group; overall survival rates were 96% and 91%, respectively. As for radiotherapy, nodal irradiation with smaller fields and lower radiation doses may outdate involved-field radiation.

The pivotal question is whether we can cure patients with early-stage Hodgkin's disease with chemotherapy alone. In a study conducted by the National Cancer Institute of Canada Clinical Trials Group and the Eastern Cooperative Oncology Group, ABVD alone was compared with ABVD plus extended-field radiation in patients with early-stage Hodgkin's disease. There was no difference in overall survival between the two groups at 5 years, although 5-year freedom from disease progression was superior in patients who had received radiotherapy. Nevertheless, whether chemotherapy alone suffices remains an unanswered question.

The use of FDG-PET with computed tomography may open a unique opportunity to assess the response to treatment, thus enabling changes in therapy according to the patient's risk of relapse and, in some patients, sparing further chemotherapy or radiotherapy. Nearly all ongoing trials of early-stage Hodgkin's disease in the United States and Europe incorporate FDG-PET with computed tomography for assessment of the response after one or two cycles of ABVD.

This editorial began with the evocation of Thomas Hodgkin, who was the "Curator and Inspector of the Dead." In 2007, physicians who treat Hodgkin's disease are the "Curators of the Survivors," and with that distinction comes an obligation to ensure that patients have a future without therapy-induced sequelae.