The Cure of Hodgkin Lymphoma

The cure of Hodgkin lymphoma in the 20th century is another one of cancer's biggest success stories. Breakthroughs in radiation therapy and chemotherapy paired with careful clinical research transformed an invariably fatal disorder into one that is routinely cured. The impact of this success story was, however, much greater because it created optimism for the treatment of cancer in general, and demonstrated the potential for a multidisciplinary approach to diagnosis and management. In the vanguard, Hodgkin lymphoma investigators conducted rigorous, randomized controlled clinical trials as a means to advance therapy. Another important lesson from the Hodgkin's experience was the price of cure. The recognition of late adverse effects from radiation therapy and chemotherapy in the form of second cancers, heart and blood vessel disease, and sterility shaped subsequent research efforts to maintain or improve cure rates with fewer complications, an important goal in a disease that primarily affects individuals in their 20s and 30s. Today, as more than 80 percent of patients are cured after primary treatment, a major emphasis is now placed on survivorship.

Sir Thomas Hodgkin is credited with the initial description of the clinical disorder that bears his name. In 1832, he reported on a group of patients with enlargement of lymph nodes and spleen that differed from the major known maladies of the day. Some 60 years later, pathologists in Germany and the U.S. independently described the diagnostic microscopic characteristics of Hodgkin lymphoma. At about the same time, two physicians applied X-rays, then newly discovered by William Roentgen, to enlarged lymph nodes in Hodgkin patients, reporting remarkable tumor reductions. These observations, together with increased understanding of the patterns of spread, led to advancements in the application of radiation therapy to larger fields in the 1930s through the 1950s. The introduction of the linear accelerator (a radiation machine used to treat cancer) in the treatment of Hodgkin lymphoma at Stanford University resulted in cures of early-stage lymphoma. Meanwhile, a team at the National Cancer Institute safely combined four chemotherapy drugs (mustard, vincristine, procarbazine, and prednisone) known as the "MOPP" regimen and reported the first cures of advanced Hodgkin lymphoma in 1964. Steadily improving techniques for defining the extent and location of disease (staging) has allowed appropriate modalities of treatment to be selected for individual patients. 

The late 1970s and 80s presented new challenges in the recognition of adverse effects associated with MOPP and radiation therapy, some of which were not apparent for decades after treatment. This time period also featured another major advance in an alternative four-drug chemotherapy regimen (doxorubicin, bleomycin, vinblastine, and dacarbazine), known as "ABVD," that proved to be more effective than MOPP in treating advanced disease and had fewer side effects. In the 1990s, even more effective and less toxic treatments for early-stage lymphoma were devised by reducing the dose and area of the body treated with radiation therapy in combination with brief chemotherapy such as ABVD. The German Hodgkin Study Group introduced an intensive seven-drug chemotherapy program, "BEACOPP," to address the fact that approximately 30 percent of advanced Hodgkin lymphoma was not cured with ABVD. Although associated with more severe early toxicity and sterility, a higher cure rate and improved survival were achieved with BEACOPP in a randomized clinical trial. Other advances in the 90s included the routine application of immunologic markers (specific proteins on the cell surface that define subsets of lymphocytes) that improved the precision of pathologic diagnosis and single-cell analyses revealing that the cell of origin of Hodgkin lymphoma, a mystery for more than 100 years, was a B cell akin to the cell that causes the majority of non-Hodgkin lymphomas.

The most recent advance in Hodgkin lymphoma management has come in the form of diagnostic imaging. FDG-PET scans are more specific for tumor identification than CT scans and can be used to assess the success of treatment at an early time point. Application of FDG-PET in clinical studies allows physicians to limit more toxic treatments to the subset of patients who are likely to benefit while sparing the majority from adverse effects. Due to the success of conventional treatments, newer biologic agents must be cautiously introduced in Hodgkin lymphoma therapy. However, high response rates have been reported with the anti-B-cell antibody rituximab in a subtype of Hodgkin lymphoma with B-cell characteristics, and there is active research with new agents that target the microenvironment (non-malignant cells and tissues surrounding sites of lymphoma that modify the activity of the tumor cells) as well as Hodgkin cells.

Today, children, adolescents, and young and older adults worldwide routinely survive Hodgkin lymphoma with modern treatment. Current efforts seek to maintain optimal health for these survivors, to define the least complicated cures for newly diagnosed patients, and, ultimately, to better understand risks for and prevention of this disease.