Chemotherapy alone versus chemotherapy plus radiotherapy for early stage Hodgkin lymphoma (2011)

“Hodgkin lymphoma is a malignancy of the lymphatic system, first described by Thomas Hodgkin in 1832. It is one of the most curable forms of cancer, and occurs in children and adults, but is more common in the third decade of life. Generally, the disease is differentiated into early and advanced stages. Of the approximately 20,000 new cases of Hodgkin lymphoma diagnosed each year in North America and Europe, 6000 to 7000 have early stage Hodgkin lymphoma, which is the focus of our new Cochrane review (1). Radiotherapy was the mainstay of treatment for patients with early stage Hodgkin lymphoma for many years. However, relapse rates above 30% have been found after radiotherapy is used on its own and large-field radiotherapy is associated with an increased risk of second cancers. This has led to a combined modality approach, in which chemotherapy is added to the radiotherapy. An individual patient data meta-analysis in the 1990s demonstrated better long-term disease control for the combination of chemotherapy and radiotherapy in patients with early stage Hodgkin lymphoma, compared to radiotherapy alone (2). The concept of minimal curative therapy, with the greatest efficacy and least toxicity, has emerged in the treatment of Hodgkin lymphoma in recent years. This is based on the assumption that avoidance of radiotherapy would result in fewer deaths from late-effects, but with no adverse impact on long-term survival. The long-term harms of radiotherapy are an important issue in Hodgkin lymphoma patients for two reasons: most patients are young at diagnosis and most of them will be cured. Therefore, they are likely to survive for a long time, during which they would be at risk of the late toxicities. For early stage Hodgkin lymphoma, both chemotherapy alone and the combination of chemotherapy plus radiotherapy have been shown to effective, but the optimal choice between these regimens remains uncertain and continues to be evaluated in randomised trials. This is the key research question for our Cochrane review, in which we compare the role of chemotherapy alone with the combination of chemotherapy plus radiotherapy in patients with early stage Hodgkin lymphoma. We included five trials, with a total of 1245 patients available for the main analyses. Chemotherapy regimens differed in these five trials, and included adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD) in two trials, CVPP (cyclophosphamide, vinblastine, procarbazine, prednisone) in two trials and EBVP (epirubicin, bleomycin, vinblastine, prednisone) in one trial. This heterogeneity across the regimens might weaken our findings, because some of the older regimens (CVPP and EBVP) are no longer used; but we found that the results of our meta-analyses were similar, regardless of which chemotherapy regimens were included or excluded. Modern radiotherapy for early stage Hodgkin lymphoma uses fields that are as small as possible, to decrease long-term side effects. Three of the five trials in our review used involved field radiotherapy. The other two used extended field radiotherapy. We found no difference in overall survival or tumour control between these different groups of trials, which is in keeping with the finding that extended field radiotherapy had little or no advantage over involved field radiotherapy in Hodgkin patients, when used alone or after effective chemotherapy. In our meta-analyses, we found that the addition of radiotherapy to six cycles of chemotherapy is a better treatment option than six cycles of the same chemotherapy alone. Our most important finding is the significant overall survival advantage for early stage Hodgkin lymphoma patients receiving chemotherapy plus additional radiotherapy compared to the same chemotherapy alone (hazard ratio: 0.40, 95% confidence interval: 0.27 to 0.61). Depending on the patient's risk of death, this means that between 11 and 55 patients needed to be treated, for one fewer to die over the subsequent five years. Considering tumour control, for every five patients treated with chemotherapy plus radiotherapy, there was one fewer relapse or progression in the five years after treatment, compared to those receiving chemotherapy on its own. We found no significant differences in adverse events between the two types of treatment. Although additional radiotherapy probably increases the long-term adverse event rate, the follow-up in the five trials is not yet long enough to detect these events or they were not reported. Long-term follow-up, to beyond 15 years, will be needed to answer questions about these late effects. Something else that should be considered in future research is better tailoring of treatment to patient groups. For example, some studies have evaluated the effects of interim positron emission tomography (PET)-based treatment adaptation in Hodgkin lymphoma patients. These scans might help predict prognosis and, thereby, identify patients who will have a poor prognosis and are most likely to benefit from intensive front-line therapy. On the other hand, clearly identifying patients in the majority who have a lower risk of relapse, might allow a minimal approach to treatment for them. In summary, the currently available evidence suggests that the addition of radiotherapy to chemotherapy reduces the risk of tumour relapse and death for patients with early stage Hodgkin lymphoma.”