Limited-Stage Hodgkin Lymphoma: Managing Uncertainty
Authors: Ralph M. Meyer
Journal: Journal of Clinical Oncology (2014)

In 1991, an editorial written by Hoppe was published in Journal of Clinical Oncology that discussed uncertainties associated with optimum management of patients with early-stage Hodgkin lymphoma; the editorial was entitled “A Choice of Treatments or a Treatment of Choice?” The editorial addressed the role of staging laparotomy to define patient-specific treatment, whether preferred management was with radiation therapy and/or chemotherapy and, within these choices, the details of the radiation treatment prescriptions and chemotherapy regimens. Considerable new evidence has been obtained since Hoppe’s 1991 editorial, and cure rates with initial therapy have improved from his descriptions of 75% to almost 90%. However, debates continue about fundamental management choices, including the role of radiation therapy and whether determinants exist that permit patient-specific decisions. In the article that accompanies this editorial, Raemaekers et al provide further insights into managing these patients. Their report illustrates the complexities associated with designing clinical trials that are hoped to bring about clarity and consensus to unresolved areas, and how caution is required if one is anticipating that new landmark evidence will emerge and lead to uniform agreement. Instead, practitioners should expect that until transformational new therapies become available, new findings will provide important incremental knowledge, but that management decisions for individual patients will continue to be associated with degrees of uncertainty about which treatment will lead to the patient’s best outcome. Raemaekers et al describe results of two randomized controlled trials (RCTs) that each test the predictive properties of positron emission tomography (PET) performed part way through a planned course of therapy. The first trial, referred to as Hodgkin 10 Favorable (H10F), includes patients with stage I to II Hodgkin lymphoma who have no defined risk factors; the second trial, Hodgkin 10 Unfavorable (H10U), includes patients with stage I to II disease associated with a risk factor, defined as patient age of 50 years or older, more than three nodal areas of disease, bulky mediastinal disease, and/or an adverse combination of B symptoms and/or an increased erythrocyte sedimentation rate. Patients assigned to the experimental arms of each trial who had a favorable midtreatment PET result received less treatment than those allocated to control arm therapy: in contrast to control arm patients, these experimental arm patients did not receive radiation therapy. Patients in the experimental arm with an unfavorable midtreatment PET result received more treatment than control arm patients: in addition to receiving the same radiation therapy as control arm patients, experimental arm patients also received additional cycles of chemotherapy with bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone, whereas control arm patients received additional cycles of doxorubicin, bleomycin, dacarbazine, and vinblastine (ABVD). Central to the design of both H10 trials is that midtreatment PET was performed in a symmetric manner for both experimental and control populations. Images were interpreted through an independent adjudication process by experts who were unaware of the randomized treatment assignment. Rather than designing each trial to report a single comparison of outcomes of all randomly assigned patients, symmetric PET testing with independent review led investigators to plan analyses of each trial, first as comparisons of patients in control and experimental arms with favorable midtreatment PET results, and second as comparisons of patients in control and experimental arms with unfavorable midtreatment PET results. In this report, Raemaekers et al describe results of H10F and H10U interim analyses comparing outcomes of patients who had favorable midtreatment PET results. Using the primary end point of progression-free survival (PFS), both analyses were designed to evaluate noninferiority of the experimental arm therapies (ie, no radiation therapy). Each interim analysis demonstrated that the null hypotheses of inferiority of experimental arm therapy would not be rejected and, thus, the conduct of both trials was altered so that all future patients would receive radiation therapy. The H10 trials are a major accomplishment; their importance rests with the primary findings of radiation treatment being associated with superior 1-year PFS of 5.1% in H10F (100% v 94.9%) and 2.6% in H10U (97.3% v 94.7%). An opportunity for multiple critiques is likely to lead to ongoing debates: for example, the H10U population is defined by a patient-related factor (age) and multiple disease-related factors (bulky disease, more disseminated disease), and the importance of a radiation therapy research question to these varied populations is debatable; the trial design has the intervention associated with the research question occurring more than 2 months after random assignment, which creates risks of compliance, cointerventions, and contamination; the specifics of PET timing and interpretation will require synthesis with other trials evaluating PET; the trial includes involved nodal radiation therapy, for which long-term disease control has not been evaluated in an RCT and which is potentially associated with issues of generalizability, including quality control; the analysis JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 32 NUMBER 12 APRIL 2