In one of the most important achievements in oncology, researchers applied combination chemotherapy and radiation therapy to patients with classical Hodgkin lymphoma (cHL), a nearly uniformly fatal disease, and transformed it into one of the most curable cancers we treat. This success, however, came at a cost of increased risk of late toxicity, largely owing to the risks of secondary malignancies and premature cardio- and cerebrovascular disease resulting from radiation. The focus in recent decades, in this disease so common in young adults, has been to define which patients can be treated with less therapy, and therefore be exposed to less risk, while not sacrificing durable remission, and more importantly, survival rates.
Randomized studies in early-stage, nonbulky cHL demonstrate that omission of radiation following successful therapy with four to six cycles of ABVD (adriamycin, bleomycin, vinblastine, decarbazine) yields similar, or in one case, improved, survival rates despite a small 5 percent increase in the risk of relapse.1,2 This is owing to both the excellent outcomes of salvage therapy (chemotherapy and autologous transplantation or radiation therapy) in relapsed early-stage cHL, as well as the late toxicities observed following radiation-containing regimens. The next question that emerged was whether fewer than six cycles of ABVD would be sufficient for a subset of patients. The observation that early interim positron emission tomography (PET) scans could be predictive of outcomes in early-stage cHL made it possible to use a scan after two cycles of ABVD chemotherapy to either escalate or de-escalate therapy. In the RAPID study, patients with nonbulky early-stage HL who achieved a Deauville 1 or 2 scored PET scan after cycle 3 were randomized to either no further therapy or involved-field radiotherapy (IFRT); the former resulted in an excellent three-year progression-free survival (PFS) of 90.8 percent, compared with 94.6 percent in the latter.3 In the H10 trial, patients were randomized to either ABVD with IFRT versus a risk-adapted approach of ABVD alone for cycle 2 PET–negative patients or escalated BEACOPP and involved nodal radiotherapy (INRT) for cycle 2 PET–positive patients.4 Although random assignment was discontinued early because of an excess of events in the risk-adapted arm and investigators felt this supported the use of combined modality therapy for all patients with early-stage cHL, the five-year PFS for both risk-adapted groups was actually quite good (>87%).
The CALGB 50604 study was designed to test the use of risk-adapted therapy based on the use of early-interim cycle 2 PET imaging in nonbulky early-stage cHL.5 The primary endpoint of this study was to demonstrate that four cycles of ABVD were sufficiently effective, with efficacy defined as a three-year PFS of greater than 85 percent. A secondary objective was to study whether escalation of therapy to escalated BEACOPP and IFRT following a positive cycle 2 PET scan could improve outcomes to that of the cycle 2 PET–negative group. Deauville scores of 1 to 3 were considered negative on this study. This was not a randomized trial, so it did not compare four versus six cycles of ABVD in the cycle 2 PET–negative group, nor did it compare six cycles of ABVD to escalated BEACOPP and IFRT in the cycle 2 PET–positive group. It did, however, demonstrate an excellent three-year PFS following four cycles of ABVD after a negative cycle 2 PET scan of 91 percent. When only Deauville 1 and 2 PET scans were compared with outcomes for Deauville 3 to 5 PET scans, the three-year PFS was expectedly better at 94 percent. However, using a less stringent definition of a negative PET spared escalated therapy in 15 percent of patients, with only a 3 percent decrease in PFS. As for the cohort whose therapy was escalated following a positive cycle 2 PET scan, there was a three-year PFS of only 66 percent, thus not matching that of the negative cycle 2 PET cohort. Nevertheless, the rates of Deauville 4 or 5 cycle 2 PET scans were quite low in this study at only 9 percent, and the authors hypothesize that this may have contributed to the outcome.
In Brief
For clinicians who believe that combined modality therapy exposes young patients with nonbulky early-stage cHL to unnecessary risk given comparable overall survival rates following a chemotherapy-alone approach, the ideal amount of chemotherapy may be in the eye of the beholder. Whether to treat with three, four, or six cycles following a negative interim PET scan depends on whether long-term PFS of 86 to 91 percent seen following abbreviated therapy is equivalent to what is seen following six cycles of ABVD; however, none of the studies that asked this question included a six-cycle arm. A 3 to 5 percent increased risk of relapse may be worth it when the alternative is a secondary malignancy or early heart attack due to radiation therapy, but would it still be worth it when the alternative is only two additional cycles of ABVD? Weighing the emotional toll of a cHL relapse and the potential for either radiation therapy and/or salvage chemotherapy and autologous stem cell transplantation against two more cycles of ABVD chemotherapy, in the absence of randomized data comparing three to four versus six cycles, is the job of an oncologist treating cHL patients today.
References
Competing Interests
Dr. Jacobson indicated no relevant conflicts of interest.
