A major European trial of 549 patients with advanced-stage Hodgkin lymphoma (HL) found a slight survival advantage for an intensified version of BEACOPP (bleomycin-etoposide-doxorubicin-cyclophosphamide-vincristine-procarbazine-prednisone) compared with the treatment standard of ABVD (doxorubicin-bleomycin-vinblastine-dacarbazin).
However, the number of severe adverse events and severe adverse reactions for the escalated BEACOPP regimen was seven times higher than for ABVD, with significantly higher rates of hematologic toxicity and early discontinuations.
As patients with HL are living longer with the use of multiagent chemotherapy, even those with advanced disease, long-term adverse effects of chemotherapy and radiotherapy need to be taken into account.
Study Methodology & Results
To examine the long-term effects of combination chemotherapy, the phase III European Organization for Research and Treatment of Cancer EORTC-20012 trial sought to clarify whether four cycles of escalated BEACOPP followed by four cycles of baseline BEACOPP (BEACOPP4+4) provides better event-free survival and leads to longer overall survival than eight cycles of ABVD (ABVD8) in patients with stage 3 or stage 4 HL (J Clin Oncol. 2016 Jun 10;34(17):2028-36).
Between 2002 and 2010, 275 patients were randomly assigned to ABVD8 and 274 to BEACOPP4+4. No radiotherapy was used. At a median follow-up of 3.6 years, the outcomes appeared to favor BEACOPP4+4. The results were reported as follows:
- estimated overall survival was 86.7 percent for ABVD8 versus 90.3 percent for BEACOPP4+4;
- event-free survival was 63.7 percent versus 69.3 percent respectively;
- disease-free survival was 85.8 percent versus 91.0 percent respectively;
- and complete response rates were 82.5 percent in both arms.
BEACOPP Toxicity Higher
However, more patients in the BEACOPP4+4 arm ended treatment prematurely as a result of immediate hematologic and infectious complications, including septic shock—one in ABVD8 versus 18 in BEACOPP4+4.
And compared with the ABVD8 arm, grade 4 hematologic toxicity was more frequent in the BEACOPP4+4 arm for neutropenia (31.6% vs. 64.7%), febrile neutropenia (5.9% vs. 33.8%), and severe adverse events and reactions (101 versus 708).
But in the ABVD8 arm respiratory-related treatment discontinuations were more frequent (seven versus five), including two deaths as a result of toxicity. However, an amendment for additional lung function tests prevented additional respiratory severe adverse events.
The cumulative incidence of second malignancies at 4 years did not differ between the two study arms: eight (3.4%) for ABVD8 (two lung, three NHL, two myeloproliferative diseases, one other) versus 10 (4.7%) for BEACOPP4+4 (one lung, two NHL, four myeloproliferative disease, three other).
The authors concluded that while the two regimens had similar event-free survival and overall survival, “BEACOPP4+4 did not demonstrate a favorable effectiveness or toxicity ratio compared with ABVD8, [and so] treatment burden, immediate and late toxicities, and associated costs must be considered before selecting one of these regimens on which to build future treatment strategies.”
Cell Kinetics Favor Escalated BEACOPP First
In follow-up questions with the authors, Carde explained that BEACOPP escalated was given before BEACOPP baseline later rather than the reverse due to cell kinetics and the results of the earlier HD12 trial of the German Hodgkin Study Group (J Clin Oncol 2011;29:4234-42).
Additionally, Carde was asked if the outcomes might have been better for BEACOPP4+4 if radiotherapy had been used. “In our experience additional radiation therapy in patients with advanced HL patients who achieved a complete remission brings treatment related mortality which exceeds any potential benefit from the radiotherapy and is responsible for a lower long-term survival,” Carde explained. “This has been shown by the EORTC in a famous randomized trial by Aleman and colleagues” (N Engl J Med 2003;348:2396-406).
Commentary: Balancing Risk-Benefit
The report on EORTC 20012 was accompanied by a commentary titled “Balancing the Risk-Benefit Ratio in the Treatment of Patients With Advanced-Stage Hodgkin Lymphoma,” by Peter Borchmann, MD, Head of the Lymphoma Program, and Andreas Engert, MD, Professor of Internal Medicine, Hematology, and Oncology, both at University Hospital of Cologne, Germany (J Clin Oncol 2016;34:1975-7).
“The study was not powered to test for significance in overall survival, however, the better overall survival is well in line with the progression-free survival difference,” they wrote.
They noted that patients were enrolled between 2002 and 2008, but the reported median follow-up for this study was only 3.6 years. “[That is] surprisingly short given these time lines. Long-term follow-up is essential for a better assessment of overall survival because effects become more pronounced over time. It is likely that an up-to-date analysis of this trial would have delivered a clearer message.”
Nonetheless, they agreed with the EORTC-20012 researchers that BEACOPP4+4 should not be regarded as the standard of care in this setting.
In a follow-up, Borchmann was asked if the similar rate of second malignancies in the two study arms puts to rest the concern clinicians have had about second malignancies in BEACOPP.
“No, I do not think [it puts the concern to rest] because the higher second malignancy rate with BEACOPP escalated is a gut feeling, [one] that was never reflected by trial results,” Borchmann noted. “There is more second acute myeloid leukemia (AML) with BEACOPP than with ABVD, however, there is more second non Hodgkin lymphoma (NHL) with ABVD than with BEACOPP, so in the end of the usually short (4-5 years) follow-up, the overall second malignancy rate has been the same in all four trials comparing ABVD and BEACOPP.”
Borchmann added that the rate of second malignancies within the observation period for progression-free survival (usually 5 years) is much too low to allow for testing for difference, even in a meta-analysis. “But again, regarding the ‘public domain,’ we are talking about gut feeling, not about statistics.”
Robert H. Carlson is a contributing writer.