Data from a network meta-analysis of clinical trials have provided evidence that there is a significant survival benefit from using a more intensive chemotherapy regimen up front in the treatment of advanced Hodgkin's lymphoma, but other experts emphasize the toxicity of this regimen.
The intense chemotherapy regimen, known as BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone), was developed in Germany.
However, few centers outside of Germany have adopted this regimen, and it is not used much in North America, where the older chemotherapy regimen of ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) is preferred.
Until now, the advantage shown for the BEACOPP regimen was improved disease control, with better progression-free survival (PFS) than is seen with ABDV. However, this came at the expense of more toxicity, including a suggestion that there may be an increased risk for secondary cancers.
Another cause for hesitation over its acceptance was the fact that the improved PFS did not appear to translate to an improvement in overall survival.
Now comes evidence of a survival benefit, in an article published online on August 13 in the Lancet Oncology.
The finding comes from a network meta-analysis reported by Nicole Skoetz, MD, and colleagues from the Cochrane Hematological Malignancies Group, working with German researchers who originally developed the BEACOPP regimen, including Peter Borchmann, MD, Volker Diehl, MD, and Andreas Engert, MD, from the German Hodgkin Study Group.
"To our knowledge, we show for the first time that the already known positive effect of BEACOPP regimens on PFS translates into a significant overall survival advantage," the researchers comment.
However, Dan Longo, MD, professor of medicine at Harvard Medical School in Boston, who was not involved with the study, recently commented that using escalated BEACOPP as the primary treatment results in "overtreating the majority of patients."
Network Meta-analysis
Dr. Skoetz and colleagues reviewed 14 trials involving 9993 patients, but the studies used a variety of different treatment regimens. Because they used a network meta-analysis approach, they compared regimens that were tested head to head in some studies, but they also used indirect comparisons from other studies in which the regimens of interest (BEACOPP and ABDV) were tested against another common comparator.
"Most clinicians are not very familiar with this statistical technique, in which direct comparisons are combined with indirect evidence," notes an accompanying editorial, authored by Marc André, MD, and André Bosly, MD. Both are from the CHU UCL Mont-Goddinne-Dinant, Yvoir, Belgium, and the Lymphoma Study Association, Lyon, France.
The German researchers report that reconstructed individual data from the network meta-analysis show that at 5 years, escalated BEACOPP has a 10% advantage over ABDV in overall survival.
Overall survival was highest in patients who received 6 cycles of escalated BEACOPP: the 5-year survival was 95%, compared with 88% for ABDV.
"This difference is certainly relevant from a clinical point of view," the editorialists comment. "However, this improvement in survival is not without side-effects," they add.
Escalated BEACOPP is undoubtedly associated with more acute hematologic toxicity than ABDV, and there is also the issue of secondary malignancies and late cardiovascular effects, they point out.
"Of course, many patients with advanced Hodgkin's lymphoma can be cured by ABDV and only some patients will really benefit from a more intensive regimen such as escalated BEACOPP," they comment.
However, there is no way of identifying who these patients are, they add.
Ongoing clinical trials are investigating the use of interim fluorodeoxyglucose positron emission tomography (PET) assessment, with scan after 2 cycles of chemotherapy, to predict final outcome.
Other ongoing studies are looking at the new product brentuximab vedotin (Adcetris, Seattle Genetics, Inc.), which is already marketed for use in refractory and relapsed Hodgkin's lymphoma and is now being investigated as an up-front therapy. The product is being used in combination with doxorubicin, vinblastine, and dacarbazine (AVD) and is being tested in comparison with ABDV in the initial treatment of advanced Hodgkin's lymphoma.
The editorialist conclude that insofar as the results from these trials with PET scans and brentuximab vendolin are not yet available, for now, "escalated BEACOP should be the standard of care for advanced Hodgkin's lymphoma because it significantly improves event-free survival, and also overall survival."
In their article, Dr. Skoetz and colleagues note that the BEACOPP regimen is already the standard of care used by the German Hodgkin Study Group (to which they belong), the Lymphoma Study Association (to which the editorialists belong), and also by the European Organisation for Research and Treatment of Cancer (EORTC).
Overtreatment of Majority
Dr. Longo, who is also deputy editor of the New England Journal of Medicine, in addition to his Harvard appointment, has addressed the BEACOPP controversy in a letter just published in the Journal of Clinical Oncology, in which he suggested that using this more intensive regimen up front is overtreatment for many patients. The correspondence followed an editorial (J Clin Oncol 2013;31:660-662) that he wrote earlier this year about progress in the treatment of advanced Hodgkin's lymphoma.
In the editorial, Dr. Longo writes that the escalated BEACOPP regimen "has not gained traction outside of Germany for several reasons," which include substantially greater acute haematologic toxicity and a much higher rate of secondary acute leukemia and myelodysplasia than ABDV. In addition, BEACOPP induces infertility in nearly all men and women who receive it, he pointed out.
"Despite the enthusiasm of the German Hodgkin Study Group," he wrote, "most physicians treating patients with Hodgkin's lymphoma had the impression that escalated BEACOPP was overtreating most patients."
It may be 6% to 8% better than ADVD, but this means that 100 patients would have to be treated with a toxic therapy in order to benefit 6 to 8 patients, and in some cases, the acute-treatment fatality rate was as high as 6% to 8%, Dr. Longo notes in the editorial.
Elaborating now in the letter, Dr. Longo comments: "when the risks are fully considered, most physicians will likely choose to cure the 70% to 75% of patients who are curable with ABDV alone, and reserve the heavier guns for the fraction of patients who really need to accept the risks."
"This strategy has been tested and proven in a clinical trial," Dr. Longo adds, referring to a trial conducted by Italian researchers and published in 2011 the New England Journal of Medicine(2011;365:203-212). As reported at the time by Medscape Medical News, that trial found that long-term outcome did not differ significantly between the 2 regimens, but an accompanying editorial noted that the more intensive BEACOPP was clearly more toxic, and that that probably tilts the clinical scales in favor of ABVD.
"If the goal is cure with the least overall toxic effects, the strategy of ABVD therapy — reserving rescue therapy with high-dose chemotherapy and autologous hematopoietic stem-cell transplantation for patients in whom the primary treatment fails — must be favored," wrote the editorialist, Joseph Connors, MD, from the BC Cancer Agency Centre for Lymphoid Cancer in Vancouver, British Columbia, Canada.
"Initial ABVD wins hands down in terms of side effects," he concluded.
Hodgkin's Not Like Other Cancers
Another point made by Dr. Longo in his letter is that Hodgkin's lymphoma is different from some other cancers, in which the first shot offers the best chance of cure, and second-line therapies are ineffective.
In Hodgkin's lymphoma, salvage therapy is important, because patients not cured by the initial treatment can go on to have second and durable complete remissions.
Dr. Longo suggests that patients not cured by BEACOPP receive less benefit from salvage therapy than patients not cured by ABDV. He cites data from a clinical trial published earlier this year (Leukemia Lymphoma 2013:54:36-40) that found that patients with relapsed disease who had initially been treated with ABDV had a 5-year progression-free survival of 76% after high-dose salvage therapy, but this was only 42% in patients who had initially been treated with BEACOPP (P = .29). "This appears to be another important distinction between ABDV and BEACOPP," Dr. Longo writes.
Dr. Skoetz and coauthors, Dr. André, Dr. Bosly, Dr. Londo, and Dr. Connors report no relevant financial relationships.
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