A response-adapted approach to the treatment of patients with advanced Hodgkin's lymphoma de-escalates treatment after an early negative PET scan and intensifies treatment in those with a PET-positive scan — those with the highest risk for treatment failure.
This clinical management, suggested from retrospective analyses, now has confirmatory evidence from a randomized clinical study published in the June 23 issue of the New England Journal of Medicine. For patients with a negative PET scan after two treatment cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD), those who continued treatment with ABVD were not significantly different than those who discontinued the full course of bleomycin and were then treated with doxorubicin, vinblastine, and dacarbazine (AVD).
In the ABVD group, 3-year progression-free survival was 85.7%, compared with 84.4% in the AVD group. However, with a difference of 1.6 percentage points at 3 years (95% confidence interval [CI], –3.2 to 5.3), the upper boundary of the 95% CI slightly exceeded the 5 percentage points specified for noninferiority. Nonetheless, the results might be clinically meaningful and relevant, given that patients in the AVD group showed a lower incidence of pulmonary toxicity, the researchers report.
"This study has demonstrated that using an early PET scan is a good way to plan treatment for people with Hodgkin's lymphoma. We have shown that de-escalating therapy in response to a good response is safe and effective. By reducing the total amount of treatment being given, we hope to see fewer long-term side effects," corresponding author Peter Johnson, MD, from the Cancer Research UK Institute at the University of Southampton, United Kingdom, told Medscape Medical News.
"The results are already changing clinical practice, and the overall results are very encouraging; they are the highest survival rates we have seen in any of our trials to date," he added.
"The elimination of bleomycin after two cycles of ABVD in patients with a negative restaging PET scan does not compromise patient outcomes, and results in a modest decrease in toxic effects," Nancy L. Bartlett, MD, from the Siteman Cancer Center at the Washington University School of Medicine in St. Louis, Missouri, writes in an accompanying editorial. However, she falls short of considering this the new standard of care.
Response-Adapted Treatment
This prospective, randomized, global study with a noninferiority design involved 1203 eligible patients with advanced classic Hodgkin's lymphoma (median age, 33 years). All were treated with two cycles of ABVD, and then 1119 patients underwent an interim restaging PET scan.
"The choice of two cycles was in response to a broad consensus among lymphoma experts, based upon retrospective data. This is now the standard time to evaluate the response to treatment," Dr Johnson explained.
Of the 937 patients (83.7%) with a negative PET scan (PET score, 1 - 3) after two cycles, 470 patients were assigned to receive ABVD and 465 patients to receive AVD. The majority (97.0%) completed six cycles of treatment.
Of the 182 patients (16.3%) with positive PET scans, 172 (94.5%) continued with treatment intensification: 94 received bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone administered in 14-day intervals (BEACOPP-14); and 78 received escalated BEACOPP.
Results in Patients With Interim PET-Positive Scans
In patients with a positive PET scan after two cycles of ABVD, a third PET scan in 160 patients showed negative PET findings for 119 (74.4%) patients. The 3-year progression-free survival was 67.5% and the 3-year overall survival was 87.8%, with no significant differences between patients receiving BEACOPP-14 and those receiving escalated BEACOPP. Some patients in this group went on to receive consolidation radiotherapy.
Study Did Not Meet Noninferiority End Point
In defining the upper boundary of the 95% CI of 5 percentage points for noninferiority, the researchers were guided by previous publications, and assumed that 75% of patients with an interim negative PET would have a 3-year progression-free survival of 95%.
After a median follow-up of 41.2 months, the 3-year progression-free survival did not meet the noninferiority end point, as noted. Overall survival at 3 years was similar in the ABVD and AVD groups (97.2% vs 97.6%).
Subgroup analysis also showed no significant difference in progression-free survival when examined by age, sex, disease stage, international prognostic score, or the presence or absence of bulky disease. The initial Ann Arbor stage was associated with risk for disease progression, with 3-year progression-free survival of 90.0%, 83.1%, and 79.6% for patients with stage II, III, and IV disease, respectively.
Grade 3 or 4 adverse events occurred in 3% of patients in the ABVD group and 1% in the AVD group (P < .05). At 1 year, the absolute difference in the diffusing capacity of the lung for carbon monoxide between the ABVD and AVD groups was –4.6%, which, although statistically significant, was not considered clinically significant, according to Dr Bartlett.
Why the Study Did Not Meet Its End Point
Dr Bartlett suggests that the study not meeting its noninferiority progression-free survival end point was probably due to an error in sample size calculation.
However, Dr Johnson indicated that the lower-than-expected progression-free survival after a negative PET scan reflected the difference between prospective and retrospective studies. He noted that the figure of 95% considered in the statistical analysis came from retrospective series, which tend to have apparently better results.
He pointed out that at the time the study was designed, these were the only data available. "All the other studies have reported their results in the last 1 to 2 years," he told Medscape Medical News. He was referring to prospective studies that showed the recurrence rate to be 15% rather than 5%.
"The findings are remarkably consistent between the different trials that have been reported," Dr Johnson said.
Clinical Management of Advanced Hodgkin's Lymphoma
Although patient outcomes were not compromised in the AVD group, these data, coupled with information from other studies showing that ABVD increased toxicity in older patients, suggest that "bleomycin can and should be eliminated in all patients older than 40 years of age who have negative PET findings after two cycles of ABVD," Dr Bartlett says.
"Whether or not this should now be considered the standard of care in all patients is less clear in light of the low incidence of serious toxic effects in both groups," she adds.
Dr Johnson told Medscape Medical News that his group is continuing with a longer follow-up of patients to make sure that the early findings hold up in terms of the probability of cure and to look at the long-term adverse effects. The group wants to determine that events are definitely lower than in earlier trials in which more extensive chemotherapy and radiotherapy were used.
In her editorial, Dr Bartlett expresses concern about the management of the 16% of patients with a positive interim PET scan after two cycles of ABVD. "In all response-adapted studies in Hodgkin's lymphoma, small patient numbers and physician bias have prevented randomization of patients with a positive PET scan to standard versus experimental treatment, severely limiting interpretation of results," she writes.
Dr Bartlett points out that in the absence of randomized or historic datasets, "the value of changing to BEACOPP with all of its associated toxic effects is questionable." She suggests that if disease progression is not observed, a reasonable approach would be to continue with ABVD for another two cycles and then to repeat a PET scan.
For Dr Johnson, there is value in changing to BEACOPP after a PET-positive finding, although he acknowledged that many clinicians in the United States would not agree with the approach. "We have found it very manageable using the BEACOPP-14 regimen, and with only limited exposure, the effects upon fertility seem less severe than when patients receive a full course of BEACOPP," he told Medscape Medical News.
"Certainly a progression-free survival rate of 65% seems higher than we would have expected from the series in which patients continued ABVD, where less than 40% remained progression-free," he added.
Dr Bartlett opines that patients with a persistently positive PET scan should undergo biopsy, if feasible, or otherwise proceed with alternative salvage therapy and transplantation. "The most we can glean from this group with positive PET findings in this study is a prospective result to serve as a bar for new approaches," she states.
Dr Johnson agrees that better treatments are required for the PET-positive group. "The newer agents, such as antibody–drug conjugates [brentuximab vedotin] and antibodies targeting the PD-1/PDL-1 pathway [nivolumab, pembrolizumab], may be a way to do this," he said.
Toward a Higher Cure Rate
With respect to the future of care to increase cure rates, Dr Bartlett indicates that only new treatment approaches can do this, not new prognostic markers that might better identify high-risk patients.
According to Dr Johnson, optimizing chemotherapy before the PET scan is going to be important because more effective treatment seems likely to result in fewer recurrences in the PET-negative group. "Incorporating newer agents, such as brentuximab vedotin, into the initial therapy might be a way to achieve this without producing too much toxicity," he added.
Dr Bartlett agrees and expresses optimism that an ongoing trial might do just that, which could result in a new standard of care. "Results of a phase 3 trial of frontline treatment for advanced-stage disease comparing ABVD with brentuximab vedotin plus AVD (ClinicalTrials.gov number, NCT01712490) are expected in 2017, perhaps resulting in a new standard of care for the first time in nearly 3 decades," she states.
However, she concludes her editorial with a cautionary note on advancing drugs in Hodgkin's lymphoma: "As we interpret results of studies testing new agents in frontline therapy, we should not forget what we have learned from response-adapted therapy: eliminate unnecessary treatments in low-risk patients and direct new approaches to those most likely to have treatment failure."
Dr Johnson said it differently. "Overall, I think it is important to emphasize that for people under the age of 60, the outlook for Hodgkin's lymphoma is very good: a lot fewer people died from the lymphoma than from other causes, emphasizing the need to minimize toxicity while maximizing cures," he said.
The study was supported by Cancer Research UK. Dr Johnson and his coauthors have disclosed no relevant financial relationships. Dr Bartlett reports receiving personal fees from Seattle Genetics for advisory work not related to this editorial.
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