In this edition of “How I Will Treat My Next Patient,” I highlight two recent studies that reinforce prior diagnostic and treatment preferences among many oncologists and will certainly influence the discussions we all will have with our patients in the coming weeks and months.
Rituximab maintenance in follicular lymphoma
The largest trial addressing the role of maintenance CD20-targeted antibody therapy was the Primary Rituximab and Maintenance (PRIMA) phase 3, intergroup study in 1,018 advanced follicular lymphoma patients with an initial response to induction chemoimmunotherapy. The induction regimen could be either of three commonly used regimens plus rituximab. Importantly, none of the induction regimens included bendamustine.
Patients were randomized to 2 years of rituximab maintenance or observation. Prior interim analyses at 3 and 6 years showed improvements for the rituximab maintenance patients in progression-free survival and other secondary endpoints, but no improvement in overall survival. Emmanuel Bachy, MD, PhD, and colleagues published the final survival data after 9 years of follow-up, including a final safety analysis (J Clin Oncol. 2019 Nov 1;37[31]:2815-24).
Among the 607 patients consenting to extended follow-up, median progression-free survival was 10.5 years with rituximab maintenance, compared with 4.1 years for observation (hazard ratio, 0.61; P less than .001). There were more patients with progression-free survival at 3 years, complete response or unconfirmed complete response at 2 years, longer time to next antilymphoma treatment, and later time to next chemotherapy. But the 10-year overall survival was similar in the two groups, as were the quality of life ratings.
Dr. Alan P. Lyss
In all, 503 patients experienced disease progression. Overall survival after progression was shorter in the rituximab maintenance arm versus the observation arm. Among the approximately 4% of patients experiencing transformation from follicular lymphoma to a more aggressive histology, there was no difference observed in time to transformation. Results were independent of the induction regimen received, response to induction, Follicular Lymphoma International Prognostic Index score, and other clinical factors.
In the safety analysis, there were more grade 3-4 adverse events among the rituximab maintenance patients – primarily cytopenia and infections – more serious adverse events, and more adverse events overall. Fatal adverse events were low in both groups (1.6 vs. 0.6%).
How these results influence practice
Many years ago, a senior mentor of mine taught that “progression-free survival is an important endpoint since the quality of life for patients is generally superior before relapse than afterwards.”
With that mantra playing in my mind and with the reality that discussions about relapse and subsequent treatment are never easy, the results of PRIMA seem straightforward: Rituximab maintenance is beneficial, despite the absence of an overall survival benefit, in a disease with multiple options for subsequent therapy and a long natural history. In this 9-year, final analysis of PRIMA, rituximab maintenance seems to have achieved its goals of deepening responses with low (but not inconsequential) toxicity and delaying substantially those difficult conversations with patients about how to proceed after relapse.
The influence of the final analysis of PRIMA, however, may be more complicated that it would initially seem. Bendamustine-containing regimens were not employed, are commonly used now, and some studies with bendamustine have suggested higher nonrelapse mortality with rituximab maintenance.
Low-grade adverse events take on greater importance for patients on long-term therapy than they do for patients receiving abbreviated treatment, and with noncurative treatment, the higher adverse event profile with 2 years of rituximab maintenance needs to be taken seriously. Induction and maintenance regimens involving rituximab alone, lenalidomide, or obinutuzumab may be preferred for some patients. For all of those reasons, the discussion about rituximab with advanced follicular lymphoma patients remains a long one, demanding detailed descriptions of risks, benefits, limitations of the data, and multiple modern day alternatives to the treatments employed in PRIMA.
Supplemental MRI for dense breast tissue
In the DENSE trial, investigators assigned 40,373 women with extremely dense breast tissue and negative results on screening mammography to be offered either supplemental MRI or mammography screening every other year only. The women were 50-75 years old and were enrolled in the Dutch population-based digital mammography screening program. The primary outcome was the difference in the number of cancers that developed in the 2-year interval between mammograms (N Engl J Med 2019;381:2091-102).
The interval cancer rate was 2.5 per 1,000 screenings among 4,783 women in the “MRI-invitation” group (41% of whom did not actually agree to have an MRI), and 5 per 1,000 in the 32,312 women in the “mammography-only” group, a difference of 2.5 per 1,000 screenings (P less than .001).
Of the 20 interval cancers diagnosed in the MRI-invitation group, 4 were diagnosed in the 59% of women who had undergone MRI (0.8 per 1,000 screenings). The remaining 16 were diagnosed in those who had declined an MRI (4.9 per 1,000 screenings) – virtually identical to the rate of interval cancers in the group that was not invited to have an MRI. This speaks against nonrandom allocation of patients between the mammography-only and the supplemental MRI groups.
Although supplemental MRI was associated with a cancer-detection rate of 16.5 per 1,000 screenings, there was a false positive rate of 8.0% (79.8 per 1,000 screenings). Of the women who underwent a breast biopsy after MRI, 73.7% did not have cancer. Among the women who had MRI-detected cancers, in general, the malignancies diagnosed were smaller, more likely node negative, better differentiated, and more often hormone receptor–positive, compared with those in the mammography-only group.
At the next screening mammogram, the cancer detection rate was lower in the MRI-screened group (2 per 1,000 screenings) than in the MRI–“offered but declined” (7.1 per 1,000 screenings) or mammogram-only groups (6 per 1,000 screenings).
How these results influence practice
American physicians are obligated to inform women with dense breast tissue about the limitations (for them) of conventional mammography, an unquantified, but elevated, risk of breast cancer in women with dense breast tissue, and the fact that there are no universally accepted recommended subsequent steps those women should take.
One side benefit of the requirement to disclose information about breast density, however, is that disclosure can prompt discussions about breast cancer risk reduction – an important discussion with multiple possible health-maintaining interventions.
The DENSE trial is very important news, with potential for even more value in future years. It is finite (2 years of study, with only one MRI scan mandated), narrow (Vopara or BI-RADs breast density grade 4 only), and oligo-institutional (eight participating centers in the Netherlands). Still, it provides randomized, rigorously gathered and analyzed data where there were previously none. Importantly, it answers the question, “So what can I do now, doctor?”
I have some concerns about whether we, as a medical community, have the discipline to restrict application of supplemental MRI screening beyond the population that was studied in the Netherlands. Will we be able to restrain ourselves from ordering MRI scans in women with heterogeneously dense – but not extremely dense – breasts? Will we truly manage patients whose MRI scans had BI-RADs readings of less than 4 in the rigorous, but conservative, fashion employed in the trial? Would we miss fewer significant cancers and subject fewer patients to potential expense and harm with annual mammography, instead of the biennial screening performed in the Netherlands? Does tomo-synthesis improve the interpretation of screening mammograms so much that the interval cancer rate is a lot closer to the rate obtained with supplemental MRI scans? Is the expense of MRI scanning, with the resultant subsequent tests and procedures, justified by the reduction in detecting relatively favorable breast cancers that may not materially impact overall survival?
The DENSE study promises to be a “gift that keeps on giving” as the investigators continue to assess a number of factors including: the value of ongoing supplemental MRI scans (compared with the one-time-only screening reported here); whether there will be a reduction in the advanced cancers and subsequent mortality benefit; the extent of over diagnosis, costs, and impact on quality-of-life; and the applicability of artificial intelligence techniques to reduce false positive MRI results.
While the study may not be practice changing in the United States at the present time, it may be just that as subsequent analyses emerge.
Dr. Lyss has been a community-based medical oncologist and clinical researcher for more than 35 years, practicing in St. Louis. His clinical and research interests are in the prevention, diagnosis, and treatment of breast and lung cancers and in expanding access to clinical trials to medically underserved populations.