An interview with Scott C Howard, MD, MSc, University of Tennessee Health Sciences Center, Memphis TN.
Many health professionals are talking about the use of real-world data and evidence to advance medical treatments.1-3 The Food and Drug Administration defines real-world evidence (RWE) as “data regarding the usage, or the potential benefits or risks, of a drug derived from sources other than traditional clinical trials.”4 This data may include electronic health records, claims and billing activities, product and disease registries, patient-generated data including in home-use settings, and data gathered from other sources that can inform on health status, such as mobile devices.4 The hope is that RWE will be able to address clinical and policy-relevant questions that cannot be answered using data from clinical trials.
Both of the feature articles in this issue of Journal of Clinical Pathways (JCP) focus on RWE, with the Perspectives piece using a case study to theoretically examine the benefits of RWE now and in future efforts in pathway design. The other article "Real-World Analysis of Outpatient Rasburicase to Prevent and Manage Tumor Lysis Syndrome in Newly Diagnosed Adults With Leukemia or Lymphoma" presents original research of retrospective data to better understand the feasibility and safety of outpatient administration of a drug.
We spoke with one of the authors of the latter article, Scott C Howard, MD, MSc, University of Tennessee Health Sciences Center (Memphis, TN), to gain greater insight on the implications of his study. Specifically, we discussed how clinicians, researchers, and other stakeholders in oncology view and approach RWE as well as the potential impact of this and other studies on care quality, the patient experience, and reimbursement.
Please explain the initial inspiration and design for your study. Why was the use of rasburicase for the management of tumor lysis syndrome (TLS)-related hyperuricemia in the outpatient setting chosen for the study focus?
Dr Howard: We investigated the safety and feasibility of the use of rasburicase for outpatients who have newly diagnosed leukemia or lymphoma because traditionally rasburicase has been reserved for use in the hospital. The reason the paper is important is because many adults who develop leukemia or lymphoma have significant complications in the first week after presentation. These complications can start as soon as the day they arrive or right after chemotherapy. In light of these complications, immediate use of rasburicase in the outpatient setting could have a range of benefits.
One of the main complications that can be life-threatening is TLS, which is basically when you treat the tumor with effective chemotherapy, then the tumor cells break apart and release their contents, including DNA that becomes uric acid that leads to hyperuricemia; potassium, which leads to hyperkalemia; and phosphorus, which leads to hyperphosphatemia. The high phosphorus actually combines with calcium and leads to low calcium, or hypocalcemia. TLS is just any two of those four bad things happening at the same time in a patient already dealing with a new diagnosis of cancer or experiencing a relapse. The reason hyperuricemia matters is because the uric acid can crystallize in the kidney and cause crystal-induced kidney damage and inflammation, which can lead to acute renal failure. This complicates the care of a new cancer patient—when you have acute kidney injury in addition to having to treat the new cancer. Chemotherapy also needs to be adjusted when renal function is bad.
Could you elaborate on the study’s findings and items of note regarding the outpatient management of TLS-related hyperuricemia?
Dr Howard: The first thing to take note of is that it is a RWE study; any real-world analysis, always has bias in the sample. In this case, the bias was: which patients actually got the rasburicase? The patients who got the rasburicase were actually older and had higher comorbidity index and, in general, were in worse shape than the patients who did not get rasburicase. Why would that be the case? Well, it actually makes perfect sense because if I am a doctor treating a new patient, and they are sort of borderline in their clinical stability, then that is the very patient I would want to make sure got rasburicase to protect their kidneys when starting the anticancer therapy. That makes a lot of sense in practice, but it did make it a little bit tricky as far as how to control for those things when doing the analysis. What we found was, in the patients who got rasburicase, despite them being older and sicker, they actually had less subsequent hospitalizations and less subsequent need for outpatient visits.
It was encouraging that you could take the sickest patients and by giving them spectacular supportive care, it could lead to an improved outcome for those patients, despite them starting out as a little bit older and a little bit sicker than the patients who did not get rasburicase.
Was this decrease in hospitalizations a surprise finding? Were there any other findings that you were relatively surprised by?
Dr Howard: That is a great question because everybody has known for the past 20 years that rasburicase immediately eliminates uric acid. What people have argued about is whether this actually is necessary for all patients, only needed for the high-risk patients, only for the intermediate- and high-risk patients, or only for inpatients.
The details of how and when to give rasburicase have been hotly debated for many years. Everybody has always known that in high-risk patients, for example, in children with high-grade B-cell lymphomas and leukemias, their rate of dialysis drops from 15% to 3% if they get rasburicase.5 This study was not a randomized study that I am referring to here, but it was a study back when rasburicase was available in France but not available in the United States. In France, they have had rasburicase, and the nonrecombinant uricase product before that, since the 1980s. For about 20 years, they had more comprehensive supportive care compared to US patients treated in the same time period. Many of us did not pick up on this finding until years later, since the information was included in a small paragraph at the very end of the Results section of the paper titled “Results of a randomized international study of high-risk central nervous system B non-Hodgkin lymphoma and B acute lymphoblastic leukemia in children and adolescents”—no one would find this paper when doing a literature search for how to prevent TLS.
What was interesting in that study, which was done in France and the US at the same time,5 is that the patients had the same eligibility criteria, the same stages of advanced disease, the same everything, and got exactly the same chemotherapy. The only difference in the two groups was that the US patients got allopurinol, because there was no access to rasburicase; the French patients got rasburicase. The terrible surprise was that 15% of US patients actually ended up requiring dialysis vs only 3% of the French patients. We had known rasburicase could protect the kidneys but did not know just how important it was for this kind of high-risk patient. For me, that was the most important nonrandomized study to show the huge impact of this drug on prevention of acute kidney injury and need for dialysis.
The tricky part has always been different financial elements. The drug costs several thousand dollars. Of course, that is much cheaper than dialysis, but even when 15% of patients require dialysis, it means 85% of patients did not get dialysis. If there were some way to say, “Well, let’s just find the 15% and treat those,” that would be ideal. Unfortunately, there is no perfect diagnostic test to definitively identify a patient who is going to need dialysis if we do not give the rasburicase, so we fall back on “high risk for TLS” or “intermediate risk for TLS,” where “risk” in this context means the risk of clinical (symptomatic) TLS or acute kidney injury.
At the end of the day, we basically just say, “This is a high-risk patient; thus, they should get rasburicase.” If it is a low-risk patient, then they do not need rasburicase. It used to be that you have to admit the patient to get the rasburicase, but many people had started using it increasingly in the outpatient setting as more and more therapies have moved to the outpatient arena. Our study looked at all those patients who had received outpatient rasburicase to make sure that it was indeed a safe strategy in the real world, for example, whether it caused undue risk, whether it was not as effective because the IV fluids might have been different, and how other components of supportive care impacted outcomes. It turns out that, in our study, rasburicase worked great for outpatients, even in older, sicker patients.
With all of the implications of your study, how do you anticipate these findings impacting care in the near future?
Dr Howard: I would say it is always a challenge to make immediate practice changes based on RWE. In this case, the real-word evidence is confirming what we already strongly suspected. Thus, we are not introducing a new way of thinking; we have just proven that this behavior that was already occurring in routine practice—giving rasburicase to outpatients—is safe and feasible.
We have to keep in mind that some patients do need hospitalization and rasburicase. Some people need hospitalization and no rasburicase. Some need rasburicase and can stay outpatient. Others can stay outpatient and do not need rasburicase. These would be two independent decisions: yes or no to hospitalization, yes or no to rasburicase, and they need not be related. In fact, our study suggests that when you do get the rasburicase, you can actually keep people out of the hospital more than if you do not give the rasburicase, which is encouraging from a resource utilization standpoint.
As we note in the paper, follow-up work on this topic would include a detailed cost-effectiveness analysis and more comprehensive study of every aspect of related costs. For instance, the drug itself has a cost, and hospitalization and dialysis also have their costs—figuring out how that all balances out can help us make sure that the most effective strategy is also cost-effective. Some studies have scratched the surface, but there have not yet been official or formal cost-effectiveness analyses of outpatient rasburicase use.
References
1. Booth CM, Karim S, Mackillop WJ. Real-world data: towards achieving the achievable in cancer care. Nat Rev Clin Oncol. 2019;16(5):312-325. doi:10.1038/s41571-019-0167-7
2. Eastman P. The value of real-world evidence in assessing cancer drug therapy. Oncol Times. 2019;41(22):24-25. doi:10.1097/01.COT.0000615212.07893.ea
3. Kornblum A. Real-world date, evidence becoming more prominent in clinical research. Medpage Today. July 23, 2019. Accessed March 4, 2020. https://www.medpagetoday.com/publichealthpolicy/fdageneral/81182
4. Food and Drug Administration (FDA). Real-world evidence. FDA. Updated May 9, 2019. Accessed March 4, 2020. https://www.fda.gov/science-research/science-and-research-special-topics/real-world-evidence
5. Cairo MS, Gerrard M, Sposto R, et al. Results of a randomized international study of high-
risk central nervous system B non-Hodgkin lymphoma and B acute lymphoblastic leukemia
in children and adolescents. Blood. 2007;109(7):2736-2743. doi:10.1182/blood-2006-07-036665
