Can Pragmatic Trials Bend the Antineoplastic Therapy Cost Curve?

Maurie Markman, MD

Clinical trials in oncology serve several purposes. Phase I studies address dosing, toxicity, and increasingly preliminary evidence of therapeutic efficacy; phase II studies more critically demonstrate clinical utility and adverse effects; and phase III randomized studies more definitively compare 2 or more approaches in seeking an answer to a clinical question. These efforts ultimately help define and, potentially, modify the “standard of care” in routine cancer management. Finally, so-called phase IV studies are frequently employed by industry sponsors to obtain additional regulatory agency approvals or, alternatively, oncology drug compendium (eg, National Comprehensive Cancer Network) listing as acceptable strategies in particular clinical settings.

There is also an interesting group of studies that have been labeled as “pragmatic clinical trials.” These efforts specifically focus on questions of relevance to treating physicians in contrast to efforts designed by sponsors whose principal goal may be FDA approval or possibly optimization of marketing opportunities.

It is not difficult to provide examples of such studies in the recently published medical literature, both within and outside the oncology sphere. For example, a recently reported trial involving 140 patients examined the value of alcohol abstinence in individuals who consumed >10 drinks per week and who were known to have developed paroxysmal or persistent atrial fibrillation.¹ The active abstinence group experienced a reduction in alcohol intake of 87.5%, whereas the control group (“continuing their usual alcohol consumption”) had a reduction of 19.5%. Patients undergoing the abstinence management approach were found to have a statistically significant reduction in the risk of these cardiac events and a longer time before recurrence compared with the control population. Of note, this was a relatively simple and non-costly strategy with a potentially highly clinically meaningful outcome.

A second notable, recently reported trial, explored early surgical intervention versus a less-invasive endoscopic approach to pain management for individuals with chronic pancreatitis.² Although this “pragmatic study” included a total population of just 44 individuals, the trial revealed superior pain relief (complete or partial) associated with surgery (58%) compared with endoscopy (39%; P = .10, not statistically significant). Further, this outcome resulting from early surgical intervention occurred with fewer required procedures (1 vs 3, P <.001), and there was no significant difference in several other measures of outcome (eg, complications, mortality, pancreatic function).

It is important to highlight that although there may not have been a statistically significant difference in the primary outcomes, the study results provide valuable information to clinicians faced with choosing optimal management in a complex setting where quite different clinical options (eg, more or less invasive, more or less costly, extent of prior evidence-based data supporting the therapy choice) may currently be rationally considered.

A similarly informative recently reported pragmatic trial in the oncology arena examined the relative clinical utility of talc poudrage versus talc slurry delivered by a chest tube in the management of malignant pleural effusions.³ A modestly sized patient population (N = 330) participated in this trial, which revealed no difference in the primary study outcome (failed pleurodesis up to 90 days after randomization). Further, there was no statistically significant difference in any secondary outcome measure. Although the authors note that the trial “may have been underpowered to detect small but potentially important differences,” it’s important to highlight that either management approach could reasonably be considered by a patient’s oncology team with the absence of major superiority demonstrated for talc poudrage, the more invasive approach. Again, the primary purpose of this pragmatic study was to provide clinicians with relevant data required to consider different management options in a specific setting.

Finally, pragmatic clinical trials can be a rational approach to the complexities of cost containment. It is possible that 2 or more reasonable strategies with data to support their routine use are available within a given setting. However, the measures may be quite different in their overall costs and use of limited or expensive healthcare resources.

Consider, for example, the not uncommon setting of metastatic disease to the spine resulting in spinal cord compression.⁴ The goals of therapy include maintenance of ambulatory status and other functions, as well as relief of severe pain. Although there is no single standard of care in this setting, multifraction radiotherapy is frequently employed, with the requirement for additional health-related resources associated with successful completion of the management plan, compared with 1 radiotherapy fraction.

In a recently reported phase III randomized trial, 686 patients with metastatic cancer to the spinal cord or cauda equina resulting in evidence of compression of the cord were managed with either a single fraction of radiotherapy or the same treatment delivered in 5 fractions over 5 consecutive days.⁴ Although the study marginally “failed” to meet the prospectively defined “noninferiority boundary” for the primary study end point (ambulatory status at 8 weeks), it is important to note that the actual difference between the 5-day (72.7% ambulatory) and 1-day (69.3% ambulatory) regimens was quite modest. Further, there was no statistically significant difference in the survival rates for the 2 groups or for the multiple additional secondary end points analyzed.

References

1. Voskoboinik A, Kalman JM, De Silva A, et al. Alcohol abstinence in drinkers with atrial fibrillation. N Engl J Med. 2020;382(1):20-28. doi: 10.1056/NEJMoa1817591.
2. Issa Y, Kempeneers MA, Bruno MJ, et al. Effect of early surgery vs endoscopy-first approach on pain in patients with chronic pancreatitis: the ESCAPE randomized clinical trial. JAMA. 2020;323(3):237-247. doi: 10.1001/jama.2019.20967.
3. Bhatnagar R, Piotrowska HEG, Laskawiec-Szkonter M, et al. Effect of thoracoscopic talc poudrage vs talc slurry via chest tube on pleurodesis failure rate among patients with malignant pleural effusions: a randomized trial. JAMA. 2020;323(1):60-69. doi: 10.1001/jama.2019.19997.
4. Hoskin PJ, Hopkins K, Misra V, et al. Effect of single-fraction vs multifraction radiotherapy on ambu-latory status among patients with spinal canal compression from metastatic cancer: the SCORAD randomized clinical trial. JAMA. 2019;322(21):2084-2094. doi: 10.1001/jama.2019.17913.