Something positive from something negative

Most know that someone who looks for something positive in every negative event will often be disappointed. Yet, many of us continue to seek the silver lining of dark clouds despite the odds. It brings to mind the joke about the parents of a child that they felt was too optimistic, so they gave the child a pile of manure as a birthday gift in an attempt to help the child realize that life isn’t always positive and happy. To the parents’ surprise, the child gleefully thanked the parents and started happily shoveling through the gift. When the parents asked why, the child answered joyfully, “There’s got to be a pony in here somewhere!”

Constantly looking for the positive aspects of clinical research even when the results are negative optimizes our ability to gain knowledge and often can provide clinically useful information. In fact, as many of us learned from our mentors, the best-designed study provides useful information whether the results are positive or negative. For this reason, journals continue to consider and publish studies even though they have negative results. In this issue of Gastrointestinal Endoscopy, Sherman et al report their study showing that a new pancreatic stent did not provide the expected pain relief for a broad category of patients with a pancreatic stricture. Thankfully, the authors saw the value in publicizing their results and did not refrain from submitting the report for consideration by this journal.

The authors designed and carried out a prospective, multicenter, single-arm clinical trial to evaluate the safety and efficacy of the WallFlex Pancreatic RX fully covered soft self-expandable metal stent (FCSEMS) (Boston Scientific) to treat pancreatic duct strictures in adults with painful chronic pancreatitis. It was concluded that the primary expected endpoints in terms of pain relief were not reached in this study and that serious adverse events were common.

So why publish this negative study? There are several clinically valuable take-aways that this report provides us. The study was masterfully designed to confidently show whether or not this novel endoscopic intervention reduced pain more effectively than surgery for this broad category of patients with pain and a pancreatic duct stricture. The authors acknowledged that a 2021 systematic review of randomized clinical trials comparing endoscopic therapy versus surgery for the treatment of chronic pancreatitis in adult patients with dilation in the main pancreatic duct concluded that surgical interventions showed superior results in terms of complete long-term pain relief. Therefore, the study design included performance goals for the endoscopic stent intervention that were set to determine whether this novel endoscopic intervention would meet or surpass the results seen with surgical intervention. Moreover, the authors thoughtfully included narcotic use in the assessment of pain control in addition to a pain scale. The results of this study convincingly show that this novel stent intervention did not surpass the set performance goals for long-term pain relief. So, the first take-away from these results is that when generally advising a patient with painful chronic pancreatitis and a pancreatic duct stricture, one can confidently say that this novel endoscopic intervention is not superior to surgery in terms of complete long-term pain relief.

However, the silver lining here, and the second take-away, is that some patients did surpass the set performance goals for long-term pain relief. In fact, a further review of the patients who responded well revealed that many experienced an early response after placement of the novel stent being studied or plastic stent placement with subsequent exchange for the novel stent. The authors appropriately point out that these are still preliminary findings and that further studies are warranted. However, these observations suggest that there may be a subset of patients within this broad category of chronic pancreatitis patients with a pancreatic duct stricture who may respond well to this novel stent and perhaps other stent interventions.

Taking into consideration the positive aspects within this study’s unfavorable results, the authors have suggested that future studies investigate patients with painful chronic pancreatitis who have a favorable pain response to initial ductal decompression with a single plastic stent and that they randomly compare 180-day treatment with multiple plastic stents versus a single FCSEMS, or randomly compare early surgery with 180-day FCSEMS treatment with multiyear follow-up care in a similar patient population. This is a perfect example of building on the experience gained from a negative study result to hopefully progress another step closer toward a goal of finding the most effective therapy for the most appropriate subset of these patients.

It is well known that persistently analyzing what works, and sometimes more importantly what doesn’t, has led to notable achievements. We all know that Thomas Edison famously commented, “I have not failed; I've just found 10,000 ways that won't work” while he was improving the incandescent light bulb. Even today, this same persistence by Elon Musk and his coworkers is responsible for the progress of the Space-X program, as outlined in the article “Every SpaceX Starship explosion and what Elon Musk and team learned from them.” Likewise, even though the studied intervention failed to achieve the performance goals set in this clinical trial, Sherman et al capitalized on their well-designed protocol to find clinically useful results as well as insights leading them to a future study design that may very well produce favorable results for a selected group within this broad category of chronic pancreatitis patients with a pancreatic stricture.

Another important take-away from this study is the reported information about safety, adverse event, and stent migration. The safety profile and stent migration information acquired here is important to consider in a comparison of the risk/benefit ratio of this intervention, so it is immediately clinically useful. It also underlines the need to seek and select the patients most likely to achieve satisfactory pain reduction, as addressed above, so the benefit side of the ratio outweighs the risk. This is important information for clinicians to have so we can minimize the risk exposure for our patients. It is also vital for the stent manufacturers and clinical investigators to use in their continual collaborative efforts to improve stent performance and reduce adverse events. Well-designed clinical trials such as this one, and the dissemination of the observations associated with them, are key to the innovation and modification of stent performance even when they produce unexpected results.

The outcomes reported by Sherman et al in this study do not deter us from following the concept of initially considering endoscopic stent placement in the broad category of chronic pancreatitis patients with pain and a pancreatic stricture in whom medical therapy has failed. The thought is that patients who will favorably respond to a decompressing procedure will be identified by placing a stent and observing the patient’s response. Surgery could then be subsequently considered because it may be more likely to be beneficial if there is recurrence of a stricture or pancreas stones, or in the event of a failure with endoscopic treatment. This approach is recommended in several published clinical practice guidelines.^{,  ,}  Although the authors’ suggestions for further studies to identify a subset of patients who will benefit from stenting are based on preliminary results, the findings of this study provide more impetus to carefully design and follow through with such studies.

So, as you can see, even though we may not be happy with this study’s results, if we were to perseverate on the negatives without looking for any positives, the door to the opportunities and clinically useful information described above would not have been opened. This brings to mind the quote by Helen Keller: “When one door of happiness closes, another opens; but often we look so long at the closed door that we do not see the one which has been opened for us.”

It is reassuring to see that we are not dismissing the value of negative studies and that we are leaving no stone unturned in our pursuit of optimal therapeutic options for patients with this devastating pancreatic disease.