Happy Days in Oncology: More Applause, Less Rigor?

H. Jack West, MD


December 01, 2020

Updated December 4, 2020 // Editor's note: The title of this commentary has been updated since its original publication.

I will confess that I usually grab my phone within the first 10 minutes of waking up to check Twitter. While I love the site, I have also noticed that Twitter has become something of a bellwether for a disconcerting trend in oncology.

By intermingling conversations among physicians and translational researchers, patient advocates, caregivers, and the media, Twitter mirrors the composition that our professional medical conferences are increasingly taking. These groups are not inherently oppositional, and there are many benefits to hearing viewpoints beyond our own respective siloes. Yet I also fear that the positive feedback loop of social media and mass media creates an echo chamber that can lead us to promote uplifting conclusions beyond what the data truly justify.

In short, we need medical leaders, not cheerleaders.

A Pattern of Complacency

A prime example of this occurred several months ago at the American Society of Clinical Oncology 2020 Plenary Session, when the ADAURA trial was more coronation than presentation.

ADAURA's results were certainly impressive. There was a very strong improvement in disease-free survival with adjuvant osimertinib vs placebo for patients with resected EGFR mutation–positive stage IB-IIIA non–small cell lung cancer (NSCLC).

However, in my opinion, the broadly zealous enthusiasm for these results downplayed a key uncertainty. The disease-free survival benefit that was demonstrated in the midst of ongoing disease-suppressive therapy may not translate to an improvement in cures or overall survival, even if patients have ready access to osimertinib upon relapse.

Despite this, the prevailing view was that these results would translate to a survival benefit and that this should change practice.

I've also observed an interesting pattern among colleagues in meetings and tumor boards. ADAURA's results compel us to perform broad next-generation sequencing (NGS) for every remotely relevant molecular marker on the planet, despite the fact that only EGFR mutations have data to support their use in clinical postoperative decision-making.

Moreover, rather than limiting testing to patients with non-squamous NSCLC, I have seen colleagues ask about the smoking history of patients with squamous NSCLC, seeking a justification for testing if the patient is a rare never-smoker or remote former smoker. Even when an extensive and ongoing smoking history is reported, their physicians may, with misplaced authority, reply, "Well, NGS testing is what every patient should be getting now."

Unfortunately, there isn't a scintilla of evidence or language in guidelines to support such conjecture. It is also arguably disdainful of finite societal resources to spend more than $5000 on molecular testing in a patient with early-stage (or more advanced) squamous NSCLC based on a pretest probability that can best be described as exceptionally low if we were to consider the evidence.

But we don't consider the evidence. I increasingly see even colleagues recognized as experts tending to operate on a principle untethered to actual clinical data on probabilities. Instead, they approximate magical thinking. They operate under the remote possibility that there is a mystical answer to the optimal treatment that is evasively just one NGS test away. This often extends beyond initial management into repeat biopsies. Many of us act as if there is no role for prospective or population-based evidence to support our compulsion to re-biopsy and send off just one more NGS test, if we can only invoke an obscure case report describing a mutation that could be targeted after being identified in the third biopsy and repeat iteration of molecular testing.

Another example of the current pattern of complacency can be found in the recent press release sharing results of the CheckMate-816 trial, which tested neoadjuvant chemotherapy with nivolumab vs chemotherapy alone in resectable early-stage NSCLC. The news highlighted that the trial met its primary endpoint of a statistically significant improvement in pathologic complete response rate. The enthusiasm for this trial shows how readily we now accept a surrogate endpoint that has not been highly correlated with the most important endpoint we have in curable cancer: overall survival. Our community was swept away by a positive result with a tenuously relevant endpoint. Apparently we are no longer disciplined enough to do the hard work of assessing new results with appropriate rigor; instead, we've become advocates blinded by the promise of a superficial advance worthy of a sound bite.

Oncologists and all other physicians want to see clinically meaningful advances that help our patients. Unfortunately, we have become so focused on easy wins that we reflexively declare that every patient requires NGS testing, no matter how dubious the probability of a favorable result. We complacently applaud when a pharmaceutical company sponsor replaces an optimal endpoint with one more surrogate endpoint, simply because it is easier to glad-hand, promote a positive result, and hope it could be helpful to patients. This ignores the inconvenient truth that we are lowering our standards and ceding our role as stewards of societal resources with a responsibility to carefully assess the data.

At the end of the day, we should acknowledge the risks of reviewing clinical care through a lens of "aspirational" outcomes and best-case scenarios. It is clearly the sunnier side of the street, but by walking it we may find ourselves veering from hopefulness into the realm of delusional optimism. I would contend that practicing in a manner untethered to population-based data not only is disdainfully wasteful of healthcare resources but also probably treats most patients suboptimally.

I hope we see more oncologists take on the harder role of scrutinizing the evidence and holding emerging clinical trials to high standards, rather than following the path of least resistance, cheering the shallow victories and practicing wishful thinking rather than evidence-based medicine.

H. Jack West, MD, associate clinical professor and executive director of employer services at City of Hope Comprehensive Cancer Center in Duarte, California, regularly comments on lung cancer for Medscape. Dr West serves as web editor for JAMA Oncology, edits and writes several sections on lung cancer for UpToDate, and leads a wide range of continuing education programs and other educational programs, including hosting the audio podcast West Wind.

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