NEJM Study Linking Exercise, Cancer Recovery Raises Two Concerns: What If It’s Wrong?  What If It’s Right?

This week featured a rare crossing of the streams, as the buttoned-down world of cancer research met the buzzy world of exercise and wellness.  One result: a randomized controlled study of exercise in 889 cancer patients published in the New England Journal of Medicine (NEJM), and accompanied by a torrent of enthusiastic coverage in the popular press.  Another: the publication of two important and thoughtful commentaries about this study, analyses that are the focus of today’s column.

About the study

The study, which ran from 2009-2024, examined the impact of a structured exercise program (compared to a health information pamphlet, essentially) on patients with colon cancer, following surgery and adjuvant chemotherapy.  The patients were randomly assigned to one of the two groups and followed for a median of 7.9 years. 

The headline result was that the exercise group demonstrated significantly better overall survival (90.3% vs 83.2%) after 8 years), as well as significantly better 5-year disease-free survival (80.3% vs 73.9%).  Phrased differently, the exercise group demonstrated a 28% reduction in the relative risk of disease recurrence, and a whopping 37% reduction in the relative risk of death. 

As the authors point out, the apparent magnitude of effect of exercise on cancer, in this context, is “similar to that of many currently approved standard drug treatments.”

This extremely encouraging result reinforces an emerging view of exercise as a remarkably powerful medical intervention.  As I discussed in my recent WSJ review of Super Agers, by Dr. Eric Topol,

“Nothing surpasses regular exercise for promotion of healthy aging,” Dr. Topol writes, calling it “the single most effective medical intervention that we know.” If you came up with a drug that delivered all the health benefits of exercise, he says, “it would be considered a miracle breakthrough.” 

I’ve also examined in TR the unreasonable benefit of a modicum of exercise, particularly going from none to some, in projected years of additional life.

Not surprisingly, on both social media and traditional media, the response (which I shared) was generally one of delight, a sense that a compelling hypothesis has now been validated in a rigorously conducted RCT published in the august New England Journal of Medicine.

Methodological critique: Dr. John Mandrola

Not so fast, says Dr. John Mandrola, a cardiologist, exercise enthusiast, and thoughtful, occasionally contrarian healthcare commentator.   

Writing in his “Sensible Medicine” blog on Substack, Dr. Mandrola essentially presents what might be called the “Reviewer 2” rebuttal (if Reviewer 2 was an extremely savvy clinical trialist), offering a list of the ways in which the study seems to fall short of its ambitious claims.  His commentary offers a valuable read for anyone interested in the critical assessment of clinical trials.

Among his objections: the effect size (37% reduction in all-cause mortality) lacks face validity – it’s unreasonably large, he argues, suggesting that something is amiss.  (While it seems a tad circular to argue a result can’t be true because it’s excessively different from what you expected, it’s also a pragmatic sense check, and one he argues the study fails.)

He was also underwhelmed by the impact on fitness-associated parameters; if the exercise program was so impactful, he asks, why didn’t the subjects in that group demonstrate a lower Body Mass Index and a lower waist circumference that the control group?  He was unimpressed by the slight differences between the groups observed in the six-minute walk test. 

The study authors, in contrast, argue that the difference between the groups – in the range of 5.2-7.4 MET-hours per week is meaningful, “equivalent to about 1.5-2.25 hours per week more of walking at 3 mph (approximately 3.3 METs).”  They note that the subjects in the control group also increased their physical activity, although not as much, which suggests the benefits of exercise might be even greater if comparison was made to patients who remained sedentary.

Dr. Mandrola also pointed out that while we think we’re looking at exercise, we may instead be looking at attention, observing that the “structured exercise group received an incredible amount of intervention in both behavioral modification and exercise.”  In other words, we may just be observing a manifestation of the Hawthorne effect, in which subjects change their behavior when they are being observed.

Again, the authors anticipate this objection and try to diffuse it by pointing to examples of cancer studies in which subjects also received considerable attention, in the context of nutrition or lifestyle interventions, yet these researchers “did not report a survival benefit.”

However, I’m not sure these examples – involving different types of cancer – effectively refute Dr. Mandrola’s point.

A related thought going through my mind when reading the paper was whether at least some of the beneficial effect might be attributable to an enhanced sense of agency experienced by the subjects in intervention group.  I’ve previously discussed in TR the concept of the agentic dividend, in the context of GLP-1 treatment. 

In the case of the present NEJM study, the benefit might accrue not just from the enhanced attention, but also from the positive effects of constructively engaging in exercise itself, which can set up a virtuous cycle — a pattern discussed in this 2021 paper, and nicely covered by Gretchen Reynolds in the New York Times. 

Dr. Mandrola raises several other objections as well. 

Yet his most valuable point may be the importance of criticism itself, even – especially! – when, as a reader, you desperately want to believe the argument the paper is making.

“The story is delightful,” Dr. Mandrola acknowledges.  “But liking the conclusion is not a reason to stop thinking.”

Amen.

Voice of the patient critique: Jennifer Goldsack

While Dr. Mandrola focused his attention on the possibility the conclusions may be wrong, Jennifer Goldsack worries about the consequences if the conclusions are right – in particular, the implications of the study for cancer patients like her.

Jennifer Goldsack is the CEO of the Digital Medicine Society (DiMe) and a former Olympic rower who has publicly discussed her journey with Stage 3 colorectal cancer.

Goldsack poignantly explains that when she first heard about the NEJM study, her reaction was “let’s celebrate. Anything that helps improve lives and reduce deaths is unequivocally good news.”  

But she writes that upon further reflection, her “thinking shifted… because I started to feel overwhelmed by the implied link between my behaviors and my survival.”

She continues,

One of the first questions I asked my oncologist after my late-stage colorectal cancer diagnosis was, “Is this my fault?”

I’ve had every genetic test you can run, and they all came back negative. As in, I should’ve made my millions selling my eggs in my 20s… bloody good breeding stock over here! 🐎

I’ve eaten clean my whole life. I’ve been active my whole life… as in, former world-record-holder active. I sleep like a champ. I’ve rarely been stressed beyond what can be well managed using the winning strategy of fruity language and regular dance breaks. I don’t even have a cavity (sidebar… shoutout to fluoride in drinking water!).

And yet, here I am.

She continues,

If my cancer comes back, will it be because I didn’t exercise enough? Didn’t eat well enough? Didn’t rest hard enough during chemo? Didn’t do something I was *supposed* to do?

There’s a specific kind of shame that comes with a diagnosis that gets lumped into the “lifestyle” category. When there’s no clear external cause, the only place left to look is inward.

And I know I’m not alone.

As we enter this MAHA era, where the administration is (rightly!) focused on nutrition, movement, and prevention, we have to be mindful. These are incredibly important strategies, but how are we making sure that we’re not creating a culture where getting sick means you’ve failed?

As she bluntly explains, “sometimes, shit just happens. Sometimes we do everything right, and it still goes wrong. We control what we can, but the reality is that it’s impossible to control everything.”

Goldsack powerfully speaks to the fine line between empowerment and blame, between the promise of marshalling all your physical and cognitive resources to fight a disease and the fear that if the illness triumphs it reflects a personal failing, a sense that in some way, you didn’t try hard enough.

A remarkably similar tension developed in the field of positive psychology, as the discipline’s founder, University of Pennsylvania professor Martin Seligman, describes in Flourish. 

He explains that a number of studies “converge on the conclusion that optimism is strongly related to protection from cardiovascular disease,” even after “correcting for all the traditional risk factors.”  He adds that “high optimism” protects people compared to average levels of optimism and pessimism, while highly pessimistic people fare worse than average.”

A similar result was observed in an experiment in which the optimism of healthy volunteers was assessed, then they were exposed to a standardized amount of cold virus via a rhinovirus injection squirted up the nose.  The remarkable result: optimistic people were the least likely to come down with a cold, while pessimistic people were the most likely, and those in the middle fell in between.

While Seligman says he was always cautious about overly generalizing from these studies – particularly to conditions such as severe cancer — the idea that you can overcome disease with positive thinking began to spread in popular culture.  It also prompted a profound backlash. 

Leading the charge was Barbara Ehrenreich and her book, Bright Sided: How the Relentless Promotion of Positive Thinking Has Undermined America.  (In case the point was missed, the British version of her book was entitled, Smile or Die.)

This takedown was motivated by Ehrenreich’s experience as a cancer patient, where (as Seligman describes it) “well-meaning healthcare workers” told her “that her breast cancer could be relieved if only she were a more positive person.”

As Seligman subsequently wrote to Ehrenreich,

[C]ardiovascular disease, all-cause mortality, and quite possibly cancer are not a function of fake smiling, but rather of PERMA [note: I’ve discussed for TR readers here, here], some configuration of positive emotion, plus meaning, plus positive relationships, plus positive accomplishment.

He noted in his letter to her that her “book – as uncongenial as I find it – is surely a meaningful and positive accomplishment.”

It’s instructive to appreciate that while Seligman may focus on the connection between a set of positive characteristics and a patient’s ability to respond to some diseases, it’s easy for much of the nuance to get lost in popularization.

While the NEJM study authors likely wouldn’t suggest that the cancer patients who experienced recurrence simply didn’t try hard enough, it’s easy to imagine how a more nuanced message might easily get distorted. By the time headlines or social media posts proclaim exercise as a “cancer drug,” the concern raised by Goldsack — that cancer will be seen as preventable if only you had done more burpees — can land as a heavy burden on patients.

Before we despair, let’s turn once more Goldsack, who concludes her piece with this wise and kind advice:

As we design policies, platforms, and headlines around “taking control of our health”, let’s not forget
1) Knowledge must be paired with compassion
2) Empowerment must come with grace
3) Health outcomes should never be weaponized into shame

Once again: amen.