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Musings of a Cancer Doctor

Wide-ranging views and perspective from George W. Sledge, Jr., MD

Wednesday, September 22, 2021

On the Limits of Endurance

By George W. Sledge, Jr., MD​

There is a concept in the material sciences called either “fatigue limit" or “endurance limit"—the terms are used interchangeably—that we who care for cancer patients should adopt, or at least explore. Imagine holding a copper wire in your hands, and then bending it back and forth, cyclically, until the wire breaks. This process is called “fatigue failure." The fatigue limit (or endurance limit), in turn, is the stress level below which fatigue failure does not occur. A related term, “fatigue life," is the number of stress cycles of a specified character that our copper wire sustains before failure occurs. This is determined by the properties of the material (copper fatigues more readily than titanium), the amplitude of the stress, internal defects, temperature, corrosion, and several other qualities.

This is a big deal for engineers and, therefore, for the rest of us. Fatigue failure caused by cyclical stress is, we are told, responsible for nine out of every 10 mechanical failures. There is an American Society for Testing and Materials (ASTM) that devotes its considerable efforts to determining (among other things) the limits of endurance. I visited the ASTM website, where the search term “endurance limits" rewards you with 1,017 results, starting with “STP1372 Fatigue Crack Growth Thresholds, Endurance Limits, and Design." The term “fatigue limits" gives you over 3,000 results. Material scientists work to improve product life and safety by minimizing fatigue. That planes do not fall out of the sky as often as they used to is a measure of their success.

Google “limits of human endurance" and a popular result is a 2019 article by Caitlin Thurber and colleagues, published in Science Advances. It is not at all what you might expect when you hear “limits of human endurance." The authors are looking for the physiologic limits to maximum energy expenditure. It turns out that we can expend a great deal of energy for a short time, but if the time frame is long, the amount of energy one can expend is limited.

They explored this in a creative way, beginning by measuring the basal metabolic rates (BMR) of endurance athletes. Athletes can expend up to 9.5 times their basal metabolic rate for a half-day triathlon. But if the same athletes take part in the 140-day transcontinental Race Across America, which is essentially a marathon (42.2 km) per day, 6 days per week, for 14-20 weeks, maximum sustained metabolic scope (the limit of human endurance) drops to ~2.5 times the BMR. Put mathematically, maximum sustained metabolic scope is not a static value, but instead follows a strong negative logarithmic relation with event duration. Beyond the 2.5 BMR limit, we increasingly draw down our body's energy stores.

One can wear out acutely as well as chronically. Exceeding the endurance limit is intrinsic to marathons, as witnessed by the event's (possibly apocryphal) origin story. In 490 BC, Athenian soldiers bested Persian invaders at the battle of Marathon, and sent their best runner, Pheidippides, back home to deliver the news. Pheidippides had just run 150 miles from Athens to Sparta in 2 days, carrying the Athenians' request for aid and then had run back with their response (“No, not yet"). Now he ran 25 miles from the battlefield at Marathon to the city, telling the anxious city elders “nikomen" (“we win") before collapsing and dying. If you wear Nike running shoes or watch the Olympic marathon, remember Pheidippides, but don't emulate him: stop short of your endurance limit.

Interestingly, the BMR endurance limit equation applies to pregnant and lactating women as well. Pregnant women are, in a very real metabolic sense, long distance runners, their maximum sustained metabolic scope peaking at around 2.2 times BMR. This in turn probably limits the size of a newborn child. The authors suggest that these limits of human endurance, both for runners and pregnant women, are due to an alimentary limit: our guts just can't absorb enough calories per day to get beyond the BMR limit. The oncologist in me wonders whether an actively metabolizing cancer beyond a certain volume—the sort that lights up a PET scan—encroaches on that limit. I'm sure someone has studied it, though I've been unable to find a paper that clearly relates SUV values to glucose consumption for a particular tumor volume.

So, a copper wire has an endurance limit, and the human body does as well, and both are related to the level of the stress applied and the duration of that cyclical stress. But when I think of the limits of endurance I tend to think not in terms of physical or metabolic limits, but in psychological ones. How much can a human being endure?

Let's travel back in time a hundred years or so to World War I, the first true modern war. After its opening moves in 1914, the war settled down into brutal trench warfare across northern France, where miserable men spent weeks in muddy trenches, constantly bombarded with massive shells thrown up by the opposing forces' artillery. Those armies experienced something previously unseen. Nineteenth century battles such as Waterloo or Borodino or Antietam were won or lost in a single day, and even the longest, like Gettysburg, might only last 3 days. The requirement for courage under fire was a short-term thing. But on the Western front, where the lines barely changed over 4 years of combat, men suffered from what was then called shell shock. Today we might lump it in with post-traumatic stress disorder.

The classic work on this is Lord Moran's The Anatomy of Courage. Moran (created a lord during World War II for his services to Great Britain) was later to become Winston Churchill's personal physician and served as a medical school dean and as head of the Royal Society of Medicine; but as a young regimental surgeon in World War I, he cared for numerous shell shock victims. Early in the war, he was asked to examine a listless sergeant who had just come back from the trenches. Moran writes:

“I found him staring into the fire. He had not shaved and his trousers were half open. I could get nothing out of him…he did not appear to be ill. We agreed to let him rest, to let him stay in his billet until his battalion came out of the trenches. But next day when everyone had gone up to the line, he blew his head off. I thought little of it at the time, it seemed a silly thing to do."

Subsequently Moran, like other physicians who discussed shell shock, came to see it as a matter of psychological attrition rather than the result of a single causal event. To quote him, “The story of how courage was spent in France is a picture of sensitive men using up their willpower under discouraging circumstances while one by one their moral props were knocked down. The call on the bank might only be the daily strain of the trenches or it might be the sudden draft that threatened to close the account."

Moran visited the “sudden draft that threatened to close the account" when he experienced bombardment himself. “My mind became a complete blank. I had a feeling I had suffered physical hurt though I was not touched, the will to do the right thing was for the moment stunned. I was dazed and at the mercy of those instincts which I had until then been able to fight." Under the repetitive stress of such shelling, he said, “men wear out like clothes."

Moran spoke in terms of courage, but courage may not be the right word for what he chronicles. What he described was endurance, as human copper wires were subjected to cyclical stresses, surpassed their endurance limit, and broke.

Which brings me, inevitably, to my clinic. I've discussed material fatigue, and metabolic limits of endurance, and shell shock, and they all make me think about my patients with metastatic triple-negative breast cancer. This disease has all the attributes of those previous things, and more.

When I sit down with a patient with metastatic triple-negative breast cancer, I tell her that the nature of her disease is that left untreated it will grow, and grow until it consumes some vital organ, ending her life. The only way to prolong her life, for cure is generally not in the cards, is with repetitive cycles of toxic chemotherapy agents, sometimes augmented with repetitive cycles of minimally less toxic checkpoint inhibitors or an antibody-drug conjugate.

So it happens that my patient, like some World War I soldier, faces a life in the trenches, being continuously shelled. I will be asked, early on, “how many treatments will I receive?" And my answer is always the same: that depends, depends on the effectiveness of the therapy and on your ability to tolerate it. But this is, I say, a marathon, not a sprint. You need to maintain your physical and emotional stores of energy. We talk about drug holidays when things get to be too much, about altering dose and schedule of our therapeutics in response to side effects, about how it is important to listen to your body, to adjust in response to circumstance. One has to operate in terms of what Leo Tolstoy suggested in War and Peace: “A man on a thousand mile walk has to forget his goal and say to himself every morning, 'Today I'm going to cover twenty-five miles and then rest up and sleep.'"

We also talk about goals of care and end-of-life strategies. I was not at all good at this early in my career, but have come to recognize it as one of the more important things I do as an oncologist, and I've tried to do it better, though I still fail all too often, and fail my patients as a result.

What I am miserable at, by analogy with the material sciences, is predicting the endurance limit and fatigue life of my patients with advanced disease. The endurance limit, you will recall, is the stress level below which fatigue failure does not occur. The fatigue life is the number of stress cycles of a specified character that one can sustain before things fall apart. The material scientists would say “before structural failure," but of course it is the treatment that fails, not the patient.

I wish I had some way of gauging this ahead of time, of being able to know what the endurance limit of therapy was for an individual. But just as—to invoke the wisdom of the material scientists—fatigue life is determined by the properties of the material, the amplitude of the stress, internal defects, temperature, and corrosion, so do many individual physical, mental, spiritual, and social properties preceding metastasis help determine the limits of human endurance. My patients also deal with the financial toxicity of treatment, family stresses, fear of impending death, uncertainty over the timing of that event, and the million other small things in daily life that drag us down. Your 2-year-old does not become any less needy because you harbor a liver metastasis, your unhappy marriage is not improved by the stress, and the bills still need to be paid on time. Sometimes it can be too much.

And all these are layered on top of the amplitude and repetitive nature (or in our usage dose, schedule, and number of cycles) of capecitabine or paclitaxel or eribulin or pembrolizumab or sacituzumab govitecan. If, as I have suggested, a large, rapidly dividing cancer shoves one up above that 2.5 times BMR limit of human endurance, especially in the context of the poor food intake and cachexia of a patient with metastatic disease, does the human body start breaking down?

Lord Moran thought that courage was a bank account that you could only draw on for so long. I am astonished, even terrified, by my patients' courage, even as I see their accounts dwindle. Clinical trial reports measure neither a patient's resilience nor her exhaustion of those resources—physical, mental, spiritual—that make her struggle possible against such daunting odds. But we all measure those resources, roughly so, often inaccurately, when deciding whether that next treatment holds value.

I have yet to encounter the algorithm that integrates all these factors, but the limits of endurance are as real for my patient as for that thin copper wire bent repetitively, and regularly come into play before I run out of FDA-approved drugs. There is a science to this that we do not yet understand, and a challenge we have yet to meet and beat.