Should cachexia equal morbidity? Medicine's biggest blind spot.

Monday, January 27, 2025 9:53 PM

The Biggest Blind Spot in Modern Medicine

only kills 7 million people a year

(This blog was originally posted on Nov. 4, 2019*) 



Duncan Caldwell


What if I told you that at least 22% of people whose deaths are attributed to cancer each year don’t actually die of it, but of a syndrome that should be considered a disease in its own right, although cancers and other diseases trigger it, since its mechanisms are quite different? What if you discovered that your own death might be hastened by the failure to focus on arresting the real killer and to train caregivers to adapt to its appearance? This is a hard-won warning that you could be just as much at risk as the 516,000 Americans who are affected by the syndrome each year, since its emergence is often seen as the benchmark for ending their lives, even though the “syndrome” might be manageable or curable. Would you be disturbed and ask why hardly anyone knows about such a nemesis? 


Let me give you an example of how this confusion between the big “C” and the two small c’s of the syndrome - cancer cachexia, which kills about 132,000 Americans a year in its own right – can kill someone like you. It’s the story of the one-two punch that killed my wife. The first one hit when health practitioners became so focused on treating Nancy’s ovarian cancer that they failed to take into account the precautions required by the arrival of the syndrome, and made a “regrettable decision” that knocked out her kidneys. The second punch landed when the syndrome’s appearance was used as the tripwire for ending everything but terminal care, although Nancy’s cancer markers had fallen close to a healthy person’s. 


Here’s how you can be dropped by a similar sequence of malpractice and self-fulfilling prophecy.


The story begins with a brilliant doctor, who had to hand over the reins as he prepared for retirement, and let them slip. The slippage occurred after he realized that the genetic profile of Nancy’s cancer cells might make them vulnerable to a drug named Pertuzumab, and, secondarily, Herceptin, which hadn’t been approved yet by the FDA or Medicare for her type of malignancy. He asked a back-office employee to apply for waivers, whereupon the woman told us on five occasions, spread over months, that various applications and appeals to Medicare and the manufacturer of both drugs – Genentech - were pending, and, finally, that the last one had been rejected. 


When Nancy was forced to call Genentech to plead her own case, she spoke to a manager who told her the cancer center employee had never filed the appeals, despite reminders from the company that the patient seemed like a prime candidate for the treatments! When Nancy forwarded the manufacturer’s email to her doctor, he responded that if he hadn’t been bald, he would have torn his hair out. Although we think of doctors and nurses as the ones who sometimes commit malpractice, this shows how it can also occur in a back office, where negligence, laziness and mendacity can lead to the loss of the window when a person’s life has a good chance of being prolonged or saved. 


But it gets worse. The effect of the employee’s malfeasance was compounded by its timing, since Nancy’s medical team had decided to put their patient into a holding pattern, which would have disastrous consequences, while it waited “briefly” for the approvals. The pattern consisted of putting Nancy on a regimen of pills for the summer (when the infusion center would be short-staffed) or rather just until the team could use its preferred drugs. There were several reasons why her caregivers should have realized they’d miscalculated. 


First of all because they were fooling themselves so badly, after losing control of their back office, that they never got approval for Pertuzumab, let alone in the two weeks they’d anticipated. 


Second, because they’d over-estimated their clout with the insurer and manufacturer, which were not about to give a small cancer center the same waivers they sometimes granted research and teaching hospitals. 


Third, because the decision to put Nancy on pills, which she was to take at home, rather than at the center, meant that her doctor had just given up his best means of keeping track of her symptoms and lab numbers – the face time when Nancy came to his facility every week or two for infusions – and replaced it with visits at longer intervals, complimented by blood work closer to home “for our convenience” while everyone sat back and waited. 


And, fourth, because he and his lieutenant - a veteran nurse practitioner - were effectively putting Nancy out-of-sight and out-of-mind precisely when they were treating my wife with an oral remedy, which they acknowledged was just a stopgap, and were likely to take their eyes off the ball while they were on vacation.


The holding pattern, which dragged on for much of the summer, must have seemed reasonable at first. But we sensed that her caregivers were becoming embarrassed as they waited for the clerk to overcome the supposed rejections from Medicare and Genentech, since it became clear that – at the very least - they didn’t have much leverage. Meanwhile, Nancy began to lose her appetite as her belly began to swell. Although neither of us knew it, cancer had gotten the better of her while her caregivers let her coast, and had triggered cachexia. 


One of the most incredible things about the situation was that my brother realized that things had gone wrong before Nancy’s medical team. One evening, when he happened to come for dinner, he was shocked to see how much her condition had deteriorated while she was in medical limbo. Seizing the reins in his capacity as a surgeon, he ordered blood work and had the results transmitted to her team at the distant cancer center. 


When the report, which showed that Nancy’s cancer marker had skyrocketed and that fluid had built up in her abdomen, and an email from me, saying that Nancy hadn’t been able to eat or drink much in days, reached her oncologist, he sent orders for her to come to his hospital immediately for three things: 

    -    a CT scan with toxic dyes, to determine the extent of the new tumors; 

    -    intravenous re-hydration beforehand to give her enough fluid to flush the dyes before they could harm her kidneys; 

    -    and aggressive chemotherapy with the one drug he’d finally been able to procure (his second option, Herceptin), after learning of his clerk’s deception. 


Although you might have thought the incidents I’ve just described amounted to the first punch, they were actually the prelude to the wallop that sent my love reeling. As Nancy’s constant companion and health advocate, I accompanied her during every procedure and exam, including when she was taken into the radiology department for the scan. When I told everyone from the receptionists and nurse’s aides to the scan techs that Nancy’s doctor had emailed us to say that she had to be intravenously hydrated before the scan, they all answered that they understood, but insisted on following procedures by taking her to the scanning chamber while checking with him. When I put my ear to the door of the control room because I suspected they were ignoring me and made out that they were talking about me dismissively and were going to conduct the scan without rehydrating Nancy, I began shouting through the thick glass and shaking the portal in an effort to force them to read the doctor’s email again on my phone. 


When they finally deigned to open the bunker, I burst in, and was told that they’d decided that the doctor must have changed his mind since he’d sent me the email, because he hadn’t put in an order for IV hydration. I couldn’t believe their logic, since it meant they were going to blindly follow schedules and procedures, despite the possibility of an oversight, even though their actions were likely to harm (if not eventually kill) the patient. 


When I redoubled my insistence that they call Nancy’s oncologist, who was off-duty, a nurse threw me a sop by calling his answering service and pager from the control room. When she failed to get through to him, she announced that she’d done her best, and that it was therefore time for me to leave. 


That’s when I forced my way into the scanning chamber, where my poor wife lay on the slide in front of the tunnel, watching me fight for her life. I can never forgive myself for what happened next. When I tried desperately to use my phone to call her doctor’s cell, which he’d been kind enough to give us, I discovered that the shielding around the radiological department prevented cell calls. I knew they’d conduct the scan if I ran out of the hospital to try again, so I grabbed the emergency red phone on the wall and insisted that the nurses get me an outside line. By this time, they were threatening to have me evicted, but hesitated just enough, when I read the doctor’s dictates aloud again, to throw me yet another sop, this time by calling a radiologist who was on call. 


After he told the nurses to go ahead with the scan despite my reading him his colleague’s email, and they’d begun sliding Nancy into the hole, I lost it, rushing to block them as I insisted that they at least try to reach the nurse practitioner, who had worked with Nancy’s doctor for decades. I felt sure she’d confirm her boss’s and mentor’s instructions. 


But she didn’t. She was like someone under an umbrella, who thought she was giving it shape. What she did was tell them it was okay to conduct the scan. That was our undoing, since the CT scan predictably compromised Nancy’s kidneys and ended her candidacy for further chemotherapy, practically sealing her fate. 


This chapter reveals that 

    -    even a patient with a strong advocate is liable to be harmed at some point by the health care system (despite all the good it does); 

    -    hospitals all too often put interests like scheduling ahead of those of their patients, even to the point of taking risks with their lives;

    -    caregivers are not trained to be sensitive to the appearance of cachexia, and the specific safeguards required by its presence, including rehydration of patients whose digestive tracts (and appetites) have been cramped by the leakage of protein-rich fluids from their cells into their chest or abdominal cavities;  

    -    and that everyone from the nurses’ aides and nurses to the doctor on call and nurse practitioner was so focused on dealing with cancer that they were unable to adapt to new requirements, even when the right protocol was stated by an esteemed colleague in writing. 


Such lapses are killers, but the worst is yet to come. After Nancy’s kidneys stopped functioning because of the dyes she was given before being prepared to receive them, her doctor grabbed the reins and tried desperately to play catch-up. After weeks of otherwise unnecessary hospitalization, Nancy finally regained enough kidney function to receive the back-up drug she should have received months earlier - if there had not been the clerical malfeasance and scan fiasco (she never received the drug, by the way, that her doctor preferred) – and, lo and behold, her cancer marker finally dropped. 


But it was too little too late, since the syndrome had now kicked in with a vengeance, requiring weekly “taps” to draw off the fluid leaking out of her cells. After being trained to give my love intravenous nutrition (TPN), I became part of Nancy’s health team just as the rest of it gave up, and told her that they were going to “send her on a chemotherapy and TPN holiday”! That’s right: the same NP who made the ultimate decision to put Nancy through the scan that night called the removal of all hope and remedial care “a holiday.” I couldn’t believe either her euphemism or the fact that they had decided to stop giving Nancy chemotherapy although her marker had fallen almost every time she had received it since regaining kidney function. And once again, I just lost it. 


That’s when the second punch landed. My sister-in-law, who used to be an army nurse, snapped, “Duncan, don’t you realize you’ve got to let Nancy go? She’s developed cancer cachexia. That’s when they pull the plug!” 


I was dumbfounded. I’d attended every one of Nancy’s exams, slept by her in every hospital; been her devoted medical investigator, and even come close to saving her kidneys when I’d tried to prevent the scan from being administered before she was ready for it, but nobody had breathed a word about this syndrome or its perceived implications. Sure, I’d noticed that practitioners were feeling for puffiness around her ankles, and that fluid kept building up in her cavities, but nobody had said these were perceived signs of morbidity or mentioned the two small “c”s. 


When I pleaded with a new oncologist to continue giving Nancy chemotherapy since her marker had continued to drop when she’d received it, the oncologist explained that she’d been taught at Yale Medical School to perceive the onset of the syndrome as the sign that there was no longer any chance of reducing or eliminating the underlying disease, and that making any efforts to do so were wasteful, cruel and unethical. Even if Nancy’s cancer marker was falling, the syndrome’s appetite suppression and protein leakage made it impossible for her to incorporate protein fast enough to replace the loss, maintain her body, and stay alive. After a titanic debate and Nancy’s decision to give “Duncan’s experiment” one last shot, the Yale oncologist made what she called the first exception of its kind in her career, and gave Nancy a final partial infusion, after which she said she’d only give Nancy more chemotherapy if Nancy could walk into the infusion clinic on her own power. Although my love never got another infusion, let alone a complete one, her marker predictably bottomed out close to a healthy person’s.  


My cousin, who became Nancy’s last doctor, when she was dropped in his lap ten days before she died, told me he was caught in a battle of his own with the hospital administration to continue giving her both TPN and chemotherapy, because the administrators saw the appearance of refractive cachexia as “the time to stop throwing good money after bad.” According to him, the syndrome was simply the industry’s morbidity benchmark, which was rarely spoken of in the presence of patients and laymen. I hadn’t heard of its little secret because there was a kind of omerta.


Now that I knew what we were facing, I threw myself into a last-minute search for remedies. What was astonishing is how little work had been done to solve a problem that affects 86% of cancer patients during the final weeks of their lives and kills at least seven million people worldwide on its own each year. You might think our guardians couldn’t have such a huge blind spot. And yet the big “C” gets so much attention that it seems to have distracted the medical establishment from dealing effectively with one of our biggest challenges – those two small “c”s of cancer cachexia. 


Don’t take it from me. Here’s what Dr. Mache Seibel of Harvard Medical School wrote me: “You’re right; we medical practitioners have gotten so used to seeing the appearance of refractive cancer cachexia as the moment when it is no longer ethical to continue treatment that we really haven’t looked at it very much as a set of symptoms that might be reversible or manageable like AIDS with tri-therapy. There is a case of ‘mistaken identity’ and confusion about what is killing the patient. All is attributed to the big ‘C.’ Not enough is attributed to or there is not enough awareness of the separate issue of the syndrome. And that lack of awareness can lead to unnecessary hospitalizations, greater suffering, the removal of therapeutic options, increased risks of malpractice and liability for hospitals and caregivers, the failure to investigate treatments of the syndrome, and shortened lives.” And here’s what Drs. Penet and Bhujwalla of the John Hopkins School of Medicine have to say: “Better treatments of cachexia are urgently required and would have a significant impact on improving the quality of life for patients and on increasing their life expectancy.” 


Although teams led by Bruce Spiegelman of Harvard Medical School, Erwin Wagner of the Spanish National Research Centre, and Xiaolan Zhou of Amgen Research have all published promising results based on rodent-studies, the establishment is united in saying “Cachexia is still largely an underestimated and untreated condition,” which is “little understood” and leaves “patients too weak to receive further treatment for their chronic disease.” In reviewing the work of Tomoyoshi Aoyagi, Alfred Goldberg, and others, who have described some of cachexia’s subtleties, I quickly realized there might be multiple avenues for suppressing it, and wished someone had told me 30 years earlier that I might have been able to save my love if I’d thrown myself into finding solutions. 


Before examining one of the avenues, we must dispel the notion that cachexia’s appearance shows that the “body is shutting down.” It’s true that the syndrome attacks some tissues, such as lean muscle, but it doesn’t affect muscle in the visceral organs, for example. That means it only targets some tissues, which shows it is not symptomatic of general breakdown and fatigue, but rather that it has particular pathways, which indicates that it can be targeted. 


How? Cachexia involves the development of anorexia, decreased secretion of anabolic hormones from non-cancer cells, and abnormalities in protein, lipid, and carbohydrate metabolism. The meshing of mutually reinforcing mechanisms means that cachexia will probably have to be fought with an array of tools – in this case a carefully dosed cocktail of drugs - that have been designed both to block particular aspects of the syndrome and work well together and with the patient. The transformation of AIDS from a death sentence to a manageable illness once sufferers receive the right cocktail shows that such approaches can be extremely effective.


And hope is on the horizon. Some of the ingredients would probably interrupt cascades and feedback loops, for example, involving systemic inflammation, which is linked to the production of a protein (CRP) that is an accurate measure of pro-inflammatory cytokine activity. That activity has been implicated both in muscle wasting and in the development of anorexia, since cytokines make endothelial cells in the brain release substances that affect appetite. Stop that loop and other pathways and you’re likely to hinder cachexia. But that will require a war on those two small c’s that affect 400,000 Americans at any one time. The magnitude of the blind spot boggles the mind, since you’d think the profits to be reaped by keeping so many people alive for months or years – during which time their cancers might be cured - would be driving research at a furious pace. And yet, the field is underfunded and trials are few and far between. 


It’s way too late for Nancy. Too late, except to pull the alarm, and Nancy would have wanted me to tug it hard! She would have wanted me to shake the establishment out of its acceptance of a largely unexamined medical and financial paradigm so researchers can begin tackling the syndrome with the full weight of society behind them. After all, all of our lives might depend on it. 


Nancy’s did, so this is her last plea and gift to the world.




* The original posting was corrupted by a traffic re-orientation bot, which took viewers to a shady Russian pharmaceutical site.