The First Cell, Part 3: Force Majeure — Oncologists are as desperate as their patients

by Azra Raza

All of the articles in this series can be found here.

Everyone agrees that early cancer detection saves lives. Yet, practically everyone is busy studying end-stage cancer.

Reviewing the history of carcinogenesis from 1911 on, I become unspeakably, depressed. Demoralized. For fifty years, massive intellectual and financial resources have been invested pursuing one dream. In the 1970s, a model evolved suggesting that one or a handful of mutations cause cancer that can be cured by one or a handful of magic bullets. Following a couple of early successes, the paradigm was tacitly accepted and has prevailed ever since. Sadly, it has not delivered as well for other cancers. Benefit to patients is nowhere near the enormity of the capital sunk.

The confidence in the model is such that most financial incentives are offered for studying advanced cancers with the wishful thinking that targeting mutations will save dying patients. Perhaps targeting mutations is the key, but all treatment works better in early disease.

It is not cancer that kills but the delay in treatment. The writing is on the wall. Treatment of end-stage cancers, for the most part, is at a dead end since 1930s. The disease has to be found early. As early as possible. There is no reason to settle for Stage I because, the treatment, even for this early stage, is still Paleolithic. We must find cancer at its birth. Every one claims to know this. So why isn’t everyone studying it?

Events surrounding early stages of cancer are naturally expected to be different than what an end-stage evolved beast of a disease manifests. Very few are focusing on studying these events. If we don’t know what cancer is like at its initial stage, how are we supposed to target it for elimination? And if we don’t know the first thing about the stresses in tissues driving a normal cell to transform itself into a murderous monstrosity, how are we supposed to devise means of preventing it?

A few years ago, I saw a film called Force Majeure. A dazzling, lovely couple with two young children, is skiing in the French Alps. Later, while lunching outdoors, they watch a controlled avalanche coming down the slope from a distance, picking up speed and snow. The husband started filming it on his phone. Suddenly, something seemed to go wrong. The enormous cloud of snow threatened to crash and wipe out the deck where they were lunching. In a moment of panic, the husband ran away. The wife shoved the children under the table and covered them with her body the best she could. When the cloud lifted, everyone was safe. But, now the husband had to return and face the family he abandoned.

What made him run away to save his own life? Not lack of love. Rather, it was something over which he had no control in that instant. Force Majeure. A greater force. We have no idea how we will behave in moments of extreme distress. Unknown compulsions make us do unimaginable things. In legalese, the term refers to a clause that frees both parties from any obligations under extraordinary circumstances beyond control. This Force Majeure thing is very bizarre but very real. I have experienced it, where, under pressure of the moment, I acted in ways I could not have predicted in a thousand years.

When a culture approves a certain behavior, we tend to follow along robotically, over time, becoming desensitized and immune to its increasingly bizarre demands and our increasingly outlandish responses. If everyone is doing it, it must be right. There is strength in numbers. Faced with dying patients, oncologists face extremely stressful emotional challenges. Our behavior shows that in many such moments, we are not ourselves. Without realizing it, we become doctors we ostensibly detest. A Force Majeure, a greater power coerces us to do things we would not ordinarily do.

Otherwise, why is hope promoted over experience in oncology? Why has Science morphed into a colonizing force shepherding researchers and oncologists alike toward settling for barely statistically significant outcomes in end-stage cancers? Why is the FDA’s bar for approval of a drug so low that the experimental agent does not even have to show improved survival of 2.5 months anymore; it just has to shrink the tumor in a fraction of patients for a brief interval. Below is one example of the mind-numbing presentations I sit through regularly. Tell me what I am saying is wrong after you read this account of how clinical research is conducted at large, reputable institutions.

On Wednesday May 19, 2021, I heard an oncologist present three clinical trials in two types of cancers. All three trials had been brought to the bedside following extensive pre-clinical in vitro work and studies in animal models. Two were designed to treat a particularly deadly form of tumor of the eyes called uveal melanoma arising in the pigment cells that give color to our eyes. Both trials were unequivocal failures. The third, targeting patients with cutaneous squamous cell cancer affecting the skin, is ongoing.

This is the background he quoted for the first failed experimental trial using a drug called selumetinib which interferes with a cascade of intracellular signals such that, instead of dividing, the cell commits suicide: “There have now been 3 randomized trials of the drug in uveal melanoma, either alone or in combination with chemotherapy.  Of those 3 randomized trials, 2 met their primary endpoints for Progression Free Survival (PFS) in favor of selumetinib vs chemo in one trial and selumetinib + paclitaxel vs selumetinib alone in the second trial, although the benefit was short-lasting in both trials.”

First, if three randomized trials have already been done, why is another one needed? Second, of the two out of three positive ones, the criterion for success is not that the treatment prolonged survival for patients. Rather, for a fraction of patients, the disease did not progress. And to add insult to injury, even that “success” was short-lived. A few weeks at best. That is success?

Now, about the second trial using a drug that also causes cells to stop dividing, here is what he reported: “The crizotinib study on the other hand was a single arm phase II adjuvant trial with truly no signal of activity despite the promising preclinical data that led to the development of the concept.”

Patients with uveal melanoma did not really benefit from either drug in three randomized trials. Instead of moving on to test something else, the oncologist, noting that since subjects in the trial experienced immune related adverse events (irAEs), “We are just getting the multidisciplinary immune-related Adverse Events conference off the ground. We have a few objectives in mind. One, to assist in providing multidisciplinary care for patients who are at high risk of or actually develop significant toxicities from immunotherapy. Two, to collect and document our institutional experience with irAE’s, and three, to facilitate the development of further research, both basic and clinical, aimed at this problem.”

Now, the primary objective is no longer to shrink the tumor, it was never about improving survival, but to study and treat the horrendous toxicities. Whole industries are arising to test agents to control side effects of immune therapies. The team has recruited thirteen members with impressive credentials and academic ranks from across disciplines. “Although treatment options are limited, we do have a trial assessing either rituximab or tocilizumab for patients who have steroid-refractory immune related adverse events”. He then concluded, rather brightly: “There is cause for optimism, however, with the improved survival data from tebentafusp and several ongoing trials we have currently open that are assessing different targets and combinations.”

Is it only me who finds this kind of rationale impossibly irrational? I can imagine the thirteen highly accomplished experts sitting in conference rooms, giving their considered opinions on dreadful drug toxicities. At the end of the hour, they will get up and leave. More patients will be accrued on trials. The performance will be repeated week after week. It is sickening. I do it all the time.

I know we mean well. If I were to suspect an ulterior motive on the part of oncologists, I would need my head examined. In my three decades of clinical practice, I have yet to meet someone who did not want to do everything to help patients. The reality is that the oncologists are as desperate as their patients. I am one of them. I confess. The state of our desperation is such that even snake oil is acceptable so long as it is blessed by key opinion leaders or the p-value in a clinical trial reached statistical significance, not to cure the disease or improve survival but to improve disease free survival.

I am not blaming individuals. I am blaming the culture that has evolved. A fog has settled upon our questioning abilities. Just look at the numbers alone in these kinds of studies. Dozens of patients are recruited, given hope, treated with agents that have unpredictable, unpleasant side effects, benefiting, at best, a third of the patients for a brief period, at obscene financial costs. Even though we know 95% clinical trials fail, we will happily open the next one offered by a sponsor looking to make money for the shareholders.

I suspect there are many reasons for our collective intellectual anesthesia. The elephant in the room is the financial incentive. Oncologists falling in line with institutional demands of bringing more and more trials to the bedside. Otherwise, how could the presenting oncologist say this with a straight face; “In cutaneous squamous cell cancer, we are just beginning a trial assessing JAK 1/2 inhibition that is based on data generated internally and, separately, at another institution.  Fingers crossed for some degree of efficacy here.”

Fingers crossed. This is what it has come down to in oncology. This attitude of hoping for success despite practically fifty years of experience to the contrary summarizes the inexplicable attitude of the oncology community today. It is impossible to reconcile the hope expressed or the confidence of the optimistic forward-looking statements in the face of disastrous results. How to explain the absurdity of future plans based on precisely the same pre-clinical testing platforms that led to the above clinical trial disasters? Even if we assume that the next trial succeeds and receives FDA approval, what exactly will it mean for patients? Will it significantly prolong their survival or improve their quality of life? Whether the answer is yes or no, are the physical and financial toxicities patients incur worth the minimal benefit?

Experience says an unqualified NO. The entire oncology + industrial complex says an enthusiastic YES.

Over the last decade, the average monthly price of anticancer drugs has more than doubled, from $4,500 to $10,000 per month. The newly introduced expensive treatments have not simply replaced the older, cheaper ones. They are add-ons. Patient are receiving old and new drugs sequentially. To justify the skyrocketing financial burden, one would expect skyrocketing benefits. Study after study shows otherwise. Clinical benefits simply do not follow the quantum leaps in pricing.

Whether the cancer is diagnosed early or late, the price patients pay is the same. Take non-small cell lung cancer, the leading cause of cancer deaths in America. A European study calculated that the cost is the same whether patients present with stage 1 or 4 disease; approximately E20,000. In stage 1, the money is spent on surgery and most patients are cured, while in stage 4, the money is spent on costly drugs and no one is cured. The authors of the study conclude that, “Stressing public health policies and campaigns against tobacco smoking is probably the main solution on which policy-makers should focus to contain the costs of lung cancer.” This recommendation is no different than what has been stressed since 1950s. Stop smoking.

Immune therapies receive glowing coverage also. A recent study reported that a combination of the two most popular “check-point inhibitors”, Nivolumab and Ipilimumab, was simply not cost-effective. The price of the immune therapy would have to be reduced from $26,425 to $5,058 a month, and the maximum duration of treatment would need to decrease from 24 to 1.4 months to become cost-effective compared with chemotherapy.

What is the value of these novel oncology drugs if the cost-benefit ratio is so grossly distorted?

I interviewed a candidate for a leadership position recently. Reviewing the CV, I noticed their role as Principal Investigator on 17 clinical trials, the vast majority testing various types of immune therapies (antibodies, vaccines, checkpoint inhibitors, CAR-T cells) alone or in combination, targeting only one specific cancer. The duration listed for most trials and associated research extended from now to 2035.

Mark Twain knew what he was talking about: Truth is stranger than fiction, but it is because fiction is obliged to stick to possibilities. Truth isn’t.

How is it possible that oncologists do not expect anything better for their patients even as far out as 2035? Why aren’t they bothered? When I pointed this out to a young faculty member in clinic recently, his response was, “We agree with you, Azra. But in the meantime, we have to pay our bills.” There it is. The Paycheck Oncology culture. The system is to blame.

A business model has been imposed upon most major cancer centers. A sponsor pays $30-100K per subject to the participating institution essentially for logistics of identifying subjects, checking eligibility criteria, obtaining informed consent and filling out the required data collection forms. The additional costs of treatment, managing toxicities, hospitalizations and clinic visits, are paid for by insurers, Medicare and Medicaid, bringing more cash to the centers. It is a phenomenal moneymaking machine. A major criterion for recruitment of young faculty is how many clinical trials they will bring to the institution.

What is needed in oncology is a profound cultural revolution. The professional attitudes and practices of everyone involved in this enterprise, the customs, practices, habits of academia and industry, the demands and regulations of funding agencies, the oversight provided by institutions, are all corroded by an intense pressure to monetize every aspect of this dreadful disease. There is a direct path to navigate ourselves out of the darkness. Instead of trying to kill the last cell, we need to find the first.

Who is willing to risk this? Not the young researchers because they could fail and failure is not good for promotion. Not the old ones who have already devoted decades studying end stage cancer. At this point, I am wondering if what I am demanding is a change in culture or in human nature?

Maybe there is hope; here is Amanda Gorman at President Biden’s inauguration:

“There is always light when we are brave enough to see it

 Brave enough to be it”


Note: Source of the picture used: