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Curing cancer - How cancer kills


Originally posted at Nat Pernick's Curing Cancer Blog on 11 April 2021, revised 4 December 2022.


Our strategic plan aims to reduce U.S. cancer deaths from 600,000 (projected cancer deaths in 2022) to 100,000 per year. To reach this ambitious goal, we must better understand how cancer actually kills people. This essay proposes that cancer often kills indirectly by promoting marked physiologic disruptions in life's essential networks; however, physicians can prevent these deaths by correcting the network changes even before the cancer itself is treated. In addition, advanced cancer kills by creating a sense of futility, which causes individuals and the medical system to give up the fight.

1. Basic principles of living systems

To understand death, we must understand life and its requirements. Human life is remarkable because it seems impossible to create and maintain. The fertilized egg, in the correct environment, must multiply and differentiate into the organs and organ systems present in adults. However, the developing organism, whether an embryo, fetus, infant or child, must also maintain adequate life functions during this time. This process involves numerous biological networks that each serve a limited purpose; yet they are interconnected in myriad ways to produce essential physiologic networks that change their functions and relationships with each other over time.

Human life is a complex system, not a sophisticated machine. In complex systems, the properties of the entire system are greater than the sum of its parts due to interactions between the parts (Pernick: The Laws of Complexity and Self-organization: A Framework for Understanding Neoplasia 2017). As a complex system, life gives us a greater capability than we might imagine from studying each organ system separately but also creates difficult problems when interdependent systems go awry. When disease occurs, we must find the correct type and timing of treatments to move each essential physiologic network towards normalcy; this is difficult because changes to each individual network affect the numerous other interconnected networks. In contrast to living systems, automobiles or other machines are just the sum of their parts; we can understand them fully by studying each part and its limited interactions with other parts. A machine part that goes bad can be replaced or fixed without concern for other parts with which it interacts.

2. Life requires a sophisticated web of stable biologic networks

Our cells function optimally only when the cardiovascular and pulmonary systems supply them with blood that provides adequate oxygen and glucose and when the concentration of essential blood components is maintained within a narrow range. These components include sodium and potassium (electrolytes), calcium and other minerals, acidity (pH) and nutrients. In addition, the immune system must limit destructive infections and premalignant or malignant cells, the coagulation system must both preserve blood flow and prevent hemorrhage and the kidney and liver must detoxify harmful substances and remove them from the body. These essential physiologic functions are typically self regulating, but may be affected by advanced cancer or other diseases.

3. Cancer often kills by promoting marked physiologic disruptions

We propose that cancer often kills by promoting marked disruptions in life's essential biologic networks. Initially, cancer risk factors cause sustained stress to biologic networks affecting epithelial cells, most commonly in the lung, colon, pancreas or breast. This causes small, unnoticeable changes to these cells without affecting neighboring cells and tissues ("the microenvironment"). However, self-organized criticality predicts that over long time periods, these small changes, acting in a nonlinear manner, may lead to an accumulation of changes (Bak, How Nature Works 1999) and possibly a malignant state, called a “cancer attractor”, that is difficult to normalize (Huang 2009). The process of producing these cancer attractor states also propagates dysfunctional features to the microenvironment and systemically.

Cancer risk factors and the malignant process promote dysfunction by several mechanisms. First, they promote continuous activation of the inflammatory system, which is itself unstable and transmits this instability to the many networks with which it interacts (Pernick: How cancer arises from chronic inflammation, based on complexity theory 2020). Second, cancer cell growth destroys normal tissue, which diminishes the effectiveness of organ systems and their cooperation with other organ systems or can even cause organ failure. Third, cancer cell growth increases metabolic demands both through their consumption of nutrients and by secreting products that disturb physiologic functions (Monardo 2020). Fourth, cancer cell growth may, over time, induce network changes that trigger cellular activities that are typically repressed in adults, such as unicellular programming of cells and embryonic differentiation. Finally, cancer cell growth may create immune system dysfunction that leads to tolerance of cells with malignant properties that would otherwise be destroyed. Together, these mechanisms may lead to a dominance of cancer attractor networks which promote and maintain malignant properties in organ systems, even against treatment, and are ultimately incompatible with life.

Our organ systems have evolved to be tightly integrated with each other for optimal performance, to respond to the usual physiologic challenges and to correct small, short term disturbances. This explains why humans typically have a prolonged lifespan that only occasionally requires significant medical intervention.

However, our organ systems are interdependent such that disturbances in one system may cripple other systems. For example, cancer causes disturbances in the blood calcium level that affects the kidney, gastrointestinal tract, central nervous system and skeletal system (Zagzag 2018). Cancer or its treatment may damage the bone marrow, leading to anemia, bleeding or infections, all of which similarly degrade the functioning of multiple organs and organ systems.

4. Countering cancer related disruptions is difficult

In general, human physiology or medical practitioners can counter the slow decline in the functional capacity of organs, particularly when there are deficiencies in only one organ system. However, cancer kills patients because (a) systems fail quickly, challenging our ability to respond promptly and appropriately; (b) it is difficult to adequately respond when multiple critical organ systems fail simultaneously because the usual treatments for single system failure may be inadequate; (c) even before the rapid decline, these organ systems are slowly diminishing due to tumor related destruction or age related changes.

When multiple organ systems are working harmoniously, we marvel at the wonders of life. However, dysfunction in multiple systems produces not just abnormal lab values that threaten life but an inability to easily return these physiologic measures to normal, as discussed above.

It is important to note that cancer typically does not kill by destroying the functional capacity of organs to the extent that they no longer sustain life. When people die of cancer, particularly if this occurs rapidly after diagnosis, they usually have adequate reserves of function in their organs or the functions of these organs can be supplemented by technology.

Rapid cancer death is similar to diabetic ketoacidosis in that both are lethal primarily due to abrupt physiologic changes, not because the patient is terminally ill. In diabetic ketoacidosis, insulin deficiency transforms an orderly physiology into chaotic, life threatening disturbances in many essential networks. Merely giving insulin does not fix the problem - instead, a sophisticated system of treatment and monitoring is required (Fayfman 2017) that is so complicated that simulations are often used in training (Roberts 2020).

Similarly, we suggest that rapid cancer deaths could be reduced with a sophisticated system of treatment and monitoring. The initial concern should be to counter the tumor's disruptive effects on network related stability so that medical therapy can restore viable physiologic characteristics and maintain life. Subsequent treatments can focus on killing the bulk of the tumor cells and achieving long term survival.

5. A sense of futility is another major cause of cancer death

Another major mechanism of cancer death is futility, the belief that there is no reasonable hope for a cure or benefit to continuing treatment. With advanced cancer, the physiologic changes are persistent, but not necessarily rapid; although medical science can halt them temporarily, patients and their physicians may believe it is futile to aggressively manage what is clearly a downhill process.

Even with progression, life can continue if patients and their physicians rationally believe there is hope to continue and as long as there are no rapid instabilities. We can limit the sense of futility and diminish or at least delay cancer related deaths if cancer is viewed as a chronic disease; one that can be managed (even if not cured), especially as newer treatments improve our ability to hold it in check. Anti-tumor treatment may incorporate the principles of adaptive therapy, which uses more dynamic treatment protocols, such as (a) suppressing the growth of resistant phenotypes, (b) creating an initially small resistant tumor cell population that is eradicated by a second treatment, (c) designing a "resistance management plan" and (d) at some point, assessing the success of treatment in each patient and determining what could be improved for future patients (Stanková 2019, Coggan 2022).

6. Cancer also kills directly

Although beyond the scope of this essay, cancer can kill directly by eroding blood vessel walls, leading to lethal hemorrhages, which either damage vital brain functions or cause loss of blood flow throughout the body, thus starving cells of oxygen and nutrients. In addition, brain tumors can cause increased intracranial pressure, leading to brainstem herniation, which blocks the nerve signals for breathing to the lungs. Cancer treatment or its persistence can also damage the immune system and bone marrow function, leading to life threatening infections, anemia or coagulation disturbances, which also cause death.

Summary

We propose that to prevent cancer related deaths, cancer treatment must also focus on countering the physiologic disruptions it creates. In addition, although the disease will not disappear, cancer should be viewed as a chronic disease that often can be managed for long periods of time.

Note: we offer grants for research related to this essay, see Grants.
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