Single-celled organisms are forced to multitask. With the evolution of multicellularity came many advantages, mostly the advantages of tissue specialization, but also, sex. There is a dark side to multicellularity, however: cancer. In fact, tumor formation is nearly universal in multicellular organisms.
Even so, the propensity to develop cancer varies widely among species: in rodents, cancer is nearly ubiquitous by the old age of two years. In contrast, elephants, over a life span of several decades, almost never develop cancer. (This is “Peto’s Paradox,” and the reason will be explained in this lecture.) Humans fall in between these extremes.
Why would cancer remain in the gene pool at all? There is evidence that the very traits that confer greater fertility to individual humans, and hence, reproductive success, also increase the risk of cancer.
On the level of the biosphere, cancer emerges along with reproductive advantages. Within the individual, cancer is an analogous evolutionary process. Cancer growth and spread takes place in an ecological system, the body, with its various metabolic niches that encourage variation in cancer cell phenotypes. (Recall from evolutionary biology that phenotype, not genotype, is the unit of natural selection.)
Cancer cells, as do any living entity, must deal with the realities of their immediate environment. The spatial arrangement of cancer cells, the “neighborhood,” and even the blocks within that neighborhood are not equal in terms of benefit to the cancer cell. Different neighborhoods give rise to different phenotypes: those cancer cells near a blood vessel enjoy greater access to oxygen, nutrients, and a pleasant, alkaline pH, whereas those farther away from the vascular supply are relatively deprived of these things. In fact, the position of a tumor cell on the pH, oxygen, and nutrient gradients within a single tumor mass determines its resistance to certain treatments, and also its propensity to metastasize, or spread.
With application of treatment, individual cancer cells susceptible to that treatment are destroyed. However, this leaves those cancer cells resistant to treatment to repopulate the tumor. With the the treatment-susceptible cells now gone, the treatment-resistant cells now have unencumbered access to all the supplies needed for unencumbered growth. They are enjoying the new lack of competition, called in evolutionary biology “competitive release.” They therefore grow quickly and repopulate the tumor.
The conventional treatment paradigm we oncologists work under advises using the “maximum tolerated dose,” MTD, applied at specific, non-varying frequencies. This is an attempt to kill as many tumor cells as possible while avoiding (sometimes just barely) killing the patient.
This model predictably engenders emergence of treatment-resistance in tumors, and such treatment has now been shown not to prolong survival, but to accelerate death in patients with “incurable” cancers. This is competitive release in action. In a bad way.
This lecture will explore recent research that has successfully challenged that approach, a new treatment paradigm called “adaptive therapy,” and based on the principles of evolution and ecology. Precedents include ecological theory that has devised successful approaches to pest management in agriculture, which mandates avoiding “competitive release” of resistant organisms. That is, total destruction of the pest is avoided in favor of “control,” a new equilibrium allowing lower—and tolerable—levels of the pest to survive.
In cancer treatment, the adaptive therapy approach uses small doses of several different drugs, applied singly or in combination, with long treatment breaks, and at intervals varying according to the patient’s response rather than calendar time. This is what differentiates adaptive therapy from “metronomic” chemotherapy.
The adaptive approach eschews “maximal tolerated dose” and maximum tumor cell kill in favor of reducing and maintaining some tumor burden indefinitely, but at a level where the patient is asymptomatic. In other words, instead of aiming for cure (not possible for the most common metastatic cancers of late adulthood), the goal is to keep the patient alive and feeling well. The population of treatment sensitive cells is put to work as competitive inhibitors of treatment-resistant cells.
Integrated into this approach are dietary maneuvers, such as carbohydrate restriction, exercise, hyperbaric oxygen therapy, etc. These may require specific timing in tumor evolution and treatment for optimal benefit.
The success of the “adaptive therapy” approach is predicted by mathematical models of cancer treatment employing “game theory.” The success of adaptive therapy over MTD has been corroborated in early clinical trials in patients with advanced metastatic prostate cancer and small cell lung cancer. However, the adaptive model is not for use in pediatric cancer, of which 85% are curable even in advanced stages, or in cancers of adulthood shown to be curable with conventional approaches.
Goals:
Participants will be able to:
• Discuss the evolutionary reasons behind Peto’s paradox: why some multicellular organisms rarely develop cancer, and why humans are prone to cancer.
• Discuss the limitations of the “maximum tolerated dose” paradigm when used in treatment of most advanced, incurable metastatic cancers of adults, and contrast it with the “adaptive therapy” model.
