A different way of looking at cancer, using a so-called "eco-evolutionary" model, has been given a boost by new results from a preclinical model of breast cancer. Adaptive therapy involving frequent administration of low-dose paclitaxel (multiple brands) was shown to significantly increase overall survival in mice with triple-negative breast cancer compared with control animals receiving standard high-dose paclitaxel.
The report from researchers at the Moffitt Cancer Center, Tampa, Florida, was published online February 24 in Science Translational Research.
"According to evolutionary principles, high-dose therapy is least likely to be successful in controlling the tumor for any length of time because it intensely selects for resistant cells and allows them to grow rapidly because the treatment has eliminated all of its competitors," corresponding author Robert Gatenby, MD, said in a Moffitt press release.
Rather than trying to aggressively shrink the tumor, drug doses should be lowered, depending on how the tumor responds, so that a small population of drug-sensitive cells are always around to suppress the growth of resistant ones, the authors suggest.
"This conceptually simple idea is not only novel, it is also wide ranging in its application," says Giannoula L. Klement, MD, of the Tufts School of Medicine, Boston, Massachusetts, in a focus article that accompanies the new results.
It changes "the existing paradigm of cancer as a foreign tissue needing eradication by high-dose chemotherapy," she writes, to "a model of cancer as an eco-evolutionary system, in which sustained suppression of tumor growth is a more appropriate therapeutic path — and one with much less toxicity."
Although the results are from a preclinical study, they have been sufficient to prompt a team of Moffit researchers, led by Jingsong Zhang, MD, PhD, to test this approach in a pilot study. They are using adaptive therapy with abiraterone (Zytiga, Janssen Pharmaceuticals, Inc) in patients with castration-resistant prostate cancer. "The purpose of this study is to find out if an on-and-off schedule of taking abiraterone would prolong the participants' cancers' response to this drug and maintain their functionality to perform their daily activities," the researchers explained.
A computerized algorithm for each patient will allow individualized treatment based on response to therapy. Levels of prostate-specific antigen (PSA) will be monitored throughout the study. Treatment with abiraterone will be stopped and only reinitiated when an increase in PSA levels of 50% or greater is observed. This approach mirrors that reported in the mouse model of adaptive therapy.
Results From Mouse Model of Breast Cancer
The preclinical study tested the adaptive therapy approach in two mouse models of breast cancer — a triple-negative model, and an estrogen-positive model.
Separate cohorts of mice were treated with paclitaxel in one of three approaches. In the standard approach, mice were given the standard maximum dose of paclitaxel, 20 mg/kg, twice a week for 2.5 weeks (ST).
In the first adaptive therapy (AT1) approach, the frequency at which paclitaxel was administered was determined by measuring tumor size. On the basis of a defined algorithm, after the initial dose of 20 mg/kg, the paclitaxel dose was decreased by an amount determined on the basis of the decrease in tumor volume.
In the second adaptive therapy (AT2) approach, paclitaxel was started at a moderately high dose, 15 mg/kg. Subsequent drug treatment was determined from the percentage of tumor growth rate measured twice weekly. Treatment was skipped if tumor volume remained constant or decreased relative to the last two measurements.
Although the ST approach led to a rapid reduction in tumor burden, complete eradication was rare. The dose-skipping approach (AT2) was also not successful because the tumors grew during the period when the dose was skipped.
However, the AT1 approach, which used frequent, low-dose delivery of paclitaxel, consistently provided tumor control and longer survival.
With the AT1 approach, from 60% to 80% of the mice could be weaned off the drug completely without relapsing for an extended period.
The study supports "a flexible treatment strategy, which varies the drug dosing and scheduling to maintain a persistent population of sensitive cells and reduce the proliferation of resistant populations" and calls attention to the eco-evolutionary model of cancer.
The Concept of Eco-Evolution
The eco-evolutionary model of cancer suggests that during high-dose cytotoxic therapy, drug-resistant cells thrive, because they are more fit and are able to withstand the environmental changes better than their wild-type counterparts.
Frequent low-dose therapy maintains a stable population of drug-sensitive cells, keeps the drug-resistant population under control, and maintains the equilibrium within the tumor ecosystem such that resistant cells do not gain evolutionary advantage, Dr Klement explained to Medscape Medical News.
Indeed, she notes in her focus article that evolutionary dynamics explain that some patients harbor malignant clones throughout their lives and do not develop disease. Occult in situ breast cancer has been observed in autopsies of young and middle-aged women who died of noncancer causes, she points out.
In a second example, she indicates that the clinical management of patients with prostate cancer that involves watchful waiting is explained on the same principle.
"More than 40% of men with normal rectal examinations in their 60s have histological evidence of malignant disease, but the prevalence of clinically apparent prostate cancer is only 1%," Dr Klement writes.
Improvements in medical imaging will overestimate disease and may lead to early intervention, disturbing the Darwinian equilibrium, she cautions.
"[E]nthusiasm for early interventions should be tempered," she recommends, "because it can disturb the equilibrium, causing inflammation, escape from dormancy, and more aggressive disease."
Low-Dose Therapy Explained
Dr Klement indicated that the aim of low-dose chemotherapy is to establish a gradual, antitumor effect, which prevents tumor progression and affects tumor size only over time.
This concept has already been evaluated in clinical practice, she told Medscape Medical News. Metronomic chemotherapy, dose-dense therapy, and adaptive therapy are well-tested approaches, and although clinical trials have supported their efficacy, the accounts of the mechanism for how these approaches work have been unsatisfactory until now, she said.
"Over the last 50 years, we have believed that maximum tolerated dose therapy works because the more you delivered, the more effect it would have," Dr Klement explained.
"This principle is flawed in humans," she argued. "The doses needed to kill cancer, which are determined from the IC50 drug concentration required to kill half the cancer cells, cannot be achieved in biologically complex cancers, which are protected by the tumor microenvironment and by normal cells," she said.
She explains in her article that maximum tolerated dose (MTD) chemotherapy and radiation are defined by dose-limiting toxicities to normal cells. Cytotoxic therapy eliminates chemotherapy- sensitive cancer cells and, along with them, native anticancer immune cells and stromal support cells. Through multiple rounds of MTD chemotherapy, these terminally differentiated cells gradually become depleted.
"Low-dose, metronomic chemotherapy, by preventing repeated cycles of myelosuppression, preserves the immune system, enhances immune surveillance, and decreases inflammation and angiogenesis," she writes.
Dr Klement told Medscape Medical News that the study's eco-evolutionary model of cancer is prompting researchers and clinicians to rethink current therapeutic strategies for cancer.
"It's an exciting time in oncology," she told Medscape Medical News. "We are moving away from the highly toxic MTD approach to the less toxic biologic-based therapy," she added.
She noted that in a recent search of clinical trials, it was heartening to find many studies that are exploring the combination of low-dose chemotherapy with targeted therapy or immunotherapy. Low-dose chemotherapy has less deleterious effects on normal cells and tissues and maintains the equilibrium between sensitive and resistant tumor cells, whereas targeted therapy hits the tumor, and immunotherapy boosts antitumor immunity, she explained.
Dr Gatenby is a member of the scientific advisory board and an investor in HealthMyne Inc. Dr Klement has disclosed no relevant financial relationships.
Sci Transl Med. Published online February 24, 2016. Full text, Focus article
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