Adaptive therapy, an ecologically inspired approach to cancer treatment, aims to overcome resistance and reduce toxicity by leveraging competitive interactions between drug-sensitive and drug-resistant subclones, prioritizing patient survival and quality of life instead of killing the maximum number of cancer cells. In preparation for a clinical trial, we used endocrine-resistant MCF7 breast cancer to stimulate second-line therapy and tested adaptive therapy using capecitabine, gemcitabine, or their combination in a mouse xenograft model. Dose modulation adaptive therapy with capecitabine alone increased survival time relative to MTD but not statistically significantly (HR = 0.22, 95% CI = 0.043–1.1, p = 0.065). However, when we alternated the drugs in both dose modulation (HR = 0.11, 95% CI = 0.024–0.55, p = 0.007) and intermittent adaptive therapies, the survival time was significantly increased compared to high-dose combination therapy (HR = 0.07, 95% CI = 0.013–0.42, p = 0.003). Overall, the survival time increased with reduced dose for both single drugs (p < 0.01) and combined drugs (p < 0.001), resulting in tumors with fewer proliferation cells (p = 0.0026) and more apoptotic cells (p = 0.045) compared to high-dose therapy. Adaptive therapy favors slower-growing tumors and shows promise in two-drug alternating regimens instead of being combined.

The standard of care for cancer patients aims to eradicate the tumor by killing the maximum number of cancer cells using the maximum tolerated dose (MTD) of a drug. MTD causes significant toxicity and selects for resistant cells, eventually making the tumor refractory to treatment. Adaptive therapy aims to maximize time to progression (TTP), by maintaining sensitive cells to compete with resistant cells. We explored both dose modulation (DM) protocols and fixed dose (FD) interspersed with drug holiday protocols. In contrast to previous single drug protocols, we explored the determinants of success of two-drug adaptive therapy protocols, using an agent-based model. In almost all cases, DM protocols (but not FD protocols) increased TTP relative to MTD. DM protocols worked well when there was more competition, with a higher cost of resistance, greater cell turnover, and when crowded proliferating cells could replace their neighbors. The amount that the drug dose was changed, mattered less. The more sensitive the protocol was to tumor burden changes, the better. In general, protocols that used as little drug as possible, worked best. Preclinical experiments should test these predictions, especially dose modulation protocols, with the goal of generating successful clinical trials for greater cancer control.

One of the main reasons we have not been able to cure cancers is that treatments select for drug-resistant cells. Pest managers face similar challenges with pesticides selecting for pesticide-resistant insects, resulting in similar mechanisms of resistance. Pest managers have developed 10 principles that could be translated to controlling cancers: (i) prevent onset, (ii) monitor continuously, (iii) identify thresholds below which there will be no intervention, (iv) change interventions in response to burden, (v) preferentially select nonchemical control methods, (vi) use target-specific drugs, (vii) use the lowest effective dose, (viii) reduce cross-resistance, (ix) evaluate success based on long-term management, and (x) forecast growth and response. These principles are general to all cancers and cancer drugs and so could be employed broadly to improve oncology. Here, we review the parallel difficulties in controlling drug resistance in pests and cancer cells. We show how the principles of resistance management in pests might be applied to cancer. Integrated pest management inspired the development of adaptive therapy in oncology to increase progression-free survival and quality of life in patients with cancers where cures are unlikely. These pest management principles have the potential to inform clinical trial design.

Adaptive therapy, as per the dose modulation, dose-skipping, or intermittent treatment protocol works well for treatment using a single cytotoxic drug, under a wide range of scenarios and parameter settings. In contrast, adaptive therapy works well only under a limited number of scenarios and parameter settings when using a single cytostatic drug. In general, adaptive therapy works best under conditions of higher fitness cost, higher replacement rate, higher turnover. Adaptive therapy works best when drug dosages are changed as soon as a change in tumor burden is detected. In general, it is better to pause treatment sooner than later, when the tumor is shrinking If the amount of drug used is too low, it is unable to control the sensitive cells and the tumor grows. However, if the drug dose is too high, it quickly selects for resistant cells and eventually the tumor grows out of control. However, there appears to be intermediate levels of dosing, which we call the minimum effective dose, which is able to control the sensitive cells but is not high enough to select for the resistant cells to grow out of control.

While the dose modulation (DM) protocols (DM Cocktail Tandem, DM Ping-Pong Alternate Every Cycle, DM Ping-Pong on Progression) involves adjusting drug dosages when the tumor burden changes, the fixed-dose (FD) protocols involves administering a specific, constant dosage of the drug only when the tumor is growing (Dose-Skipping) or when the absolute tumor burden is above the baseline level until it reduces to a certain percentage of the baseline (Intermittent). Moreover, two different drugs can be administered simultaneously (cocktail), or the drugs can be switched such that only one drug is applied at a given time (ping-pong), either every cycle (ping-pong alternate every cycle) or when the tumor grows (ping-pong on progression). The dose modulation protocols work well when treated with two cytotoxic drugs, however, the ping-pong protocols (DM Ping-Pong Alternate Every Cycle, DM Ping-Pong on Progression, FD Ping-Pong Intermittent) work well when treated with two cytostatic drugs. In general, adaptive therapy, using either two cytotoxic or two cytostatic drugs works best under conditions of high competition, such as high fitness cost, high replacement rates, and high turnover, although treatment using two cytostatic drugs works best under low turnover in many cases. Adaptive therapy works best when drug dosages are changed as soon as a change in tumor burden is detected, and it is best to pause treatment sooner rather than later when the tumor is shrinking. Adaptive therapy works best when an intermediate level of drug dosage is used, and both treatment with too little or too much drug leads to poor survival outcome.

One of the main reasons we have not been able to cure cancers is that treatments select for drug-resistant cells. Pest managers face similar challenges with pesticides selecting for pesticide-resistant insects, resulting in similar mechanisms of resistance. Pest managers have developed 10 principles that could be translated to controlling cancers: (i) prevent onset, (ii) monitor continuously, (iii) identify thresholds below which there will be no intervention, (iv) change interventions in response to burden, (v) preferentially select nonchemical control methods, (vi) use target-specific drugs, (vii) use the lowest effective dose, (viii) reduce cross-resistance, (ix) evaluate success based on long-term management, and (x) forecast growth and response. These principles are general to all cancers and cancer drugs and so could be employed broadly to improve oncology. Here, we review the parallel difficulties in controlling drug resistance in pests and cancer cells. We show how the principles of resistance management in pests might be applied to cancer. Integrated pest management inspired the development of adaptive therapy in oncology to increase progression-free survival and quality of life in patients with cancers where cures are unlikely. These pest management principles have the potential to inform clinical trial design.