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Stereotactic radiosurgery (SRS) is an established treatment for patients with brain metastases (BMs). However, damage to the healthy brain may limit the tumor dose for patients with multiple lesions.

In this study, we investigate the potential of spatiotemporal fractionation schemes to reduce the biological dose received by the healthy brain in SRS of multiple BMs, and also demonstrate a novel concept of spatiotemporal fractionation for polymetastatic cancer patients that faces less hurdles for clinical implementation.

Spatiotemporal fractionation (STF) schemes aim at partial hypofractionation in the metastases along with more uniform fractionation in the healthy brain. This is achieved by delivering distinct dose distributions in different fractions, which are designed based on their cumulative biologically effective dose () such that each fraction contributes with high doses to complementary parts of the target volume, while similar dose baths are delivered to the normal tissue. For patients with multiple brain metastases, a novel constrained approach to spatiotemporal fractionation (cSTF) is proposed, which is more robust against setup and biological uncertainties. The approach aims at irradiating entire metastases with possibly different doses, but spatially similar dose distributions in every fraction, where the optimal dose contribution of every fraction to each metastasis is determined using a new planning objective to be added to the BED‐based treatment plan optimization problem. The benefits of spatiotemporal fractionation schemes are evaluated for three patients, each with >25 BMs.

For the same tumor BED₁₀and the same brain volume exposed to high doses in all plans, the mean brain BED₂can be reduced compared to uniformly fractionated plans by 9%–12% with the cSTF plans and by 13%–19% with the STF plans. In contrast to the STF plans, the cSTF plans avoid partial irradiation of the individual metastases and are less sensitive to misalignments of the fractional dose distributions when setup errors occur.

Spatiotemporal fractionation schemes represent an approach to lower the biological dose to the healthy brain in SRS‐based treatments of multiple BMs. Although cSTF cannot achieve the full BED reduction of STF, it improves on uniform fractionation and is more robust against both setup errors and biological uncertainties related to partial tumor irradiation.

We consider the following scenario: A radiotherapy clinic has a limited number of proton therapy slots available each day to treat cancer patients of a given tumor site. The clinic's goal is to minimize the expected number of complications in the cohort of all patients of that tumor site treated at the clinic, and thereby maximize the benefit of its limited proton resources.

To address this problem, we extend the normal tissue complication probability (NTCP) model–based approach to proton therapy patient selection to the situation of limited resources at a given institution. We assume that, on each day, a newly diagnosed patient is scheduled for treatment at the clinic with some probability and with some benefit from protons over photons, which is drawn from a probability distribution. When a new patient is scheduled for treatment, a decision for protons or photons must be made, and a patient may wait only for a limited amount of time for a proton slot becoming available. The goal is to determine the thresholds for selecting a patient for proton therapy, which optimally balance the competing goals of making use of all available slots while not blocking slots with patients with low benefit. This problem can be formulated as a Markov decision process (MDP) and the optimal thresholds can be determined via a value‐policy iteration method.

The optimal thresholds depend on the number of available proton slots, the average number of patients under treatment, and the distribution of values. In addition, the optimal thresholds depend on the current utilization of the facility. For example, if one proton slot is available and a second frees up shortly, the optimal threshold is lower compared to a situation where all but one slot remain blocked for longer.

MDP methodology can be used to augment current NTCP model–based patient selection methods to the situation that, on any given day, the number of proton slots is limited. The optimal threshold then depends on the current utilization of the proton facility. Although, the optimal policy yields only a small nominal benefit over a constant threshold, it is more robust against variations in patient load.