(ISS-PT) Optimization of Treatment Planning in Proton Radiotherapy to Protect the Immune System

At a glance

What is ISS-PT about?

More than half of all cancer patients undergo radiotherapy (RT). RT is a double-edged sword—highly curative yet may lead to serious normal tissue toxicities. A significant concern is the suppression of the immune system, particularly through the destruction
of immune cells, lymphocytes, both within and outside the tumor volume. Radiation-induced lymphopenia has been associated with markedly poorer clinical outcomes, including reduced survival rates. Radiation can also stimulate the immune system by
inducing immunogenic tumor cell death. This immune activation, especially when combined with immunotherapy, has the potential to eliminate both primary and metastatic tumors. A key objective in current cancer research is to enhance the ratio of immune stimulation to immune suppression. Lymphocytes are particularly vulnerable to low and intermediate radiation “dose baths”.

This project will develop novel techniques for optimizing IMPT plans, focusing on minimizing the dose to lymphocyte-rich structures and reducing the incidence and severity of lymphopenia. Our hypothesis is that by incorporating specific dose tolerance constraints and optimizing beam configurations, it is possible to significantly reduce lymphocyte depletion and enhance overall treatment outcomes.

What critical challenges is ISS-PT addressing?

Whilst the volumes to treat can be irradiated using almost any admissible directions, a proper choice of beam configurations is known to improve organ sparing. However, lymphocyte-rich structures are not usually included in treatment plan optimization.
Moreover, the number of treatment fractions can also be considered in the treatment planning optimization, since there is evidence that hypofractionation contributes to a reduction of the loss of lymphocytes. However, hypofractionation increases the
impact of inherent uncertainties in IMPT. These uncertainties may behave differently than with other organs-at-risk, due to the specificities of the structures to be considered (like large blood vessels).

How will ISS-PT help the mitigation of radiation-induced lymphopenia?

Radiation-induced lymphopenia mitigation can be maximized using beam configuration optimization in combination with appropriately optimized IMPT dose distributions that maximally spare circulating lymphocytes and lymphocyte-rich organs. This can be achieved without symptomizing tumor dose and tolerances of other organs-at-risk.

Moreover, we assert that immune checkpoint inhibitors in combination with IMPT, optimized to maximally spare the immune system, may eventually be among the most effective ways of treating cancers. Including in the treatment planning workflow additional structures, as well as additional objectives or constraints, will possibly increase the complexity of this procedure, motivating the development of new modelling and algorithmic approaches.

How is ISS-PT contributing to radiotherapy research?

ISS-PT is well aligned with the UN Sustainable Development Goals (3 and 9). The expected developments will benefit patient care. Developing automated radiation-induced lymphopenia mitigation treatment planning procedures will simplify the treatment workflow, making better use of the existing human resources, keeping healthcare affordable and allowing more patients to be treated. It will open avenues for truly personalized radiotherapy treatment planning, supporting better integrated treatment options, considering explicitly the impact of RT-induced lymphopenia and consequences for overall survival. This research will contribute to rising the quality of radiation treatment of patients, potentially resulting in increased cure or reduced incidence of severe radiation-induced morbidity.