Emerging Treatment Paradigms in Radiation Oncology

Abstract

Rapid advancements in radiotherapy and molecularly targeted therapies have resulted in the development of potential paradigm-shifting use of radiotherapy in the treatment of cancer. In this review, we discuss some of the most promising therapeutic approaches in the field of radiation oncology. These strategies include the use of highly targeted stereotactic radiotherapy and particle therapy as well as combining radiotherapy with agents that modulate the DNA damage response, augment the immune response, or protect normal tissues.

Figure 1

Summary of the progress of radiation technologies over the last 65 years. A, The top row, from left to right, shows the following:

1. Picture of the first linear accelerator that was employed for clinical use in the Western hemisphere, treating a 7-month old boy suffering from retinoblastoma with subsequent tumor control (Stanford 1955).

2. Fluoroscopic x-ray simulation of a lung cancer for conventional 2-dimensional (2D) radiotherapy

3. Picture of a modern linear accelerator with a 360 degree rotating gantry to treat deep-seated tumors.

4. Dose distribution of a 3-dimensional (3D) radiation treatment plan superimposed on an axial computed tomography (CT) image of a thoracic tumor.

5. Depiction of intensity modulated radiation treatment (IMRT) of a thoracic tumor using inhomogenous beam intensity from multiple directions.

The bottom row, from left to right, shows the following:

1. Dose distribution of an IMRT plan superimposed on an axial CT image of a thoracic tumor, showing much lower dose to the adjacent spinal cord.

2. Depiction of stereotactic body or ablative radiation treatment (SBRT/SABR) of hepatic tumors using non-coplanar multiple narrow beams from multiple directions.

3. Dose distribution of the SBRT/SABR plans for two hepatic tumors superimposed on a coronal CT image.

4. Profile of a particle beam covering the cancer at depth without exit dose behind the tumor.

5. Dose distribution of particle beam (proton) therapy covering the entire cranio-spinal axis in a child with medulloblastoma, showing no exit dose to the lung or abdomen.

B, The graph reflects the progress of radiation delivery over time, starting with conventional 2-dimensional (2D) radiotherapy in ~1950’s to the most recent introduction of particle beam therapy in ~2010.

Figure 2

The effect of radiation on the tumor, its microenvironment and adjacent normal tissues.

1. Global view of radiation targeting a solid tumor, showing that it affects not only tumor cells but also neighboring non-tumor cells and vascular structures.

2. DNA damaging effect of radiation on tumor cells, leading to DNA damage repair, cell cycle arrest, transcriptional response and eventual cell death

3. The effect of radiation on the immune compartment, leading to upregulation of inhibitory immune checkpoints and recruitment of myeloid derived suppressor cells (MDSC), resulting in immune suppression and anergy

4. Acute and late adverse radiation effects on surrounding normal tissues and strategies to counteract such an effect. PHD stands for prolyl hydroxylase

BDMC, Bone marrow derived macrophage; EPC, Endothelial precursor cell; TCR, T-cell receptor.

Figure 3

Schematics of DNA damage response, leading to G1 arrest, S-phase delay and G2 arrest, providing the rationale for targeting CHK1, CHK2 and WEE1.

Figure 4

An example of how an immune check point inhibitor such as anti-PD-1 or anti-PD-L1 antibody can be used together with radiotherapy to enhance the effect of radiation locally and distantly. MDSC, myeloid derived suppressor cells; TCR, T-cell receptor.