Page 56 - SRPSKO DRUŠTVO ISTRAŽIVAČA RAKA

Serbian Association for Cancer Research SDIRSACR

L02

Novel Approaches in Radiation Oncology with a Special Focus on Combination Therapies

Katalin Hideghety 1,2

1 Oncotherapy Department, University Szeged, Hungary
2 The Extreme Light Infrastructure ERIC | ALPS Facility, Szeged, Hungary

Keywords: Chemoradiotherapy, Radiosensitization, Immuno-radiotherapy, UHDR, LaserDriven Particle Beam

1. Combination of radiation-systemic agent
The integration of cytotoxic chemotherapy with radiotherapy has historically been motivated by spatial cooperation
and independent cytotoxicity. With growing clinical evidence, chemoradiotherapy has become a standard treatment
modality for several malignancies, including glioblastoma, head and neck squamous cell carcinoma (HNSCC), cervical
cancer, non–small cell lung cancer (NSCLC), and gastrointestinal tumors. The rationale behind combining chemotherapy
with radiotherapy lies in their overlapping and complementary mechanisms. Chemotherapy agents, particularly
temozolomide, cisplatin and fluoropyrimidines, act as radiosensitizers by inhibiting DNA repair, synchronizing cell
cycles, and increasing oxidative stress within tumor cells [1-3]. Molecular targeted agents interact with RT by inhibiting
the repair of radiation-induced double-strand breaks (novel small molecule inhibitors of DNA damage response
(e.g., PARP inhibitors) or by interfering with cell cycle checkpoints Notably, inhibitors of ATR, DNA-PK, and CHK1 have
demonstrated in vitro and in vivo radiosensitization across multiple cancer models, often yielding ≥2-fold increases in
tumor growth delay when administered concomitantly with low LET radiation [4]. Moreover, chemotherapeutic agents
can influence the tumor microenvironment to potentiate radiotherapy. For instance, platinum compounds not only
induce DNA crosslinks that impede replication but also promote immunogenic cell death, releasing tumor-associated
antigens and damage-associated molecular patterns (DAMPs) that activate dendritic cells. Anthracyclines and taxanes
similarly trigger immunostimulatory pathways, augmenting local inflammation and cytotoxic T cell infiltration
following irradiation. Such immunomodulatory properties lay the groundwork for tripartite combination regimens—
chemotherapy, radiotherapy, and immune checkpoint blockade—whereby chemotherapy intensifies radiosensitivity
while simultaneously facilitating the generation of an adaptive anti-tumor immune response [5-6]. Optimization of
sequencing, dosing, and fractionation remains critical. Personalized regimens guided by tumor genomics and functional
imaging biomarkers (e.g., γH2AX PET for DNA damage, FLT PET for proliferation) are under active clinical investigation
to refine synergistic potential while safeguarding normal tissues [7].

2. Hypofractionated High Dose Radiation Combined with Immunotherapy
Hypofractionation—delivering larger doses per fraction over fewer sessions is applied in stereotactic body radiotherapy
(SBRT) and stereotactic radiosurgery (SRS), achieving local control rates exceeding 90% in select oligometastatic
and primary tumor settings due to additional microenvironmental effects. Beyond high local efficacy, high dose
fractions induce unique immunogenic effects, including enhanced release of tumor neoantigens, upregulation of
type I interferon pathways, and increased expression of MHC class I molecules. These radiation-mediated changes
prime the tumor microenvironment for immune checkpoint inhibitors (ICIs), such as anti-PD-1/PD-L1 and anti-CTLA-4
antibodies, promoting immunogenic cell death, augmenting dendritic cell cross-presentation of tumor antigens, and
increasing chemokine gradients that recruit effector lymphocytes. Clinically, early-phase trials in non-small cell lung
cancer, melanoma, and renal cell carcinoma have demonstrated promising response rates when SBRT is administered
to a single lesion followed by systemic ICI therapy, with manageable toxicity profiles. PEMBRO-RT in metastatic NSCLC
hasshown improved progression-free survival when pembrolizumab was combined with SBRT. Further prospective
studies are now comparing concurrent versus sequential approaches, investigating optimal irradiated volume,
fractionation schedules (e.g., 3 × 8 Gy vs. 5 × 6 Gy), and combination partners (e.g., dual checkpoint blockade).
Additionally, biomarker research is focusing on circulating tumor DNA, immune cell repertoire dynamics, and spatial
transcriptomics to predict responders and tailor treatment intensity.

3. Laser Driven Particle Beams and FLASH Radiotherapy
While combination therapies harness biological synergy, advances in beam physics have led to an increased
therapeutic window. The FLASH effect—defined as ultra high dose rate (UHDR) irradiation (≥40 Gy/s) delivered in less
than a second—has garnered intense interest due to its remarkable ability to spare normal tissues while retaining
tumoricidal efficacy. Conventional accelerator systems face technical and size constraints in achieving UHDRs suitable
for clinical FLASH implementation. High-power laser sources, however, offer a novel approach to particle generation
and acceleration. Through laser-plasma interactions, electrons, protons, and neutrons can be produced in ultra-short,

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