Lattice or Oxygen-Guided Radiotherapy: What If They Converge? Possible Future Directions in the Era of Immunotherapy

Abstract

Palliative radiotherapy has a great role in the treatment of large tumor masses. However, treating a bulky disease could be difficult, especially in critical anatomical areas. In daily clinical practice, short course hypofractionated radiotherapy is delivered in order to control the symptomatic disease. Radiation fields generally encompass the entire tumor mass, which is homogeneously irradiated. Recent technological advances enable delivering a higher radiation dose in small areas within a large mass. This goal, previously achieved thanks to the GRID approach, is now achievable using the newest concept of LATTICE radiotherapy (LT-RT). This kind of treatment allows exploiting various radiation effects, such as bystander and abscopal effects. These events may be enhanced by the concomitant use of immunotherapy, with the latter being ever more successfully delivered in cancer patients. Moreover, a critical issue in the treatment of large masses is the inhomogeneous intratumoral distribution of well-oxygenated and hypo-oxygenated areas. It is well known that hypoxic areas are more resistant to the killing effect of radiation, hence the need to target them with higher aggressive doses. This concept introduces the "oxygen-guided radiation therapy" (OGRT), which means looking for suitable hypoxic markers to implement in PET/CT and Magnetic Resonance Imaging. Future treatment strategies are likely to involve combinations of LT-RT, OGRT, and immunotherapy. In this paper, we review the radiobiological rationale behind a potential benefit of LT-RT and OGRT, and we summarize the results reported in the few clinical trials published so far regarding these issues. Lastly, we suggest what future perspectives may emerge by combining immunotherapy with LT-RT/OGRT.

Keywords: GRID radiotherapy; Oxygen guided radiotherapy; abscopal effect; bulky tumors; bystander effect; lattice radiotherapy; spatially fractionated radiotherapy; stereotactic radiotherapy; tumor biology.

Figure 1

Schematic representation of Lattice radiotherapy with IMRT delivery (on the left) and GRID radiotherapy with a sieve-like physical filter (on the right) for a bulky tumoral mass, inside which seven high dose spheres (red vertices) are shown.

Figure 2

Three-Dimensional (3D) rendering of bulky metastatic iliac lymph node packets from urothelial bladder cancer in a patient candidate for a salvage pelvic radiotherapy (on the left). On the right, 3D dose distribution with a lattice simulation approach. Blue is for the conventional standard dose, red for high peak ones.

Figure 3

Dose distribution in the axial plane (left), the coronal plane (middle), and the sagittal plane (right).

Figure 4

The hypothesis to explain lattice radiotherapy mechanism: pink line delineates global tumor volume, the yellow line shows the necrotic core, and red spheres represent high dose regions and are approximately located at the boundary between the necrotic and normoxic areas (hypoxigenated interface) to radially elicit the bystander effect (blue arrows), accurately avoiding high dose delivery in the green strip due to the hazardous closeness of bowel (Organ At Risk: OAR).