Radiotherapy

Once biological systems are exposed to ionizing radiation, charged particles interact with atoms of the irradiated cells ionizing and exciting them. Ionization and excitation trigger chemical reactions that ends with broken molecules and breakage of chemical bonds. These molecules or free radicals seek to establish an electronic charge equilibrium and subsequently generates changes in biologically important molecules like DNA. Most of the generated damages will be

repaired and those injuries that cannot be repaired will result in cell death during interphase, mitosis or even after several cell divisions after exposure to radiation (Joiner & Kogel 2019).

In radiotherapy, high radiation dose is delivered to well define target volume in order to kill tumor cells and cure the patient (curative intent) or to manage the symptoms caused by the tumor (palliative intent). Radiotherapy treatments use different types of radiation: Charged particles (electrons, protons and carbon ions), photons (high energy X-rays, gamma rays) and neutrons. Radiation modalities differ from each other on penetration and energy transfer properties. Furthermore, costs and availability of the radiation modalities differs significantly.

High energy X-rays and electrons are most commonly used on radiotherapy (Sibtain et al. 2012, Rodrigues et al. 2013).

Radiation dose is typically given in multiple daily fractions to take advantage of reoxygenation and reassortment of tumor cells. Also, fractionation enables the normal tissue repair and repopulation and thus, increase the normal tissue tolerance to radiation. (Sibtain et al. 2012, Rodrigues et al. 2013). Typical fraction dose is 2 Gy / day. If more than 2 Gy delivered on a fraction treatment is called hypofractionation and if fraction dose is less than 2 Gy treatment is called hyperfractionation (Joiner & Kogel 2019).

Radiotherapy can be divided in two main categories: One defined as external beam radiotherapy (EBRT) if radiation is delivered from an external source to the patient using, for example, Linear accelerators. And a second defined as brachytherapy if radiation is delivery from a source that is transferred inside the patient (World Health Organization & International Atomic Energy Agency 2021). In the present review, all evaluated radiotherapy treatments were given using EBRT, high energy X-rays and hypofracionation.

Goals of cancer therapy include survival-based endpoints, tumor control endpoints, health related QOL, and various palliative or symptom control endpoints. In bone metastases main goals are decrease pain and prevention of the morbidity associated to it. General considerations

for radiotherapy are patient immobilization, simulation, treatment planning and treatment.

(Rodrigues et al. 2013).

2.2.1 Radiotherapy techniques

As described by WHO and IAEA (2021) radiotherapy techniques can be two-dimensional (2D), three dimensional conformal (3D-CRT), intensity–modulated radiotherapy (IMRT), image-guided radiotherapy (IGRT) or stereotactic radiotherapy:

• 2D: Based on 2D imaging as radiographs and anatomical references. Dose calculation are simple performed manually or computerized. Organs at risk (OAR) sparing is difficult. See figure 2.

• 3D-CRT: Based on 3D imaging as CT. Treatment planning is computerized. One or multiple radiation fields are delivered from different gantry angles. Radiation fields are shaped according to target volume using multi leaf collimator (MLC). More conformal treatment plans than with 2D some OAR sparing can be achieved.

• IMRT: Based on 3D imaging. Inverse treatment planning is used to create complex dose distributions allowing effective OAR sparing while high coverage to target volume is maintained. IMRT can be delivered using fixed gantry angle beams or during continuous arc. If arc is used technique is commonly referred as Volumetric modulated arc therapy (VMAT)

• IGRT: To improve the accuracy of the treatments several on-board imaging systems have been introduced for targeting radiotherapy treatments. Cone beam computed

tomography, 2D kV imaging, MRI and optical systems are currently used for image guidance in radiotherapy. Using daily imaging uncertainty margins of treatment volume could be decreased. To take into account breathing motion optical systems can be used to track chest wall movement and treatment can be delivered during a triggered part of breathing cycle or more commonly during deep inspiratory breath hold. For some systems online treatment adaptation to breathing motion is possible.

Figure 2. CT Planning comparison of (a) conventional radiotherapy (2D RT); (b) 3D-CRT;

and (c) IMRT plan for head-neck cancer. Source: (Gupta et al. 2010)

• SBRT Development of accurate modern radiotherapy techniques and sophisticated image guidance systems have made stereotactic radiotherapy widely available for treatment of extra cranial targets. In SBRT treatment, highly conformal dose distribution is delivered in submillimetre accuracy to well defined target volume. Additionally, modern image

guidance system is used to ensure the patient position and location of the target volume before and/or during the treatment delivery. Typically, SBRT treatments are delivered in high fraction doses using small number of fractions (Sahgal et al. 2012, World Health Organization & International Atomic Energy Agency 2021).

2.2.2 Stereotactic body radiation therapy and bone metastases

Bone metastases are frequent in cancer patients. Symptoms related to bone metastases are localized pain, SREs or deficits from compression of the spinal cord, nerve roots or peripheral nerves. With pain as the most common symptom requiring intervention. SBRT shows promise in the treatment of these patients. (Vassiliou et al. 2014). General consideration for SBRT treatment path for bone metastases are:

• Therapeutic considerations: Concurrent treatments as bisphosphonates, radionuclides, kyphoplasty, vertebroplasty, surgical decompression or stabilization (Rodrigues et al.

2013).

• Patient immobilization: Immobilization is required for effective simulation and

treatment. In order to minimize movement during radiotherapy fraction and improve the position reproducibility between the fractions. Typical devices for immobilization are vacuum systems, head and foot rests, thermoplastic masks, or motion management techniques (Garcia 2019, Rodrigues et al. 2013).

• Simulation: Obtain information for treatment planning. Includes the definition and localization of targets, normal tissues and patient anatomy including the external contour of the patient. MRI or PET-CT registered to treatment planning CT can be used to guide the delineation of target and normal tissues. Four-dimensional computed tomography (4DCT) can be used to evaluate margins needed to take into a count the respiratory movement (Garcia 2019, Rodrigues et al. 2013).

• Treatment planning: Modern inverse planning techniques are typically used with SBRT.

To delivered high fraction dose to target tissue highly conformal dose distribution is created and dose to normal tissues surrounding the target is minimized. Regular quality assurance measurement is warranted to verify that dose distribution calculated with treatment planning software is in line with dose delivered to patients (Garcia 2019, Rodrigues et al. 2013).

• Treatment: Accurate image guidance is required for verification of patient positioning and monitoring the patient movements during the treatment fraction when frameless treatment delivery is used. For stereotactic treatments localization accuracy under 1 mm is recommended. Regular quality assurance measurements are warranted to evaluate the end-to-end accuracy of the treatment system (Garcia 2019, Rodrigues et al. 2013).

SBRT can be delivered in multiple equipment including gantry based linear accelerators (LINAC) (for example, Infinity, Elekta AB, Stockholm, Sweden, figure 3.), Robotic LINAC (Cyber knife, Accuray, CA,USA), Bore based LINAC (Halcyon Varian, CA, USA), or Cobalt system (Gamma Knife, Elekta AB, Stockholm, Sweden).

Figure 3. Gantry based LINAC in Kuopio university hospital (KUH) (Infinity, Elekta). Image;

radiotherapy unit of KUH.

2.2.3 Global context

In 2021 World health Organization (WHO) and International Atomic Energy Agency (IAEA) published “Technical specifications of radiotherapy equipment for cancer treatment”. A report aimed to provide technical specifications for radiotherapy equipment commonly used in the treatment of cancer and referred SBRT as an emerging technique. This report addresses the lack of robust evidence to support SBRT. However, reinforce the current results that favor SBRT in terms of reducing the overall treatment time by reducing the number of fractions been possible to increase the number of patients to be treated by the oncology department (World Health Organization & International Atomic Energy Agency 2021)

Literature providing standardization or consensus still growing, some examples are

“International consensus on palliative radiotherapy endpoints for future clinical trials in bone metastases”, “RTOG 0631 phase 2/3 study of image guided stereotactic radiosurgery for localized (1-3) spine metastases: phase 2 results” and “Defining oligometastatic disease from a radiation

oncology perspective: An ESTRO-ASTRO consensus document” (Chow et al. 2002, Lievens et al.

2020, Ryu, S. et al. 2014). The international commission on radiation units & measurements (ICRU) recently publish ICRU report 91adressing aspects on small field dosimetry, accuracy requirements for volume definition and planning algorithms, and the precise application of treatment by means of image guidance. Also, recommendations for prescribing, recording, and reporting (Wilke et al. 2019).

Other standard recommendations and nomenclature relevant for SBRT are ICRU reports number 50, 62 and 83. These reports provide information as definition of concepts for gross target volume (GTV), clinical target volume (CTV), internal target volume (ITV) and planning target volume (PTV) as well as OAR and planning organ at risk volumes (PRV) (Wilke et al. 2019).

Associations like ESMO, JASTRO and ASTRO constituted an international reference to identified dose regimes, imaging protocols, consensus, and definitions. Also, suitable research end points, multiple guidelines, and standards for SBRT.

Patterns of SBRT for OM disease are still not fully consensual. In a profound review by Lewis et al. (2017) a total of 1007 completed surveys were reported from radiation oncologists in 43 countries reveling the most common SBRT regimes, dose (Gy) and fraction (Fx) used for oligometastases by region:

• Western Europe 20 Gy / 1 Fx, 54 Gy / 3 Fx and 60 Gy / 8 Fx

• United States 48 Gy / 4 Fx, 50 Gy / 5 Fx and 30 Gy / 5 Fx

• Japan 48 Gy / 4 Fx, 50 Gy / 5 Fx, 60 Gy / 8 Fx and 45 Gy / 15 Fx

• Canada 60 Gy / 5 Fx, 48 Gy / 4 Fx, 35 Gy / 5 Fx, 30 Gy / 5 Fx and 20 Gy / 5 Fx