Spatially fractionated radiotherapy, also known as grid therapy (GRID), has been used for more than a century to try to treat several kinds of lesions. Yet, the grid technique remains a relatively unknown and uncommon treatment modality nowadays. Spatially fractionated beams, instead of conventional homogeneous fields, have been used to exploit the experimental finding that normal tissue can tolerate higher doses when smaller tissue volumes are irradiated. This increase in tolerance with reducing beam size is known as the dose-volume effect. Despite the fact that targets were given inhomogeneous dose distribution, sometimes with some volumes receiving close to no dose, good results in the form of shrinking of bulky tumors have been observed in palliative treatments. The biological processes responsible for this effect are still under discussion, with several possible causes. However, numerous experiments on mice, rats and pigs have confirmed the existence of such effect, which in turn motivates the present development of grid therapy.While mainly photons have been used in grid therapy, proton and ion grid therapies are also emerging as potential alternatives. In this work, an innovative form of grid therapy was proposed. Grids of proton beamlets were interlaced over a target volume with the intention of achieving two main objectives: (1) to keep the grid pattern (made of adjacent high and low doses) from the skin up to the vicinity of the target while (2) delivering nearly homogeneous dose to the target volume. This interlaced proton grid therapy was explored with the use of different beam sizes, from conventional sizes deliverable at modern proton facilities, down to millimeter sized beams. Other considerations that would prevent its clinical use, such as the variable relative biological effectiveness of protons or the use of cone beam computed tomography, were also evaluated. The overall aim was to assess if, and how, such treatment modality could be applied clinically, from a physics and dosimetry point of view. While it presented several theoretical advantages, its potential issues of concern and limitations were also evaluated.

The use of ionizing radiation for treatment of cancer diseases is continuously increasing as patient survival is improving and new treatment techniques are emerging. While this development is beneficial for curing primary tumors, concerns have been raised regarding the unwanted dose contribution to healthy tissues of patients and the associated risk of radiation-induced second cancer (RISC). This is especially important for younger patients receiving radiotherapy more often than before and for whom the risk of developing RISC is elevated in comparison to the typical adult radiotherapy patient. In order to estimate the risk of RISC associated with modern radiotherapy and imaging, the associated radiation doses must be determined.

Patients undergoing radiotherapy receive in-field doses from the primary beam but also out-of-field doses originating from secondary radiation produced in the beamline and within the patient. Over the last years, the use of proton pencil beam scanning (PBS) therapy has rapidly increased due to its potential to reduce the in-field doses to healthy tissues in comparison to photon therapy. One of the drawbacks with proton therapy is the production of neutrons capable of travelling large distances and depositing out-of-field doses to organs located far from the primary treatment field. The dose reduction associated with proton PBS therapy could consequently be affected by the out-of-field doses originating from secondary radiation.

The sharp dose gradients associated with modern treatment techniques, such as photon intensity-modulated radiotherapy (IMRT) and proton PBS therapy require more frequent and accurate patient imaging in comparison to conventional treatment techniques such as three-dimensional conformal radiotherapy (CRT). Setup verification images could be acquired with cone-beam computed tomography (CBCT) producing three-dimensional patient images at the cost of an increased patient dose in comparison to planar x-ray imaging. Concerns have been raised regarding the cumulative patient doses from repeated CBCT imaging versus the dose-saving benefits associated with modern radiotherapy techniques like IMRT and proton PBS.

In this thesis, a study on the in-field and out-of-field doses to healthy tissues from photon IMRT and CRT treatments of head and neck tumors showed that the risk of RISC was unaffected by the employed treatment technique and indicated that the lifetime risk of cancer induction was of the order of 1-2%.

Results from measurements and Monte Carlo simulations showed that the out-of-field absorbed doses and equivalent doses associated with proton PBS treatments of brain tumors were up to 60 µGy/Gy and 150 µSv/Gy, respectively. The risk of RISC associated with these out-of-field doses was in the range of approximately one induced cancer in ten thousand treated patients. A simulation study on the doses from a proton gantry-mounted CBCT system showed that repeated CBCT imaging could result in cumulative organ doses of almost 2 Gy. The conclusion from these studies is that the dose-sparing effects of proton PBS therapy are not overshadowed by the out-of-field doses originating from secondary radiation for brain tumor treatments, but that the cumulative doses from repeated CBCT imaging could have a relevant impact on the overall dose reduction.