The scope of a radiotherapy treatment is to induce damage to tumor cells by irradiating them with ionizing radiation. The radiation should target the tumor as visible in images, also called the macroscopic disease. There is, however, a risk of small, invisible groups of cancer cells in the area surrounding the macroscopic tumor, the microscopic disease. For an optimal clinical outcome of radiotherapy, the microscopic disease needs to be irradiated as well. In current treatment planning, the macroscopic tumor is extended with a margin to better ensure full disease coverage. Because there is uncertainty in the extent of the microscopic disease, also the margin definition is uncertain. Moreover, in current planning, the same margin is used for all patients, and there is no patient-specific exploration of the trade-offs between dose extensions to cover potentially present microscopic disease vs radiation-induced toxicity because of enhanced dose in organs at risk (OARs) surrounding the tumor. This study aimed to explore whether the margin concept could be replaced by more advanced, individualized approaches for irradiation of volumes just outside the macroscopic tumor. All plans were generated automatically to avoid bias by human planners and to reduce workload. Two novel treatment planning approaches were investigated. The first focused on increasing dose coverage of the microscopic disease while at the same time controlling the resulting increased dose to the healthy tissues surrounding the macroscopic tumor, including OARs. Several treatment plans were generated to explore a range of trade-offs between dose in microscopic disease and dose in OARs. The results showed that for optimal microscopic disease irradiation, both low and high OAR doses needed to worsen. However, the most significant increase in microscopic disease coverage could be obtained when accepting higher OAR low doses, that is generally less important for induction of negative side-effects.
In the second approach, an expected Tumor Control Probability (expected TCP) cost function was used to control dose delivery in areas close to the macroscopic tumor. Basis of the expected TCP model was a function describing the probability of finding microscopic disease at a specific distance from the macroscopic tumor. The results again demonstrated opportunities to increase dose to areas close to the tumor, at the cost of enhanced doses in OARs. In conclusion, both approaches had a positive impact on microscopic disease dose coverage. However, improved irradiation of the microscopic disease was always at a price of enhanced dose in OARs. Complementary studies, involving clinicians, need to be carried out to investigate if and how the approaches could be used to replace the current planning with fixed margins.

Very high energy electron (VHEE) radiotherapy is being investigated as a potential replacement of photon therapy. VHEE pencil beams have a small penumbra and strong depth dependence for radiotherapy when compared to photons. This allows a lower dose to healthy tissue. Generating these high electron energy beams could be achieved by using laser accelerators. These accelerators allow the equipment to be smaller than currently possible and make it possible to fit them in a standard radiotherapy treatment bunker. This makes VHEE a potential middle ground between photon and proton therapy in relation to equipment costs and treatment quality. The purpose of this project is to compare photon based Intensity Modulated Ra­diation Therapy (IMRT) and VHEE treatment plans for treatment of prostate cancer.  For 10 prostate cancer patients IMRT treatment plans were generated with 23 beams. These plans were optimized using Erasmus MC in-house developed Erasmus-iCycle automated treatment plan optimization tool. The dependence of VHEE plan quality on beam energy (200, 300 and 400 MeV) and number of equi-angular beams (9, 18 and 36) was investigated. The treatment plans were optimized using the multi-criterial optimizer Erasmus-iCycle. For each patient VHEE pencil beam dose distributions were pre-calculated using TOPAS MC, a Monte Carlo simulation program based on Geant4.  Results: VHEE treatment plans show either a reduced or similar mean OAR dose when compared to IMRT treatment plans except for the 9 beam 200 MeV plan which was worse compared to IMRT. All treatment plans were normalized to a PTV coverage of 99 % V57Gy.  It is found that the mean rectum dose reduces from 13.5 Gy for IMRT to between 9.2 and 11.9 (p=0.002-0.004) for the VHEE plans. For the anus dose a reduction in mean dose was found for all VHEE treatment plans except for the 9 beam 200 MeV and the 18 beam 200 MeV VHEE treatment plans. The mean anus dose reduced from 12.4 Gy for IMRT to 7.0 - 10.6 Gy (p=0.002-0.014) for the VHEE treatment plans. The bladder dose reduced from 20.1 Gy to between 15.2 and 18.2 Gy (p=0.002).  Increasing the number of VHEE beams in a treatment plan reduces the OAR dose. Comparing 9, 18 and 36 beam treatment plans with 300 MeV. The mean rectum dose reduces from 14.0 Gy for the 9 beam plan to 11.1 Gy (p=0.002) and 9.9 Gy (p=0.002) for the 18 and 36 beam plan, respectively. The same pattern is found for the anus and bladder.  Treatment plans with a higher beam energy reduces the dose to OAR. The mean rectum dose reduces from 13.4 Gy for the 200 MeV plan to 11.1 (p=0.002) and 10.0 (p=0.002) Gy for the 300 and 400 MeV plans. The same pattern is found in the mean bladder dose with 18.2 Gy, 16.8 Gy (p=0.002) and 15.9 Gy (p=0.002). The right femoral head maximum dose increases from 28.0 Gy for 200 MeV to 29.4 Gy(p=0.002) and 29.6 Gy (p=0.049) for the 300 and 400 MeV treatment plans.  VHEE is a potential replacement for IMRT due to the reduced dose to healthy tissue while maintaining similar target coverage compared to IMRT. By increasing the number of beams and/or the electron beam energy we can further reduce doses to the healthy tissue.