Purpose: Proton therapy has been proposed as an alternative to conventional photon therapy for the treatment of locally advanced cervical cancer (LACC) since these patients experience toxicities. Proton therapy may allow for significant sparing of the organs at risk, reducing the incidence of treatment-related morbidities. The aim of this study is to develop a treatment strategy that is robust to motion and uncertainties in intensity-modulated proton therapy (IMPT) for the treatment of LACC.
Materials and methods: Data from 14 LACC patients was included in this study. For each patient, a full and empty bladder planning CT (pCT) scan before treatment and four weekly repeat CT (reCT) scans after daily fraction were available. The full and empty pCT scans were used to create the patient-specific motion model of the cervix-uterus. An anisotropic CTV-to-ITV margin to expand this motion model was explored to account for uterine interfraction target motion. Subsequently, the motion model was divided into subranges to create a library of 1 to 4 plans, depending on the uterine motion due to bladder filling. Range and geometric uncertainties in the treatment of LACC are accounted for by robust optimization and evaluation. For each plan in the plan library, a treatment plan is created using the Erasmus-iCycle treatment planning system, taking into account EMBRACE-II constraints. To investigate whether the combination of margins, plan library, and robustness recipe is safe considering geometric and range uncertainties, ten treatments for each of the fourteen patients were simulated. These simulations were performed by recalculating the optimized treatment plans on the reCT scans with added uncertainties. We assumed that the target coverage was sufficient if the D95 of the target volumes was greater than or equal to 95% in at least 90% of the patients.
Results: Of the 3430 margin recipes that were tested, the margin recipe with 95% cervix-uterus overlap and the smallest target volume was 1, 5, 7, 3, and 3 mm in the left/right, posterior, anterior, cranial, and caudal directions, respectively. The subranges of the motion model were expanded with the anisotropic margin recipe, after which robust optimization (setup robustness 5 mm, range robustness 3%) and evaluation (32 scenarios) of the treatment plans were performed. The treatment simulations showed that the D95 was greater than 42.75 for 99% and 92% of the patients for the cervix-uterus target volume and nodal target volume, respectively.
Conclusion: The anisotropic margin and robustness recipe was robust to motion, geometric uncertainties, and range uncertainties when treating LACC patients with IMPT. Both values comfortably met the delivered dose criterion, indicating the strategy can be further improved.

Introduction: The Erasmus MC and TU Delft started the ARCHITECT project to develop a personalized applicator design approach for performing brachytherapy in patients with cervical cancer.
Workflow for executing brachytherapy differs a lot between institutions.
An overview of the workflow was created and time analysis of the steps was performed to identify bottlenecks and points of improvement in the current clinical practice of brachytherapy in cervical cancer. This overview could also be used as a reference for future research.
Methods: An overview of the workflow was created, the time needed for the different steps was registered and patients were asked to fill out questionnaires on patient experience. The current clinical practice was observed to create the workflow overview and define the steps of which time should be registered. As some steps occurred in parallel the radiotherapy technicians, radiation oncologists and nurses were asked to assist in reporting of times. Matlab was used to calculate the duration of the steps and SPSS was used to determine the descriptive statistics.
The research protocol written for the patient experience study was approved but the medical ethics committee. Patients were informed on the study so they could provide informed consent.
The EQ-5D questionnaire was used to asses initial pain, anxiety and quality of life. A questionnaire on pain, anxiety and duration of each step during treatment day that was used for evaluating patient experience.
Result: A workflow overview per location was created. Data of forty implantations in fifteen patients were included for time analysis. The general steps and mean time needed for these steps were: operating room (55 minutes), waiting before arrival at imaging (80 minutes), applicator reconstruction (57 minutes), contouring (50 minutes), treatment planning (50 minutes), clinical physicist check (22 minutes) and treatment room (41 minutes). The mean total procedure time from patient entering the operating room until leaving the treatment room was 391 minutes.
The time needed for implantation of subsequent treatment fractions compared to the first treatment fraction decreased in sixteen out of the twenty fractions. The time needed at the operating room in patients receiving spinal anesthesia did not differ from patients receiving general anesthesia.
Four patients provided informed consent and filled out the questionnaires on patient experience. Patient experience differed a lot in these four patients. Overall, highest anxiety scores were found during the first brachytherapy day and highest pain scores were found during the waiting time at the short stay unit.
Discussion: The steps observed in the Erasmus MC did not agree on all steps that were found in literature. Time needed for these steps also differed when comparing to literature. The total waiting time could be decreased when enabling a more smooth transition between the recovery room and imaging step.
Adaptions to the time registration sheet should include the time needed for assembling the applicator at the operating room. The contouring step should be separated in contouring of the OAR and target volume. Time needed for imaging is not that important as the imaging protocol is the same in all patients. The decrease in waiting time for imaging when using the hyperthermia MRI should be evaluated. The influence of the amount of patients treated during one day would also be interesting to evaluate when more data has been collected. Another interesting factor would be differences in duration of the steps and pain experienced in patients treated with the Venezia applicator compared to the Utrecht applicator. More patients need to be included in the questionnaire study to draw conclusions on patient experience.

Each year, more than 800 women in the Netherlands are diagnosed with cervical cancer, of which approximately half have locally advanced disease. The standard treatment for locally advanced cervical cancer (LACC) is external beam radiotherapy (EBRT) with concurrent chemotherapy followed by brachytherapy. Many patients experience some degree of treatment-related toxicity, mainly concerning the bowel, urinary tract, or vagina. Another important morbidity is hematologic toxicity (HT) due to bone marrow suppression, which might negatively impact the efficacy of adjuvant therapies. Treatment-related morbidity has a profound impact on patients’ quality of life. Proton therapy allows easier sparing of organs at risk (OARs), which might result in a decrease of treatment-related morbidities. One initiative to reduce treatment morbidities for LACC-patients was proposed in a collaborative project between Erasmus Medical Center (Erasmus MC), Leiden University Medical Center (LUMC), and Holland Proton Therapy Center (HollandPTC): the PROTECT-project. A clinical pilot study will be conducted to determine differences in dose to OARs and in morbidity outcomes when comparing state-of-the-art photon therapy with adaptive intensity-modulated proton therapy (aIMPT) for patients with LACC. Additionally, bone marrow sparing capabilities of both delivery techniques will be evaluated. The focus of this thesis is on the clinical implementation of aIMPT to facilitate the pilot-study and consists of three parts.

The thesis started with a systematic review of the literature about the relationship between bone marrow dose and HT in LACC-patients treated with primary chemoradiation. The review has been submitted for publication. There was a scarcity of studies investigating the relationship between bone marrow dose and HT and clinically useful prediction models were not available yet. The majority of the studies defining bone marrow as the whole pelvic bone found a significant association between bone marrow and HT, in contrast to studies evaluating lower density marrow spaces or active bone marrow. Future studies may use whole pelvic bone contouring to develop normal tissue complication probability models.

Secondly, the development and implementation of the treatment planning strategy for LACC-patients in HollandPTC were proposed. Uncertainties arising from proton therapy delivery were identified and strategies to address these uncertainties were determined. The proposed aIMPT-strategy for LACC-treatment consisted of a plan-of-the-day-approach with margins and robust planning. Further work includes establishing the balance between robustness settings and margins and optimizing the clinical implementation of the plan-of-the-day-strategy.

Lastly, the workflow for LACC-patients in Erasmus MC was translated into the HollandPTC environment. Requirements for the new workflow were generated with input from both the investigator and a risk evaluation with the users. A workflow was designed and translated into HollandPTC's situation. Secondly, the implementation of the plan-of-the-day-strategy in the treatment management process of the oncology information system ARIA was investigated. Recommendations were made to finalize and validate the implementation of the workflows.

This thesis provides a base for the clinical implementation of aIMPT for LACC in HollandPTC. The systematic review gives guidance for bone marrow sparing techniques in Erasmus MC and HollandPTC. Additionally, a combination of a plan-of-the-day-approach with margins and robust planning was identified as the most optimal treatment planning strategy. Lastly, an implementation strategy for the clinical workflow and treatment management process in HollandPTC was determined. Further work should focus on finalizing and validating the clinical implementation to facilitate PROTECT's clinical pilot study in HollandPTC.