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.